Developing Iodoarene Derivatives for Useful Oxidative

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Developing Iodoarene Derivatives for UsefulOxidative Transformations and Biodegradable X-ray MaterialsTimothy R. LexClemson University, [email protected]

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DEVELOPING IODOARENE DERIVATIVES FOR USEFUL OXIDATIVE TRANSFORMATIONS AND BIODEGRADABLE X-RAY MATERIALS

A Dissertation Presented to

the Graduate School of Clemson University

In Partial Fulfillment of the Requirements for the Degree

Doctor of Philosophy Chemistry

by Timothy Robert Lex

August 2019

Accepted by: Dr. Daniel C. Whitehead, Committee Chair

Dr. Brian N. Dominy Dr. Sourav Saha

Dr. Modi Wetzler

ii

ABSTRACT

This thesis discloses two distinct applications of synthesized iodoarene-containing

compounds: as hypervalent iodine (HI) organocatalysts and as biodegradable X-ray

contrasting agents. This thesis also details a short chapter regarding the synthesis of

rarely accessible chemical moieties: diazacyclobutenes and 2-imidothioimidates.

Recently, organohypervalent iodine compounds have prevailed as valuable

synthetic reagents. These reagents have the ability to efficiently perform transition

metal-like transformations while possessing environmentally friendly properties.

However, a persistent obstacle in utilizing hypervalent iodine (HI) reagents has been

promoting synthetic reactions with high reactivities and enantioselectivities. To this fact,

it is necessary to further improve upon the field of hypervalent iodine chemistry,

especially in the context of the development of new, modular, and tunable catalyst

scaffolds.

The first chapter of this thesis reviews the background and history of hypervalent

iodine compounds. The second chapter describes the progress that has been made in the

field of catalysis, with emphasis on asymmetric organocatalysis. The third chapter details

the advances that were made to design, develop, and understand the reactivity of

iodoarene-containing catalysts in hypervalent iodine(III)-mediated transformations.

Furthermore, the third chapter provides insight on merging the fields of hypervalent

iodine chemistry with organocatalysis and asymmetric synthesis to generate chiral

catalysts that can be used in valuable organic transformations. These organocatalysts

iii

have the potential to be broadly applicable and to impact synthetically useful

transformations by imparting high yields and stereoselectivities.

Synthetic materials have proven to have a key role in the medical field. In

particular, polymeric materials have exhibited significance as contrast imaging agents

due to their inherent biodegradable and biocompatible profile. The fourth chapter of this

thesis describes the efficient synthesis, characterization, and X-ray evaluation of several

iodoarene-containing polyesters.

Synthetic chemists are continuously searching for novel and efficient bond-

forming methods to produce new chemical species. The final chapter of this thesis

describes a new strategy to generate unique chemical motifs (diazacyclobutenes and 2-

imidothioimidates) via a formal [2+2] cycloaddition between electron rich alkynes and

azodicarbonyl reagents.

iv

Dedicated to my incredible parents, Kathy “Momma Dukes” and Carmen “Knooch” Lex, for being the best role models I could have ever asked for.

v

ACKNOWLEDGMENTS

I would like to express my sincere gratitude to all who have helped me throughout

my journey in graduate school. Without the help, support and encouragement of several

people, this doctoral thesis would not have been possible.

First, I would like to thank my research advisor, Professor Daniel C. Whitehead. Dan

is one of the most intelligent, supportive, and witty persons I have ever met. I have learned a

great deal from you, and would not be the scientist I am today without your guidance and

advice. I am especially thankful for the intellectual conversations we have had, which always

seemed to spark new ideas, or prompt new avenues to overcome experimental shortcomings.

I will always cherish the group outings and cook-outs, as well as the weekly dose of music

jams we have shared throughout the years. I am also grateful to the members of my

committee: Dr. Brian N. Dominy , Dr. Sourav Saha, and Dr. Modi Wetzler. Thank you for

your dedication and mentorship during my time at Clemson University.

I would like to thank past and present group members of the Whitehead group, as

well as other Clemson graduate students, who have made graduate school the best it could be:

Heeren Gordhan, Beau Brummel, Maria Swasy, Daniel Willett, Timmy Thiounn, McKenzie

Campbell, Brad Stadelman, Kerrick Rees, Anthony Santilli, Chandima Narangoda, Eddie “on

the weekends” Hoegg, Sam Rackley, Alfredo Picado, Soham Panda, Mohamed Fathy Attia,

and Brock Miller. I will always cherish the memories we have made inside and outside of

the lab.

Lastly, I want to thank my incredible family, especially my parents, Kathy and

Carmen, my sister, Steph, my brothers Carmen and Chris, and my grandmother “Grams”,

who have helped me through the tough times. I love you all and can’t wait to see you soon!

vi

TABLE OF CONTENTS

Page

TITLE PAGE ................................................................................................................... i

ABSTRACT ..................................................................................................................... ii

DEDICATION ................................................................................................................ iv

ACKNOWLEDGMENTS ................................................................................................ v

LIST OF TABLES ........................................................................................................ viii

LIST OF FIGURES ........................................................................................................ ix

LIST OF SCHEMES ..................................................................................................... xii

CHAPTER

1 GENERAL ASPECTS OF HYPERVALENT IODINE COMPOUNDS ...................... 1 1.1 HYPERVALENCY ................................................................................. 1 1.2 IODINE AS A HYPERVALENT ELEMENT ........................................ 2 1.3 HYPERVALENT IODINE(III) STRUCTURAL FEATURES ............... 6 1.4 REACTIVITY OF HYPERVALENT IODINE COMPOUNDS ............ 8 1.5 REFERENCES ...................................................................................... 16

2 SYNTHETIC UTILITY OF ASYMMETRIC PEPTIDE-BASED ORGANOCATALYSTS.................................................................................................................................. 21

2.1 INTRODUCTION TO CATALYSIS .................................................... 21 2.2 HOMOGENEOUS AND HETEROGENEOUS CATALYSTS ........... 25 2.3 GENERAL ASPECTS OF ORGANOCATALYSIS ............................ 26 2.4 THE IMPORTANCE OF ASYMMETRIC SYNTHESIS .................... 29 2.5 ASYMMETRIC ORGANOCATALYSTS BASED ON ACTIVATION

MODE .................................................................................................... 30 2.6 ASYMMETRIC ORGANOCATALYSIS FOR 𝛼-CARBONYL

FUNCTIONALIZATIONS .................................................................... 32 2.7 PEPTIDES ............................................................................................. 37 2.8 LICENSE AGREEMENT TO USE FIGURE 2.4 ................................ 45 2.9 REFERENCES ...................................................................................... 46

3 IODOARENE-CONTAINING ORGANOCATALYSTS FOR HYPERVALENT IODINE(III) OXIDATIVE TRANSFORMATIONS .................................................. 55

3.1 HYPERVALENT IODINE ORGANOCATALYSIS ............................ 55

vii

Table of Contents (Continued) Page

3.2 GENERAL REMARKS ON OXIDATIONS ........................................ 56 3.3 CHIRAL HYPERVALENT IODINE(III) REAGENTS FOR

ENANTIOSELECTIVE OXIDATIVE TRANSFORMATIONS ......... 56 3.31 ASYMMETRIC OXIDATION OF SULFIDES TO SULFOXIDES

.................................................................................................... 57 3.32 ASYMMETRIC OXIDATIVE DEAROMATIZATION .......... 59 3.33 ALPHA FUNCTIONALIZATION OF CARBONYLS ............ 65

3.4 IODOARENE-CONTAINING ORGANOCATALYSTS FOR HYPERVALENT IODINE(III) OXIDATIVE TRANSFORMATIONS .. ................................................................................................................ 77

3.5 FUTURE WORK FOR PEPTIDE-BASED HYPERVALENT IODINE(III) CATALYSTS ................................................................. 105

3.6 MACROCYCLES AS CHIRAL HYPERVALENT IODINE(III) CATALYSTS ...................................................................................... 112

3.7 CONCLUSIONS ................................................................................. 117 3.8 EXPERIMENTAL ............................................................................... 119 3.9 REFERENCES .................................................................................... 231

4 IODOARENE-CONTAINING BIODEGRADABLE X-RAY MATERIALS ............ 239 4.1 INTRODUCTION ............................................................................... 239 4.2 MEDICAL IMAGING AND X-RAYCONTRAST AGENTS ........... 240 4.3 DESIGNING BIODEGRADABLE X-RAY CONTRAST AGENT .. 242 4.4 CONCLUSIONS ................................................................................. 250 4.5 FUTURE WORK ................................................................................. 251 4.6 EXPERIMENTAL SECTION ............................................................. 253 4.7 REFERENCES .................................................................................... 268

5 SYNTHESIS OF DIAZACYCLOBUTENES VIA A FORMAL [2 + 2] CYCLOADDITION ................................................................................................ 270

5.1 PREFACE ............................................................................................ 270 5.2 INTRODUCTION ............................................................................... 270 5.3 FUTURE WORK ................................................................................. 278

5.4 REFERENCES .................................................................................... 280 5.5 EXPERIMENTAL ............................................................................... 282

viii

LIST OF TABLES

Table Page

1.1 Oxidative ⍺-oxytosylation of propiophenone at 48 hours and room temperature ............................................................................................ 83

1.2 Oxidative ⍺-oxytosylation of propiophenone at 4 hours and room temperature ............................................................................................ 84

1.3 Oxidative ⍺-oxytosylation of propiophenone at 24 hours and 50 ℃ .... 85

1.4 Oxidative ⍺-oxytosylation of propiophenone at 1 hour and 50 ℃ ........ 86

1.5 Structural analogs of lead Catalyst 11 for the Oxidative ⍺-oxytosylation of propiophenone at 4 hours and room temperature .............................. 88

1.6 Oxidative cyclization of 5-oxo-5-phenylvaleric acid at 24 hours and 50 ℃................................................................................................................ 90

1.7 Oxidative ⍺-oxytosylation of propiophenone derivatives ..................... 91

1.8 Oxidative ⍺-oxytosylation of propiophenone at 24 hours and room temperature catalyzed by Cbz-protected amino methyl ester hypervalent iodine(III) catalysts ................................................................................ 97

1.9 Catalytic ⍺-oxytosylation of propiophenone at 4 hours and room temperature ............................................................................................ 98

1.10 Oxidative ⍺-oxytosylation of propiophenone at 24 hours and room temperature using aniline catalysts ...................................................... 104

1.11 Oxidative ⍺-oxytosylation of propiophenone at 24 hours and 50 ℃ using aniline catalysts .................................................................................... 105

ix

LIST OF FIGURES

Figure Page

1.1 Examples of iodine compounds with different oxidation states .............. 2

1.2 Martin-Arduengo Nomenclature .............................................................. 3

1.3 Notable hypervalent iodine(III) and iodine(V) reagents .......................... 5

1.4 Geometric structure of aryl-l3-iodanes .................................................... 7

1.5 Molecular orbitals to describe the 3c-4e bond in hypervalent iodine(III) compounds ............................................................................................... 7

1.6 Leaving group abilities of various nucleofuges ..................................... 14

2.1 Simplified catalytic cycle ....................................................................... 22

2.2 Reaction coordinate diagram of a catalyzed versus uncatalyzed reaction . ................................................................................................................ 24

2.3 Examples of heterogeneous and homogeneous catalysts ....................... 26

2.4 The amount of publications pertaining to organocatalysts from 1968-2008................................................................................................................ 27

2.5 Select examples demonstrating how chirality affects chemical properties and reactivities ....................................................................................... 29

3.1 Chiral sulfoxide containing drugs .......................................................... 57

3.2 Important pharmaceutical agents that contain an 𝛼-functionalized carbonyl moiety .................................................................................................... 65

3.3 Select examples of chiral hypervalent iodine(I) precatalyst scaffolds ... 74

3.4 Envisioned peptide-based catalytic scaffolds that contain an iodoarene active site at the N-terminus .................................................................. 78

x

List of Figures (Continued)

Figure Page

3.5 N-butyl-iodobenzamide catalysts with corresponding amidation yields ................................................................................................................... 80

3.6 1H relative rate study of the oxidation of Catalysts 11, 8, and 4 to their iodine(III) state ....................................................................................... 89

3.7 Utilizing Fmoc-Solid-Phase-Peptide-Synthesis to incorporate iodoarene active sites into the side chain of peptide scaffolds ............................... 93

3.8 Cbz-protected amino methyl ester catalysts that contain an iodoarene active site ............................................................................................... 95

3.9 Incorporation of Fmoc-Solid-Phase-Peptide-Synthesis compatible catalyst 6l into a peptide sequence ...................................................................... 99

3.10 Hypothetical peptides that contain an iodoarene within the backbone of the scaffold ................................................................................................. 100

3.11 Iodoarene containing aniline derivatives that function as hypervalent iodine(III) catalysts .............................................................................. 101

3.12 Incorporating the iodoarene active site anywhere within the peptide scaffold ................................................................................................. 107

3.13 Illustrating the possible enol geometries of propiophenone in acidic conditions ............................................................................................. 108

3.14 Enol/enolate equivalents of propiophenone as a way to control enol geometry .............................................................................................. 111

3.15 Generic iodoarene-containing macrocycles ......................................... 112

3.16 Structure, yield, and enantioselectivity of cyclic and acyclic catalysts in the oxidative 𝛼-oxytosylation of propiophenone at 24 hours and room temperature .......................................................................................... 116

3.17 Plausible iodoarene-containing macrocyclic derivatives that can be synthesized ........................................................................................... 116

xi

List of Figures (Continued)

Figure Page

4.1 Utilizing iodinated monomers for X-ray enhancements ...................... 240 List of Figures (Continued)

4.2 [A] 1H NMR spectral overlay of (1a) lactide, (1b) aryl-iodo lactide (iLA), (1c) poly(lactic) acid (PLA), and (1d) aryl-iodo poly(lactic) acid (iPLA). [B] FTIR characterization of the aryl-iodo lactide (iLA), poly(lactic) acid(PLA), and the aryl-iodo poly(lactic)acid (iPLA ................................. 245

4.3 (a) Relative X-ray intensity of iodinated polymers compared to non-iodoinated PLA. (b)Relative X-ray intensity of iodinated and non-iodinated PLA copolymer with varying amounts ................................ 247

4.4 Quantitative measurements of relative X-ray intensity. (a) Relative X-ray intensity of iodinated poly(lactic) acid (iPLA) synthesized using various reaction times, in comparison to iodinated polycaprolactone (iPLC). (b) Depiction of polymeric pellets (10 mg) composed of poly(lactic) acid (PLA), iodinated polycaprolactone (iPLC), and iodinated poly(lactic) acid (iPLA) copolymers synthesized using 6, 12, and 24-hour reaction times. (c) In vitro imaging of iPLA powder through different depth of chickentissue .................................................................................................... 249

4.5 Degradation of iPLA pellets over time (days) which was incubated into PBS (pH 7.4) at 37 ℃ .......................................................................... 250

4.6 Biomedical monomers as drug delivery platforms .............................. 252

5.1 Historical examples of diazacyclobutene motifs ................................. 272

5.2 Substrate scope in a [2 + 2] cycloaddition to diazacyclobutene motifs ..... .............................................................................................................. 274

5.3 Substrate scope in a [2 + 2] cycloaddition to 2-imidothioimidate motifs .. .............................................................................................................. 277

xii

LIST OF SCHEMES

Scheme Page

1.1 General structure and oxidative pathways of iodine species ................... 4

1.2 Comparing reactivities of hypervalent iodine species to transition metals .................................................................................................................. 9

1.3 Generic ligand coupling reaction in hypervalent iodine(III) reagents ... 11

1.4 Typical reactivity of electrophilic hypervalent iodine(III) species ........ 13

2.1 Cinchona alkaloids as chiral catalysts from chiral mandelonitriles ....... 32

2.2 A 1960 enantioselective ketene methanolysis by Pracejus .................... 32

2.3 Intramolecular aldol reactions catalyzed by proline .............................. 33

2.4 Intermolecular aldolization using a proline chiral catalyst .................... 34

2.5 Enamine catalysis in natural product synthesis ..................................... 34

2.6 Various asymmetric 𝛼-functionalizations of carbonyls mediated by proline catalysts .................................................................................................. 36

2.7 Early examples of peptide-based asymmetric catalysts in organic synthesis................................................................................................................ 38

2.8 Direct aldolization using peptide-based chiral catalysts ........................ 39

2.9 Kinetic resolution of hydroxyamide ...................................................... 40

2.10 Enantioselective Baylis-Hillman reactions with peptide catalysts ........ 41

2.11 Alcohol cross-coupling for kinetic resolution of diols using peptide catalysts .................................................................................................. 42

2.12 Cinchona alkaloid PTCs for asymmetric ⍺-amino acid derivatives ...... 43

xiii

List of Schemes (Continued)

Scheme Page

3.1 Enantioselective oxidations of sulfides to sulfoxides using hypervalent iodine(III) reagents ................................................................................. 59

3.2 Kita’s first asymmetric dearomatizing spirolactonizations using a hypervalent iodine(III) reagent .............................................................. 60

3.3 Proposed mechanistic pathways for the oxidation of phenols via hypervalent iodine(III)-reagents ............................................................ 61

3.4 Asymmetric dearomatizing spirolactonizations using hypervalent iodine(III) reagents ................................................................................. 63

3.5 Enantioselective hydroxylations using hypervalent iodine(III) reagents ... ................................................................................................................ 64

3.6 Typical reactivity to functionalize ketones via hypervalent iodine(III) “umpolung” reactivity ............................................................................ 66

3.7 Asymmetric ⍺-arylation of indanone derivatives via hypervalent iodine(III) reagents ................................................................................ 68

3.8 Hypervalent iodine(III)-mediated asymmetric oxidative cycloetherification................................................................................................................ 68

3.9 Proposed reaction pathway for in-situ 𝛼-oxytosylation of ketones ....... 69

3.10 Putative mechanistic pathways for the ⍺-oxytosylation of propiopheneone mediated by a hypervalent iodine(III) reagent ....................................... 71

3.11 Asymmetric 𝛼-oxytosylation transformations via hypervalent iodine(III) reagents .................................................................................................. 72

3.12 Legault and Badevant’s utilization of enol acetates for asymmetric catalysis .................................................................................................. 76

3.13 Standard synthesis of the N-butyl-iodobenzamide catalysts ................ 79

xiv

List of Schemes (Continued)

Scheme Page

3.14 Utilizing Fmoc-solid-phase-peptide synthesis to easily generate libraries of peptide-based hypervalent iodine(III) chiral catalysts ....................... 92

3.15 Cbz-protected amino methyl ester catalysts that contain an iodoarene active site ............................................................................................... 94

3.16 Protective group manipulation for the synthesis of Fmoc-Solid-Phase-Peptide synthesis suitable catalysts ........................................................ 98

3.17 Synthetic operations to access the aniline amide Catalyst 4e ............. 102

3.18 Proposed stereoselective effect of enol geometry in the ⍺-oxytosylation of propiophenone mediated by a hypervalent iodine(III) chiral catalyst . 109

3.19 Accessing the E and Z boronate esters of propiophenone in a highly selective fashion ................................................................................... 111

3.20 Synthetic route towards iodoarene macrocycles .................................. 114

4.1 The synthesis of aryl-iodinated biodegradable monomers .................. 243

4.2 Tin-mediated ring opening polymerization ......................................... 244

5.1 General synthetic route toward diazacyclobutenes .............................. 271

5.2 General synthetic route toward N,N-dicarbamoyl 2-iminothioimidates .............................................................................................................. 275

5.3 Synthesis of oxygen and nitrogen derived diazacyclobutenes and 2-imidoimidates. ...................................................................................... 278

1

CHAPTER ONE

GENERAL ASPECTS OF HYPERVALENT IODINE (HI) COMPOUNDS

1.1 HYPERVALENCY

In 1916, Gilbert N. Lewis disclosed a critical scientific concept known as the ‘rule

of eight’ or as later named, the ‘octet rule’.1, 2 This rule states that central atoms are more

stable when their valence shell is filled with eight electrons, thereby attaining a similar

electron configuration as the noble gases. This rule-of-thumb, heuristic device serves to

help predict the position, as well as the bonding, of the atoms and lone pair electrons that

make up a molecule.3 Although this concept has been fundamental in understanding

molecular bonding, it is not directly compatible with molecules that contain atoms with

expanded octets.4-9

In 1969, Jeremy I. Musher coined the term ‘hypervalent’ to describe the ability of

a central, non-metallic atom confined within a molecule to expand its valence shell

beyond the limits of the octet rule.10, 11 Hypervalent molecules are often assembled from

elements within groups 15-18 that can accommodate the expanded octet within its

valence shell.12, 13 One element that has the capacity to formally break the octet rule, and

thereby become hypervalent, is iodine.14, 15

2

1.2 IODINE AS A HYPERVALENT ELEMENT

Iodine, isolated in 1811 by Bernard Courtois, is a chemical element of the

periodic table with an atomic number of 53. Iodine-containing reagents have intrigued

chemists due to their distinct chemical properties. In relation to the other non-radioactive

group 17 elements, iodine is the largest, heaviest, most electropositive, and most

polarizable.

Due to these unique properties, iodine is able to form stable polycoordinate,

multivalent compounds.16-18 Generally, iodine atoms form bonds with elements within

the second period of the periodic table. These kinds of bonds are relatively weak. For

instance, a carbon-iodine bond is the weakest carbon-halogen bond, with a bond

dissociation energy of approximately 57 kcal/mol.19 The formal electron configuration of

iodine is [Kr]d10s2p5, with seven electrons in its valence shell. While iodine prefers to

have an oxidation state of –1, the electronic makeup and large atomic radius permit it to

exist in various oxidation states ranging from –1 to +7 (Figure 1.1).18, 20, 21

Figure 1.1 Examples of iodine compounds with different oxidation states

I

Iodobenzene+1

IF3

Iodine trifluoride+3

OI

O

AcO OAcOAc

Dess-Martin periodinane+5

IOOO

O Na

Sodium periodate+7

HI

Hydroiodic acid-1

1a 1b 1c 1d 1e

3

Polyvalent compounds are classified by using Martin-Arduengo N-X-L

nomenclature, where N represents the number of valence electrons associated with the

central atom, X, and L signifies the number of ligands bound to the central atom (Figure

1.2).22 It should be noted that historically, iodine compounds with a +3 oxidation state

were referred to as iodinanes and iodine compounds with a +5 oxidation state were

referred to as periodinanes. However, IUPAC suggests the use of lambda notation (ln)

when considering compounds with varying valence. This notation specifies an atom with

an abnormal valence state.23, 24 While iodine has a normal valence state of 1, iodine(III)

and iodine(V) compounds contain a non-standard valence, and are respectively named as

l3-iodanes and l5-iodanes.

The large range of possible oxidation states allows for iodine to form up to 7

chemical bonds. These bonds are typically constructed through oxidations and ligand

associations (Scheme 1.1).23 In short, the oxidative addition occurs when an iodine(I)

compound utilizes a lone pair of electrons to attack an electrophilic species (L+), which

thereby leaves a positive charge on the central iodine atom (Scheme 1.1, 1f). The ligand

association can then take place, whereby a nucleophilic reagent (L-) attacks a positively

[N-X-L]

Number of valence electrons

Central atom

Number of ligands bound to central atom

Figure 1.2 Martin-Arduengo Nomenclature

4

charged iodine, to form a 10 electron, three coordinate iodane species (Scheme 1.1, 1g).

This process of oxidative addition (Scheme 1.1, 1f and 1h) and ligand association

(Scheme 1.1, 1g and 1i) allows for the formation of iodine species with various

oxidation states. Although iodine can adapt to several oxidation states, the most widely

used iodine compounds rely on the +3 and +5 oxidation states.

While the aforementioned nomenclature can help classify polyvalent iodine

compounds, many well-known and widely used reagents are referred to by their trivial

names. The most noteworthy HI(III) and HI(V) compounds are derived from

iodobenzene and can be seen in Figure 1.3.25 In 1886, German chemist Conrad

Willgerodt combined iodobenzene and chlorine gas to produce the first multivalent

iodine reagent: (dichloroiodo)benzene, i.e. PhICl2 (1j).26 Although the first hypervalent

iodine (HI) molecule was discovered over a century ago, their synthetic utility was not

exploited until the last few decades. Most notably, the commercially available

L I L IL

L L IL

LL

L IL

LLL

L IL

L

LL

L

Scheme 1.1 General structures and oxidative pathways of iodine species

+18-l-1

+38-l-2

+310-l-3

+510-l-4

+512-l-5

Oxidative addition Ligand Association

IL

O

LL

LIL

L

LL

L

+714-l-6

+714-l-7

LL

L


1f 1g 1h 1i

5

aryliodine(III) carboxylates, such as phenyliodine diacetate (PIDA) (1k) and

phenyliodine bis(trifluoroacetate) (PIFA) (1l), and organosulfonates, like

[hydroxy(tosyloxy)iodo]benzene (HTIB) (1m), are commonly utilized in synthetic

chemistry as oxidants. The commercially available organoiodine(V) reagent known as

Dess-Martin periodinane (DMP) (1o), a five-membered iodine-containing heterocycle

with acetate ligands, is frequently used to oxidize primary and secondary alcohols to

aldehydes and ketones, respectively.27, 28 Extensive work has been completed by several

laboratories to synthesize these, as well as analogous, hypervalent iodine reagents.12, 16-18,

23, 29-31 While both HI(III) and HI(V) compounds are synthetically useful, the work

described herein focuses on HI(III) compounds due to their more desirable properties. In

comparison to HI(III) species, HI(V) compounds are more shock-sensitive and difficult to

Iodine(III) compounds

ICl

ClIOCOR

OCORIOTs

OH

1jWillgerodt’s reagent

R = CH3 (PIDA) 1kR = CF3 (PIFA) 1l

1mKoser’s reagent

(HTIB)

IO

1niodosobenzene

Iodine(V) compounds

1oDess-Martin periodinane

(DMP)

1p2-iodoxybenzoic acid (IBX)

1qiodoxybenzene

Figure 1.3 Notable hypervalent iodine(III) and iodine(V) reagents

OI

O

OI

O

O OH

IO2

AcO OAcOAc

6

prepare, have lower thermal stabilities, and are less soluble in many common organic

solvents.16, 25

1.3 HYPERVALENT IODINE(III) STRUCTURAL FEATURES

While the traditional definition of a hypervalent state, in which an atom breaks the

octet rule by bearing more than four pairs of electrons in its valence shell, has been

highly debated, the conventional interpretation will be applied in this work.8, 32-42 Akiba

considered the bonding within multivalent iodine species to rationalize the possibility of

expanded octets.13 He reasoned that hypervalent atoms can carry more than eight

electrons in their outermost shell by two plausible modes: (1) utilizing higher energy d-

orbitals to form hybridized dsp3 or d2sp3 orbitals or (2) utilizing orbitals other than d-

orbitals to form highly ionic orbitals. Contemporary computational research has

demonstrated that d-orbitals have little to no contribution in hypervalent bonds.13, 34, 37

The most widely accepted theory to describe hypervalent bonding is the concept of a

highly polarized bond known as a three-center, four-electron (3c-4e) bond. The 3c-4e

bond was independently introduced in 1951 by G.C. Pimentel and R. E. Rundle.38, 39

This concept can be conceptualized by reviewing the structural features of hypervalent

iodine(III) species and how it relates to molecular orbital theory.

7

The most common trivalent iodine species are the aryl-l3-iodanes (ArL1L2). As

shown in Figure 1.4, the atoms that constitute aryl-l3-iodanes share ten valence electrons

(decet structure) to form a distorted trigonal bipyramidal geometry with an overall T-

shape.12, 23 The central iodine atom is bound to two apically positioned ligands (L1 and

L2), one equatorial aryl substituent (Ar), and two equatorial lone pairs of electrons. The

iodine and aryl group overlap orbitals to form a conventional two-center, two-electron

(2c-2e) covalent, carbon-iodine𝜎-bond with 5sp2 hybridization. A highly polarized 3c-

4e bond is created from the interaction of a filled 5p orbital of iodine and half-filled

orbitals of each ligand. This results in three molecular orbitals: a bonding, non-bonding,

and anti-bonding orbital (Figure 1.5). Four valence electrons, two electrons from iodine

and one electron from each ligand, are shared between the three atoms (iodine and two

ligands). Consequently, this electron distribution allows for the two lower molecular

orbitals, the bonding and non-bonding orbitals, to each be filled with two electrons, while

the antibonding orbital is unfilled.

I

L1

L2

Arẟ+

ẟ-

ẟ-

Figure 1.4 Geometric structure of aryl-!3-iodanes

8

The highly polarized nature of the 3c-4e bond is invoked at the highest occupied

molecular orbital (HOMO), in this case, the non-bonding orbital, in which a node is

situated at the central iodine position. This allows for the development of charge

distributions; in particular, there is an intrinsic partial positive charge on the central

iodine atom (+1.0 charge), and a partial negative charge (-0.5 charge) on each apically

positioned ligand.23 Ligands that can better stabilize this partial negative charge (e.g.

halide, tosylate, carboxylate, hydroxyl) tend to reside at the apical positions around the

positively charged central iodine, while the least electronegative ligand, the aryl group,

occupies the equatorial position. Furthermore, the more electropositive the central atom

is the more energetically stable the polycoordinated, multivalent species is, hence aryl-l3-

iodanes are more stable than the related aryl-l3-chloranes and aryl-l3 bromanes.12, 18, 43, 44

1.4 REACTIVITY OF HYPERVALENT IODINE COMPOUNDS

•

IR R

bonding orbital

non-bonding orbital

antibonding orbital

Figure 1.5 Molecular orbitals to describe 3c-4e bond in HI(III) compounds

Ener

gy

Ψ3*

Ψ2

Ψ1

9

Iodine species with expanded octets can result in distinct and interesting chemical

structures, properties, and reactivities. With the ability to possess multiple oxidation

states, it has been suggested that hypervalent iodine species have reactivity patterns that

resemble transition metals. This is apparent when considering the quintessential

reactions involved in both transition metals and polyvalent iodine reagents: oxidative

additions, ligand exchanges, and reductive eliminations (Scheme 1.2).23

The transition metals (1r) and iodine species (in this case, iodoarene 1w) undergo

an increase in coordination number or oxidation state through an oxidative addition. An

exogeneous nucleophile (Nu) can then readily add to the central iodine through an

Oxidative addition

LnM R-L LnM Nu LnM

-L

Ligand Exchange Reductive Elimination

RNu

LnM

General reactivity of transition metal reagents

IL

LPhPh I

L IL

Ph L


General reactivity of hypervalent iodine reagentsAssociative pathwayfor ligand exchange

Dissociative pathwayfor ligand exchange

NuIL

LPh

INu

LPh

Nu

L

I

Nu

8-I-22b

12-I-4 (trans)1z

10-I-32c

L

R R

Nu

LINu

LPh L

12-I-4 (cis)2a

Reductive Elimination orLigand Coupling

- PhI

LNu

L

Ph

Scheme 1.2 Comparing reactivities of hypervalent iodine species to transition metals

1w 1x 1y 2d2e

1r1s 1t 1u

1v

10

associative or dissociative ligand exchange process to form the active species (Scheme

1.2, 1t and 2c). Subsequently, a reductive elimination, or as it is analogously called in

hypervalent terminology, ligand coupling, allows for the new bond to form (1v and 2e),

while also liberating the byproducts: the metal reagent (1u) or iodobenzene (2d).

Numerous experimental and computational studies have been conducted to

validate the mechanistic pathway for ligand exchange in hypervalent iodine species.12, 45-

49 The two pathways that have been probed are the associate pathway and the

dissociative pathway. The associative mechanism involves the addition of a nucleophile

to the electropositive central iodine to give a trans 12 electron, 4 ligand (12-I-4) iodate

(1z).12, 49-51 This trans intermediate is in equilibrium with the cis 12-I-4 iodate (2a),

which gives a favorable structural geometry for one of the ligands (L) to depart,

furnishing the desired 10-I-3 hypervalent iodine(III) species (2c). Conversely, the

dissociative pathway commences with the ejection of a ligand (L) to form a cationic 8-I-2

iodonium species (2b). This process typically requires a strong electrophile to assist in

the removal of the ligand.12 This species is then subjected to a nucleophilic addition at

the central iodine atom to afford the trivalent aryl-l3-iodane (2c). Due to the lack of

experimental evidence of the high energy dicoordinated (8-I-2) iodium ion (2b), in the

dissociative pathway, the associative pathway has been the more widely accepted ligand

exchange pathway of l3-iodanes.12, 23

Ligand couplings involved in hypervalent species were presented by Oae to

explain the formation of an intramolecular bond between two ligands that were bound to

the central hypervalent atom.52, 53 As depicted in Scheme 1.3, reductive eliminations, a

11

concept widely invoked in organometallic chemistry, are when the central metal atom

decreases in oxidation state and forms a new bond between the bound ligands. It should

be noted that in non-transition metal chemistry, the term ‘reductive elimination’ has also

been used in several other fashions, for example in the synthesis of alkenes.54, 55 The

aryl-l3-iodanaes can be subjected to a reaction known as ligand coupling (Scheme 1.3).

There is limited experimental evidence of the ligand coupling mechanism, but it has been

proposed that due to the configurational instability of organo-l3-iodanes, rapid

psuedorotation occurs to generate an appropriate coupling configuration (2g). This

psuedorotation is followed by a favorable and concerted coupling of the ligands (Nu and

L) to form the desired product (2i) with retention of configuration of the ligands.13, 52, 56-59

Another detail that illustrates the similarity between hypervalent iodine

complexes and transition metals is the trans influence phenomenon.60-64 This

I

Ph

L

Nu

Nu L

LNu

- PhI

Reductive Elimination

Ligand Coupling

- PhI

psuedorotation

Scheme 1.3 Generic ligand coupling reaction in hypervalent iodine(III) reagents

2g

2h

2i

I

Nu

L

Ph

2f

12

phenomenon states that most electronegative ligands bound to the central atom tend to

configure trans to each other in order to form stable complexes. The mutual influence of

the two ligands occurs when the central atom preserves the ns2 lone pair of electrons.61

In T-shaped hypervalent iodine(III) compounds, such as the generic structure shown in

Figure 1.4, the central iodine atom retains the 5s2 lone pair of electrons, and the I-L1

trans bond becomes influenced by the 𝜎-donating ability of the trans configured ligand

(L2).60 The 3c-4e bond of these hypervalent iodine(III) complexes experience a trans

influence, which is attributed to the inductive effects of the trans positioned ligands, L1

and L2. This phenomenon has been studied and utilized by Ochiai to account for the

stabilities of various HI(III) species.31, 64, 65 In metal complexes, the metal-ligand bond

(M-X) is affected by a trans oriented ligand (L), which weakens the M-X bond.66, 67 In

both metal and hypervalent species, the trans positioned substituents share a central atom,

and can influence and effect each other’s bonding abilities, stabilities, and reactivities.

While multivalent iodine reagents have comparable reactivity profiles as heavy

metal reagents (e.g. Hg(II), Pb(IV), Cr(III), Os(VIII)), the main appeal toward utilizing

hypervalent iodine compounds stems from their environmentally benign character.18, 23, 30,

68 Their less-toxic nature allows hypervalent iodine species to be employed as

sustainable alternatives to the more toxic heavy metal-based reagents, and thus

contributes to ‘greener’ replacement methods in organic synthesis.69

Although organic molecules bearing hypervalent iodine moieties were discovered

over a century ago, they were not employed in synthetically useful transformations until

the last few decades. Due to the partial positive charge around the central iodine atom

13

(cf. Figure 1.4), hypervalent iodine(III) compounds are inherently electrophilic agents.

The distinct 3c-4e bond involved in these species has been investigated, showing that the

iodine to ligand (L) bonds are longer and weaker than analogous covalent bonds, giving

important reactive characteristics to this class of compounds. Allen et al. disclosed a

study concerning the bond length in a hypervalent iodine(III) compound named

diphenyliodonium chloride (Ph2ICl), and showed that the iodine to chlorine bond length

was notably longer (3.06 Å) than the average covalent bond length (2.56 Å).70 These

unique characteristics have contributed to l3-iodane reagents to be routinely utilized as

versatile and selective oxidants and electrophiles. The strong electrophilic nature of l3-

iodanes can be observed as shown in Scheme 1.4.

The predominant reactive property of highly electrophilic HI(III) compounds is

their aptness to readily exchange with nucleophiles by means of a low energy process.

IX

XNu I

Nu

X

X

INu

X

RI

X

Nu R

Scheme 1.4 Typical reactivity of electrophilic hypervalent iodine(III) species

2j 2k

2n

2k 2o

2l

2l

2m

14

Generally, the aryl-λ3-iodane (2j) is susceptible to nucleophilic attack at the positively

charged iodine atom, which affords 2k and the newly displaced ligand 2l. An external

nucleophile (2m) is then added to afford the new Nu-R bond formation (2o).

The functional group known as phenyliodonio (PhIX), highlighted in blue within

structure 2k, is considered to be a potent nucleofuge, or leaving group that retains the

electrons from the broken bond. In fact, Ochiai referred to the phenyliodonio group as a

‘hypernucleofuge’, or an exceptional hypervalent leaving group that has a better leaving

group ability than a “super leaving group”. The phenyliodonio group is estimated to

possess a 1013 times greater leaving group ability than iodine and 106 times higher leaving

ability than triflate (Figure 1.6).12, 13, 71 Furthermore, by using Hammett substituent

constants, Mironova et al. probed the electron nature of phenyl-l3-iodanyl groups, and

Figure 1.6 Leaving group ability of various nucleofuges

Me2S+

Acetoxy (AcO)

F

Cl

CF3CO2

NO3

Br

Nucleofuge krel Nucleofuge krel

I

Mesylate (MsO)

Triflate (TfO)

p-MePh(BF4)I

Ph(BF4)I

p-ClPh(BF4)I

1.4 X 10-6

9.0 X 10-6

5.3 X 10-2

1.0

2.5

7.2

1.4 X 10

9.1 X 10

3.0 X 104

3.7 X 104

1.4 X 108

6.2 X 1013

1.2 X 1014

2.9 X 1014

Tosylate (TsO)

15

showed that they have powerful electron-withdrawing capabilities due to inductive

effects.72

This reaction (Scheme 1.4) proceeds due to the remarkable leaving and electron-

withdrawing ability of the hypervalent iodine group, which can be ascribed from the

entropic favorability of having one molecule (2k) split into three: the anionic

electrophilic ligand (2l), iodoarene (2n), and the intended product (2o). The

thermodynamic driving force of aryl hypervalent iodine(III) reactions is due to the

formation of the highly stable iodoarene by-product (2n).

Chemists have employed l3-iodanes in numerous synthetic transformations due to

their versatility and environmentally benign character. Many aryl-substituted l3-iodanes

are commercially available, and are commonly used as mild and selective reagents in

synthetic chemistry. As described above, these species have a potent electrophilic and

oxidative chemical character, and thus have been particularly impactful in a multitude of

synthetic applications including: oxidations, oxidative rearrangements and

fragmentations, cyclizations, carbon-carbon/carbon-heteroatom/heteroatom-heteroatom

bond forming reactions, and even in total syntheses of natural products.12, 18, 23, 29, 44, 68, 73

The second chapter of this thesis will focus on the utilization of asymmetric

organocatalysts in various synthetic transformations.

16

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22. Perkins, C. W.; Martin, J. C.; Arduengo, A. J.; Lau, W.; Alegria, A.; Kochi, J. K., An electrically neutral .sigma.-sulfuranyl radical from the homolysis of a perester with neighboring sulfenyl sulfur: 9-S-3 species. J. Amer. Chem. Soc. 1980, 102 (26), 7753-7759.

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24. Powell, W. H., Treatment of variable valence in organic nomenclature (lambda convention). Pure Appl. Chem. 1984, 56 (6), 769-778.

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29. Varvoglis, A., Chemical transformations induced by hypervalent iodine reagents. Tetrahedron 1997, 53 (4), 1179-1255.

30. Zhdankin, V. V.; Stang, P. J., Recent developments in the chemistry of polyvalent iodine compounds. Chem. Rev. 2002, 102 (7), 2523-2584.

31. Zhdankin, V. V.; Stang, P. J., Chemistry of Polyvalent Iodine. Chem. Rev. 2008, 108 (12), 5299-5358.

32. Coulson, C. A., Valence. Clarendon Press: Oxford, 1952; p vii, 338 p. 33. Pauling, L., The nature of the chemical bond, and the structure of molecules and

crystals : an introduction to modern structural chemistry. 2nd ed.; Cornell University Press: Ithaca, N.Y., 1948; p xvi, 450 p.

34. Kutzelnigg, W., Chemical Bonding in Higher Main Group Elements. Angew. Chem. Int. Ed. Engl. 1984, 23 (4), 272-295.

35. Magnusson, E., Hypercoordinate molecules of second-row elements: d functions or d orbitals? J. Amer. Chem. Soc. 1990, 112 (22), 7940-7951.

36. Coleman, W. F., Structure and Bonding in Hypervalent Iodine Compounds. J. Chem. Educ. 2010, 87 (9), 999-1000.

37. Reed, A. E.; Schleyer, P. v. R., Chemical bonding in hypervalent molecules. The dominance of ionic bonding and negative hyperconjugation over d-orbital participation. J. Am. Chem. Soc. 1990, 112 (4), 1434-1445.

38. Pimentel, G. C., The Bonding of Trihalide and Bifluoride Ions by the Molecular Orbital Method. J. Chem. Phys. 1951, 19 (4), 446-448.

18

39. Hach, R. J.; Rundle, R. E., The Structure of Tetramethylammonium Pentaiodide. J. Am. Chem. Soc. 1951, 73 (9), 4321-4324.

40. Cioslowski, J.; Mixon, S. T., Rigorous Interpretation of Electronic Wave Functions. 2. Electronic Structures of Selected Phosphorus, Sulfur, and Chlorine Fluorides and Oxides. Inorg. Chem. 1993, 32 (15), 3209-3216.

41. Molina, J. M.; Dobado, J. A., The three-center-four-electron (3c-4e) bond nature revisited. An atoms-in-molecules theory (AIM) and ELF study. Theor. Chem. Acc. 2001, 105 (4-5), 328-337.

42. Cooper, D. L., Spin-coupled Description of the Chemical Bonding to Hypercoordinate Chlorine. Theor. Chem. Acc. 2001, 105 (4-5), 323-327.

43. Amey, R. L.; Martin, J. C., Synthesis and reaction of substituted arylalkoxyiodinanes: formation of stable bromoarylalkoxy and aryldialkoxy heterocyclic derivatives of tricoordinate organoiodine(III). J. Org. Chem. 1979, 44 (11), 1779-1784.

44. Varvoglis, A., The organic chemistry of polycoordinated iodine. VCH Publishers: New York, N.Y., 1992; p xii, 414 p.

45. Moriarty, R. M.; Prakash, O., Hypervalent Iodine in Organic-Synthesis. Acc. Chem. Res. 1986, 19 (8), 244-250.

46. Yusubov, M. S.; Nemykin, V. N.; Zhdankin, V. V., Transition metal-mediated oxidations utilizing monomeric iodosyl- and iodylarene species. Tetrahedron 2010, 66 (31), 5745-5752.

47. Richter, H. W.; Cherry, B. R.; Zook, T. D.; Koser, G. F., Characterization of species present in aqueous solutions of [hydroxy(mesyloxy)iodo]benzene and [hydroxy(tosyloxy)iodo]benzene. J. Am. Chem. Soc. 1997, 119 (41), 9614-9623.

48. Ochiai, M.; Miyamoto, K.; Yokota, Y.; Suefuji, T.; Shiro, M., Synthesis, characterization, and reaction of crown ether complexes of aqua(hydroxy)(aryl)iodonium ions. Angew. Chem. Int. Ed. 2005, 44 (1), 75-78.

49. Edwards, A. J., Crystal Structure of Trichlorosulphonium(IV) Tetrachloroiodate(III). J. Chem. Soc., Dalton Trans. 1978, (12), 1723-1725.

50. Kajigaeshi, S.; Ueda, Y.; Fujisaki, S.; Kakinami, T., Halogenation Using Quaternary Ammonium Polyhalides. XV. An Effective Chlorinating Agent Benzyltrimethylammonium Tetrachloroiodate, Benzylic Chlorination of Alkylaromatic Compounds. Tetrahedron Lett. 1988, 29 (45), 5783-5786.

51. Koser, G. F.; McConville, D. B.; Rabah, G. A.; Youngs, W. J., Crystal and molecular structure of 1-chloro-1,2-benziodoxolin-3(1H)-one center dot tetra-n-butylammonium chloride. J. Chem. Crystallogr. 1995, 25 (12), 857-862.

52. Oae, S.; Uchida, Y., Ligand-coupling reactions of hypervalent species. Acc. Chem. Res. 1991, 24 (7), 202-208.

53. Finet, J.-P., Ligand Coupling Reactions with Heteroatomic Compounds. Pergamon: Oxford, 1998; p xv, 291 p.

54. Kocienski, P. J.; Lythgoe, B.; Waterhouse, I., The Influence of Chain-branching on the Steric Outcome of Some Olefin-forming Reactions. J. Chem. Soc., Perkin Trans. 1 1980, (4), 1045-1050.

19

55. Ono, N.; Tamura, R.; Hayami, J. I.; Kaji, A., Reductive elimination reaction of β-nitrosulfones via one electron transfer process. A new synthetic method for the preparation of α,β-unsaturated nitriles and esters. Tetrahedron Lett. 1978, (8), 763-764.

56. Hoffmann, R.; Howell, J. M.; Muetterties, E. L., Molecular Orbital Theory of Pentacoordinate Phosphorus. J. Am. Chem. Soc. 1972, 94 (9), 3047.

57. Martin-Santamaria, S.; Carroll, M. A.; Carroll, C. M.; Carter, C. D.; Pike, V. W.; Rzepa, H. S.; Widdowson, D. A., Fluoridation of heteroaromatic iodonium salts - experimental evidence supporting theoretical prediction of the selectivity of the process. ChemComm. 2000, (8), 649-650.

58. Ochiai, M.; Shu, T.; Nagaoka, T.; Kitagawa, Y., alpha-Vinylation of 1,3-dicarbonyl compounds with alkenyl(aryl)iodonium tetrafluoroborates: Effects of substituents on the aromatic ring and of radical inhibitors. J. Org. Chem. 1997, 62 (7), 2130-2138.

59. Koser, G. F.; Relenyi, A. G.; Kalos, A. N.; Rebrovic, L.; Wettach, R. H., One-step .alpha.-tosyloxylation of ketones with [hydroxy(tosyloxy)iodo]benzene. J. Org. Chem. 1982, 47 (12), 2487-2489.

60. Sajith, P. K.; Suresh, C. H., Quantification of the Trans Influence in Hypervalent Iodine Complexes. Inorg. Chim. Acta 2012, 51 (2), 967-977.

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64. Ochiai, M.; Sueda, T.; Miyamoto, K.; Kiprof, P.; Zhdankin, V. V., trans Influences on hypervalent bonding of aryl lambda(3)-iodanes: Their stabilities and isodesmic reactions of benziodoxolones and benziodazolones. Angew. Chem. Int. Ed. 2006, 45 (48), 8203-8206.

65. Kiprof, P., The Nature of Iodine Oxygen Bonds in Hypervalent 10-I-3 Iodine Compounds. Arkivoc 2005, 19-25.

66. Rigamonti, L.; Forni, A.; Manassero, M.; Manassero, C.; Pasini, A., Cooperation between Cis and Trans Influences in cis-Pt-II(PPh3)(2) Complexes: Structural, Spectroscopic, and Computational Studies. Inorg. Chem. 2010, 49 (1), 123-135.

67. Rigamonti, L.; Rusconi, M.; Manassero, C.; Manassero, M.; Pasini, A., Quantification of cis and trans influences in [PtX(PPh3)(3)](+) complexes. A P-31 NMR study. Inorg. Chim. Acta 2010, 363 (13), 3498-3505.

68. Wirth, T.; Antonchick, A. P., Hypervalent iodine chemistry. In Topics in Current Chemistry, [Online] Springer,: Cham, 2016; pp. 1 online resource (viii, 316 pages).

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21

CHAPTER TWO

SYNTHETIC UTILITY OF ASYMMETRIC PEPTIDE-BASED ORGANOCATALYSTS

2.1 INTRODUCTION TO CATALYSIS

Chemical synthesis is an essential method used by scientists to construct particular

chemical compounds. From medicines and herbicides to foods and dyes, chemical

synthesis is a fundamental field that impacts several branches of life. Researchers are

constantly searching for new strategies to progress the field of synthesis, and a common

area of exploration involves the use of new reagents to carry out reactions.

Although metal-based reagents continue to demonstrate their importance in the

facilitation of chemical transformations, recent efforts have been made to develop

nontoxic, metal-free synthetic methodologies; it should be noted that while metal

reagents may have drawbacks, they also possess many advantages, especially in the

context of redox chemistry. Small organic molecules, which lack a metallic component,

have become attractive alternatives as they are considered to be “greener” alternatives to

metal reagents.74 In comparison to metal species, metal-free organic molecules are

typically cheaper and more environmentally friendly, with potential to attain highly

efficient synthetic processes.

In 1836, the Swedish chemist J. J. Berzelius introduced the term ‘catalysis’.

According to Berzelius75, catalysis can be conceptualized as a situation whereby:

“…several simple or compound bodies, soluble and insoluble, have the property of exercising on other bodies an action very different from chemical affinity. By means of

22

this action they produce, in these bodies, decompositions of their elements and different recombinations of these same elements to which they remain indifferent.”

In other words, Berzelius hypothesized that chemical reactions can occur by catalytic

contact. During this time in history, the concept of reaction rate was unknown; instead

scientists believed the driving force of a reaction was due to either an ‘affinity’ force, or

as Berzelius stated, a ‘catalytic’ force.75, 76

Catalysts are compounds used in chemical transformations that speed up reactions. In

short, a catalyst forms a bond with a reactant, a chemical reaction transpires to form a

Figure 2.1 Simplified catalytic cycle

23

product, and a subsequent detachment of the unconsumed catalyst from the product

occurs (Figure 2.1).77 When the catalyst is separated from the product, it is available to

be used again in the next reaction sequence, hence the term catalytic cycle. To illustrate a

general catalytic cycle, Figure 2.1 shows a catalyst interacting with compound A and

compound B to form a complex. When bound to the catalyst, A and B react to give a

product, P. The cycle is complete when the catalyst desorbs and departs from the

product, allowing for the cycle to repeat.

The catalyst increases a reaction’s rate by lowering the activation energy that is

needed to get over the high energy activated complex, the transition state. As shown in

Figure 2.2, a reaction coordinate diagram can emphasize the differences between a

catalyzed (red line) versus an uncatalyzed reaction (blue line).15 In a catalytic reaction,

the energy of the substrate can be lowered when bound to a catalyst, in comparison to the

free, uncatalyzed substrate. Furthermore, the binding between the transition state and the

catalyst can be strong, allowing for a lower activation energy than the uncatalyzed route

(ΔG °‡cat < ΔG °‡

uncat). With a lower activation energy, the rate of the reaction increases.

Therefore, catalysis is accomplished when the catalyst can stabilize the transition state at

a greater extent than it can stabilize the ground state. To put it another way, a catalyst

can react with a starting material to generate a lower energy transition state (in

comparison to the noncatalyzed reaction), and as a result, less energy is needed to

overcome the activation energy barrier; this in turn, accelerates the rate of the reaction.

The catalyst does not change the position of equilibrium between the reactants and

24

products, but instead lowers the energy of the rate-determining step. Catalysis is

therefore considered to be a kinetic, and not a thermodynamic, process.15, 78

Nature has harnessed the power of catalysis to perform virtually all biochemical

transformations of life through the development of a novel type of catalyst known as an

enzyme. Enzymes have the ability to selectively bind to the active site of a substrate, and

this complex maintains an optimal configuration for catalysis to occur.79 Enzymes have

many advantages, in that they are highly efficient catalysts that can exhibit exquisite

selectivities, however they can also exhibit disadvantages; for instance, in order to be

Figure 2.2 Reaction coordinate diagram of a catalyzed vs. uncatalyzed reaction

Binding the transition state

Binding the ground state

ΔG°ΔGuncat

ΔGcat

ΔGcat < ΔGuncat

Reaction Coordinate

Transition state for catalyzed reaction

Transition state for uncatalyzed reaction

°‡

°‡

°‡ °‡

25

effective, they may require specific conditions (temperature, pH, pressure, etc.), and

while they can provide exquisite selectivities, each enzyme has a rather limited substrate

scope. Consequently, leveraging enzymatic catalysis in the laboratory can be tedious,

and it can be difficult to discover/evolve enzymes for broad applicability. To expand the

synthetic chemistry toolbox, scientists have worked toward the development and

application of new catalysts.

2.2 HOMOGENEOUS AND HETEROGENEOUS CATALYSTS

Catalysts can be categorized in many ways, but based on their state of aggregation,

the two main classes are homogeneous or heterogeneous catalysts.77 A homogeneous

catalyst is one that operates in the same phase as the reactant(s) while a heterogeneous

catalyst operates in a separate phase than the reactant(s).77, 80, 81 Ordinarily, for a reaction

to occur with a heterogeneous catalyst, the reactant must first adsorb onto the surface of

the catalyst. On the other hand, homogeneous catalysts merely have to be added to the

reaction mixture. Some of the more notable homogeneous and heterogeneous catalysts

are seen in Figure 2.3.

26

2.3 GENERAL APSECTS OF ORGANOCATALYSIS

A pivotal advancement in the field of synthetic chemistry has been the

implementation of organocatalysts, or small organic molecules that serve as catalysts.

Organocatalysis has been known and described for over a century, yet this field has only

recently emerged as a prominent concept.82, 83 As reported by MacMillan, a staggering

statistic shows the growing interest of utilizing organic catalysts (Figure 2.4).84 From

1968-1997, there were no review articles, and only a limited number of manuscripts

disclosing the use of organocatalysts, however from 1998-2008, more than 1,500

publications reported the use of organic molecules to catalyze over 130 distinct reaction

types.

Figure 2.3 Examples of heterogeneous and homogeneous catalysts

Heterogeneous catalyst

Type of CatalystCatalystProcess

Contact process

Haber-Bosch process

Ostwald process

Product Synthesized

Sulfuric acid (H2SO4)

Ammonia (NH3)

Nitric acid (HNO3)

Vanadium oxides (V2O5)

Iron oxides on alumina (Al2O3)

Unsupported Pt-Rh

Andrussov oxidation Hydrogen cyanide (HCN)

Ziegler-Natta polymerization Polymerized olefins TiCl3 or MgCl2





Pt-Rh

Homogeneous catalystHydrolysis of esters

Hydrogenation of olefins

Enzymatic catalysis

Carboxylic acids

Alkanes

Acid

Wilkinson’s or Crabtree’s catalyst

Carbonic anhydrases

Cativa process Acetic acid (CH3CO2H)

Wacker process Acetaldehyde (CH3CHO)

Homogeneous catalyst




Iridium complex

CO2

Pd(II)

27

Organocatalysts can be considered homogeneous or heterogeneous, and each type of

catalyst has advantages and disadvantages.85-87 The common benefits of using

homogeneous organocatalysts hinge on their ease of modification, and that they have

well-understood structures and predictable reaction mechanisms.88 However, a major

drawback of homogeneous catalysis involves the difficulty in separating the catalyst from

the intended product. Heterogeneous catalysts can be difficult to fine-tune and typically

have poorly-characterized reaction mechanisms, yet they can be easily separated from the

reaction mixture.

Figure 2.4 The amount of publications pertaining to organocatalysis from 1968-200812

28

While biocatalysis78, 87, 89-91 and metal catalysis78, 92-94 continue to be valuable within

the realm of synthesis, organocatalysis has become a complementary, and often superior

strategy to effectively catalyze chemical transformations.15, 95-101 The energy-efficient

nature of organocatalysis enable chemists to obtain desired products in a timely and

practical fashion. Organocatalysts are typically more stable to air and moisture, and are

readily accessible and operationally simple to implement. Furthermore, because organic

catalysts are metal-free and are used in substoichiometric amounts without being

consumed, they are considered to be more atom-economical and sustainable alternatives,

with the potential to be recovered, recycled, and reused.88 It should be noted that the

metal-free aspect of organocatalysts is particularly crucial within the pharmaceutical and

food industries, owing to the fact that the FDA has placed strict regulations on metal

contamination, even at trace amounts, of final products, due to possible adverse

toxicological effects.88

Organocatalysis has become an attractive area of research over the last decade.95, 97, 98

Scientists have applied organocatalysts in a vast array of important synthetic

transformations.74, 95-98 Some of the more well-known reactions that have been impacted

by organocatalysis include: Hajos–Parrish reactions102, Knoevenagel condensations103, 104,

esterifications105, Baylis-Hillman reactions106, Stetter reactions107, Aldol reactions108, 109,

Diels-Alder cycloadditions110, 111, Michael reactions112, Mannich transformations113-115,

and natural product syntheses116, 117. While organic catalysts have been successfully

utilized in various synthetic transformations, one of the most pivotal aspects has been

their capacity to act as enantioselective catalysts.

29

2.4 THE IMPORTANCE OF ASYMMETRIC SYNTHESIS

Many scientific areas depend on the chirality of organic molecules. Depending on the

chemical connectivity, or simply put, how atoms are arranged within a compound, can

affect a compound’s properties and reactivity. When enantiomers are in an achiral

environment, they maintain the same chemical and physical properties (other than the

direction in which they rotate plane-polarized light). However, in chiral conditions, the

spatial arrangement of the atoms can have drastic effects. As an example, the difference

in smell between oranges and lemons can be attributed to the existence of the

enantiomeric forms of limonene: (R)-limonene and (L)-limonene (Figure 2.5).118

Similarly, the enantiomeric forms of carvone can give discrete smells of either spearmint

or caraway seed. Another, more extreme example, involves the formerly prescribed drug

named thalidomide. In the 1960s, many West European countries advocated pregnant

women to use thalidomide to alleviate the symptoms of morning sickness.119 Although

Figure 2.5 Select examples demonstrating how chirality affects chemical properties and reactivities

O

H

O

H

(R)-carvoneSpearment oil smell

(S)-carvoneCaraway oil smell

N

O

O

NHO

O N

O

O

NHO

O

(R)-thalidomideEffective sedative

(S)-thalidomideTeratogenic

H H

(R)-limoneneFresh citrus, orange smell

(S)-limoneneSharp, lemon smell

H H

30

some women responded well to the thalidomide medication, other women witnessed

severe birth defects in their newborn babies. The drug was administered as a mixture of

enantiomers, and doctors soon realized that one of the isomers, the (S)-enantiomer of

thalidomide, was causing birth defects.

Since scientists have recognized the extent in which enantiomers can impact science

and life, there has been an increase of interest in the field of enantioselective synthesis.

One of the more elegant and eco-friendly strategies that can install chirality into a

molecule is to apply a substoichiometric amount of a metal-free chiral catalyst; this is the

basis of asymmetric organocatalysis.95, 97, 98, 100 Asymmetric organocatalysis can be

broadly defined as an enantioselective process that is accelerated through the use of a

catalytic amount of organic-based chiral reagent. In contrast to transition metal and

enzymatic catalysis, the key detail to recognize is that asymmetric organocatalysis

employs small organic molecules to carry out the chemical reaction. These chiral

organocatalysts are typically more stable, more affordable, less toxic, and easier to

synthesize and apply to various chemical transformations.88, 100

2.5 ASYMMETRIC ORGANOCATALYSTS BASED ON ACTIVATION MODE

In general, organocatalytic transformations can be classified based on how they

interact with a substrate, which is referred to as their mode of action. The

organocatalysts react mainly as Lewis bases, Lewis acids, Brønsted bases, and Brønsted

acids, but these can be simplified into two main modes of action: covalent and non-

covalent organocatalysts.99, 101, 120 Covalent organocatalysts involve a strong interaction

31

between a substrate and the catalyst in which a new covalent bond is formed. The

covalent modes of action commonly encompass enamine, iminium, singly occupied

molecular orbital (SOMO), carbene, and Lewis-base catalysts. Non-covalent

organocatalysts depend on weak bonds between the substrate and organocatalyst. The

non-covalent modes of action predominantly involve hydrogen bonding, Brønsted base,

Brønsted acid, bifunctional, and phase transfer catalysts. While publications related to

asymmetric organocatalysis continue to flourish, in the interest of brevity, the following

content will feature a select few chiral organic frameworks that illustrate the innovations

that have been made in asymmetric organocatalysis. Particular emphasis will be placed

on asymmetric organocatalysts that closely relate to the work displayed in this thesis: 𝛼-

functionalizations of carbonyl compounds, oxidations, and peptide related

organocatalysts. This review is intended to only cover specific topics, and therefore

many pioneering works will not be represented. However, for a more thorough and all-

inclusive understanding of asymmetric organocatalysis, the reader is directed to the

remarkable multitude of books87, 99, 101, 121 and reviews74, 84, 96, 120, 122-138 that have been

published. Some of the more influential works that pertain to asymmetric

organocatalysis will not be discussed but that are worth mentioning include: Fu’s planar-

chiral catalysts139, MacMillan chiral imidazolidinones for Diels-Alder, Friedel-Craft

alkylations, direct alkylations of furans and indoles, and Mukaiyama−Michael

additions110, 140-143,and Shi144, Yang145, and Denmark146 catalytic scaffolds for

asymmetric epoxidations.

32

2.6 ASYMMETRIC ORGANOCATALYSIS FOR 𝛼-CARBONYL

FUNCTIONALIZATIONS

The earliest report to render a reaction catalytic with an organic catalyst appeared in

1912 by Bredig and Fiske (Scheme 2.1).82, 147 Although low enantiomeric excesses

(<10% ee) were detected in catalyzing the addition of hydrogen cyanide to aldehydes,

this seminal work revealed the possibility of using organic, chiral reagents (i.e. cinchona

alkaloids in this case) in synthetic chemistry.

In 1960, Pracejus was able to impart the first synthetically useful enantioselective

H

O HC N

H

OHCN

*

Scheme 2.1 Cinchona alkaloids as chiral catalysts form chiral mandelonitriles

Catalyst 1 or Catalyst 2

<10% ee

N

N

O

H

OHH

Catalyst 1

N

N

O

H

OH

Catalyst 2

Scheme 2.2 A 1960 enatioselective ketene methanolysis by Pracejus

C O1 mol% Catalyst 3MeOH (1.1 eq.)PhMe, -111 °C

93% yield, 76% ee

OMe

ON

N

O

H

OBnH

Catalyst 3

*

33

reaction through the methanolysis of phenylmethylketene by utilizing an O-

benzoylquinine organocatalyst (Catalyst 3) (76% ee) (Scheme 2.2). Soon after, Hajos

and Parish102, and later Wynberg148, independently detailed an intramolecular aldol

condensation catalyzed by L-proline (Catalyst 4) to afford enantioenriched bicyclic

intermediates (Scheme 2.3, eq. 1).147 The selectivity of this reaction has been attributed

to the hydrogen bonding that occurs between the carbonyl starting material and the

carboxylic acid of the catalyst after enamine formation with the substrate (Scheme 2.3,

eq. 1, Int-1). This enantioselective, intramolecular aldol reaction was extended by Hajos

and Parrish149, as well as Weichert, Sauer, and Eder150, to generate a Robinson

Annulation product, the Wieland-Miescher ketone. This is an important synthetic

building block for the synthesis of natural products (e.g. steroids and terpenoids)

O

O

O

3 mol% Catalyst 4

NH

O

OH

DMF, 20 °C

Catalyst 4(L-proline)

O

OOH

Scheme 2.3 Intramolecular aldol reactions catalyzed by proline

quant. yield, 93% ee

**

O

47 mol% Catalyst 41N HClO4 O

87% yield, 84% ee

*O

O

O

Hajos-Parrish Reaction

Wieland-Miescher ketone

(1)

(2)

Robinson Annulation

MeCN, 20 °C

N

O

O

OH O

Int-1

34

(Scheme 2.3, eq. 2).125, 148, 151, 152 These catalytic scaffolds have helped solve major

synthetic challenges and have demonstrated their applicability in organic synthesis.

List and Barbas reported a carbon-carbon bond forming reaction by means of a

direct asymmetric intermolecular aldol condensation.37 Proline was used as the amine-

based catalyst, and similar to the Hajos-Parrish reaction (Scheme 2.3, eq. 1), it has been

suggested that the enantiofacial selectivity arises from the stereodirecting carboxylate of

proline (Scheme 2.4, Int-2).108, 125, 153 Further research from Woodward154 and

Danishefsky155 exhibited the utilization of enamine catalysts in application to natural

products such as erythromycin (Scheme 2.5, eq. 1) and estrone (Scheme 2.5, eq. 2).

Me Me

O

H

O 30 mol% Catalyst 4

DMSO, rtMe

O

97% yield96% ee

Intermolecular aldol reactionH OH

Scheme 2.4 Intermolecular aldolization using a proline chiral catalyst

N

O

MeOH O

Int-2

H

N O O

O

N

O

O

200 mol% Catalyst 5MeCN, HClO4

80 °C82% yield, 86% ee

HO

O

NH2

Catalyst 5((S)-phenylalanine)

S

O

S

O

O

S

O

S

OH

OH

H

70% yield, 36% eeCatalyst 4

Erythromycin

Scheme 2.5 Enamine catalysis in natural product synthesis

Estrone precursor

(1)

(2)

7ak

35

The ability to use small, organic compounds, such as the natural amino acid

proline, to catalyze chemical reactions has allowed for an expanded repertoire in the field

of organocatalysis. As shown in Scheme 2.6, many carbonyl moieties have been

functionalized at the ⍺-position with use of L-proline as the organocatalyst. The

asymmetric Mannich reaction (Scheme 2.6, eq. 1) can generate syn β-amino ketones and

aldehydes.113, 153, 156, 157 This has become an attractive enantioselective strategy for

constructing decorated 𝛼-amino acids and alcohols.153, 157 MacMillan158, Hayashi159, and

Zhong160 independently published enantioselective methods to assemble new carbon-

oxygen bonds at the alpha position of aldehydes and ketones (Scheme 2.6, eq. 2). The

proposed transition state (Scheme 2.6, eq. 2, int-3) involves hydrogen bonding to the

nitrogen atom of the nitroso species, which has an enhanced Brønsted basic character,

and allows for O-regioselectivity.161 These procedures have been exploited to produce

optically active 𝛼-oxy-functionalized carbonyl compounds, which can be transformed

into biologically relevant chiral compounds.161 Strategies that utilize asymmetric

organocatalysis to form carbonyl compounds equipped with nitrogen substituents at the

𝛼-position have been disclosed by Jørgensen 162 and List163 (Scheme 2.6, eq. 3). These

approaches can accompany the enantioselective Strecker and Mannich reactions toward

𝛼-amino carbonyl compounds, however, List and Jørgensen illustrate a direct 𝛼-

amination by reacting enamines with alkyl diazodicarboxylates.162 Proline has also been

utilized to afford a direct asymmetric catalytic dihydroxylation (Scheme 2.6, eq. 4). This

process is the first to exercise small organic catalysts en route to enantiopure anti-1,2-

diols, and has been used as a complementary protocol to the Sharpless dihydoxylation.164

36

This methodology was further expanded by MacMillan in an asymmetric direct aldehyde-

aldehyde coupling (Scheme 2.6, eq. 5).165, 166 The mechanism relies on distinct functions

Scheme 2.6 Various asymmetric !-functionalizations of carbonyls mediated by proline catalysts

R1

O

R2 H CO2Et

NAr

30 mol% Catalyst 4

DMSO, rt

R1, R2 = H, alkyl

R1

O

R2CO2Et

NHAr

86% yield95% ee

Mannich reaction

H

O

R1 H R2


DMF, 4℃

R2 = non-enolizable

H

O

R1R2

OH

88% yield99% ee

Cross aldehyde aldol coupling

R1

O

R2

5 mol% Catalyst 4

CHCl3, 4℃

R1 = H, alkyl

R1

O

R2

ONH

95% yield97% ee

!-Oxygenation

NOPh Ph

R1

O

R2

10 mol% Catalyst 4

MeCN, rt

R1 = H, alkyl

R1

O

R2

NNH

92% yield99% ee

!-AminationCO2R

(1)

(2)

(3)

O

H R1


DMSO, rt

O

OHR1

OH

95% yield97% ee

Dihydroxylation

OH

(4)

CO2R

NNCO2RRO2C

R1 = H, alkyl

N

HO O

O NR2

Ph R1

Int-3

H

N

O CO2R1R2

Int-4

(5)

37

of the two aldehydes, one aldehyde must function as a nucleophilic donor while the other

operates as an electrophilic acceptor. The donor aldehyde transposes to an enamine form,

and permits the enantioinduction to ensue to form the desired product, a β-hydroxy

aldehyde, which is an important building block for the synthesis of natural products; the

intermediate is shown in Scheme 2.6, eq. 5, Int-4. The aforementioned reactions have

made it possible for small organic catalysts to be applied in various organic reactions, and

thereby gives additional evidence of the prominent role that organocatalysts play in chiral

catalytic transformations.74

2.7 PEPTIDES

One innovative strategy that has spawned from proline-type catalysts has been the

utilization of short peptide-based chiral organocatalysts.128, 167-169 Peptide scaffolds are

highly modular and easy to fine-tune due to the immense “chiral space” provided by the

various commercially available and structurally diverse amino-acid residues. The easily

iterative and facile assembly of peptides can be attributed to the development of Fmoc

solid-phase peptide synthesis (Fmoc SPPS).170-172 Peptides are unique in that they can

have small molecule characteristics (e.g. relatively low molecular weight, broad substrate

scope), yet can mimic many sophisticated features of enzymes (e.g. site-selectivity,

chemoselectivity).173, 174 The synthetic accessibility of peptides allows for large catalyst

libraries to be generated, and these libraries can be rapidly tested using combinational

optimization/selection and high-throughput methods.167, 175-177 Asymmetric catalysis

38

mediated by short peptide-based compounds has proven to be a practical approach in

furnishing enantiopure products.168, 169, 178, 179

In the 1979, Inoue and Oku catalyzed the cyanation of benzaldehyde to

cyanohydrine via a catalytically active cyclic dipeptide (Scheme 2.7, eq. 1). This was the

first example of utilizing peptide-based chiral catalysts for carbon-carbon bond forming

reactions.168, 180, 181 Encouraged by these results, cyclic dipeptides were used as chiral

catalysts for asymmetric epoxidations.182 Soon after, Jacobsen disclosed a highly

H

O HC N HO2 mol% Catalyst 697% yield, 97% ee

CN

NH

HNO

O

PhHN

N

Catalyst 6

O tBu

O

tBu

HO

N

NH

NH

OHN

O

Ph

tBu

Catalyst 7

N HC N NH

2 mol% Catalyst 7quant. yield, 95% ee

CN

Ph Ph

Scheme 2.7 Early examples of peptide-based asymmetric catalysts in organic synthesis

(1)H

CF3 CF3

Asymmetric Strecker reaction

(2)

39

enantioselective Strecker-type reaction by using a rigidified peptide-urea catalyst

(Scheme 2.7, eq. 2) .183-186 The direct asymmetric aldolization of acetone with aldehydes

was established by utilizing tripeptides that incorporate a secondary amine moiety

(proline) (Scheme 2.8).187 The difference in reactivity and selectivity when using

catalyst 8 versus catalyst 9 has been ascribed to the secondary structure of the peptide

chiral catalyst. In fact, the two catalysts give products with opposite absolute

configurations.

Remarkable advances in the domain of peptide-based asymmetric organocatalysis

have been accomplished by the Miller laboratory.128, 167, 169, 173, 178, 179, 188 With short

peptide catalysts, Miller’s group successfully performed kinetic resolutions to produce

enantiopure alcohols (Scheme 2.9).189 The enantiodiscrimination of the reaction is

enabled by a well-documented β-turn secondary conformation190-193 within catalyst 10

Scheme 2.8 Direct aldolization using peptide-based chiral catalysts

NH O

N

ONH

NH2

O

CO2H

NH

O

HN HN

ONH2

O

CO2HCatalyst 8 Catalyst 9

H

OCatalyst 8 (1 mol%)

or

Catalyst 9 (10 mol%)

OH O

Acetone, rtWith Catalyst 8: 69% yield, 78% ee (S)With Catalyst 9: 58% yield, 66% ee (R)

*

40

and catalyst 11, allowing for hydrogen bond interactions to trigger the kinetic

resolution.169, 188, 194-197

In Miller’s ensuing publications, NMR techniques and solvent titrations were

investigated to confirm the secondary structure of the peptide. They found that the highly

ordered structure is suggested to be induced through intramolecular hydrogen bonding

networks that occur within the peptide-based catalysts.189, 198, 199 In 2001, Miller used

similar tactics to effectively resolve tertiary alcohols, a previously stubborn and difficult

resolution to attain.200

NHAc

OH

(±)

OH5 mol% Catalyst 10or 2 mol% Catalyst 11

Ac2O (1 eq.)toluene, 0 ℃

NHAc

OAc OAc

NO

BocHN

N

O

NH O

HN

Ph

NCatalyst 10

84% ee

NN

NHBocNH

Oi-PrHN

Oi-Pr

N

OONH

O

NH

O

HN

i-Bu O

NH

i-Pr

OMe

O

i-Pr

Catalyst 11

With Catalyst 10: 84% eeWith Catalyst 11: Krel = 51

Scheme 2.9 Kinetic resolution of hydroxyamide

41

The Miller group was able to assemble new carbon-carbon bonds in an

asymmetric Morita-Baylis-Hillman (MBH) reaction of ketones.201, 202 This

transformation constructs new carbon-carbon bonds that supply functionalized allylic

alcohols. The combination of two catalysts, a peptide and proline, were found to promote

enantioselective Baylis-Hillman reactions (Scheme 2.10, eq. 1),201 and without the dual

catalysis platform, the reaction is sluggish. Miller and coworkers also established an

intramolecular variant by using a two catalytic system that provides highly

O O O OH

≤ 84% ee

Ac2OO O

> 98% ee

O

R H

O O

R

OH

Scheme 2.10 Enantioselective Baylis-Hillman reactions with peptide catalysts

≤ 81% ee

N

NMe

BocHNNH

OHN

O

NH

OHN

O

MeMe

O NH-Trt

Ph

N

OO H

NNH

O

OMe

O

Catalyst 12

10 mol% Co-catalyst 410 mol% Catalyst 12

CHCl3, rt

N

NMe

BocHNNH

OHN

O

NH

OHN

Oi-PrPh

NH

O

Catalyst 13

Me Ot-BuN-TrtN

HN

O

Me

Met-BuO

NH

O

OMe

O

Me

Me

10 mol% NMI20 mol% Pip

HN

OH

O

Acetic pipecolinic acid (Pip)

Toluene, rt

O

THF/H2O, rt

(1)

(2)

N

N

N-methylimidazole (NMI)

5 mol% Catalyst 12

42

enantioselective transformations (Scheme 2.10, eq. 2).202 The products obtained contain

a new substituent at the carbonyl ⍺-position, as well as a newly set stereocenter at the β-

position.

The concept of utilizing a peptide-based catalyst that contains a conformational

rigid scaffold has been implemented in various other selective reactions.203-208 In 2015,

Schreiner kinetically resolved racemic diols, in conjunction with a catalyzed alcohol

cross coupling, to form enantioenriched esters (Scheme 2.11).209 This enantioselective

reaction was catalyzed by a peptidic catalyst that incorporates a sterically bulk adamantyl

group, a moiety that causes structural rigidification.210, 211

N

HN

OO

NH

OHN

ONH

OHN O

ON

NCatalyst 14

1.) 2.5 mol% Catalyst 14m-CPBA, toluene, rt

OH

OH

R1

OH O

OH

O

R1

⩽97% ee

2.) DIC (2 eq.), rt

3.)

Scheme 2.11 Alcohol cross-coupling for kinetic resolution of diols using peptide catalysts

43

Phase transfer catalysts (PTC) have had a substantial impact on the field of

asymmetric organocatalysis.212-214 O’Donnell213, 215, Corey216, and Lygo212 have applied

chiral Cinchona alkaloid phase transfer catalysts (PTC) to generate 𝛼-enriched amino

acid derivatives. The catalyst is conformationally organized through non-covalent

interactions, allowing it to possess exquisite facial selectivity to the substrate.99, 215 An

example is illustrated in Scheme 2.12, in which a Cinchona alkaloid PTC is able to

effectively trigger an enantioselective monoalkylation at the 𝛼-carbonyl position.212, 213,216

The advances described above have given the field of organocatalysis exceptional

applicability. In particular, peptide-based catalysts have presented themselves as

multifaceted organic catalysts, in which they portray characteristics of enzymes and small

molecules. These unique features have validated the impact that peptidic catalysts can

have on chemical synthesis, especially in the context of asymmetric catalysis. Scientists

Catalyst 15

N

N

O

Br

Ph

Ph

NO-tBu

O10 mol% Catalyst 15

CsOH•H2ODCM, -78 ℃

Ph

Ph

NO-tBu

O

97% ee

Scheme 2.12 Cinchona alkaloid PTCs for asymmetric !-amino acid derivatives

44

have geared toward using “greener” and more environmentally benign catalysts, and

organocatalysts meet these desires. One area of research that has also gained attraction as

a versatile, yet eco-friendly strategy has been the implementation of hypervalent iodine

organic catalysts. While many remarkable achievements have been made, the integration

of hypervalent iodine chemistry with peptide-based organocatalysts has remained widely

unexplored. Developing methodologies that can exercise the unique aspects of chiral

peptide-based catalysts and hypervalent iodine species offers a potential new paradigm to

construct complex molecular skeletons in a highly reactive and enantioselective fashion.

The next chapter of this thesis will describe the efforts that have been made in utilizing

chiral hypervalent iodine(III) catalysts as versatile and “greener” alternatives to toxic

heavy metal chiral catalysts.

45

2.8 LICENSE AGREEMENT TO USE FIGURE 2.4

46

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CHAPTER THREE

IODOARENE-CONTAINING ORGANOCATALYSTS FOR HYPERVALENT IODINE(III)

OXIDATIVE TRANSFORMATIONS

3.1 HYPERVALENT IODINE ORGANOCATALYSIS

To facilitate asymmetric transformations, the scientific community has turned a great

deal of attention toward the use of chiral organocatalysts. Recently, one area that has

witnessed tremendous growth has been the employment of chiral, hypervalent iodine

organocatalysts. As discussed in Chapter 1, hypervalent iodine species can act as highly

efficient and selective electrophiles and/or oxidants, and are appealing due to their mild

and environmentally friendly nature.18, 30, 44, 68 Although organic molecules bearing

hypervalent iodine moieties were discovered over a century ago, chiral hypervalent

iodine reagents were not utilized as asymmetric organocatalysts until the last few

decades. The following chapter will highlight the work that has helped advance

asymmetric chemistry in the context to hypervalent iodine-mediated catalysis. Particular

focus will be placed on chiral hypervalent iodine(III) catalysts that assist in oxidative

transformations and/or that furnish alpha-functionalized carbonyl products. For a more

broad overview of the contributions that have been made toward asymmetric

transformations mediated by hypervalent iodine compounds, the reader should survey the

exceptionally thorough books13, 23, 44, 68 and reviews217-226 that have recently appeared.

Significant hypervalent iodine-mediated developments that will be featured at a minimum

but that warrant a mention include: hypervalent iodine(V) reagents68, 217, 225-227,

56

asymmetric rearrangements217, 223, 228-230 alkene functionalizations217, 228, 231-233, and

alcohol oxidations234-236.

3.2 GENERAL REMARKS ON OXIDATIONS

At the most basic level, an oxidation/reduction (redox) reaction is a process that

involves the transfer of an electron from one species to another. Oxidation refers to a

loss of electron(s), and reduction indicates a gain in electron(s). Oxidative reactions are

central for life and are commonly performed in nature as well as in the laboratory. In

fact, approximately 30% of total chemical production involves oxidation, which

represents the second largest chemical process utilized in industry.237 A functional group

is commonly converted to a more highly oxidized form by the addition of oxygen and/or

removal of hydrogen.81 The currently available oxidation methods allow for scientists to

synthesize many key chemicals and intermediates, including aldehydes, ketones,

alcohols, epoxides, esters, and carboxylic acids. Despite the advances that have been

made toward oxidative transformations, oxidation methods have been traditionally

dominated by the use of toxic and heavy metal reagents or catalysts. To further improve

and expand upon the synthetic chemist’s arsenal of asymmetric oxidation methods, the

following review will familiarize the reader with the progress that has been made in

utilizing chiral hypervalent iodine(III) reagents to effectively carry out asymmetric

oxidative transformations.

3.3 CHIRAL HYPERVALENT IODINE(III) REAGENTS FOR

ENANTIOSELECTIVE OXIDATIVE TRANSFORMATIONS

57

3.31 ASYMMETRIC OXIDATION OF SULFIDES TO SULFOXIDES

Chiral sulfoxides have dominated as premier chiral organosulfur compounds and

have displayed great importance in many chemical applications. Two of the more

impactful areas in which enantiopure sulfoxides have been used are: as chiral auxiliaries

and chiral ligands in asymmetric synthesis238, 239 and as pharmaceutically active

compounds240 such as Nexium®, Nuvigil® and Clinoril® (Figure 3.1). The preparation of

optically active chiral sulfoxides has been a challenging area of organic chemistry, yet

there is a growing interest in seeking synthetic routes in order to obtain this valuable class

of chiral compounds.

The introduction of chiral hypervalent iodine reagents can be attributed to Pribam,

Amey and Martin. In 1906, Pribam synthesized diphenyliodonium tartrate to use as the

first chiral hypervalent iodine reagent.241 In the 1970s, Amey and Martin described the

synthesis of cyclic, chiral iodanes.242 While these were essential discoveries, chiral

hypervalent iodine compounds were not synthetically utilized until decades later. In

1986, Imamoto and Koto oxidized prochiral sulfides (3d) to enantio-enriched sulfoxides

N

O

S

N

N

ONa

Nexium® (Esomeprazole sodium)Proton pump inhibitor

Nuvigil® (Armodafinil)Wakefulness stimulant

Figure 3.1 Chiral sulfoxide containing drugs

SO

FCOOH

Clinoril® (Sulindac)Antiarthritic

OS

NH2

OO

58

(3e) with the use of aryl-l3-iodane reagents (3c) (Scheme 3.1, eq. 1).68, 243 Interestingly,

the chiral oxidizing agent (3c), which was generated in situ from reacting an L-tartaric

acid anhydride derivative (3a) with iodosylbenzene (3b), was only able to induce high

enantioselectivities when a C2-symmetric shape was incorporated into the proposed

seven-membered ring (3c). When using chiral acetyl-L-lactic acids, the authors reported

racemic mixtures of sulfoxides. Koser also created an in situ active chiral I(III) agent by

adding either (diacetoxyiodo)benzene (3f, PIDA) or iodosylbenzene (3b) to tartaric

anhydride analogs (3a).244 In contrast to Imamoto’s work, Koser suggested that the active

chiral iodine(III) benzoyl tartrate reagent was a polymer (3g) rather than a seven-

membered ring as previously proposed (i.e. 3c).

Varvoglis and co-workers245 generated novel (+)-camphorsulfonic acid

derivatives (3i) to act as chiral hypervalent iodine(III) reagents, and Chen246 utilized a

similar methodology for the preparation of organosulfonyloxy analogs (3j) in good

yields, but poor enantioselectivies (Scheme 3.1, eq. 2). In 1990, another asymmetric

strategy toward the synthesis of optically active sulfoxides was detailed by Koser and

Ray (Scheme 1.3, eq. 3).247 Through ligand exchange, (+)- or (–)-menthol (3k) could be

attached to an iodine(III) moiety, thereby creating an efficient enantioselective iodine(III)

reagent (3l). Following recrystallization and base-mediated hydrolysis, this method

furnished chiral sulfoxides (3m) in up to 99% ee.

59

3.32 ASYMMETRIC OXIDATIVE DEAROMATIZATION

Aromatic arenes and heteroarenes are ubiquitous in nature and are widely utilized

in many areas of the molecular sciences. To manipulate aromatic moieties, many

O

O

O

O

O

H

H

IOO

3a 3b 3c (2 eq.)R1 = Me, Ph, t-Bu

(1)

(2)

R1 SR2

rt R2 SR3

O

R2, R3 = alkyl, aryl

rt3e

SO2O I

OH

O

⩽ 95% yield⩽ 53% ee

SO2OH

O PIDA(3f)MecNH2O3h 3i (1 eq.)

⩽ 92% yield⩽ 14% ee

R1SR2

O

3jR1, R2 = alkyl, aryl

O I OTsOH

(+)- or (-)-3l (1 eq.)3k(+)-menthol

or(-)-menthol

DCM

PhI(OCH3)OTS (MTIB)R1 S

R2

O

R1, R2 = alkyl, aryl3m

⩽ 94% yield⩽ 99% ee

1.)

2.) NaOH, H2O

DCM (3)

R2 SR3

DCM, rt

Scheme 3.1. Enantioselective oxidations of sulfides to sulfoxides using hypervalent iodine(III) reagents

O

R1

O

R1

O

O

H

H

O

R1

O

R1 OI

OO

O

3g (2 eq.)

Ph O

O

OO

O

PhO

O

OI

Phn

3d

IOCOCH3

OCOCH3

3f (PIDA)

60

chemists rely on well-established transformations, such as Friedel-Crafts and Sandmeyer

reactions. One specific transformation, dearomatization, has perpetually sparked interest

in the synthetic community. Dearomatization reactions have the potential to transform

aromatic substrates into more complex ring systems or into nonaromatic products that can

act as valuable synthetic building blocks.248-251

Siegel and Antony252 were the first to utilize hypervalent iodine reagents for

dearomatizations, however Kita253 further developed this chemistry by disclosing the first

enantioselective dearomatization strategy. Kita’s asymmetric phenolic oxidation was

carried out with a novel l3-iodane reagent that contained a conformationally rigid

spirocyclic backbone (Scheme 3.2, 7n).

OH

R

OO

O

RCHCl3, -50 ℃

⩽ 86% yield⩽ 86% ee

OH

O

Scheme 3.2 Kita’s first asymmetric dearomatizing spirolactonizations using a hypervalent iodine(III) reagent

3n0.55 eq

I

IO

OAc

OAc

61

The two generally accepted mechanistic pathways for phenolic oxidative

dearomatization reactions mediated by hypervalent iodine(III) reagents are illustrated in

Scheme 3.3.254-260 In Pathway A, a ligand exchange occurs between the HI(III) reagent

B, (e.g. iodobenzene diacetate) and the phenol substrate A, to produce iodonium

intermediate C1. The iodine(III) component of C1 collapses into iodobenzene and

acetate, while concomitantly producing a resonance-stabilized phenoxenium ion D,

which is subsequently trapped by a nucleophile to furnish the dieonone product E. In

Pathway B, the dienone product E is produced directly after a nucleophilic attack, via an

SN2′-type substitution at the para position of the arene ring in C2, which oxidizes the

phenoxyl group and reductively eliminates the iodine(III) component to iodobenzene and

acetate. Generally, to induce enantioselectivity in phenolic oxidative dearomatization

OH

RO

R

IPh

OAc

O

R

IPh

OAc

Nu

O

RNu

O

R Nu

Ph IOAc

OAcB

(PIDA)

Ph IOAc

OAc

B (PIDA)

Pathway A

Pathway B

Scheme 3.3 Proposed mechanistic pathways for the oxidation of phenols via HI(III)-reagents

A

C1 D

C2

E

62

reactions, the optimized conditions should favor Pathway B.220

Kita’s methodology was later improved to allow for a catalytic variant, in which a

diiodo chiral scaffold 3o was oxidized by a co-oxidant, m-chloroperbenzoic acid (m-

CPBA), to afford chiral, ortho-spirolactones in up to 69% ee (Scheme 3.4, eq. 1).253, 261,

OH

R

OO

O

R

DCM, 0 ℃

m-CPBA (1.3 eq.)AcOH (1 eq.)

IOO NHMes

O

MesHN

O

(1)

3o (R1 = H)0.15 eq.

3p (R1 = Et)0.15 eq.

⩽ 70% yield⩽ 69% ee

OH

O

With 3o:

With 3p:⩽ 96% yield⩽ 92% ee

OHO

OO

CH3Cl, 0 ℃

m-CPBA (1.3 eq.)AcOH (1 eq.) (2)OH

O

3q (0.15 eq.)Mes = mesityl

⩽ 60% yield⩽ 92% ee

Scheme 3.4 Asymmetric dearomatizing spirolactonizations using hypervalent iodine(III) reagents

3r⩽ 52% yield⩽ 88% ee

OO

O

O

II

R1

R1

63

262 To understand the structural influence the catalyst had on the chiral induction, Kita et

al. investigated the ortho positioned R1 groups relative to the aryl iodine.263 By

synthesizing various spirobiindane-containing chiral reagents, they found an ethyl

substituent in the ortho-position (3p) could increase the enantioselectivity of the

dearomatizing spirocyclization of napthols up to 92% ee. With the optimized conditions,

Kita subjected Ishihara and co-worker’s C2-symmetrical chiral hypervalent iodine(III)

scaffold (3q)264, 265 to the oxidative dearomatization of naphthols, which returned an

unsubstituted spirocyclic product in a similar 92% ee (Scheme 3.4, eq. 2).263 It should be

noted that while this reaction is successful with lower equivalents of the co-oxidant, if

five or more equivalents of m-CPBA are added, the olefin-containing product is

selectively oxidized to an epoxide (Scheme 3.4, eq. 2, 3r).264

This work was extended by Quideau to allow for an iodoarene-mediated

asymmetric hydroxylative phenol dearomatization, which can provide chiral o-quinols

(Scheme 3.5, eq. 1, 3u).266 The active catalyst was generated in situ with use of a co-

oxidant, m-CPBA, but as similarly described by Kita and Ishihara, if the co-oxidant is in

excess, the resulting product undergoes subsequent epoxidation (3v). Harned et. al.

applied DFT calculations to design tricyclic chiral catalyst 3x, a dimethyl tartrate

derivative.260, 267 This chiral aryl iodide catalyst was employed in an asymmetric

oxidative dearomatization reaction to yield enantioenriched p-quinols (Scheme 3.5, eq. 2,

3y). Quideau also performed an intramolecular hypervalent iodine-induced oxidative

dearomatization to generate a 2,5-cyclohexadienone derivative 3aa in 40% ee (Scheme

3.5, eq. 3).260

64

I

OH

O

O

OH O

O

OH

O

OH

OO

OMesHN

ONHMes

I

OHR1

R2

R3

O

R3 OH

R1

R2

3t (1 eq)

m-CPBA (1 eq.)DCM, rt

3u≤ 71% yield≤ 47% ee

3v3s

(1)

Scheme 3.5 Enantioselective hydroxylations using hypervalent iodine(III) reagents

3x(0.1 eq)

m-CPBA (2.2 eq.)9:1 MeCN/H2O, rt

3y≤ 71% yield≤ 60% ee

3w

(2)

Mes = mesityl

OH OHTBS

m-CPBA (2.2 eq.)MeCN, 0 ℃

0.1 eq. 3x OTBS

O

3aa≤ 50% yield≤ 40% ee

3z

(3)

65

3.33 ALPHA FUNCTIONALIZATION OF CARBONYLS

Enantiopure 𝛼-functionalized carbonyl compounds are valuable and versatile

chiral synthons that enable rapid access to synthetic targets.96, 133, 224, 226 They can be

used for the construction of complex natural products, pharmaceutical agents, or key

synthetic intermediates. For example, Figure 3.2 highlights several pharmaceutically

active molecules that contain an α-functionalized carbonyl moiety. A significant amount

of progress toward the α-functionalization of carbonyl compounds through the use of

selective hypervalent iodine(III) reagents is presented below.

The general reactivity profile of carbonyl compounds in the context of

hypervalent iodine(III) reagents is illustrated in Scheme 3.6.268 Under acidic or basic

conditions, ketones (Scheme 3.6, eq. 1, 3ab) can equilibrate to their enol/enolate isomers

(3ac). A lone pair of electrons from the oxygen can swing down to produce a C=O π-

bond, which breaks the C=C π-bond, and subsequently permits the α-carbon to trap an

electrophile. This overall process generates an 𝛼-substituted carbonyl compound (3ad),

in which the electrophile is trapped at the α-position. Similarly, the same enolizable

Figure 3.2 Important pharmaceutical agents that contain an !-functionalized carbonyl

ON

Amfepramone (diethylpropion)Appetite suppressant

Cl

N

S

O

H3CO

Plavix® (Clopidogrel)Antiplatelet agent

H3CO

O HN

Ritalin® (Methylphenidate)Central nervous system stimulant

N

S

O

AcO

F

Effient® (Prasugrel)Antiplatelet agent

66

carbonyl compound (Scheme 3.6, eq. 2, 3ae) can trap an electrophilic species, in this

case a hypervalent iodine(III) species, to produce the α-substituted intermediate 3af.

However, due to the highly electrophilic nature of the iodine(III) species, this unstable

intermediate is susceptible to a subsequent nucleophilic attack. Upon nucleophilic attack,

the iodine(III) collapses to a univalent iodine by-product (iodobenzene) via reductive

elimination, to yield an α-substituted carbonyl product that formally contains a

nucleophile in the α-position (3ag). It can be reasoned that this reaction efficiently

proceeds to 3ag, owing to some key factors: (1) The iodine(III) is highly electrophilic,

O

RZ

O

RZ

R

EO

RZ

E

Typical reactivity of enolates with electrophiles

“Umpolung” reactivity of enolates with nucleophiles

O

RZ

R

IIIIO

RZ

IIIINu O

RZ

Nu

Scheme 3.6 Typical reactivity to functionalize ketones via HI(III) “umpolung” reactivity

3ab 3ac 3ad

3ae 3af 3ag

(1)

(2)

R, Z = substituentNu = Generic nucleophileE = Generic electrophileIIII = Generic iodine(III) reagent

67

and is considered a hypernucleofuge, allowing for it to act as an excellent leaving group,

(2) The iodine(III) leaving process is entropically favorable, in which one molecule (3af)

is split into three molecules (the product 3ag, iodobenzene, and an anionic ligand that

was supplied by the iodine(III) reagent) (cf. chapter 1, Scheme 1.4), (3) The high stability

of the iodobenzene by-product thermodynamically drives the reaction forward.

Therefore, hypervalent iodine(III) compounds have the unique ability to alter the typical

reactivity profile of enolizable carbonyl compounds by trapping a nucleophile, rather than

an electrophile, in the α-position; this inversion of polarity is known as an umpolung

strategy. The umpolung nature of hypervalent iodine(III) species has been exploited in

various chemical transformations.268, 269

Whilethe synthesis of α-functionalized chiral carbonyl compounds has

immensely advanced over the last decade, the introduction of α-carbonyl substituents in

an asymmetric fashion mediated by hypervalent iodine compounds has only recently

emerged.223, 224, 226 In 1990, Ochaia and co-workers synthesized chiral diaryliodonium

salts (Scheme 3.7, eq. 1, 3ai) to induce the first hypervalent iodine-mediated direct 𝛼-

phenylation of cyclic β-ketoesters (3aj).270 The chiral l3-organoiodane gave a moderate

enantioinduction (up to 53% ee), but prevailed as a highly regioselective reagent (i.e. no

O-phenyl congener was isolated). Metal-free enantioselective arylations were further

developed by Olofsson and Wirth.14, 230, 271, 272

68

Ishihara, Uyanik, Okamoto, and Yasui developed chiral quaternary

ammonium(hypo)iodite catalysts (Scheme 3.8, 3al) to supply enantioenriched

dihydrobenzofuran derivatives (3am) in up to 96% ee.273 The oxidative

cycloetherification was accomplished by an active iodine catalyst that was generated in

IPhBn

Scheme 3.7 Asymmetric !-arylation of indanone derivatives via HI(III) reagents

O

CO2CH3

OCO2MePh

t-BuOK, rt

3aj≤ 68% yield≤ 53% ee

BF4

3ai

3ah

OH

O

N

N

R1

R2

O

N

N

R1R2Et2O:H2O (5:1), rt

30% H2O2 (2 eq.)

O

N

Ar

ArI

3al (0.1 eq.)

3ak 3am≤ 99% yield≤ 96% ee

Scheme 3.8 Hypervalent iodine(III)-mediated asymmetric oxidative cycloetherification

69

situ with hydrogen peroxide as the co-oxidant.

While many oxidations mediated by hypervalent iodine(III) compounds have

been established, they typically rely on the use of stoichiometric amounts of l3-iodanes.

In 2005, Ochai274 and Kita262 independently disclosed processes that utilize a suitable co-

oxidant (m-CPBA) to render the process catalytic (Scheme 3.9).217, 228, 236, 275 These

methods allow for the in situ preparation of l3-iodanes, in which the precatalyst (e.g. the

iodine(I) reagent (3ap)), can be readily oxidized to its active iodine (III) state (3aq) in the

presence of an acid (e.g. (3an) para-toluenesulfonic acid, p-TsOH), and a stoichiometric

chemical oxidant (m-CPBA 3ao) (Scheme 3.9).262, 274, 276, 277 If the co-oxidant (3ao)

selectively reacts with the iodine-containing precatalyst (3ap), rather than the substrate

Scheme 3.9 Proposed reaction pathway for in situ !-oxytosylation of ketones

I

IOTs

OH

Cl O

OOH

3aom-CPBA

SO

O

OH

Cl OH

O

3anp-TsOH

m-CBA3ar

R1 R2O

OTs

R1R2

O

R1 R2OH

3aqKoser’s reagent (HTIB)

3apiodobenzene

3as

3au3at

70

(3at), the catalytic cycle can continue by a re-oxidation of the reduced iodine(I) (3ap) by-

product to regenerate the active HI(III) catalyst (3aq).

The enantioselective α-functionalization of carbonyl compounds has been an

attractive approach toward the production of valuable chiral carbonyl synthons.224, 226

Hypervalent iodine(III) compounds in conjunction with acidic conditions (e.g. p-TsOH)

can allow for ketones, such as propiophenone, to become susceptible to an

enantioselective α-oxysulfonylation process, which delivers an enantioenriched 𝛼-

substituted carbonyl compound that is equipped with an excellent leaving group at the α-

carbon stereocenter. The putative mechanistic pathways of this reaction are shown in

Scheme 3.10. Theoretical and experimental evidence has been reported in the literature

to determine which pathway is operative, yet the reports seem to dispute one another and

the true course of transformation remains unclear.59, 68, 278, 279 The two competing

mechanistic proposals for this transformation that have emerged, invoke either an SN2’ or

an SN2 displacement (Scheme 3.10 , Pathway 1 and Pathway 2 , respectively).277, 280-282

Both mechanistic pathways commence with the ketone (4a) existing in an acid-catalyzed

equilibrium with its (E) and (Z) enol tautomers (4c and 4d, respectively). Mechanistic

Pathway 1 (shown using red arrows) involves the hypervalent I(III) species (4e, Koser’s

reagent) undergoing a nucleophilic attack from the enol oxygen atom, resulting in an O-

bonded iodono intermediate (4f). This intermediate expels water to form the O-bonded

iodonium ion (4g). The iodonium intermediate subsequently undergoes an SN2’

displacement by the tosylate ion to create the observed product (4h). In this scenario, the

SN2’ nucleophilic attack is the stereo-defining step.281 Mechanistic Pathway 2 (shown

71

using blue arrows) utilizes the carbon atom of the enol to attack the hypervalent I(III)

reagent, which leads to a C-bonded iodono intermediate (4i); this is the stereo-defining

step. This intermediate ejects water to form the C-bonded iodonium ion (4j), which

undergoes an SN2 displacement from the tosylate ion to form the chiral 𝛼-substituted

ketone product (4h); in this pathway, the trapping of the enol is the stereo-defining

step.278, 282-284

Wirth investigated the first enantioselective approach to catalyzing ⍺-

oxytosylations of ketones with a chiral iodoaryl catalyst (Figure 3.3, 4q). The chiral

information of the catalyst is appended on the aryl ring such that it is ortho relative to the

iodine 285, 286 The ⍺-oxytosylation of propiophenone was conducted in a good yield (78%

yield) but with modest enantiopurity (27% ee) (Scheme 3.11, eq. 1, Figure 3.3, 4q). A

Ph

OH+

Ph

OH

I

OH

OTs

I

OH

OTs

Ph

O

Ph

O

I

IHO

HO

H

*

-H2O

-H2O

Ph

OI

Ph

O

I*

Ph

O

OTs

OTs

nvisioned

-ArI

-ArI

*

Ph

OH

Ph

OH

Z-enol tautomer

E-enol tautomer

SN2

SN2’

4a 4b

4c

4d

4e

4e4f

4i

4g

4j

4h

Pathway 1

Pathway 2

Scheme 3.10 Putative mechanistic pathways for the !-oxytosylation of propiophenone mediated by a HI(III) reagent

72

cyclic substrate, 1-indanone (4n), was synthesized in a 79% yield with 21% ee (Scheme

3.11, eq. 2). Wirth further catalyzed the formation of α-tosyloxylated ketones by

designing additional iodoarene chiral catalysts.287 One catalyst contains an o-menthyl

group that can chelate iodine, and supply the chiral propiophenone product in up 42%

yield and 39% ee (Figure 3.3, 4r).284, 287 Wirth et. al. were able to obtain the ⍺-

oxytosylation product in a higher yield (70%) by synthesizing another ester-containing

chiral catalyst (Figure 3.3, 4s), yet the enantioselectivity was slightly diminished (26%

ee).288

Scheme 3.11 Asymmetric !-oxidative transformations via HI(III) reagents

O O

OTsm-CPBAMeCN, rt

p-TsOH独H2Ocat. Ar-I catalyst

O

OH

O

OO

O

O O

OTs

4l

4n

(1)

(2)

(3)

m-CPBAMeCN, rt


m-CPBAMeCN, rt


4p

*

*

*

4k

4m

4o

73

Moran and Rodríguez synthesized and assessed chiral aryl iodides in an

intermolecular as well as an intramolecular asymmetric oxidation. (Scheme 3.11, eq. 1

and eq. 3).289 The most interesting catalyst was a pseudoephedrine derivative (Figure

3.3, 4t) that oriented the iodine ortho in relation to the chiral information. In the a-

oxytosylation of propiophenone, the catalyst supplied the intended product (4l) in a

moderate yield (59% yield), but with a negligible enantioselectivity (3% ee).

Nonetheless, catalyst 4t was able to selectively induce the asymmetric oxylactonization

of 5-oxo-5-phenylvaleric acid in 51% ee (Scheme 3.10, eq. 3), which was a significant

increase in selectivity over Wirth’s reagent (Figure 3.3, 4s, ~3% ee).288

Legault’s laboratory was able to apply iodoaryloxazoline-based chiral catalysts

for ⍺-functionalizations (Figure 3.3, 4u).277, 278 The most effective catalyst was

comprised of an aryl ring that accommodates an o-methyl and p-chlorine substituent

(relative to iodine) (4u). With slow addition of m-CPBA to the reaction mixture,

propiophenone was converted to ⍺-oxytosylpropiophenone in an 80% yield with a

stereoinduction of 48% ee (Scheme 3.10, eq. 1, Figure 3.3, 4u). It should be noted that

without the ortho methyl substituent, the reaction did not proceed.278

Through a seven-step synthesis, Zhang was able to synthesize spirobiindane-

based chiral iodoarenes, which he utilized as catalysts in the enantioselective ⍺-

oxytosylation of propiophenone (Scheme 3.11, eq. 1, Figure 3.3, 4v). With ethyl acetate

as the optimal solvent, Zhang’s catalyst gave an enantio-enriched product in 53% ee.290

Brenet, Berthiol, and Einhorn suggested that sterics around the iodine center may play an

74

important role in the chiral induction process.291 This group synthesized a sterically

encumbered 3,3′-diiodo-BINOL-fused maleimide catalyst that contained C2-symmetry

Cl SO2t-BuI

4qWirth

78% yield, 27% eea

79% yield, 21% eeb

IOMe

I

Cl

I

O

NPh

Et

I

O

O

Br

4sWirth

70% yield, 26% eea

≤ 67% yield, ≤ 3% eec

I

N

O

OH

4uLegault

80% yield, 48% eea

60% yield, 33% eeb

4vZhang

53% yield , 53% eea

4rWirth

42% yield, 39% eea

II

4xWirth

79% yield, 12% eea

4yMasson

75% yield, 67% eea

IOO

4wBerthiol

47% yield, 46% eea

O

ON

O

O

O

O

O

OI

I

4tMoran

59% yield, 3% eea

≤ 47% yield, ≤ 51% eec

a ⍺-oxytosylation of propiophenone (Scheme 3.11, eq. 1)b ⍺-oxytosylation of 1-indanone (Scheme 3.11, eq. 2) c oxidatative cyclization of 5-oxo-5-phenylvaleric acid (Scheme 3.11, eq. 3)

Figure 3.3 Select examples of chiral hypervalent iodine(I) precatalysts

75

(Figure 3.3, 4w). In the ⍺-oxytosylation of propiophenone, catalyst 4w imparted an

enantioselective outcome with up to 46% ee.

Richardson and Wirth also implemented axial chirality by synthesizing a

binaphthyl-based chiral diiodo catalyst (Figure 3.3, 4x).286 This catalyst gave poor

enantioselectivities (£12% ee) but moderate yields (79% yield) in the oxytosylation of

propiophenone (Scheme 3.11, eq. 1). Wirth and Mizar further developed protocols that

employ silyl enol ethers and nucleophiles other than tosylates to broaden the scope of the

α-functionalization of carbonyl compounds.268, 286, 287 In 2017, Masson disclosed the use

of chiral, non C2-symmetric iodoarene catalysts for the direct α‑oxysulfonylation of

ketones (4y).220 This unique catalyst can offer respectable yields (75% yield) and

enantioselectivities up to 67% ee in the α-oxytosylation of propiophenone (Scheme 3.11,

eq. 1).

Legault and Basdevant made great strides in the area of α-oxytosylated ketones.

By coupling the use of Ishihara’s bis-lactate-derived, C2-symmetric iodoarene catalyst

scaffold (Scheme 3.12, 4y) and preformed enol acetate substrates (4z), enantio-enriched

α-oxytosylated ketones (5b) were accessible in synthetically useful yields and

enantioselectivities (up to 70% yield and 90% ee).292 While this is an impressive feat, the

requirement to use preformed enol acetates is cumbersome, entailing the in situ

preparation of lithium diisopropylamide (LDA), a very strong and moisture/air sensitive

base, as well as a tedious dropwise addition protocol over 13 h. Furthermore, when

utilizing these conditions in the direct α-oxytosylation of ketones, this method produces

76

low enantioselectivities. Finally, under catalytic conditions, the only substrate that gave a

high steroinduction was propiophenone. While a broader scope of ketones underwent the

reaction in synthetically useful enantioselectivities, they were only evaluated using a

stoichiometric amount of the chiral catalyst 5a.292

The previously described studies include some of the pioneering breakthroughs

that have greatly advanced methodologies designed for catalytic asymmetric oxidative

transformations. Nevertheless, a persistent obstacle has been the inability to promote

hypervalent iodine-mediated organic reactions in an a direct, catalytic, and

enantioselective manner. Particularly problematic in this regard are two of the most

studied hypervalent asymmetric iodine-mediated reactions: the α-oxytosylation of

propiophenone and the oxidative cyclization of 5-oxo-5-phenylvaleric acid. These

particular reactions have been studied for decades, however efficiently promoting the

formation of products with synthetically useful enantioselectivity and high yields has

O O

OTsm-CPBA (1.1 eq.)MeCN, rt, 13 h

p-TsOH独H2O (1.1 eq)0.2 eq. Ar-I catalyst

O

IOO N

O

N

O

Me Me

5a

Me Me

Scheme 3.12 Legault and Basdevant’s utilization of enol acetates for asymmetric catalysis

5b70% yield90% ee

4z

77

proven to be a formidable challenge which warrants further investigation. Furthermore,

most of the hypervalent I(III) asymmetric catalysts described in this chapter require

lengthy and sometimes tedious protocols for their preparation, which limits the ability to

make iterative changes to the catalyst scaffold for further optimization. The efforts

described below aim to resolve the aforementioned obstacles associated with HI(III)-

mediated oxidative transformations by synthesizing and implementing modular and

tunable iodoarene-containing catalysts that are capable of providing high yielding,

enantiopure products.

3.4 IODOARENE-CONTAINING ORGANOCATALYSTS FOR HI(III)

OXIDATIVE TRANSFORMATIONS

Our group has investigated the incorporation of an iodoarene functional group

into a chiral framework, such that the chiral information can be transferred from the

HI(III) reagent to the substrate in order to generate high yielding, enantioenriched

products. We envisioned the use of peptide-based scaffolds, that contain an active

iodoarene component, to operate as the chiral inducing agent. As discussed in Chapter 2,

peptides have the ability to induce high enantioselectivities in organic transformations

due to the immense chiral space they provide, and can thereby create a chiral

environment for selective substrate recognition.128, 168, 169 Fmoc Solid-Phase Peptide

Synthesis (SPPS) techniques allow for the rapid access and evaluation of catalytic

libraries.293 Figure 3.4 illustrates our envisioned generic peptide-based scaffolds that

incorporate iodoarene moieties (highlighted in blue) at the N-terminus of a linear (6a) or

β-turn (6b) scaffold, which has been documented in literature to be nucleated from a D-

78

Ala-Pro sequence.128, 169, 173, 190, 294, 295 The overall goal of this research is to unite the

fields of hypervalent iodine(III) catalysis with peptide-mediated asymmetric synthesis to

generate chiral HI(III) peptide-based catalysts that can effectively induce enantioselective

and high yielding outcomes in a range of synthetically useful oxidative transformations.

Initial investigations were focused on the installation of the catalytically active

iodoarene moiety into a highly modular chiral peptide framework. We considered that

this concept can be achieved through a peptide bond, or more specifically a benzamide

linkage, as portrayed in blue in Figure 3.4. The amide linkage presents itself as a facile

method for installing aryl iodo active sites onto a variety of amino acid side chains,

thereby allowing for iterative modifications. Therefore, in the context of our strategy,

probing the influence of an amide bond on the catalysis of the desired transformations

was critical in order to ensure that this strategy for incorporation of the catalytic site into

the peptide framework could be done while maintaining acceptable activity. To reveal

NH2

HN

NH

O

IR

O

OR2

R1 n

6a

Figure 3.4 Envisioned peptide-based catalytic scaffolds that contain an iodoarene active site at the N-terminus

6bLinear peptide-scaffold

H2N

NH

HNO

O

OR1

R2

NH

CH3O

NO

NH

R3

I

O

Rβ-turn peptide-scaffold

79

the steric and electronic properties that affect catalytic performance, a series of twelve

iodoarene containing amides (Figure 3.5, Catalysts 1-12) were synthesized (Scheme

3.13, yields shown in parentheses) and then utilized in the direct α-oxytosylation of

propiophenone.296 A generic amidation reaction, which was used to synthesize the N-

butyl-iodobenzamide organocatalysts, is shown in Scheme 3.13. This conventional

amidation reaction allows for an iodoarene-containing carboxylic acid substrate (6c) to

react with thionyl chloride to form an acyl chloride (6d), which can be displaced by N-

butyl amine to form the desired amide (e.g. Catalyst 3) (Scheme 3.13).

The suite of iodoarene containing catalysts shown in Figure 3.5 were chosen due

to their varying electronic and steric substituents. The influence of the electron-

withdrawing amide motif was probed in the α-oxytosylation of propiophenone (Table

1.1). The α-oxytosylation reaction was conducted at room temperature on a 0.1 mmol

scale with acetonitrile as the solvent, para-toluenesulfonic acid monohydrate (p-TsOH･

H2O) as the acid and nucleophile, iodo-benzamide as the catalyst (Catalysts 1-12), and

OH

O 1.) Thionyl Chloride2.) Butylamine

Dry DCM0-25 °C

NH

O

Catalyst 3 (93%)6c

Scheme 3.13 Standard synthesis of the N-butyl-iodobenzamide catalysts

Cl

O

6d

I

I

I

80

mCPBA as the co-oxidant. A standard work up of the reaction mixture was also

necessary in order to isolate the desired product for gas chromatography (GC) analysis.

Reactions were quenched with dimethyl sulfide at prescribed times followed by GC

analysis. Yields were calculated from a product standard curve that was generated over

concentrations ranging from 0.005 to 0.1 M. Reported yields and standard deviations

ONH

I ONH

IO

NH

I

ONH

H3CO

I

OCH3

ONH

I

OCH3

ONH

I

CH3

ONH

IH3C

ONH

ICH3

O

NH

I

H3C

ONH

H3CO

ONH

I

OCH3

ONH

H3C

Catalyst 2 (92%) Catalyst 3 (93%)Catalyst 1 (94%)

Catalyst 4 (88%) Catalyst 5 (90%) Catalyst 6 (93%)



I

OCH3

I

Figure 3.5 N-butyl-iodobenzamide catalysts with corresponding amidation yields

81

were collected from averaged triplicate runs with tetraglyme being utilized as the internal

standard.

Conducting 48-hour reactions revealed the relative rates of the differently

substituted iodoarene catalysts (Entries 1-12, Table 1.1). Relative to the iodine, meta-

and para-positioned amides were more effective as catalysts than ortho-substituted

amides (Entries 1-3, Table 1.1). This suggests that the sluggish behavior observed with

using Catalyst 1 may be due to steric hindrance as well as the inductive electron

withdrawing nature of the ortho positioned amide. Catalysts 4-7 were synthesized to

investigate how electronics and sterics can affect the rate in relation to the parent ortho-

substituted iodoarene (Catalyst 1). With the aim to diminish the electron-withdrawing

nature of the amide, an electron donating group (i.e., methoxy) was positioned para to the

amide substituent (Catalyst 4). An additional electron donating group, such as a

methoxy or methyl group, was situated para to the iodine with the intent to generate a

more electron rich iodine center (Catalysts 4-6). These analogs were inspired by the

work done by Wirth284 and Legault278, who reported slight increases in catalytic activity

when iodine was situated para to an electron-releasing group. With little to no rate

enhancement detected, these studies indicate that electronics may play a rather minor role

in the catalytic activity of the iodobenzamides (Table 1.1, entries 4-6). Catalyst 7 was

created to induce the “hypervalent twist” phenomenon, which in essence, states that

catalysts can achieve higher relative rates if sterically bulky substituents are located ortho

to the iodine.278, 284, 297 With an approximate 10 fold increase in rate, the “hypervalent

twist” phenomenon appears to be validated in our system (Table 1.1, entry 1 vs. entry 7).

82

Legault’s computational research suggests that if a Lewis base (e.g. an amide) is

positioned ortho to the aryl iodine(I) precatalyst, when activated to iodine(III), the

catalyst is stabilized, which slows down the ensuing displacement, and therefore

decreases catalytic reactivity.278 Invoking this reasoning, Catalyst 1 underperforms in

the oxidative 𝛼-oxytosylation of propiophenone, when compared to Catalyst 2 and

Catalyst 3 (Table 1.1, entry 1 vs. entries 2 and 3). This same concept becomes apparent

when comparing two “hypervalent twist” congeners, Catalyst 7 and Catalyst 8, in which

a meta positioned amide relative to the iodine, performs at a much higher rate than an

ortho positioned amide (Table 1.1 entry 7 versus entry 8). Finally, the “hypervalent

twist” was probed between meta positioned amide catalysts, Catalyst 8 and Catalyst 9.

Evidently, the “hypervalent twist” phenomenon is inoperable when the Lewis base and

the iodine are distal to each other, and instead ortho-positioned steric effects play a large

role in influencing the rate of catalysis (Table 1.1, entry 8 and 9). Finally, electron

donating groups were situated around a meta positioned amide (relative to iodine), which

gave the α-oxytosylated product in relatively good to quantitative yields (Table 1.1

entries 10-12).

83

The highest relative rates obtained after 48 h were quantitative yields (Table 1.1

entries 2, 11, and 12), and as a result these, as well as the other top four catalysts, were

subjected to a four-hour reaction time in order compare the catalysts prior to completion

Entry Catalyst Yield (%)a,b

1 1 3 ± 0

2 2 quant.

3 3 82 ± 6

4 4 2 ± 0

5 5 2 ± 0

6 6 3± 0

7 7 29 ± 4

8 8 91 ± 3

9 9 76 ± 3

10 10 67 ± 4

11 11 quant.

12 12 quant.

Table 1.1 Oxidative ⍺-Oxytosylation of Propiophenone (48 h, rt)

a Average yields of triplicate runs employing tetraglyme as the ISTD.b 0.1 mmol scale.

O O

OTs

mCPBA (3 equiv)pTSA•H2O (3 equiv)Catalyst (0.1 equiv)

MeCN (1 mL)48 hrs, r.t.

*

4k 4l

84

(Table 1.2, entries 1-7). The catalyst that gave the most significant rate acceleration was

observed to be Catalyst 11, thereby supporting Wirth284 and Legualt’s277 findings that

electron donating substituents in the para position (relative to I) can promote increases in

reaction rates (Entry 6, Table 1.2). These rate studies provide the idea that attaching the

amide functionality onto the iodoarene can potentially have tremendous effects on

catalytic activity.


1 2 39 ± 3

2 3 19 ± 3

3 8 28 ± 2

4 9 24 ± 3

5 10 36 ± 1

6 11 44 ± 2

7 12 40 ± 1

Table 1.2 Oxidative α-Oxytosylation of Propiophenone (4 h, rt)


O O

OTs

mCPBA (3 equiv)pTSA•H2O (3 equiv)Catalyst (0.1 equiv) *

MeCN (1 mL)4 h, r.t.4k 4l

85

All 12 catalysts were evaluated in the oxytosylation of propiophenone over a 24 h

time period at 50 ℃, and the top seven catalysts were further screened at 50 ℃ for 1 hour

(Table 1.3 and Table 1.4, respectively). Similar trends were witnessed in the 50 ℃


1 1 16 ± 4

2 2 96 ± 2

3 3 96 ± 3

4 4 11 ± 3

5 5 12 ± 2

6 6 16 ± 3

7 7 65 ± 1

8 8 92 ± 4

9 9 quant.

10 10 quant.

11 11 97 ± 2

12 12 60 ± 5

Table 1.3 Oxidative α-Oxytosylation of Propiophenone (24 h/50 ºC)


O O

OTs


MeCN (1 mL)24 hr, 50 ℃

*

4k 4l

86

trials, as those observed in the room temperature reactions. The catalyst that repeatedly

furnished the oxytosylated ketone (4l) in the highest yield was Catalyst 11. This catalyst

therefore became our lead catalyst, and provided the oxytosylated ketone in high yields.

To further investigate how the amide moiety may affect the overall catalytic

activity of iodoarenes, two significant studies were completed. The first study entailed

subjecting a series of structural analogs of lead Catalyst 11 to four-hour reaction

conditions (Table 1.5, entries 1-7). The second study involved kinetic 1H NMR rate

studies involving the best, an intermediate, and an inefficient catalyst (Catalyst 11,


1 2 63 ± 2

2 3 57 ± 2

3 8 43 ± 1

4 9 52 ± 3

5 10 63 ± 1

6 11 68 ± 1

7 12 48 ± 1

Table 1.4. Oxidative α-Oxytosylation of Propiophenone (1 h/50 ºC)


O O

OTs


MeCN (1 mL)1 hr, 50 ℃

*

4k 4l

87

Catalyst 8, and Catalyst 4, respectively) in order to examine the relative rates of

oxidation from their iodine(I) to iodine(III) active state (Figure 3.6).

The structural analog study revealed that an amide bond, which will link the

active iodoarene containing catalyst and the peptide, is a valid strategy since there is no

appreciable effect on the catalytic activity when incorporating an amide functionality

(Table 1.5, entry 2 versus entries 1, 3-7). It seems that by positioning a methoxy group

para to the iodine, and placing the iodine meta to the deactivating amide, an effective

catalyst template is established (i.e. Catalyst 11). This presents a distinct catalytic

platform that differs from many other HI(III) scaffolds, in which an o-iodo scaffold is

required for an effective catalytic, chiral outcome (see Figure 3.3).

88

The kinetic 1H NMR rate study demonstrated that more electron rich iodoarenes

(e.g. Catalysts 11 and 8) oxidize to their active hypervalent iodine(III) state more

efficiently than electron poor iodoarenes (e.g. Catalyst 4). Catalyst 11 and Catalyst 8,


1 3 19 ± 3

2 11 44 ± 2

3 4-iodoanisole 13 33 ± 4

4 4-iodotoluene 14 30 ± 3

5 3-iodotoluene 15 53 ± 1

65-iodo-2-methoxy benzoic acid 16 40 ± 3

7 Iodobenzene 17 52 ± 2a Average yields of triplicate runs employing tetraglyme as the ISTD.b 0.1 mmol scale.

OCH3

I

CH3

I

O

OH

OCH3

I

CH3

I13 14 15 16

O O

OTs

mCPBA (3 equiv)pTSA•H2O (3 equiv)

Ar-I Catalyst (0.1 equiv)


*

O

NH

3

I

O

NH

I

OCH3

11

Table 1.5 Structure Analogues of Lead Catalyst 11

I

17

4k 4l

89

which orient the iodine meta to the amide, access the hypervalent iodine(III) state faster

than Catalyst 4, which bears an ortho iodine, and performed more effectively as catalysts

in the α-oxytosylation of propiophenone (Figure 3.6). Interestingly, the most effective

catalyst, Catalyst 11, is oxidized to an active hypervalent iodine(III) state at roughly the

same rate as the mediocre catalyst, Catalyst 8, indicating that catalytic rates may be

determined by rate of oxidation as well as the subsequent attack from the nucleophile.

Figure 3.6 1H NMR relative rate study of the oxidation of Catalysts 11, 8, and 4 to their I(III) state.

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10 11 12

Conv

ersio

n (%

)

Reaction Time (hrs)

Catalyst 11

Catalyst 8

Catalyst 4

90

The suite of iodo-arene containing catalysts (Catalysts 1-12, Figure 3.5) were

also applied to an intramolecular transformation, in which a ketocarboxylic acid is

converted to a ketolactone via oxidative cyclization mediated by hypervalent iodine(III)


1 2 12 ± 1

2 3 54 ± 3

3 7 24 ± 2

4 8 58 ± 4

5 9 52 ± 4

6 10 64 ± 3

7 11 71 ± 3

8 12 61 ± 3

Table 1.6 Oxidative Cyclization of 5-oxo-5-phenylvaleric acid (24 h/50 ºC)

PhO

OHO

OO

Ph O


a Average yields of triplicate runs employing tetraglyme as the ISTD.b 0.1 mmol scale.c Isolated yields after silica gel column chromatography.d 1 mmol scale.e pTSA•H2O (1.5 eq.), Catalyst (0.2 eq.)f 1.3 mmol scale.

9c,d

10c,e,f

11

11

72

89

MeCN (1 mL)24 hrs, 50 ◦C

*

4o 4p

91

catalysts (Table 1.6). This is a prominent transformation because not only are lactones

prevalent in nature, they have found great importance in the synthetic and medicinal

community.298-300 The catalytic scaffold that achieved the highest yielding product (11b)

at 50 ℃ was again Catalyst 11, which includes a meta positioned iodine and para

positioned methoxy group (Table 1.6, entry 7). The oxidative cyclization of 5-oxo-5-

phenylvaleric acid (4o) was also carried at 1 and 1.3 mmol scales in the presence of either

10-20 mol % Catalyst 11, to afford the oxylactone (4p) in decent (72%, entry 9) to good

yields (89 %, entry 10).

Entry R Product n Time (hr) Temperature (ºC) Yield (%)a,b

1 CH3 18 1 36 50 87

2 OCH3 19 1 40 50 72

3 F 20 1 24 50 94

4 Cl 21 1 24 50 75

5 Br 22 1 24 50 85

6 H 23 0 24 50 94

7 H 4l 1 24 50 99

8 H 4l 1 48 r.t. 94

O

Table 1.7. Oxidative α-Oxytosylation of Propiophenone Derivatives

R

n

O

R

nOTs

mCPBA (3 equiv)pTSA•H2O (3 equiv)

Ar-I Catalyst 11 (0.1 equiv)

MeCN (1 mL)

a Isolated yields after silica gel column chromatography.b 1 mmol scale.

92

To exemplify and assess the value of our most reactive catalyst, Catalyst 11, a

small substrate scope was evaluated (Table 1.7, entries 1-8). Propiophenone,

acetophenone, and propiophenone derivatives with various para-substituents on the

phenyl ring were successfully synthesized in good isolated yields in up to a 1 mmol scale.

The previously mentioned studies have allowed our group to understand how an

amide linkage, which appends the iodine-containing active site to the peptide scaffold,

influences the catalytic reactivity, and possibly selectivity, in hypervalent iodine(III)-

mediated oxidations. In the context of the well-known reactivity-selectivity principle

(RSP)301, which states that there tends to be an inverse relationship between the reactivity

and selectivity of a reagent, it appears evident that being able to access a tunable scaffold

may greatly impact the efficiency of the developed asymmetric catalytic system. With

the use of Fmoc solid-phase peptide synthesis protocols, we have the capability of

O

OHI

6eOCH3

OCH3

In

O

NH

R2 O

R1O

HN

Fmoc Solid Phase Peptide Synthesis

NH2

Scheme 3.14 Utilizing Fmoc-SPPS to easily generate libraries of peptide-based HI(III) chiral catalysts

6f

6g

H2N

NH

HNO

O

OR1

R2

NH

CH3O

NO

NHR3

O

I

OCH3

93

installing the most active catalysts as caps on the N-terminus of the peptide (Figure 3.4

and Scheme 3.14). For example, we can mimic the most effective iodoarene benzamide

(Catalyst 11), by utilizing the carboxylic acid version (6e), and through well-established

Fmoc solid-phase peptide synthesis, we can cap the N-terminus of peptide-based

scaffolds with active iodoarenes to quickly build up peptide-based catalyst libraries (e.g.

Scheme 3.14, 6f and 6g). The peptide-based scaffolds are amendable to easy iterations

through the use of various commercially available amino acids that contain diverse side

chains.

To diversify the concept further, we next devised strategies that allow for the

active site to be incorporated anywhere in the peptide sequence. We generated chiral

amino acids that allow for the incorporation of the iodine active site into the amino acid

side-chain, thereby allowing us to assimilate the active site in a new, variable location

(Figure 3.7).302

This study was designed around the synthesis of Fmoc-protected amino acids that

integrate the aryl-iodo active site onto the amino acid side chain through an amide

H2NHN

NH

O

IR3

O

O R2

R1 n

H2NHN

O

O

R1 nNH

IR3

HNO

O HN

R2

Figue 1. Strategies for incorporating an aryl-iodo active site into a chiral peptide paradigmPrevious work: Reactive iodoarene-containing n-butyl amide catalysts to be used as caps in peptide scaffolds

New Strategy: Incorporating aryl-iodo active sites into the side chain of peptide scaffolds

O

NH

IO

NH

I

OCH3

O

NH

I

OCH3

Figure 3.7 Utilizing Fmoc-SPPS to incorporate iodoarene active sites into the side chain of peptide scaffolds

94

linkage. The initial route involved the synthesis of Nα-protected carboxybenzyl (i.e. Cbz)

diamino methyl esters that contain an iodoarene active site (Scheme 3.15). This was

accomplished by first converting commercially available Cbz-protected diamino acids

(6h) into their corresponding methyl esters (6i) via thionyl chloride and methanol.

Through a conventional amidation coupling reaction, involving thionyl chloride and

triethyl amine, the aryl iodo moiety (6j) was installed onto the side-chain of the diamino

acid (6k). This synthetic route is attractive for multiple reasons, chiefly in the fact that it

is high yielding, and based on an X-Ray crystal structure, little to no racemization occurs

(see experimental section for X-ray crystallography information).

This synthetic route successfully provides a suite of Cbz-protected methyl ester

catalysts (Figure 3.8), which vary in electronic and structural makeup based on their aryl

iodo active site and the length between the active site and the amino acid scaffold (carbon

tether length i.e. n =1-4). Catalysts 1a-1d feature an iodoarene active site with the iodine

situated in the meta position relative to the amide, with one to four carbons tethered

between the active site and the amino acid chain. The most effective iodoarene moiety

that was uncovered in our previous studies contained a meta positioned iodine, with a

6iQuantatative yields

Scheme 3.15 Cbz-protected amino methyl ester catalysts that contain an iodoarene active site

6h

HN

O

ONH

n

O

O

O

I

R1 R2

H2N nHN

O

OH

O

OH2N n

HN

O

O

O

O1.) SOCl2, 0°C2.) MeOH Et2O

OH

OI

R1 R2R1 = H, CH3R2 = H, OCH3

NEt3, Dry DCMSOCl2, 0°C

6k73-96 % yields over 2 steps

n = 1, 2, 3, 4

6j

95

methoxy group para to that element as well (refer back to Figure 3.5, Catalyst 11); this

functionality was incorporated into Catalysts 2a-2d. The final catalyst scaffold

encompassed a methoxy and methyl substituent on the arene ring coinciding with a meta

positioned iodine (Catalysts 3a-3d). These catalysts were synthesized in moderate to

excellent yields (73-96% yields), and were investigated in the direct, catalytic α-

oxytosylation of propiophenone (Table 1.8). The relative rates for the formation of the

desired product (4l) were acquired by means of gas chromatography, and the

enantioselectivities (%ee) were obtained via chiral stationary phase HPLC analysis.

The direct α-oxytosylation of propiophenone was initially conducted at 24 h at

room temperature in the presence of 10 mol % catalyst (Table 1.8). These data suggest

that an iodoarene that situates the iodine meta to the amide, and methoxy group(s) ortho

and/or para to the iodine will have a relatively high reaction rate (Table 1.8, entries 5-

12); this recapitulates the conclusions that were found when using the N-butyl-

iodobenzamides as catalysts (refer back to Figure 3.5). Furthermore, the optimal carbon

tether length appears to be two or three methylenes away from the amino ⍺-carbon

HN

OON

Hn

CH3

O

OO

IHN

OON

Hn

CH3

O

OO

I

OCH3HN

OON

Hn

CH3

O

OO

I

H3C OCH3

Catalyst 1a (n = 1), 84 % yieldCatalyst 1b (n = 2), 79 % yieldCatalyst 1c (n = 3), 81 % yieldCatalyst 1d (n = 4), 86 % yield



Figure 3.8 Cbz-protected amino methyl ester catalysts that contain an iodoarene active site

96

(Table 1.8, entries 2, 3, 6, 7, 10, and 11). The Cbz-protected amino methyl ester

precatalysts that include a 5-iodo-2-methoxy moiety and that contain a two to three

carbon spacer (Figure 3.8, Catalysts 2b and 2c) were shown to afford the product 4l in

quantitative yields (Table 1.8, entries 6 and 7). Two additional precatalysts granted

quantitative yields (Table 1.8, entries 10 and 11), and those rely on a 5-iodo-2-methoxy-

4-methyl iodoarene scaffold (Figure 3.8, Catalysts 3b and 3c). The top four catalysts

were screened in the same reaction conditions, but were quenched with dimethylsulfide

after four hours; the results are shown in Table 1.9. While all four catalysts oxidized

propiophenone (4k) into oxytosylated propiophenone (4l) at about the same relative rate,

the catalyst that produced the highest yield was Catalyst 3c (49%, Table 1.9, entry 4).

The structure of Catalyst 3c is derived from ornithine, and the active arene ring bears a

meta iodine and two electron donating groups (methoxy and methyl). With no surprise,

in all cases, Catalysts 1a-3d returned the desired product 4l with very low enantiomeric

excess (%ee).

97

Table 1.8 α-Oxytosylation of Propiophenone (24 h, rt) catalyzed by Cbz-protected amino methyl ester HI(III) catalysts

a GC yield (Average yields of triplicate runs) employing tetraglyme as the ISTD.b 0.1 mmol scale.c Enantiomeric excess determined by chiral HPLC.

O O

OTs



*

4k 4l

Catalyst Yield of 4k (%)a,b

Entry

1

2

3

4

5

6

7

8

9

10

11

12

1a

1b

1c

1d

2a

2b

2c

2d

3a

3b

3c

3d

1

2

3

4

1

2

3

4

1

2

3

4

n ee of 4l(%)c

47 ± 3 -1.2

82 ± 3 -0.9

84 ± 1 -1.6

35 ± 2 -1.5

-1.779 ± 3

quant. -2.0

-3.8quant.

84 ± 1 -0.7

-2.693 ± 3

quant. -2.1

-0.1quant.

92 ± 3 -0.3

98

By utilizing protective group manipulation, the amino acid catalyst can be

modified such that it is Fmoc-SPPS ready, and can therefore become incorporated into

Scheme 3.16 Protective group manipulation for the synthesis of Fmoc-SPPS suitable catalysts

HN

O

ONH

O

O

O

I

Catalyst 1a

2.) TMSI, Dry DCM

1.) NaOH, Dry MeOH

3.) Fmoc-OSu, DIEA MeCN, H2O

HN

O

OHNH

OI

6l (1.8 g, 81 % over 3 steps)O

O

Table 1.9 Catalytic α-Oxytosylation Propiophenone (4 h, rt)

a GC yield (Average yields of triplicate runs) employing tetraglyme as the ISTD.b 0.1 mmol scale.c Enantiomeric excess determined by chiral HPLC.

O O

OTs



*

4k 4l

Catalyst Yield of 4k (%)a,b

Entry

1

2

3

4

2b

2c

3b

3c

2

3

2

3

n ee of 4l(%)c

46 ± 1 -1.4

42 ± 0 -0.6

42 ± 1 +1.3

49 ± 1 -0.9

99

the side chain of a peptide sequence (Scheme 3.16). The methyl ester can be hydrolyzed

to a free carboxylic acid in the presence of sodium hydroxide (NaOH). Subsequently, the

Cbz protecting group can be removed with the addition of trimethylsilyl iodide (TMSI),

leaving a free amine.303 To render this molecule as a suitable catalyst for solid-phase

peptide synthesis, Fmoc-succinimide (Fmoc-OSu) was added for the reprotection of the

free amine.304, 305 This synthetic process was applied to Catalyst 1a and produced Fmoc-

SPPS compatible compound 6l in 81% over the three steps. By means of standard Fmoc-

SPPS, 6l was incorporated into a small peptide sequence (Ac-Ile-3-I-Dap-Pro-D-Ala-Ala-

Ala) (Figure 3.9). This proof of concept demonstrates the feasibility to synthesize

peptide-based scaffolds that incorporate iodoarene active sites into the side chains of the

amino acids. Moreover, this gives another valuable synthetic approach to varying where

the active site can be situated on the peptide scaffold, and thereby allows for an even

more modular catalytic system.

NHN

NH

H2N

O

O

CH3

O

O

NH

O

O

HN

H3CO

NH

O

I

Figure 3.9 Incorporation of Fmoc SPPS compatible catalyst 6l into a peptide sequence

100

To further progress this strategy in generating novel peptide-based iodoarene

catalysts, we investigated a strategy that can integrate the critical iodoarene active site

into the backbone of the peptide framework (Figure 3.10, 6m and 6n). Achieving this

goal was anticipated through the synthesis of iodoarene containing aniline acetamides

(Figure 3.11, Catalysts 4a-4h).

H2N

NH

HNO

O

OR1

R2

NH

CH3O

NO

HN

O R1

OR2

NH

O

n

IHN

O

R3

NH

OHN

R4 nONH2

I

NHO

HN R3

O

Figure 3.10 Hypothetical peptides that contain an iodoarene within the backbone

6m 6n

101

I

NH

O I

NH

OHN

O NH

O

NH

OI

NH

O

I

NH

O

HN

O

NH

OI

NH

OI

NH

OHN

O INH

O

I

HN

O

NHO

NH

O

Catalyst 4a (70% over 2 steps) Catalyst 4b (46% over 4 steps) Catalyst 4c (41% over 4 steps)

Catalyst 4d (55% over 3 steps) Catalyst 4e (9% over 5 steps) Catalyst 4f (73% over 2 steps)

Catalyst 4g (63% over 3 steps) Catalyst 4h (68% over 2 steps)

Figure 3.11 Iodoarene containing aniline derivatives that function as HI(III) catalysts

102

The aniline acetamide catalysts were accessed through the chemical manipulation

of commercially available nitro, amino, iodo, and/or carboxylic acid containing arene

rings. As an example, the synthesis of Catalyst 4e is illustrated in Scheme 3.17. Briefly,

commercially available 3,5-dinitrobenzoic acid (6o) was partially reduced by iron powder

in glacial acetic acid to afford nitroaniline 6p.306-308 A diazotization/iodination sequence

transformed the nitroarene into iodoarene derivative 6q.306, 308-311 The second nitro group

was reduced in the presence of Mohr’s salt and concentrated ammonium hydroxide to

give the iodo aniline carboxylic acid 6r in a 68% yield.306, 312 Next, a traditional

amidation employing thionyl chloride and butyl amine was carries out. Subsequently, the

aniline nitrogen was acylated with acetic anhydride to produce the aniline acetamide

Catalyst 4e.

Scheme 3.17 Synthetic operations to access the aniline amide Catalyst 4e

6o

COOH

NO2O2N

COOH

NH2O2N

Fe PowderGlacial acetic acid (120 ºC)

COOH

IO2N

conc. HClNaNO2, H2O, 0 ºCKI (90 ºC)

6p45%

6q59%

conc. NH4OHMohr’s salt, H2O

COOH

IH2N

1.) NEt3, Dry DCMSOCl2, 0 ºC

2.) NEt3, Dry DCM

NH2

IH2N

OHN

6r68%

pyridine, r.t. INH

OHN

O

6s73%

Catalyst 4e64%

O

O O

103

These catalysts incorporate an aryl iodo active site that is flanked by an electron

donating substituent, an aniline, and an electron withdrawing substituent, an amide. The

electron withdrawing amide functionality is necessary to mimic the peptide linkage that

we utilize in our strategy for the incorporation of the active site into the peptide scaffold.

The “push/pull” electronic nature of the compounds, due to the electron-donating aniline

acetamide and the electron-withdrawing N-butyl amide, respectively, could have

immense effects on the catalytic performance.. Therefore, these catalysts were subjected

to the ⍺-oxytosylation of propiophenone in a 24 h reaction at room temperature, as well

as reaction at 50 ˚C (Table 1.10 and Table 1.11). Interestingly, only one catalyst was

relatively effective in the oxytosylation of propiophenone. Catalyst 4f was drastically

superior as a catalyst in comparison to the other aniline acetamide derivatives, and

supplied the oxytosylated propiophenone product 4l in a moderate 73% yield at room

temperature and 80% yield at 50 ℃ (Table 1.10, entry 6 and Table 1.11, entry 6).

Catalyst 4f positions the electron withdrawing N-butyl amide moiety in the meta position

relative iodine while the aniline acetamide is oriented in the para position. The other

catalysts showed comparatively poorer catalytic rates. Although Catalyst 4f and

Catalyst 4d orient the iodine meta to the amide, Catalyst 4d is more sterically

incumbered by the ortho aniline. Comparing the reactivity of these catalysts, Catalyst 4f

supplies the product in a much higher yield (Table 1.10, 73% vs 17% yield), suggesting

that sterics may be an important factor when designing aniline acetamide HI(III)

catalysts. As our previous studies have shown, evidently, an effective catalyst relies on

positioning arene substituents in such a way that the iodine is more electron rich. A

104

catalyst configuration that fits this description involves orienting the iodine meta to the

electron withdrawing amide, and aligning an electron donating group (i.e. aniline or

methoxy) para to the iodine. This study illustrates that drastic effects on catalytic

activity can be present depending on the positioning of the arene substituents, and gives

another variance in which the iodoarene active site can be placed in the backbone of the

peptide scaffold.


O O

OTs


MeCN (1 mL)24 h, rt

8

13 ± 27

6c

5c

4

3

2

73 ± 3

17 ± 1

16 ± 1

15 ± 2

11 ± 21

Entry Catalyst Yielda,b

9 ± 2

9 ± 1

Table 1.10 Oxidative α-Oxytosylation of Propiophenone Using Aniline Catalysts (24 h/rt)

4h

4g

4f

4e

4d

4c

4b

4a

4k 4l

105

3.5 FUTURE WORK FOR PEPTIDE-BASED HI(III) CATALYSTS

The preceding studies were directed toward oxidations by means of hypervalent

iodine(III) catalysis, and emphasized how sterics and electronics can affect the catalytic

performance. In particular, we explored how an amide linkage, which joins the active

site to the peptide, influenced the catalytic reactivity. While the majority of known

HI(III) catalysts scaffolds orient the necessary chiral information in the ortho position of

the arene relative to I, in our hands, it appears that orienting the chiral information in the


O O

OTs


MeCN (1 mL)24 h, 50 °C

8

25 ± 17

6c

5c

4

3

2

28 ± 3

26 ± 1

28 ± 2

24 ± 11

4h

4g

4f

4e

4d

4c

4b

4a

Entry Catalyst Yielda,b

15 ± 2

17 ± 2

80 ± 3

Table 1.11 Oxidative α-Oxytosylation of Propiophenone Using Aniline Catalysts (24 h/50 ℃)

4k 4l

106

meta position can exhibit a higher active catalyst. Of course, a balance must be struck

between achieving optimal catalytic activity to ensure high yields while also maintaining

optimal positioning of the chiral information for productive enantioinduction in the

transformation. Furthermore, as demonstrated previously by Legault277 and Wirth229,

positioning a suitable electron donating group (i.e. methoxy or aniline) para to the iodine,

can also promote reasonable catalytic activity. These findings provide a scaffolding

template that can allow for the construction of highly reactive hypervalent iodine

catalysts. The developed methodology is compatible with Fmoc-SPPS, and has been

validated as a way to generate functional peptides that can be employed as catalysts in a

variety of synthetic transformations mediated by hypervalent iodine catalysis. Current

efforts are focused on installing and evaluating our most reactive iodoarene-containing

Fmoc-protected amino acids and anilines into peptide scaffolds. We have demonstrated

that highly reactive iodoarenes (i.e. Catalyst 11 Figure 3.5, Catalyst 3c Figure 3.8, and

Catalyst 4f Figure 3.11) can be easily installed anywhere along the peptide scaffold,

including at the N-terminus, on the side-chain of the amino acid, or within the peptide

backbone (Figure 3.12). Libraries of modified peptide scaffolds can be generated in a

facile manner through the use of well-established Fmoc-SPPS protocols, and these

compounds have the capability to be utilized as chiral organocatalysts in various HI-

mediated organic transformations, including, but not limited to, the ⍺-oxytoslyation of

propiophenone, the ⍺-oxytoslyation of 1-indanone, and the oxidative lactonization of 5-

oxo-5-phenylpentanoic acid (Scheme 3.11, eq. 1-3).

107

In the context of the uncertainty related to the involved mechanistic pathway(s) in

HI(III)-mediated oxidations (refer to Scheme 3.10), another area that warrants further

investigation is the influence of enol geometry on the reactivity and selectivity of ⍺-

oxytoslyation reactions. Regardless of which mechanism is operative, the geometry of

the incoming enol is presumed to substantially affect the enantioselectivity of the

reaction. In fact, as described previously (see Scheme 3.12), it seems that Legault and

Basdevant selectively isolated a single enol acetate stereoisomer in order to induce high

enantioselectivities in the α-tosyloxylation of ketones.313 Therefore, it is apparent that

understanding the influence of the enol geometry on enantioselective outcome is of great

importance when designing a chiral HI(III) catalyst.

nR1

R2 O

O

O

NH

HN

NH2I

R2

HN

O

ONH

NH R1

O

O

HN

NH2

I

OCH3

HN

O R1

OR2

NH

O

nNH2

I

NHO

HNR3

NH

OR4

O

OCH3

n

Iodoarene at N-terminus cap

Iodoarene on side-chain of amino acid Iodoarene within peptide backbone

Figure 3.12 Incorporating the iodoarene active site anywhere within the peptide scaffold

n

108

To further clarify this concept, Figure 3.13 illustrates the enol isomers that are

likely to form from propiophenone in acidic conditions, and Scheme 3.18 represents the

effect the enol geometry can have on the enantioselective process. Under acid

conditions, propiophenone is rapidly distributed into an equilibrium of Z (7a1/7a2) and E

(7b1/7b2) enol tautomers (Figure 3.13).313 The enols display separate enantiotopic faces,

in which if looking from the top face (orange arrow), the (Z)-enol (7a1) presents a Re

enantiotopic face, while the (E)-enol (7b1) presents a Si enantiotopic face; conversely, if

looking from the back side (green arrow), the enols will undoubtedly show opposite

enantiotopic faces. The contrasting enantiotopic faces can lead to divergent selectivities,

and Scheme 3.18 assists in demonstrating the effect in which the enol geometry can

impose on the enantioinduction. Note that this is a simplified illustration in that only the

SN2 mechanistic pathway is shown, however the SN2’ pathway could conceivably be

Ph

OH

Ph

OH

View fromths side

View fromths side

enantiotopic faces of propiophenone enols

Ph

OH

H

1 2

3clockwiseRe face

2

31H

OHclockwiseRe face

7a1(Z)-enol

7b2(E)-enol

anticlockwiseSi face

Ph

OHH

1 3

2

7b1(E)-enol

3

2 1

H

OH

anticlockwiseSi face

7a2(Z)-enol

Ph

Ph

Figure 3.13 Illustrating the possible enol geometries of propiophenone in acidic conditions

(Z-enol)

(E-enol)

109

affected by the E/Z enol population as well. In short, with the SN2 pathway being

operative, one could reasonably expect that the (Z)-enol would produce the S-enantiomer

(7e), while the (E)-enol would likely generate the R-enantiomer (7i) even if the catalyst

promotes complete facial selectivity during the course of the reaction (Scheme 3.18).

The geometry of the enol can thus lead to different enantiomeric products, and if a

mixture of (E)- and (Z)-enols are present in the reaction mixture, the product will reflect

this ratio and will be generated as a mixture of enantiomers. Therefore, even if a chiral

catalyst was able to exclusively deliver the iodine(III) to one face of the substrate, the

enantioselective outcome could only be as selective as the population of (E)- and (Z)-

tautomers present at equilibrium. On that account, in order to develop a highly

enantioselective chiral catalyst, considerable attention must be dedicated to controlling,

or at least understanding, the enol geometry in HI(III)-mediated oxidative reactions.

One method to control the enol geometry is to selectively synthesize the (E)- and

(Z)-enol, such that they are stereo-defined, and can be subjected to HI(III)-oxidative

conditions, such as the ⍺-oxytoslyation of propiophenone. The relative rates and

OHH CH3 PhOH

CH3

H

(Z)-enol IOH

ArOTs Ph

OPh CH3

IPh

OH

OTsPh

OCH3

OTs*

S-enantiomer

PhOH

HCH3

(E)-enol IOH

ArOTs Ph

OH

IPh

OHPh

OCH3

OTs*

R-enantiomer

CH3

H

PhO

CH3

IPh

OH

*OTs

HPhH CH3

HO

Scheme 3.18 Proposed stereoselective effect of enol geometry in the ⍺-oxytosylation of propiophenone mediated by a HI(III) chiral catalyst

7c

7d7e

7f

7g 7h

7i

110

enantioselectivities could be evaluated, and could ultimately provide evidence on the

influence of the enol geometry. Our group, as well as others, have been unsuccessful in

utilizing silyl enol ethers for the catalytic ⍺-oxytoslyation of propiophenone, as the silyl

group quickly decomposes in acidic conditions (i.e. pTsOH).313, 314 One could envision

the use of enol/enolate equivalents, such as those shown in Figure 3.14, to selectively

trap desirable enol confirmations. In particular, one convenient method to selectively

control the conversion of ketones to preferred geometries is through the use of boronate

esters. Historically, boron reagents have been used to selectively convert ketones into

enol boronates for directed stereoselective aldol reactions.315, 316 By using tertiary amines

in the presence of dialkylboron reagents, ketones can be converted into boronate ester

analogs with very high selectivities and yields (Scheme 3.19). Brown et. al. utilized

diisoproylethylamine (DIPEA) as a tertiary amine, and 9-BBN triflate (7k) to generate

the (Z)-enol boronate of propiophenone (7l) in a 80% yield with a significant selectivity

of 99:1 (Z:E) (Scheme 3.19, eq. 1).316 By using triethylamine and

chlorodicyclohexylborane (7m), they were able to afford the (E)-boronate ester (7n) in a

96% yield with a very high selectivity of 1:99 (Z)/(E) (Scheme 3.19, eq. 2). With this

methodology, we could preferentially form the (E)- and/or (Z)-boronate esters of ketones,

and thereby assess the influence of enol geometry in order to achieve broadly applicable,

highly enantioselective catalysts in ketone α-oxytosylation reactions.

111

O O

Dry Et2O (Argon), 0 °C

O OB

E-boronate ester>1:99 (Z:E)96% yieldDry Et2O (Argon), 0 °C

BTfO

DIPEA

B

Z-boronate ester>99:1 (Z:E)80% yield

BCl

NEt3

Scheme 3.19 Accessing the E and Z boronate esters of propiophenone in a highly selective fashion

7j 7k

7j

7l

7m 7n

(1)

(2)

O

N

NH

O

S

OSiCH3H3C

H3C

Enamine

Enamide

Silyl enol ether

Thioenol

Figure 3.14 Enol/enolate equivalents of propiophenone as a way to control the enol geometry

112

3.6 MACROCYCLES AS CHIRAL HI(III) CATALYSTS

Recently, our group has explored the implementation of macrocycles as an

alternative strategy toward achieving high yields and enantioselectivities in HI-mediated

transformations. In general, a macrocycle is a molecule that contains at least one cyclic

framework of eight or more atoms.317, 318 In comparison to their acyclic analogs,

macrocycles are conformationally restricted, possessing a lower number of rotatable

bonds, and are thus capable of having powerful stereoselective abilities.317, 319

Macrocycles are unique in that they combine beneficial features of small molecules,

including relative ease of synthesis and small molecular weights, and complex

biomolecules (i.e. enzymes and proteins), such as highly selective target engagement.320

Macrocycles have been successfully applied as chiral reagents in various asymmetric

organic reactions.317, 319-326

We envisioned the use of iodoarene-containing chiral macrocycles to be used as

chiral catalysts in hypervalent iodine-mediated oxidative transformations (Figure 3.15,

7o and 7p). As frequently reported in the literature, structural rigidity of a chiral agent

N

O

RR

NNN

O

HN

I

Figure 3.15 Generic iodoarene-containing macrocycles

N

O

R

R

NNN

O

HN

I7o 7p

113

can play a significant role in enantioselective recognition.168, 327, 328 This approach has

the possibility of providing a novel and robust method to generate enantioenriched

species and reinforce the relationship between structural rigidity and enantioselective

control. The routes toward synthesizing iodoarene-containing macrocycles, such as 7o

and 7p (Figure 3.15), are illustrated in Scheme 3.20.329 The synthesis of Macrocycle A

began with the conversion of commercially available L-phenylalanine (7q) to ⍺-azido

acid 7r via a copper(II)-catalyzed diazo transfer; 7r was used at a later synthetic stage.329,

330 Commercially available propargylamine (7s) was transformed into N-(2,4-

dimethoxybenzyl)propargylamine hydrochloride (7u) by means of a reductive

elimination with sodium borohydride. The propargyl hydrochloride 7u was coupled to

commercially available Fmoc-4-iodo-L-phenylalaine (7v) with the use of an amide

coupling agent known as hexafluorophosphate azabenzotriazole tetramethyl uronium

(HATU); this produced the Fmoc-protected, iodoarene containing alkyne 7w in an 88%

yield. 7w was converted into the azido terminal alkyne 7x in a 69% yield over the

following two steps: (1) Fmoc deprotection in the presence of diethylamine, (2) HATU -

coupling with the ⍺-azido acid 7r. Lastly, a copper catalyzed alkyne-azide cycloaddition

was accomplished with use of sodium ascorbate and a dilute sample of 7x to generate

Macrocycle A.331-333 Similar synthetic steps were utilized to produce macrocyclic

derivatives that contained a phenyl (Macrocycle B) or tert-butyl (Macrocycle C)

substituent, rather than a benzyl group (Macrocycle A) (Figure 3.16). The macrocycles

(Macrocycles A-C) and their acyclic precursors (7x-7z) were evaluated in the ⍺-

oxytosylation of propiophenone at room temperature for 24 hours (Figure 3.16). Under

114

the optimized conditions (i.e. same conditions as Table 1.8), each macrocycle provided

the oxytosylated product 4l at about the same relative rate (approximately 32-38% yield),

however, when comparing the enantioselectivity between each cyclic vs. acyclic

congener, the cyclic catalysts showed slightly improved enantioinductions. For instance,

Macrocycle B supplied 4l in a 14 % ee, yet the acyclic counterpart furnished 4l in only

4% ee. In comparison to their linear counterpart, the macrocyclic catalysts have

demonstrated enhanced enantioselectivies, indicating that there may be a relationship

between the structural rigidity of the iodoarene catalyst and the enantioselectivity output

that the catalyst can supply.

N

O

R3

R1

R2

NNN

O

HN

OMeMeO

HNH2N

1. MeOH2. NaBH43. HCl

ONH

I

O

O OH

N

O

NH

I

O

O

HATUDIPEA, 0 ºC

N

O

NH

I

O

N3

7w88% yield

2.) HATU, DIPEA, 0 ºC

OH

O

N3

R1= BnIR2= BnR3 = Dmb

7x69% yield (over 2 steps)

OMeMeO

OMeO OMe

MeO OMe

Cl

H2O/tBuOH (2:1), r.t.

CuSO4•5H2OSodium Ascorbate

Macrocycle A64% yield

7s

7t 7u92% yield

7v

7r

1.) Et2NH, MeCN

Scheme 3.20 Synthetic route towards iodoarene containing macrocycles

OH

O

NH2

1.) Tf2O, NaN32) CuSO4•5H2OK2CO3, H2O, MeOH, DCM OH

O

N3

7r61% yield

7q

115

Current efforts are geared toward synthesizing macrocyclic iodoarene-containing

derivatives that can further improve the steroinduction process, and corroborate the

structure-stereoselectivity relationship. Figure 3.17 exemplifies some of the derivatives

that could be constructed in order to better understand the role that iodoarene cyclic

catalysts play in the ⍺-oxytosylation of propiophenone. One cogent modification

involves the use of starting materials with the opposite chiral configuration in order to

furnish enantiomeric (Figure 3.17, 8a) or diastereomeric (8b and 8c) versions of the

parent macrocycle (Macrocycle A, Figure3.16). Another idea would be to vary the

electronics and sterics around the ring that bears the iodine (R group highlighted in pink)

and/or the chiral substituent that is appended at the gamma position (R group highlighted

in green) in relation to the active site (Figure 3.17, 8d). To probe the effect of the

dimethoxy benzene substituent, one could deprotect the macrocyclic backbone with a

known protocol, such as with a solution of trifluoroacetic acid, trimethylsilyltriflate and

anisole (8e converted to 8f).329 A known concept in click-chemistry is that the clickable

units can favor dimerization, oligomerization, and/or polymerization, thus if the reaction

conditions are altered so that there is a higher concentration of the azide alkyne (i.e. 7x,

Figure 3.20) in the reaction mixture, one could form a dimer/oligomer/polymeric species

(8g).306, 311, 327, 334-336 Another added element of diversity would be to attach the aryl iodo

active site alpha, rather than delta, to the triazole (8j); this can be envisioned by applying

a copper(II)-catalyzed diazo transfer to a substrate that already harbors an iodoarene,

such as the commercially available 4-iodo-L-phenylalanine (Figure 3.17, 8h).

116

I

OH

O

NH2

1.) Tf2O, NaN32) CuSO4•5H2OK2CO3, H2O, MeOH, DCM

I

OH

O

N3

8i

N

O

NNN

O

HN

OMe

OMe

I

N

O

NNN

O

HN

OMe

OMe

I

N

O

NNN

O

HN

OMe

OMe

I

N

O

NNN

O

HN

R

OMe

OMe

I

NH

O

NNN

O

HN

I

TFATMSOTfAnisoleN

O

NNN

O

HN

OMe

OMe

I

NNN

O

OMe

MeO

I

NH

ONN N

O

HN

IN

O

MeO

OMe

N

Dimer

Figure 3.17 Plausible iodoarene-containing macrocyclic derivatives that can be synthesized

N

O

NNN

O

HN

OMe

OMe

I

R

R

8a 8b 8c 8d

8e 8f 8g

8h 8j

N

O

NNN

O

HN

OMe

OMe

I

N

O

NNN

O

HN

OMe

OMe

I

Macrocycle C yield: 12 % (over 6 steps)4l yield using Macrocycle C: 32 ± 2a,b

4l % ee using Macrocycle C: 8 % ee (54:46 er)b,c

4l % ee using 11x: 0 % ee (50:50 er)b,c

Macrocycle B yield: 27 % (over 6 steps)4l yield using Macrocycle B: 38 ± 4a,b

4l % ee using Macrocycle B: 14 % ee (57:43 er)b,c

4l % ee using 11w: 4 % ee (52:48 er)b,c

a Average yields of triplicate runs employing tetraglyme as the ISTD.b 0.1 mmol scale.c Enantiomeric excess determined by chiral HPLC.

Macrocycle CMacrocycle B

N

O

NNN

O

HN

OMe

OMe

I

Macrocycle A yield: 21 % (over 6 steps)4l yield using Macrocycle A: 35 ± 2a,b

4l % ee using Macrocycle A: 12 % ee (56:44 er)b,c

4l % ee using 11v: 4 % ee (52:48 er)b,c

Macrocycle A

Figure 3.16 Structure, yield, and selectivitie of cyclic and acyclic catalysts in the oxidative α-Oxytosylation of Propiophenone (24h, rt)

N

O

N3

O

HN

OMe

OMe

I 7z7y7x

N

O

N3

O

HN

OMe

OMe

I

N

O

N3

O

HN

OMe

OMe

I

117

3.7 CONCLUSIONS

The more eco-friendly nature of hypervalent iodine compounds has attracted attention

from the scientific community as they can be utilized as sustainable alternatives to more

toxic, heavy metal and halogen-based reagents. Recent advancements in the field of

hypervalent iodine have demonstrated that polyvalent iodine reagents are essential tools

in synthetic organic chemistry. Nevertheless, this field of chemistry is still in its infancy

and has proven to be a demanding discipline. The presented work has assisted in trying to

improve upon the difficulties associated with hypervalent iodine chemistry. A

particularly efficient catalyst framework has been disclosed in which the aryl iodo

catalytic site sustains an electron rich nature by orienting the iodine meta to the amide,

and situating an electron donating group para to the iodine. We can attach this highly

proficient iodoarene active unit anywhere along a peptide scaffold through a

straightforward amide linkage. By incorporating iodoarene-containing pre-catalysts into

small peptide sequences, we have revealed a unique strategy that can potentially render

hypervalent iodine mediated reactions highly reactive and enantioselective. Furthermore,

this approach demonstrates synthetic value due to the modular aspect of the designed

catalyst scaffolds. Iodoarene-containing macrocycles have also emerged as a new

paradigm toward hypervalent-iodine-mediated asymmetric transformations. The

macrocycles provide a rigid framework that can potentially induce enantioselectivity, and

have shown to outperform their acyclic analogs. Chemists can apply these versatile

chiral iodine(III) reagents in various synthetic transformations, and due to their easily

iterative nature, they can be tuned and optimized in regard to the reaction at hand. This

118

research has assisted in progressing the hypervalent iodine field by designing new and

efficient methodologies that be used with broad applicability.

119

3.8 EXPERIMENTAL

General Experimental Information

All reagents were purchased from commercial suppliers and used without further

purification. Purification via flash column chromatography was done using silica gel SDS

60 C.C. 40−63 μm. All known compounds and starting materials had 1H NMR and 13C

NMR spectra consistent with previous literature reports. 1H NMR and 13C NMR spectra

were collected at ambient temperature on a 500 or 300 MHz NMR spectrometer.

Chemical shifts are reported in parts per million (ppm) and referenced to residual solvent

peaks (i.e., δ 7.28 ppm for 1H NMR, 77 ppm for 13C NMR) in CDCl3, MeOD (i.e., δ 3.31

ppm for 1H NMR, 49 ppm for 13C NMR), or (CDC3)2SO (i.e., δ 2.50 ppm for 1H NMR,

39.5 ppm for 13C NMR). Data are presented as follows: chemical shift, integration,

multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet),

and coupling constants (J, in hertz). Infrared (IR) spectra, reported in cm−1, were

collected using a Fourier transform spectrophotometer. Bands are characterized as strong

(s), medium (m), weak (w), and broad (br). Gas chromatograph (GC) analyses were

conducted using an autosampler and a flame ionization detector (FID). The GC was

equipped with a 30 m × 0.32 mm × 0.25 μm GC column with an HP-5 stationary phase.

GC analyses were carried out within the following parameters: inlet temperature: 250.0

˚C; split injection (4 µL) at 280 mL min-1; column flow: 2.8 mL min-1, constant pressure;

carrier gas: helium; FID temperature: 300 ˚C; temperature program: 100 ˚C for 3 min.;

ramp to 320 ˚C at 20 ˚C min-1, hold for 3 min. Enantiomeric excess (% ee) of selective

products were determined using chiral high performance liquid chromatography (HPLC).

120

Chiral samples were run on an Agilent 1260 Infinity system equipped with a diode array

detector (G4212-60008), and an Agilent 1260 Infinity auto sampler. The chiral stationary

column used was a Chiralpak-AD (250mm X 4.6 mm). The mobile phase consisted of

iso-propyl alcohol/hexanes mixture (50:50). The flow rate was set at 1 mL/min and the

elution of analytes was monitored at 254 nm.

General Procedure for Preparation of the N-Butyl-iodobenzamides (Figure 3.5,

Catalysts 1-12 and refer to Scheme 3.13 as the general synthesis is illustrated for

Catalyst 3). N-Butyl-iodobenzamide Catalysts 1-12 were synthesized from their

corresponding carboxylic acids via a conventional amidation reaction by the formation of

the acid chloride and subsequent displacement by n-butyl amine.

A representative procedure for the synthesis of n-butyl-4-iodobenzamide

(Catalyst 3) is as follows337: The substrate 4-iodobenzoic acid (0.2 g, 0.66 mmol, 1.0

equiv.) and triethylamine (0.18 mL, 1.32 mmol, 2.0 equiv.) were dissolved in anhydrous

DCM (2 mL) and stirred for 5 min at room temperature under nitrogen in a flame-dried

round-bottom flask. The solution was cooled to 0 °C. Thionyl chloride (0.053 mL, 0.726

mmol, 1.1 equiv.) was slowly added (dropwise over 20 min), and the resulting solution

was allowed to stir at 0 °C for 1 hour. The resulting mixture was brought to room

temperature and stirred for 30 min. This solution was concentrated under vacuum and

then redissolved in anhydrous DCM (2 mL). To this solution was added (dropwise over

10 min) 1-butylamine (0.072 mL, 0.726 mmol, 1.1 equiv.), anhydrous DCM (2 mL), and

triethylamine (0.18 mL, 1.32 mmol, 2.0 equiv.). The resulting solution was stirred

121

overnight at room temperature under nitrogen. The crude mixture was concentrated by

rotary evaporation, diluted in DCM, and washed with 1 M HCl, and the aqueous layers

were extracted with DCM (×3). The organic layers were washed with H2O (×2) and

saturated brine (×1) and dried over sodium sulfate. The resulting product was filtered and

concentrated by rotary evaporation. The crude product was purified by column

chromatography on silica gel (20:80 EtOAc:hexanes) to give Catalyst 3 as an orange

solid (0.2819 g, 93%), mp 121−122 °C. IR (neat): 3312 (br), 3075 (w), 2959 (w), 2929

(w), 2862 (w), 1632 (s), 1587 (w), 1543, 1468 (w), 1008 (w) cm−1. 1H NMR (500 MHz,

CDCl3): δ 0.97−0.99 (3H, t, J = 7.5 Hz), 1.39−1.47 (2H, m), 1.59−1.65 (2H, m), 3.44−

3.48 (2H, m), 6.14 (1H, s, br), 7.50, 7.51 (2H, d, J = 8.5 Hz), 7.79, 7.81 (2H, d, J = 8.0

Hz) ppm. 13C NMR (500 MHz, CDCl3): δ 13.7, 20.1, 31.7, 39.9, 98.1, 128.5, 134.3,

137.8, 166.7 ppm. HRMS (ESI): m/z found 304.0200, calcd for C11H15INO (M + H)+

304.0198.

General Procedure for α-Oxytosylation of Propiophenone313, 338 (Scheme 3.11, eq. 1

and Tables 1.1-1.5, Tables 1.7-11, 4l). The relative rates of the prepared Catalysts 1-12,

Catalysts 1a-3d, and Catalysts 4a-4h were evaluated in the α-oxytosylation of

propiophenone using the following representative procedure with Catalyst 1.

Propiophenone 4k (13.3 μL, 0.1 mmol, 1.0 equiv), p-toluenesulfonic acid monohydrate

(57.1 mg, 0.3 mmol, 3 equiv), m-chloroperoxybenzoic acid (51.8 mg, 0.3 mmol, 3 equiv),

and N-butyliodobenzamide Catalyst 1 (3.0 mg, 0.01 mmol, 0.1 equiv) were dissolved in

acetonitrile (1 mL) and stirred for the appropriate time (48, 24, 4, or 1 h) and temperature

122

(room temperature or 50 °C). After the prescribed time, the reaction was quenched upon

addition of dimethyl sulfide (3 equiv). This solution was concentrated by rotary

evaporation, diluted in DCM, and washed with aqueous saturated sodium bicarbonate

(×3). The organic layers were dried over sodium sulfate, filtered, and concentrated by

rotary evaporation. The resulting product and a 0.05 mmol aliquot of tetraglyme [as

internal standard (ISTD)] were added to 1 mL volumetric flasks, and the final volume

was taken to 1 mL with DCM. All trials were run in triplicate and injected into the GC in

order to evaluate percent yields and their standard deviations (see procedure details

below).

General Procedure for Preparation of GC Standard Curves. Stock solutions (1 M) of

the desired tosylated propiophenone 4l and ISTD (tetraglyme) were prepared in DCM.

Varying amounts of desired product (0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08,

0.09, and 0.100 mmol) and a constant 0.05 mmol aliquot of ISTD were added to 1 mL

volumetric flasks. The final volume was taken to 1 mL with DCM. These samples were

injected into the GC, and the peak area ratio [(product area)/(ISTD area)] was calculated.

This ratio was plotted versus the concentration of the desired product to yield a linear

relationship (r2 values greater than 0.997), thus correlating GC chromatogram peak areas

with product concentration. Reported yields and standard deviations were collected from

averaged triplicate runs with tetraglyme (0.05 M) employed as the ISTD.

123

General Procedure for Percent Yield Determination via GC Analysis. GC analyses

were carried out within the following parameters: inlet temperature, 250 °C; 20:1 split at

130 mL/min; column flow, 6.5 mL/min; constant pressure; carrier gas, helium; FID

temperature, 300 °C; temperature program, 100 °C for 3 min, 20 °C/ min ramp to 320 °C.

Reactions were quenched with dimethyl sulfide (3 equiv) at prescribed times followed by

GC analysis. Yields were calculated from a standard curve of the product in

concentrations ranging from 0.005 to 0.1 M. Reported yields and standard deviations

were collected from averaged triplicate runs with tetraglyme (0.05 M) employed as the

ISTD.

General Procedure for Scaleup and Isolated Yield Determination (i.e., Data for

Table 1.7). Utilizing our best catalyst, Catalyst 11, scaled-up syntheses (1 mmol scales)

of α-oxtosylated propiophenone 4l and a brief substrate scope were conducted to give

isolated yields for 4l as well as compounds 18-23.

Representative procedure for the synthesis of 1-oxo-1-p-tolylpropan-2-yl 4-

methylbenzenesulfonate 18 (Table 1.7)277: 4′-methylpropiophenone (149 μL, 1.0 mmol,

1.0 equiv), p-toluenesulfonic acid monohydrate (571 mg, 3 mmol, 3 equiv), m-

chloroperoxybenzoic acid (518 mg, 3 mmol, 3 equiv.), and iodobenzamide Catalyst 11

(33 mg, 0.1 mmol, 0.1 equiv.) were dissolved in acetonitrile (10 mL) and stirred for 36 h

at 50 °C. The reaction was immediately quenched with dimethyl sulfide (3 equiv.). This

solution was concentrated by rotary evaporation, diluted in DCM, and washed with

aqueous saturated sodium bicarbonate (×3). The organic layers were dried over sodium

124

sulfate, filtered, and concentrated by rotary evaporation. The crude product was purified

by column chromatography on silica gel (20:80 EtOAc:hexanes) to give 18 as a white

solid (0.2783 g, 87%). Rf = 0.29. 1H NMR (300 MHz, CDCl3): δ 1.59, 1.61 (3H, d, J =

6.9 Hz), 2.44 (6H, s, br), 5.79 (1H, q, J = 7.2 Hz), 7.30−7.27 (4H, m), 7.82−7.63 (4H, m)

ppm. 13C NMR (90 MHz, CDCl3): δ 18.8, 21.6, 21.7, 76.6, 128.0, 128.9, 129.5, 129.8,

131.1, 133.5, 144.9, 145.0, 194.3 ppm.

General Procedure for NMR Kinetic Profiles (i.e., Figure 3.6). The activity of

Catalysts 11, 8, and 4 was evaluated by monitoring oxidation rates of the catalysts from

their iodine(I) state to their corresponding iodine(III) state. The kinetic profiles were

generated by dissolving m-chloroperoxybenzoic acid (51.8 mg, 0.3 mmol, 3 equiv) and

the respective iodobenzamide catalyst (0.01 mmol, 0.1 equiv) in CD3CN (1 mL). Due to

rapid oxidation of Catalyst 11 and 8, 1H NMR spectra were recorded every 5 min for 1 h

and then were recorded every hour after the first hour (recorded spectra up to 12 h).

Catalyst 4 had a slower oxidation rate; thus,1H NMR spectra were recorded every hour

starting at 0 h (recorded spectra up to 12 h). The percent conversion of the I(I) catalyst to

its corresponding I(III) was determined via changes in well-resolved NMR signal

integration values as a function of time.

Characterization Data for All Reported Compounds.

N-Butyl-2-iodobenzamide, Catalyst 1339 Brown solid (0.2839 g, 94%), mp 90−91 °C. IR

(neat): 3287 (br), 3055 (w), 2953 (s), 2865 (m),1649 (s), 1585 (m), 1539 (s), 1463 (m),

125

1015 (w) cm−1 . 1H NMR (500 MHz, CDCl3): δ 0.97−1.00 (3H, t, J = 7.0 Hz), 1.40−1.47

(2H, m), 1.59− 1.65 (2H, m), 3.45−3.49 (2H, m), 6.11 (1H, s, br), 7.18−7.21 (1H, t, J =

8.0 Hz), 7.73−7.74 (1H, d, J = 8.0 Hz), 7.84 (1H, q, J = 8.0 Hz), 8.10−8.11 (1H, t, J = 1.5

Hz) ppm. 13C NMR (125 MHz, CDCl3): δ 13.8, 20.2, 31.5, 39.9, 92.4, 128.2, 128.3,

131.0, 139.8, 142.5, 169.4 ppm. HRMS (ESI): m/z found 304.0204, calcd for C11H15INO

(M + H)+ 304.0198.

N-Butyl-3-iodobenzamide, Catalyst 2340 White solid (0.2776 g, 92%), mp 70−71 °C. IR

(neat): 3280 (br), 3063 (m), 2958 (s), 2930 (s), 2870 (m), 1634 (s), 1592 (m), 1555 (s),

1467 (s), 1062 (w) cm−1; 1H NMR (500 MHz, CDCl3): δ 0.97−1.00 (3H, t, J = 7.5 Hz),

1.40−1.47 (2H, m), 1.59−1.65 (2H, m), 3.45−3.49 (2H, m), 6.13 (1H, s, br), 7.17−7.20

(1H, t, J = 7.5 Hz), 7.72, 7.74 (1H, d, J = 10.5 Hz), 7.83, 7.85 (1H, d, J = 8.0 Hz), 8.11

(1H, s) ppm. 13C NMR (125 MHz, CDCl3): δ 13.8, 20.2, 31.7, 40.0, 94.3, 126.1, 130.2,

135.9, 137.0, 140.2, 166.0 ppm. HRMS (ESI): m/z found 304.0201, calcd for C11H15INO

(M + H)+ 304.0198.

N-Butyl-4-iodobenzamide, Catalyst 3 as an orange solid (0.2819 g, 93%), mp 121−122

°C. IR (neat): 3312 (br), 3075 (w), 2959 (w), 2929 (w), 2862 (w), 1632 (s), 1587 (w),

1543, 1468 (w), 1008 (w) cm−1. 1H NMR (500 MHz, CDCl3): δ 0.97−0.99 (3H, t, J = 7.5

Hz), 1.39−1.47 (2H, m), 1.59−1.65 (2H, m), 3.44− 3.48 (2H, m), 6.14 (1H, s, br), 7.50,

7.51 (2H, d, J = 8.5 Hz), 7.79, 7.81 (2H, d, J = 8.0 Hz) ppm. 13C NMR (500 MHz,

126

CDCl3): δ 13.7, 20.1, 31.7, 39.9, 98.1, 128.5, 134.3, 137.8, 166.7 ppm. HRMS (ESI): m/z

found 304.0200, calcd for C11H15INO (M + H)+ 304.0198.

N-Butyl-2-iodo-4,5-dimethoxybenzamide, Catalyst 4.341 Brown solid (0.5207 g, 88%),

mp 104−106 °C; IR (neat): 3264 (br), 2957 (m), 2930 (m), 2869 (w), 1638 (s), 1593 (m),

1543 (m), 1501 (m), 1025 (w) cm−1; 1H NMR (500 MHz, CDCl3) δ 0.97−1.00 (3H, t, J =

7.0 Hz), 1.43−1.51 (2H, m), 1.62−1.67 (2H, m), 3.45−3.49 (2H, m), 3.90 (6H, s, br), 5.87

(1H, s, br), 7.03 (1H, s), 7.22 (1H, s) ppm. 13C NMR (125 MHz, CDCl3) δ 13.8, 20.3,

31.4, 40.0, 56.1, 56.3, 80.8, 112.0, 122.0, 134.6, 149.2, 150.4, 168.9 ppm. HRMS (ESI):

m/z found 364.0411, calcd for C13H19INO3 (M + H)+ 364.0410.

N-Butyl-2-iodo-5-methoxybenzamide, Catalyst 5. Brown solid (0.2699 g, 90%), mp

80−81 °C. IR (neat): 3287 (br), 3069 (w), 2957 (m), 2932 (m), 2862 (w) 1642 (s), 1584

(m), 1542 (m), 1467 (m), 1009 (w) cm−1. Rf = 0.12 (20:80 EtOAc:hexanes). 1H NMR

(500 MHz, CDCl3): δ 0.97−1.00 (3H, t, J = 7.0 Hz), 1.43−1.50 (2H, m), 1.62− 1.68 (2 H,

m), 3.45−3.49 (2H, m), 3.81 (3H, s), 5.82 (1H, s, br), 6.69−6.71 (1H, m), 6.98, 6.99 (1H,

d, J = 3.0 Hz), 7.70−7.71 (1H, d, J = 9.0 Hz) ppm. 13C NMR (125 MHz, CDCl3): δ 13.7,

20.2, 31.4, 39.9, 55.6, 80.6, 114.2, 117.6, 140.4, 143.2, 159.7, 169.1 ppm. HRMS (ESI):

m/z found 334.0310, calcd for C12H17INO2 (M + H)+ 334.0304.

N-Butyl-2-iodo-5-methylbenzamide, Catalyst 6. White solid (0.2250 g, 93%), mp

106−107 °C. IR (neat): 3292 (br), 2957 (w), 2925 (w), 2864 (w) 1643 (s), 1541 (m), 1458

127

(w), 1012 (w) cm−1. Rf = 0.44 (20:80 EtOAc:hexanes). 1H NMR (500 MHz, CDCl3): δ

0.98−1.00 (3H, t, J = 7.5 Hz), 1.43−1.51 (2H, m), 1.62−1.68 (2H, m), 2.33 (3H, s),

3.45−3.49 (2H, m), 5.76 (1H, s, br), 6.92−6.94 (1H, m), 7.23− 7.24 (1H, d, J = 2.0 Hz),

7.72−7.73 (1H, d, J = 8.0 Hz) ppm. 13C NMR (125 MHz, CDCl3): δ 13.8, 20.2, 20.9,

31.5, 39.8, 88.2, 129.2, 132.0, 138.4, 139.6, 142.3, 169.5 ppm. HRMS (ESI): m/z found

318.0374, calcd for C12H17INO (M + H)+ 318.0355.

N-Butyl-2-iodo-3-methylbenzamide, Catalyst 7. Yellow solid (0.2153 g, 89%), mp

68−69 °C. IR (neat): 3283 (br), 2957 (m), 2686 (w) 1640 (s), 1546 (m), 1476 (m), 1036

(w) cm−1. Rf = 0.19 (20:80 EtOAc:hexanes). 1H NMR (500 MHz, CDCl3): δ 0.97−1.00

(3H, t, J = 3.5 Hz), 1.42−1.49 (2H, m), 1.61−1.67 (2H, m), 2.50 (3H, s), 3.45−3.49 (2H,

m), 5.75 (1H, br), 7.10−7.13 (1H, m), 7.26−7.27 (2H, t, J = 2.0 Hz) ppm. 13C NMR (125

MHz, CDCl3): δ 13.8, 20.2, 29.2, 31.4, 39.8, 99.3, 125.0, 128.1, 130.3, 142.8, 144.3,

170.4 ppm. HRMS (ESI): m/z found 318.0377, calcd for C12H17INO (M + H)+ 318.0355.

N-Butyl-3-iodo-2-methylbenzamide, Catalyst 8. Light brown solid (0.2178 g, 90%),

mp 98−99 °C. IR (neat): 3286 (br), 2955 (w), 2928 (w), 2862 (w), 1634 (s), 1581 (w),

1536 (m), 1433 (w), 999 (w) cm−1. Rf = 0.28 (20:80 EtOAc:hexanes). 1H NMR (500

MHz, CDCl3): δ 0.97−1.00 (3H, t, J = 7.5 Hz), 1.40−1.47 (2H, m), 1.58− 1.64 (2H, m),

2.52 (3H, s), 3.43−3.48 (2H, m), 5.75 (1H, s, br), 6.90−6.93 (1H, t, J = 7.5 Hz), 7.30 (1H,

d, J = 0.50 Hz), 7.88−7.90 (1H, m) ppm. 13C NMR (125 MHz, CDCl3) δ 13.8, 20.1, 25.6,

128


318.0377, calcd for C12H17INO (M + H)+ 318.0355.

N-Butyl-3-iodo-4-methylbenzamide, Catalyst 9. Brown oil (0.0871 g, 72%). IR (neat):

3300 (br), 2957 (m), 2929 (m), 2870 (w), 1636 (s), 1600 (w), 1547 (s), 1481 (m), 1032

(w) cm−1. Rf = 0.33 (20:80 EtOAc:hexanes). 1H NMR (500 MHz, CDCl3): δ 0.97−1.00

(3H, t, J = 7.5 Hz), 1.40−1.47 (2H, m), 1.59−1.65 (2H, m), 2.48 (3H, s), 3.44−3.48 (2H,

m), 6.10 (1H, s, br), 7.30 (1H, s), 7.65−7.66 (1H, m), 8.20 (1H, d, J = 2.0 Hz) ppm. 13C

NMR (125 MHz, CDCl3): δ 13.8, 20.2, 28.1, 31.7, 39.9, 100.9, 126.7, 129.6, 134.0,

137.4, 145.0, 165.8 ppm. HRMS (ESI): m/z found 318.0377, calcd for C12H17INO (M +

H)+ 318.0355.

N-Butyl-3-iodo-4-methoxybenzamide, Catalyst 10. Brown solid (0.4105 g, 69%), mp

71−72 °C. IR (neat): 3315 (br), 2958 (m), 2932 (m), 2870 (w), 1631 (s), 1595 (s), 1548

(s), 1487 (s), 1016 (w) cm−1. Rf = 0.32 (20:80 EtOAc:hexanes). 1H NMR (500 MHz,

CDCl3): δ 0.95−0.99 (3H, t, J = 7.5 Hz), 1.38−1.45 (2H, m), 1.58−1.64 (2H, m), 3.42−

3.46 (2H, m), 3.93 (3H, s), 6.20 (1H, s, br), 6.82−6.84 (1H, d, J = 0.50 Hz), 7.78−7.80

(1H, m), 8.17−8.18 (1H, d, J = 2.5 Hz) ppm. 13C NMR (125 MHz, CDCl3): δ 13.8, 20.2,

31.8, 39.9, 56.6, 85.6, 110.2, 128.9, 129.0, 138.1, 160.4, 165.7 ppm. HRMS (ESI): m/z

found 334.0333, calcd for C12H17INO2 (M + H)+ 334.0304.

129

N-Butyl-5-iodo-2-methoxybenzamide, Catalyst 11. White solid (0.2240 g, 75%), mp

41−42 °C. IR (neat): 3405 (br), 2957 (m), 2930 (m), 2870 (w), 1643 (s), 1586 (m), 1534

(s), 1477 (s), 1019 (m) cm−1. Rf = 0.31 (20:80 EtOAc:hexanes). 1H NMR (500 MHz,

CDCl3): δ 0.94−0.97 (3H, t, J = 7.0 Hz), 1.37−1.44 (2H, m), 1.56−1.62 (2H, m), 3.42−

3.46 (2H, m), 3.94 (3H, s), 6.72,6.74 (1H, d, J = 9.0 Hz), 7.66−7.69 (1H, m), 7.75 (1H, s,

br), 8.45−8.46 (1H, d, J = 2.0 Hz) ppm. 13C NMR (125 MHz, CDCl3): δ 13.8, 17.6, 20.2,


334.0333, calcd for C12H17INO2 (M + H)+ 334.0304.

N-Butyl-5-iodo-2-methoxy-4-methylbenzamide, Catalyst 12. Brown solid (0.1164 g,

98%), mp 117−118 °C. IR (neat): 3401 (br), 2955 (m), 2935 (m), 2859 (w), 1646 (s),

1593 (m), 1530 (s), 1460 (m), 1033 (w) cm−1. Rf = 0.22 (20:80 EtOAc:hexanes). 1H

NMR (500 MHz, CDCl3): δ 0.97−0.99 (3H, t, J = 7.0 Hz), 1.39−1.47 (2H, m), 1.58− 1.64

(2H, m), 2.47 (3H, s), 3.45−3.49 (2H, m), 3.96 (3H, s), 6.86 (1H, s), 7.76 (1H, s, br), 8.58

(1H, s) ppm. 13C NMR (125 MHz, CDCl3): δ 13.8, 20.3, 28.4, 31.6, 39.5, 56.1, 90.6,

113.0, 121.1, 142.0, 146.1, 157.3, 163.7 ppm. HRMS (ESI): m/z found 348.0491, calcd

for C13H19INO2 (M + H)+ 348.0460.

1-oxo-1-p-tolylpropan-2-yl 4-methylbenzenesulfonate,18 (Table 1.7).

White solid (0.2783 g, 87%). Rf = 0.29 (20:80 EtOAc:hexanes). 1H NMR (300 MHz,

CDCl3): δ 1.59, 1.61 (3H, d, J = 6.9 Hz), 2.44 (6H, s, br), 5.79 (1H, q, J = 7.2 Hz),

130

7.30−7.27 (4H, m), 7.82−7.63 (4H, m) ppm. 13C NMR (90 MHz, CDCl3): δ 18.8, 21.6,

21.7, 76.6, 128.0, 128.9, 129.5, 129.8, 131.1, 133.5, 144.9, 145.0, 194.3 ppm.

1-(4-Methoxyphenyl)-1-oxopropan-2-yl 4-Methylbenzenesulfonate, 19 (Table 1.7).313


CDCl3): δ 1.59, 1.61 (3H, d, J = 6.9 Hz) 2.43 (3H, s), 3.89 (3H, s), 5.76 (1H, q, J = 6.9),

7.27−7.30 (2H, m), 7.76, 7.79 (2H, d, J = 8.4), 7.88−7.93 (2H, m) 7.89−7.91 ppm (2H,

m) ppm. 13C NMR (90 MHz, CDCl3): δ 18.9, 21.7, 55.6, 76.8, 114.0, 126.5, 128.0, 129.7,

131.2, 133.5, 145.0, 164.1, 193.1 ppm.

1-(4-Fluorophenyl)-1-oxopropan-2-yl 4-Methylbenzenesulfonate, 20 (Table 1.7).277


CDCl3): δ 1.60, 1.61 (3H, d, J = 7.0 Hz), 2.44 (3H, s), 5.72 (1H, q, J = 7.0 Hz), 7.14−7.17

(2H, t, J = 8.0 Hz), 7.29− 7.31 (2H, m), 7.76−7.78 (2H, m), 7.95−7.98 (2H, m) ppm. 13C

NMR (125 MHz, CDCl3): δ 18.6, 21.7, 76.8, 115.9, 116.1, 128.0, 129.8, 131.6, 131.7,

133.4, 145.2, 165.1, 167.1, 193.4 ppm.

1-(4-Chlorophenyl)-1-oxopropan-2-yl 4-Methylbenzenesulfonate, 21(Table 1.7).277


CDCl3): δ 1.60, 1.61 (3H, d, J = 7.0 Hz), 2.45 (3H, s), 5.71 (1H, q, J = 7.0 Hz), 7.30,

7.31(2H, d, J = 8.0 Hz), 7.44, 7.46 (2H, d, J = 8.5 Hz), 7.75, 7.77 (2H, d, J = 8.5 Hz),

131

7.85, 7.87 (2H, d, J = 9.0 Hz) ppm. 13C NMR (125 MHz, CDCl3): δ 18.6. 21.7, 76.8,

128.0, 129.1, 129.8, 130.3, 132.0, 133.3, 140.4, 145.2, 194.0 ppm.

1-(4-Bromophenyl)-1-oxopropan-2-yl 4-Methylbenzenesulfonate, 22 (Table 1.7).338


CDCl3): δ 1.59, 1.61 (3H, d, J = 6.9 Hz), 2.44 (3H, s), 5.69 (1H, q, J = 6.9 Hz), 7.31 (2H,

s), 7.59− 7.63 (2H, m), 7.74−7.80 (4H, m) ppm. 13C NMR (90 MHz, CDCl3): δ 18.6,

21.7, 76.8, 127.9, 129.2, 129.9, 130.3, 132.1, 132.4, 133.3, 145.2, 194.1 ppm.

α-Tosyloxyacetophenone, 23 (Table 1.7).338 White solid (0.2729 g, 94%). Rf = 0.24

(20:80 EtOAc:hexanes). 1H NMR (500 MHz, CDCl3): δ 2.47 (3H, s), 5.29 (2H, s), 7.36,

7.38 (2H, d, J = 8.0 Hz), 7.48−7.51 (2H, m), 7.61−7.64 (1H, m), 7.85−7.88 (4H, m) ppm.

13C NMR (125 MHz, CDCl3): δ 21.7, 70.0, 128.0, 128.2, 128.9, 129.9, 132.7, 133.8,

134.2, 145.3, 190.3 ppm.

General Procedure for Preparation of the Iodoarene Amino Methyl Esters

(Catalysts 1a-3d, Figure 3.8 and Scheme 3.15).

Iodoarene Nα-Z-amino methyl ester Catalysts 1a-3d were prepared from their

corresponding Nα-protected Z-diamino acids and iodobenzoic acids. The Z-diamino

acids, L-diaminopropanoic acid (Dap), L-diaminobutanoic acid (Dab), L-ornithine (Orn)

and L-lysine (Lys), were first converted to their corresponding methyl esters and without

132

further purification the free amine side chain was coupled to appropriate iodoarene active

site (cf. Scheme 3.15).

A representative two step procedure for the synthesis of Catalyst 1a is as follows:

Step 1: To a cooled (0 °C) suspension of Nα -Cbz-L-2,3-Diaminopropionic acid (Z-L-

DAP-OH) (5 g, 21 mmol, 1 equiv.) in 100 mL of MeOH was added thionyl chloride (23

mmol, 1.1 equiv.) over 20 min (dropwise). The resulting solution was allowed to stir at

room temperature overnight. After approximately 18 h, the solvent was removed in

vacuo, and the residual solid was stirred with 150 mL Et2O for 0.5 h. The resulting crude

compound was obtained following rotary evaporation to give Nα-Z-diaminopropanoic

acid as a white solid, (5.29 g, quant. yield).

Step 2: A solution of 3-iodobenzoic acid (4.6 g, 18.5 mmol, 1.0 equiv) and

trimethylamine (3.78 g, 37.1 mmol, 2 equiv) in anhydrous dichloromethane (150 mL)

was allowed to stir at room temperature for 10 min while under nitrogen atmosphere.

The mixture was cooled to 0°C, and after 30 min, thionyl chloride (20.4 mmol, 1.1 equiv)

was added dropwise and allowed to stir for 1.5 hours. The reaction mixture was brought

to room temperature, with continued stirring for 30 minutes followed by rotary

evaporation to dryness. The reaction mixture was then redissolved in anhydrous DCM

(150 mL). A separate solution of the Z-diamino methyl ester (5.15 g, 20.4 mmol, 1.1

equiv) was prepared by dissolving this substrate in anhydrous DCM (100 mL) followed

by dropwise addition of triethylamine (3.78 g, 37.1 mmol, 2 equiv). This freshly

prepared solution was then slowly added to the flask containing the 3-iodobenzoic acid

and allowed to stir for 18 h at room temperature under nitrogen. The resulting crude

133

mixture was concentrated by rotary evaporation, diluted in DCM and washed with 1M

HCl. The aqueous layers were extracted with DCM (3X). Organic layers were washed

with H2O (2X), saturated brine (1X), and dried over sodium sulfate. Following filtration

and rotary evaporation, the resulting crude product was purified by column

chromatography on silica gel (gradient to 1:9 MeOH:DCM) to produce the dark brown

oil, Catalyst 1a (7.5 g, 84%); Rf = 0.79 (1:9 MeOH:DCM) ; IR (neat): 3337 (br), 3068

(m), 3031 (m), 2953 (m), 2930 (m), 1759 (s), 1748 (s), 1643 (m), 1551 (m), 1543 (m),

1438 (s), 1270 (w), 1066 (w) cm-1; 1H NMR (500 MHz, CDCl3): δ 3.75 (3 H, s), 3.81-

3.84 (2 H, t), 4.51-4.58 (1 H, q), 5.09 (2H, s), 5.30 (Residual DCM solvent peak), 6.19-

6.21 (1 H, d), 7.07-7.13 (1H, t), 7.27-7.39 (5H, m), 7.67-7.70 (1H, d), 7.78-7.81 (1H, d),

8.11 (1H, s) ppm; 13C NMR (500 MHz, CDCl3) δ 42.3, 53.0, 54.3, 67.3, 94.3, 126.3,

128.1, 128.3, 128.5, 130.2, 135.8, 135.9, 136.2, 140.6, 156.6, 166.8, 170.8 ppm.

3-Iodoarene-Z-L-Dab-Amino Methyl Ester, Catalyst 1b: dark brown oil, (0.148 g, 74%).

Rf = 0.75 ; IR (neat): 3385 (br), 3066 (m), 3040 (m), 2953 (m), 2922 (w), 1760 (s), 1745

(s), 1644 (s), 1556 (m), 1540 (m), 1454 (w), 1448 (w), 1267 (w), 1062 (w) cm-1; 1H NMR

(500 MHz, CDCl3) : 1.82-1.83 (1 H, m), 2.20-2.23 (1 H, m), 3.18-3.21 (1 H, m), 3.69

(3H, s), 3.86-3.88 (1 H, m), 4.46-4.49 (1H, m), 5.14 (2H, s), 5.97 (1H, s, br), 7.13-7.16

(1H, m), 7.32-7.35 (5H, m), 7.52 (1H, s, br), 7.79-7.81 (2H, m), 8.22 (1H, s) ppm; 13C

NMR (500 MHz, CDCl3) δ 32.8, 36.1, 51.6, 52.8, 67.4, 94.4, 126.2, 128.1, 128.3, 128.6,

130.2, 136.0, 136.1, 136.3, 140.4, 156.8, 166.0, 172.6 ppm.

134

3-Iodoarene-Z-L-Lys-Amino Methyl Ester, Catalyst 1c: dark brown oil, (0.167 g, 81%).

Rf =0.74 (1:9 MeOH:DCM); IR (neat): 3377 (br), 3070 (m), 3063 (m), 2939 (m), 2926

(m), 2854 (m), 1758 (s), 1714 (s), 1643 (s), 1566 (m), 1538 (m), 1454 (m), 1380 (w),

1266 (m), 1063 (w) cm-1; 1H NMR (500 MHz, CDCl3) : 1.68-1.72 (2 H, m), 1.78-1.95 (2

H, m), 3.41-3.56 (2 H, m), 3.75 (3H, s), 4.39-4.42 (1 H, m), 5.13 (2H, s), 5.58-5.61 (1H,

d), 6.73 (1H, br), 7.13-7.18 (1H, t), 7.35 (5H, m), 7.74-7.77 (1H, d), 7.80-7.83 (1H, d),

8.14 (1H, s) ppm; 13C NMR (500 MHz, CDCl3) δ 25.3, 30.4, 39.4, 52.6, 53.3, 67.2, 94.2,

126.3, 128.1, 128.3, 128.6, 130.2, 136.0, 136.1, 136.5, 140.3, 156.1, 166.1, 172.6 ppm.

3-Iodoaryl-Z-L-Orn-Amino Methyl Ester, Catalyst 1d: dark brown oil, (0.182 g, 86%). Rf

= 0.78 (1:9 MeOH:DCM); IR (neat): 3366 (br), 3063 (m), 3042 (m) 2940 (m), 2933 (m),

2861 (m), 1751 (s), 1720 (s), 1692 (s), 1644 (s), 1556 (m), 1538 (m), 1463 (m), 1455 (m),

1267 (m), 1193 (w), 1052 (w) cm-1; 1H NMR (500 MHz, CDCl3) : 1.45-1.67 (2 H, m),

1.71-1.87 (2 H, m), 2.05-2.09 (2 H, m), 3.37-3.44 (2 H, m), 3.75 (3H, s), 4.40 (1H, br),

5.04-5.12 (2H, m), 5.53-5.54 (1H, d), 6.51 (1H, br), 7.11-7.14 (1H, t), 7.34-7.36 (5H, m),

7.74-7.76 (1H, d), 7.79-7.81 (1H, d), 8.13 (1 h, br) ppm; 13C NMR (500 MHz, CDCl3) δ

22.5, 28.7, 32.3, 39.7, 52.5, 53.5, 67.1, 94.2, 126.3, 128.1, 128.2, 128.6, 130.2, 136.0,

136.2, 136.7, 140.2, 156.2, 166.2, 172.9 ppm.

5-Iodo-2-Methoxy-arene-Z-L-Dap-Amino Methyl Ester, Catalyst 2a: dark brown oil,

(0.175 g, 95%). Rf = 0.76 (1:9 MeOH:DCM); IR (neat): 3337 (br), 3068 (m), 3031 (m),

2953 (m), 2930 (m), 1759 (s), 1748 (s), 1643 (), 1551 (), 1543 (m), 1438 (s), 1270 (w),

135

1066 (w) cm-1; 1H NMR (500 MHz, CDCl3): δ 3.40-3.41 (2 H, m), 3.70 (3 H, s), 3.88 (3

H, s), 4.33-4.34 (1 H, br), 5.08 (2H, s), 5.59-5.62 (1 H, d), 6.67-6.70 (1H, d), 7.26-7.42

(5H, m), 7.64-7.67 (1H, d), 7.76 (1H, d), 8.43 (1H, s) ppm; 13C NMR (500 MHz, CDCl3)

δ 29.0, 39.3, 52.4, 56.2, 66.9, 83.7, 113.7, 123.6, 128.0, 128.1, 128.5, 136.3, 140.6, 141.1,

156.1, 157.2, 163.9, 172.9 ppm.

5-Iodo-2-methoxy-arene-Z-L-Dab-Amino Methyl Ester, Catalyst 2b: dark brown oil,


2953 (m), 2922 (w), 1760 (s), 1745 (s), 1644 (s), 1556 (m), 1540 (m), 1454 (w), 1448

(w), 1267 (w), 1062 (w) cm-1; 1H NMR (500 MHz, CDCl3) : 1.82-1.87 (1 H, m), 2.18-

2.22 (1 H, m), 3.21-3.23 (1 H, m), 3.68 (3H, s), 3.83-3.87 (1 H, m), 3.95 (3H, s), 4.47-

4.50 (1H, m), 5.13 (2H, s), 5.82-5.84 (1H, d), 6.72-6.74 (1H, d), 7.33-7.36 (5H, m), 7.68-

7.70 (1H, d), 8.34 (1H, s, br), 8.46 (1H, s) ppm; 13C NMR (500 MHz, CDCl3) δ 32.9,

35.7, 51.7, 52.6, 56.1, 67.1, 83.4, 113.7, 123.4, 128.0, 128.2, 128.6, 136.2, 140.6, 141.3,

156.5, 157.5, 164.1, 172.8 ppm.

5-Iodo-2-methoxy-Iodoarene-Z-L-Lys-Amino Methyl Ester, Catalyst 2c: dark brown oil,


2942 (m), 2932 (m), 2882 (m), 1772 (s), 1728 (s), 1640 (s), 1560 (m), 1544 (m), 1426

(m), 1378 (w), 1263 (m), 1060 (w) cm-1; 1H NMR (500 MHz, CDCl3) : 1.67-1.78 (2 H,

m), 1.94-1.97 (2 H, m), 3.48-3.49 (2 H, m), 3.77 (3H, s), 3.95 (3 H, s), 4.43-4.46 (1H,

m), 5.13 (2H, s), 5.46-5.47 (1H, d), 6.75-6.77 (1H, d), 7.34-7.38 (5H, m), 7.73-7.74 (1H,

136

d), 7.80 (1H, br), 8.48 (1H, s) ppm; 13C NMR (500 MHz, CDCl3) δ 25.6, 30.1, 39.2, 52.6,

53.7, 56.2, 67.1, 83.8, 113.7, 123.5, 128.1, 128.2, 128.6, 136.2, 140.8, 141.2, 155.9,

157.2, 163.9, 172.7 ppm.

5-Iodo-2-methoxy-Iodoarene-Z-L-Orn-Amino Methyl Ester, Catalyst 2d: dark brown oil,

(0.140 g, 70%). Rf = 0.76 (1:9 MeOH:DCM); IR (neat): 3378 (br), 3058 (m), 3048 (m)

2936 (m), 2940 (m), 2858 (m), 1760 (s), 1728 (s), 1700 (s), 1640 (s), 1562 (m), 1530 (m),

1458 (m), 1458 (m), 1270 (m), 1190 (w), 1048 (w) cm-1; 1H NMR (500 MHz, CDCl3) :

1.41-1.48 (2H, m), 1.61-1.67 (2H, m), 1.72-1.79 (1H, m), 1.89-1.93 (1H, m), 3.42-3.50

(2H, m), 3.75 (3H, s), 3.94 (3H, s), 4.36-4.41 (1H, m), 5.12 (2H, s), 5.47-5.48 (1H, d),

6.73-6.75 (1H, d), 7.36 (5H, m), 7.70-7.72 (1H, d), 7.77 (1H, s, br), 8.49 (1H, s) ppm; 13C

NMR (500 MHz, CDCl3) δ 22.6, 29.1, 32.1, 39.3, 52.4, 53.8, 56.2, 66.9, 83.8, 113.7,

123.6, 128.1, 128.2, 128.5, 136.3, 140.8, 141.2, 156.0, 157.2, 163.9, 172.9 ppm.

5-Iodo-2-methoxy-4-mehtyl-Z-L-Dap-Amino Methyl Ester, Catalyst 3a: dark brown oil,

(0.149 g, 83%). %). Rf = 0.76 (1:9 MeOH:DCM); IR (neat): 3348 (br), 3072 (m), 3026

(m), 2950 (m), 2936 (m), 1760 (s), 1748 (s), 1640 (s), 1551 (s), 1538 (m), 1440 (s), 1262

(w), 1060 (w) cm-1; 1H NMR (500 MHz, CDCl3): 2.45 (3 H, s), 3.79 (3 H, s), 3.80-3.88

(2H, m), 3.89 (3H, s), 4.54-4.55 (1H, d), 5.09-5.16 (2H, m), 6.01-6.03 (1H, d), 6.84 (1H,

s), 7.31-7.35 (5H, m), 8.07 (1H, s, br), 8.52 (1H, s) ppm; 13C NMR (500 MHz, CDCl3) δ

17.6, 28.5, 41.5, 54.8 (Residual DCM solvent peak), 54.8, 56.1, 67.0, 90.6, 113.0, 120.2,

128.0, 128.2, 128.5, 136.2, 142.1, 146.9, 156.1, 157.5, 164.9, 171.1 ppm.

137

5-Iodo-2-methoxy-4-mehtyl -Z-L-Dab-Amino Methyl Ester, Catalyst 3b: dark brown oil,

(0.152 g, 82%). %). Rf = 0.74 (1:9 MeOH:DCM); IR (neat): 3390 (br), 3062 (m), 3040

(m), 2948 (m), 2926 (w), 1760 (s), 1752 (s), 1642 (s), 1560 (m), 1548 (m), 1468 (w),

1442 (w), 12664 (w), 1058 (w) cm-1; 1H NMR (500 MHz, CDCl3) : 1.84-1.89 (1H, m),

2.16-2.25 (1H, m), 2.45 (3H, s), 3.19-3.24 (1H, m), 3.68 (3H, s), 3.83-3.87 (1H, m), 3.96

(3H, s), 4.48-4.49 (1H, d), 5.14 (2H, s,), 5.73-5.74 (1H, d), 6.85 (1H, s), 7.32-7.39 (5H,

m), 8.30 (1H, s, br), 8.56 (1H, s) ppm; 13C NMR (500 MHz, CDCl3) δ 17.7, 28.5, 33.0,

35.6, 51.7, 55.9, 67.1, 90.4, 112.9, 120.7, 128.0, 128.2, 128.6, 136.2, 141.9, 146.4, 156.4,

157.6, 164.1, 172.8 ppm.

5-Iodo-2-methoxy-4-mehtyl -Z-L-Lys-Amino Methyl Ester, Catalyst 3c: dark brown oil,


2944 (m), 2924 (m), 2849 (m), 1760 (s), 1712 (s), 1648 (s), 1572 (m), 1544 (m), 1456

(m), 1388 (w), 1264 (m), 1066 (w) cm-1; 1H NMR (500 MHz, CDCl3) : 1.60-1.68 (2H,

m), 1.72-1.95 (2H, m,), 2.46 (3H, s), 3.46-3.47 (2H, d), 3.76 (3H, s), 3.94 (3 H, s), 4.42-

4.43 (1H, d), 5.12 (2H, s), 5.48-5.49 (1H, br), 6.86 (1H, s), 7.37 (5H, m), 7.79 (1H, s, br),

8.56 (1H, s) ppm; 13C NMR (500 MHz, CDCl3) δ 25.7, 28.5, 30.1, 39.1, 52.5, 53.7, 56.1,

67.0, 90.7, 112.9, 120.8, 128.1, 128.2, 128.6, 136.2, 142.1, 146.4, 155.9, 157.4, 163.9,

172.7 ppm.

138

5-Iodo-2-methoxy-4-mehtyl -Z-L-Orn-Amino Methyl Ester, Catalyst 3d: dark brown oil,

(0.187 g, 96%). Rf = 0.77 (1:9 MeOH:DCM); IR (neat): 3398 (br), 3078 (m), 3052 (m)

2956 (m), 2940 (m), 2858 (m), 1750 (s), 1728 (s), 1690 (s), 1648 (s), 1554 (m), 1532 (m),

1464 (m), 1442 (m), 1266 (m), 1190 (w), 1040 (w) cm-1; 1H NMR (500 MHz, CDCl3) :

1.19-1.25 (2H, m), 1.65-1.77 (2H, m), 1.91 (2H, m), 2.42 (3H, s). 3.42-3.44 (2H, m,) 3.72

(3H, s), 3.90 (3H, s), 4.38-4.40 (1H, d), 5.09 (2H, s), 5.64-5.67 (1H, d), 6.82 (1H, s),

7.24-7.38 (5H, m), 7.78 (1H, s, br), 8.50 (1H, s) ppm; 13C NMR (500 MHz, CDCl3) δ

25.7, 28.5, 29.5, 29.9, 39.1, 52.5, 53.7, 56.1, 66.9, 90.6, 112.9, 120.8, 128.0, 128.2, 128.5,

136.2, 141.9, 146.3, 156.0, 157.3, 163.9, 172.7 ppm.

Synthesis of 3-iodoarene-Nα-Fmoc-L-diaminopropionic acid, 6l, occurred over 3 steps

including:

Hydrolysis of Iodoarene Amino Methyl Ester Catalyst 1a. The iodoarene amino methyl

ester Catalyst 1a (10 g, 20.7 mmol) was dissolved in dioxane (50-100 mL) and cooled to

0 °C. Sodium hydroxide (2N) (10 equiv.) was slowly added and the resulting mixture was

allowed to stir for 18 hours at room temperature. The organic solvent was evaporated off,

and then H2O (mL) was added. The solution was acidified to pH ≈ 6 with 3M HCl. This

solution was extracted with EtOAc (x4) and the organic layers were washed with brine

(x1) and dried over Na2SO4. The crude product was obtained following rotary

evaporation, and carried on to next step without purification.

139

Cbz deprotection of Catalyst 1a303 While under at argon atmosphere, the hydrolyzed

product (2.5 g, 5.3 mmol) was dissolved in anhydrous DCM (60 mL). The solution was

cooled to 0 °C, and trimethylsilane (11.7 mmol, 2.2 equiv.) was slowly added. This

mixture was stirred at 0 °C for 3 h, and then 12 h at room temperature. The mixture was

concentrated to dryness and the residue was taken up in water. The pH was adjusted to ≈

6 with 0.2N NaOH, and the pale-yellow precipitate was collected, dried via high pump

vacuum, and carried on to the next step without purification.

N-Fmoc Protection (6l)304 A round-bottomed flask was charged with the amino acid

(1.34 g, 4 mmol), H2O (100 mL), and diisopropylethylamine (DIPEA) (0.78 g, 6.02

mmol, 1.5 equiv). The reaction was cooled in an ice bath, followed by the addition of

Fmoc-OSu (1.47 g, 4.37 mmol, 1.1 equiv) in MeCN (100 mL) and was stirred for 30

minutes. The reaction was stirred at room temperature overnight. The solvent was

rotovapped off, and the resulting mixture was dissolved in water (100 mL) and then

acidified with 2N HCl to pH ~ 3. The aqueous layer was extracted with ethyl acetate

(x3), and dried over Na2SO4. The crude product was purified via column

chromatography (gradient from 100% DCM to 1:9 MeOH/DCM) to give 6l: off white

solid, (1.8 g, 81% over 3 steps); Rf = 0.14 (Gradient 1:9 MeOH:DCM); IR (neat): 3480

(br), 3180 (w), 2571 (br), 1697 (br), 1635 (m), 1601 (br), 1558 (m), 1447 (m), 1423 (m),

1404 (m), 1354 (m), 1288 (w), 1249 (w), 736 (s), (m), 1426 (m), 1378 (w), 1263 (m),

1060 (w) cm-1; 1H NMR (500 MHz, (MeOD) : 3.39-3.76 (1H, m), 3.82-3.85 (1H, dd),

4.18-4.20 (1H, m), 4.23-4.27 (1H, m), 4.37-4.40 (2H, m), 7.18-7.20 (1H, d), 7.21-7.27

140

(2H, m), 7.28 (1H, br), 7.35-7.39 (2H, m ), 7.63-7.64 (2H, m), 7.77-7.86 (4H, m), 8.17

(1H, s) ppm; 13C NMR (500 MHz, MeOD) δ 42.1, 42.3, 54.4, 66.7, 93.3, 119.5, 124.9,

126.3, 126.8, 127.3, 129.9, 136.1, 136.3, 140.2, 141.1, 143.9, 157.1, 167.5, 174.4 ppm.

Crystal Structure of Catalyst 2a (C20H21IN2O6)

Crystal Structure Report for D8_2036_MS163_EtOH

A specimen of C20H21IN2O6, approximate dimensions 0.027 mm x 0.029 mm x 0.388

mm, was used for the X-ray crystallographic analysis. The X-ray intensity data were

measured.

The integration of the data using an orthorhombic unit cell yielded a total of 16298

reflections to a maximum θ angle of 25.50° (0.83 Å resolution), of which 3958 were

independent (average redundancy 4.118, completeness = 99.5%, Rint = 3.30%, Rsig =

3.06%) and 3792 (95.81%) were greater than 2σ(F2). The final cell constants of a =

4.8220(2) Å, b = 13.9582(6) Å, c = 31.7890(14) Å, volume = 2139.60(16) Å3, are based

upon the refinement of the XYZ-centroids of reflections above 20 σ(I). The calculated

minimum and maximum transmission coefficients (based on crystal size) are 0.8771 and

1.0000.

The structure was solved and refined using the Bruker SHELXTL Software Package,

using the space group P 21 21 21, with Z = 4 for the formula unit, C20H21IN2O6. The final

anisotropic full-matrix least-squares refinement on F2 with 268 variables converged at R1

141

= 2.31%, for the observed data and wR2 = 5.49% for all data. The goodness-of-fit was

1.123. The largest peak in the final difference electron density synthesis was 0.380 e-/Å3

and the largest hole was -0.994 e-/Å3 with an RMS deviation of 0.087 e-/Å3. On the basis

of the final model, the calculated density was 1.590 g/cm3 and F(000), 1024 e-.

142

143

Table 1. Sample and crystal data for D8_2036_MS163_EtOH. Identification code D8_2036_MS163_EtOH Chemical formula C20H21IN2O6 Formula weight 512.29 g/mol Temperature 140(2) K Wavelength 0.71073 Å Crystal size 0.027 x 0.029 x 0.388 mm Crystal system orthorhombic Space group P 21 21 21 Unit cell dimensions a = 4.8220(2) Å α = 90° b = 13.9582(6) Å β = 90° c = 31.7890(14) Å γ = 90° Volume 2139.60(16) Å3 Z 4 Density (calculated) 1.590 g/cm3 Absorption coefficient 1.534 mm-1 F(000) 1024 Table 2. Data collection and structure refinement for D8_2036_MS163_EtOH. Theta range for data collection 2.41 to 25.50°

Index ranges -5<=h<=5, -16<=k<=16, -38<=l<=38 Reflections collected 16298 Independent reflections 3958 [R(int) = 0.0330]

Max. and min. transmission 1.0000 and 0.8771

Structure solution technique direct methods

Structure solution program SHELXT-2014 (Sheldrick 2014)

Refinement method Full-matrix least-squares on F2 Refinement program SHELXL-2014 (Sheldrick 2014) Function minimized Σ w(Fo2 - Fc2)2 Data / restraints / parameters 3958 / 2 / 268

Goodness-of-fit on F2 1.123 Δ/σmax 0.002

144

Final R indices 3792 data; I>2σ(I) R1 = 0.0231, wR2 = 0.0542

all data R1 = 0.0249, wR2 = 0.0549

Weighting scheme w=1/[σ2(Fo2)+(0.0280P)2+0.1408P] where P=(Fo2+2Fc2)/3

Absolute structure parameter -0.0(0)

Largest diff. peak and hole 0.380 and -0.994 eÅ-3

R.M.S. deviation from mean 0.087 eÅ-3

Table 3. Atomic coordinates and equivalent isotropic atomic displacement parameters (Å2) for D8_2036_MS163_EtOH. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. x/a y/b z/c U(eq) I1 0.79969(5) 0.51368(2) 0.84588(2) 0.03603(10) O1 0.2988(6) 0.36512(15) 0.70696(8) 0.0313(6) O2 0.0091(5) 0.66481(18) 0.58967(9) 0.0304(6) O3 0.3672(5) 0.5705(2) 0.61011(9) 0.0329(7) O4 0.7479(11) 0.3631(2) 0.54951(12) 0.0906(16) O5 0.0397(9) 0.2617(2) 0.58074(10) 0.0547(9) O6 0.9626(6) 0.63738(18) 0.70624(8) 0.0356(7) N1 0.9333(7) 0.4510(2) 0.68548(10) 0.0284(7) N2 0.9346(6) 0.5114(2) 0.59928(9) 0.0244(6) C1 0.0008(8) 0.4135(2) 0.61069(12) 0.0254(8) C2 0.8597(7) 0.3844(2) 0.65225(12) 0.0279(8) C3 0.1616(8) 0.4393(2) 0.70849(11) 0.0232(8) C4 0.2450(7) 0.5185(2) 0.73803(10) 0.0224(7) C5 0.1532(8) 0.6143(2) 0.73659(11) 0.0259(8) C6 0.2565(9) 0.6807(2) 0.76521(12) 0.0327(10) C7 0.4453(8) 0.6535(3) 0.79560(12) 0.0312(9) C8 0.5329(8) 0.5594(3) 0.79791(11) 0.0264(8) C9 0.4360(7) 0.4932(2) 0.76886(10) 0.0244(7) C10 0.1249(8) 0.5807(3) 0.60082(12) 0.0241(8) C11 0.1987(9) 0.7463(2) 0.58822(13) 0.0337(9)

145

x/a y/b z/c U(eq) C12 0.0578(8) 0.8230(2) 0.56285(12) 0.0271(8) C13 0.8394(8) 0.8757(2) 0.57918(12) 0.0297(9) C14 0.7114(10) 0.9464(3) 0.55561(13) 0.0373(9) C15 0.8026(11) 0.9651(3) 0.51527(13) 0.0427(10) C16 0.0182(10) 0.9139(3) 0.49849(13) 0.0430(12) C17 0.1467(9) 0.8422(3) 0.52222(12) 0.0353(10) C18 0.9123(10) 0.3451(3) 0.57604(13) 0.0369(10) C19 0.9662(16) 0.1877(3) 0.55087(17) 0.079(2) C20 0.8745(11) 0.7350(3) 0.70233(14) 0.0444(12) Table 4. Bond lengths (Å) for D8_2036_MS163_EtOH. I1-C8 2.094(4) O1-C3 1.230(4) O2-C10 1.347(4) O2-C11 1.460(5) O3-C10 1.213(5) O4-C18 1.184(5) O5-C18 1.324(5) O5-C19 1.447(6) O6-C5 1.371(5) O6-C20 1.433(4) N1-C3 1.331(5) N1-C2 1.451(5) N1-H1 0.83(2) N2-C10 1.335(5) N2-C1 1.449(5) N2-H2 0.84(2) C1-C18 1.518(5) C1-C2 1.540(5) C1-H1A 1.0 C2-H2A 0.99 C2-H2B 0.99 C3-C4 1.505(5) C4-C9 1.390(5) C4-C5 1.409(5) C5-C6 1.391(5) C6-C7 1.380(6) C6-H6 0.95 C7-C8 1.383(5) C7-H7 0.95 C8-C9 1.387(5) C9-H9 0.95 C11-C12 1.503(5) C11-H11A 0.99 C11-H11B 0.99 C12-C13 1.385(6) C12-C17 1.387(5) C13-C14 1.385(5) C13-H13 0.95 C14-C15 1.381(6) C14-H14 0.95 C15-C16 1.370(6) C15-H15 0.95 C16-C17 1.398(6) C16-H16 0.95 C17-H17 0.95 C19-H19A 0.98 C19-H19B 0.98 C19-H19C 0.98 C20-H20A 0.98 C20-H20B 0.98 C20-H20C 0.98

146

Table 5. Bond angles (°) for D8_2036_MS163_EtOH. C10-O2-C11 115.3(3) C18-O5-C19 116.1(4) C5-O6-C20 118.9(3) C3-N1-C2 121.6(3) C3-N1-H1 117.(3) C2-N1-H1 120.(3) C10-N2-C1 121.6(3) C10-N2-H2 118.(3) C1-N2-H2 119.(3) N2-C1-C18 110.4(3) N2-C1-C2 111.4(3) C18-C1-C2 109.4(3) N2-C1-H1A 108.5 C18-C1-H1A 108.5 C2-C1-H1A 108.5 N1-C2-C1 110.4(3) N1-C2-H2A 109.6 C1-C2-H2A 109.6 N1-C2-H2B 109.6 C1-C2-H2B 109.6 H2A-C2-H2B 108.1 O1-C3-N1 121.7(3) O1-C3-C4 120.0(3) N1-C3-C4 118.3(3) C9-C4-C5 118.1(3) C9-C4-C3 115.5(3) C5-C4-C3 126.3(3) O6-C5-C6 122.9(3) O6-C5-C4 117.2(3) C6-C5-C4 119.9(3) C7-C6-C5 120.7(3) C7-C6-H6 119.6 C5-C6-H6 119.6 C6-C7-C8 120.0(3) C6-C7-H7 120.0 C8-C7-H7 120.0 C7-C8-C9 119.6(3) C7-C8-I1 121.1(3) C9-C8-I1 119.3(3) C8-C9-C4 121.6(3) C8-C9-H9 119.2 C4-C9-H9 119.2 O3-C10-N2 125.8(4) O3-C10-O2 124.4(4) N2-C10-O2 109.7(3) O2-C11-C12 106.8(3) O2-C11-H11A 110.4 C12-C11-H11A 110.4 O2-C11-H11B 110.4 C12-C11-H11B 110.4 H11A-C11-H11B 108.6 C13-C12-C17 118.8(4) C13-C12-C11 121.4(3) C17-C12-C11 119.8(4) C14-C13-C12 121.0(4) C14-C13-H13 119.5 C12-C13-H13 119.5 C15-C14-C13 119.7(4) C15-C14-H14 120.2 C13-C14-H14 120.2 C16-C15-C14 120.3(4) C16-C15-H15 119.8 C14-C15-H15 119.8 C15-C16-C17 120.0(4) C15-C16-H16 120.0 C17-C16-H16 120.0 C12-C17-C16 120.3(4) C12-C17-H17 119.9 C16-C17-H17 119.9 O4-C18-O5 125.2(4) O4-C18-C1 124.9(4) O5-C18-C1 109.9(4) O5-C19-H19A 109.5 O5-C19-H19B 109.5

147

H19A-C19-H19B 109.5 O5-C19-H19C 109.5 H19A-C19-H19C 109.5 H19B-C19-H19C 109.5 O6-C20-H20A 109.5 O6-C20-H20B 109.5 H20A-C20-H20B 109.5 O6-C20-H20C 109.5 H20A-C20-H20C 109.5 H20B-C20-H20C 109.5 Table 6. Anisotropic atomic displacement parameters (Å2) for D8_2036_MS163_EtOH. The anisotropic atomic displacement factor exponent takes the form: -2π2[ h2 a*2 U11 + ... + 2 h k a* b* U12 ] U11 U22 U33 U23 U13 U12

I1 0.03463(14) 0.04674(15) 0.02670(13) -0.00231(11) -0.00304(10)

-0.00369(11)

O1 0.0403(15) 0.0195(12) 0.0343(14) -0.0048(10) -0.0065(13) 0.0047(13) O2 0.0202(14) 0.0244(13) 0.0465(18) 0.0080(12) -0.0037(12) -0.0041(11) O3 0.0165(14) 0.0351(15) 0.0470(18) 0.0040(13) -0.0014(12) -0.0002(11) O4 0.161(5) 0.0463(18) 0.065(2) -0.0160(17) -0.073(3) 0.018(3) O5 0.090(3) 0.0275(15) 0.047(2) -0.0080(14) -0.007(2) 0.0066(17) O6 0.0535(19) 0.0239(14) 0.0293(15) 0.0009(11) -0.0023(14) 0.0127(13) N1 0.0320(18) 0.0263(16) 0.0268(17) -0.0040(14) -0.0028(15) 0.0036(14) N2 0.0180(14) 0.0236(16) 0.0315(16) 0.0035(14) -0.0048(13) -0.0004(14) C1 0.027(2) 0.0226(18) 0.027(2) -0.0001(16) -0.0052(17) 0.0016(16) C2 0.031(2) 0.0291(17) 0.0236(18) -0.0010(16) -0.0021(17) -0.0055(14) C3 0.028(2) 0.0228(17) 0.0189(18) 0.0012(14) 0.0092(16) -0.0007(17) C4 0.0250(19) 0.0213(15) 0.0208(16) 0.0008(13) 0.0066(13) -0.0009(15) C5 0.032(2) 0.0225(17) 0.0228(19) 0.0028(14) 0.0046(16) 0.0023(16) C6 0.050(3) 0.0167(15) 0.031(2) -0.0005(14) 0.0083(19) 0.0020(17) C7 0.044(2) 0.0234(19) 0.026(2) -0.0076(16) 0.0058(18) -0.0100(17) C8 0.027(2) 0.0300(19) 0.0222(19) 0.0010(15) 0.0035(15) -0.0067(16) C9 0.0280(17) 0.0204(17) 0.0248(18) -0.0018(15) 0.0058(14) -0.0007(15) C10 0.026(2) 0.027(2) 0.0194(18) 0.0030(15) 0.0016(15) 0.0008(16) C11 0.0254(19) 0.0292(18) 0.047(2) 0.0026(16) -0.003(2) -0.0099(18) C12 0.029(2) 0.0209(18) 0.031(2) 0.0001(15) -0.0038(17) -0.0116(16) C13 0.034(2) 0.0301(18) 0.025(2) -0.0001(15) 0.0012(17) -0.0107(18) C14 0.041(2) 0.0285(17) 0.042(2) -0.0021(17) 0.000(2) -0.002(2) C15 0.058(3) 0.029(2) 0.041(2) 0.0072(17) -0.014(2) -0.007(2) C16 0.062(3) 0.044(3) 0.024(2) 0.0060(19) 0.003(2) -0.018(2) C17 0.040(3) 0.033(2) 0.033(2) -0.0041(17) 0.0063(18) -0.0077(18) C18 0.057(3) 0.029(2) 0.026(2) 0.0027(17) -0.005(2) -0.0030(19) C19 0.154(6) 0.032(2) 0.051(3) -0.017(2) -0.004(4) 0.000(3)

148

U11 U22 U33 U23 U13 U12 C20 0.064(3) 0.030(2) 0.039(3) 0.0063(18) 0.005(2) 0.018(2) Table 7. Hydrogen atomic coordinates and isotropic atomic displacement parameters (Å2) for D8_2036_MS163_EtOH. x/a y/b z/c U(eq)

H1 -0.141(7) 0.5044(19) 0.6864(13) 0.03

H2 -0.232(5) 0.527(3) 0.5959(12) 0.03

H1A 0.2062 0.4082 0.6144 0.031 H2A -0.3441 0.3841 0.6484 0.033 H2B -0.0815 0.3189 0.6602 0.033 H6 0.1965 0.7455 0.7638 0.039 H7 0.5150 0.6996 0.8149 0.037 H9 0.5018 0.4291 0.7700 0.029 H11A 0.3759 0.7276 0.5748 0.04 H11B 0.2381 0.7697 0.6170 0.04 H13 -0.2234 0.8631 0.6070 0.036 H14 -0.4385 0.9820 0.5672 0.045 H15 -0.2846 1.0137 0.4991 0.051 H16 0.0804 0.9270 0.4707 0.052 H17 0.2954 0.8065 0.5105 0.042 H19A 0.0715 0.1294 0.5571 0.119 H19B -0.2328 0.1742 0.5529 0.119 H19C 0.0101 0.2095 0.5223 0.119 H20A -0.2609 0.7403 0.6795 0.067 H20B -0.2110 0.7559 0.7288 0.067 H20C 0.0351 0.7757 0.6961 0.067 Table 8. Hydrogen bond distances (Å) and angles (°) for D8_2036_MS163_EtOH. Donor-

H Acceptor-H

Donor-Acceptor Angle

N1-H1...O6 0.83(2) 2.02(3) 2.688(4) 137.(4) N2-H2...O3 0.84(2) 2.08(3) 2.879(4) 160.(4) C2-H2A...O1 0.99 2.55 3.227(5) 125.6

149

Donor-H

Acceptor-H

Donor-Acceptor Angle

C7-H7...O1 0.95 2.58 3.202(4) 123.7 C20-H20B...O1 0.98 2.58 3.508(5) 157.2

Synthesis of Ac-Ile-3-I-Dap -Pro-D-Ala-Ala-Ala Peptide, Figure 3.9:

Compound 6l was installed into a peptide as described: Following standard Fmoc-SPPS

protocols, peptide precatalyst 6l, with the sequence, Ac-Ile-3-I-Dap -Pro-D-Ala-Ala-Ala,

was prepared on solid support using the commercially available Rink Amide MBHA

resin (200 mg, 0.3–0.8 meq/g, 200-400 mesh). Rink Amide MBHA resin comes pre-

loaded with an Fmoc-protected amine for the preparation of C-terminal amide peptides.

Therefore, amino acid residues were built on the solid support beginning at the C-

terminus, more specifically Ala-Ala-D-Ala-Pro-3-I-Dap-Ile. Double couplings were

achieved using a 5 equiv. excess of the appropriate Fmoc-amino acid, HCTU as the

coupling agent, and DIPEA in DMF as the solvent. Fmoc-deprotections were completed

upon triple treatments with a basic solution of 20% 4-methylpiperidine in DMF. A step-

wise procedure for the Fmoc-solid-phase synthesis of the peptide is given below.

Resin Swelling: The Rink Amide MBHA resin (200 mg) was added to the barrel of a 10

mL fritted syringe and swelled by a 4 mL DCM wash, followed by soaking for 5 min. in

an additional 5 mL of DCM. The residual DCM was purged from the syringe and the

resin was washed with DMF (3 x 4 mL).

150

Fmoc-Deprotection: The initial Fmoc-deprotection of the Rink Amide resin was

performed by three sequential one-min treatments with 2 mL of 20% 4-methylpiperidine

in DMF solution. The deprotected resin was then washed three times with 5 mL of DMF,

resulting in a free amine ready for the first amino acid coupling.

Amino acid couplings: The peptide was assembled on the solid-support beginning at the

C-terminus. Therefore, 5 equiv. (relative to resin loading) of Fmoc-L-alanine, HCTU, and

DIPEA were added to a 3 ml screw-top vial. The solids were then dissolved in 1 mL of

DMF. This prepared mixture was then taken up into the fritted syringe, containing the

resin, and agitated for 2 min. This first coupling mixture was then ejected. The resin was

subsequently treated with a second aliquot of the Fmoc-L-alanine amino acid mixture for

2 min. Following this double amino acid coupling procedure, the resin was once again

washed with DMF (3 x 5 mL). The Nα-Fmoc group was then removed following the

above described Fmoc-deprotection protocol in order to achieve the next amino acid

residue coupling of another Fmoc-L-alanine residue. This deprotection-coupling pattern

was repeated until the desired amino acid residues were assembled as follows: Resin-Ala-

Ala-D-Ala-Pro-3-I-Dap-Ile. Where the 3-I-Dap amino acid residue represents the

incorporation of Catalyst 1a as its Fmoc-SPPS ready derivative 3-iodoarene-Nα-Fmoc-L-

diaminopropionic acid, 6l.

N-terminal Acetate Capping: The fully assembled peptide, sequence Ile-3-I-Dap -Pro-D-

Ala-Ala-Ala, was N-caped with an acetate group following double, 5 min, treatments

151

with a 4 mL aliquot of a 5% acetic anhydride in DMF solution. After the allotted time for

the double treatment, the solution was ejected from the syringe into a waste container and

the resin was washed with DMF (3 x 5 mL).

Peptide Cleavage and Isolation: Following N-terminal acetate capping of the resin-bound

peptide, the resin was washed with DCM (3 x 5 mL), and methanol (3 x 5 mL). The resin

was dried in a vacuum oven at room temperature for 24 h. The resin-bound peptide was

cleaved from and R-side chain deprotected via a 2 h treatment with an acidic cleavage

cocktail of trifluoroacetic acid: H2O: triisopropylsilane (95:4.5:0.5). Following,

evaporation of the cleavage cocktail and precipitation with ice cold ether, the peptide was

isolated as a white powdery solid and characterized by MALDI-TOF mass spectrometry.

Ac-Ile-3-I-Dap -Pro-D-Ala-Ala-Ala peptide precatalyst as shown in Figure 3.9: white

solid, (0.140 g, 72%)

A representative procedure for the n-butyl amidation of Catalysts 4a-4h is as follows,

using the starting materials for Catalyst 4a as an example337:

To a flame dried round bottom flask was added 3-amino-2-iodobenzoic acid 4aa

(1.1 g, 4.18 mmol, 1.0 equiv) and triethylamine (1.17 mL, 8.4 mmol, 2.0 equiv) in

anhydrous DCM (40 mL) while under nitrogen. This homogeneous solution was stirred

I

OH

OH2N

I

NH

OH2N

4ab74%

1.) NEt3, Dry DCMSOCl2 (0ºC)

2.) NEt3, Dry DCM

NH2

I

NH

OHN

OCatalyst 4a

94%

Acetic anhydridepyridine, r.t.

4aa

152

for 5 min at room temperature under nitrogen. The solution was cooled to 0 °C. Thionyl

chloride (0.34 mL, 4.6 mmol, 1.1 equiv) was slowly added (dropwise over 20 min), and

the resulting solution was allowed to stir at 0 °C for 1 h. The resulting mixture was

brought to room temperature and stirred for 30 min. This solution was concentrated under

vacuum and then redissolved in anhydrous DCM (40 mL). To this solution was added

(dropwise over 10 min) 1-butylamine (0.45 mL, 4.6 mmol, 1.1 equiv), anhydrous DCM

(20 mL), and triethylamine (1.17 mL, 8.4 mmol, 2.0 equiv). The resulting solution was

stirred overnight at room temperature under nitrogen. The crude mixture was

concentrated by rotary evaporation, diluted in DCM, and washed with 1 M HCl, and the

aqueous layers were extracted with DCM (×3). The organic layers were washed with H2O

(×2) and saturated brine (×1) and dried over sodium sulfate. The resulting product was

filtered and concentrated by rotary evaporation. The crude product was purified by

column chromatography on silica gel (Gradient to 95:5 DCM:MeOH + 2% NEt3) to give

3-amino-N-butyl-2-iodobenzamide (4ab) as a yellow solid (0.98 g, 74%). 1H NMR (500

MHz, MeOD): δ 0.98−1.01 (3H, t), 1.46−1.52 (2H, m), 1.60−1.66 (2H, m), 3.26−3.30

(2H, q), 6.58-6.60 (1H, dd), 6.82-6.84 (1H, d), 7.12-7.15 (1H, d) ppm. 13C NMR (500

MHz, CDCl3): δ 13.8, 20.1, 31.3, 39.7, 46.3 (residual DCM), 82.3, 115.3, 116.9, 129.0,

143.8, 147.8, 170.4 ppm.

A representative procedure for the acetylation of Catalysts 4a-4h is as follows,

using Catalyst 4a as an example337:

153

3-amino-N-butyl-2-iodobenzamide 4ab (0.50 g, 1.06 mmol) in tetrahydrofuran

(THF) (10 mL) was mixed with a mixture of acetic anhydride (1 mL, 10.6 mmol) and

pyridine (86 μL, 1.06 mmol), and the mixture was stirred overnight at RT. The reaction

mixture was then acidified with 1% HCl and the final product was extracted into ethyl

acetate (3 X 20 mL). The organic phase was washed with brine, dried over sodium

sulfate and concentrated in vacuo to give the crude product. The crude product was

purified by column chromatography on silica gel (Gradient to 50:50 EtOAc:Hex) to give

Catalyst 4a as a yellow solid (0.53 g, 94%). IR (neat): 3264 (br), 2920 (s), 2851 (m),

1643 (s), 1543 (m), 1454 (m), 1257 (m), 1092 (w), 1018 (s), 799 (s) cm-1. 1H NMR (500

MHz, CDCl3): δ 0.95−0.98 (3H, t), 1.41−1.50 (2H, m), 1.60−1.63 (2H, m), 2.33 (3H, s),

3.41-3.43 (2H, t), 6.28 (1H, s, br), 6.98-6.99 (1H, d), 7.20-7.29 (1H, m), 7.87-7.94 (1H,

d) ppm. 13C NMR (500 MHz, CDCl3): δ 13.8, 20.2, 24.6, 31.4, 39.8, 90.5, 123.6, 128.9,

129.4, 139.0, 144.0, 168.8, 169.7 ppm.

General Synthesis of Catalyst 4b (Org. Lett. 2018, 20, 2345-348):

A representative procedure for diazotization/iodination is described using 4ba as

the substrate to produce 4bb:

I

OH

O

4bc90%

O2N

I

OH

O

H2N

I

OH

O

4bd90%


2.) NEt3, Dry DCM

NH2

I

NH

O

NH

O

NH Catalyst 4b

79%

NH2

OH

O

O2N

NaNO2 (0ºC)KI (90ºC)

HCl/H2O4ba 4bb

72%

Fe powder, NH4ClH2O/EtOH (60ºC)

Acetic anhydridepyridine, r.t. O

154

2-amino-4-nitro-carboxylic acid 4ba (1.82 g, 10 mmol) was added to a 100 mL

round bottom flask. To this flask was added conc. HCl (14 mL) and water (14 mL). The

suspension was cooled in an ice bath to 0 ℃. When cooled, sodium nitrite (0.83 g, 12

mmol, 1.2 equiv.) in 5 mL of water was slowly added. The reaction was stirred for 30

minutes at 0 ℃. Subsequently, KI (3.32 g, 20 mmol, 2 equiv.) in in 5 mL of water, was

slowly (over 10 minutes) added to the solution. The reaction was heated to 90 ℃ for 90

minutes. The reaction was cooled and quenched with a saturated solution of sodium

sulfite, and then transferred to a 500 mL separatory funnel with ethyl acetate. This was

acidified with conc. HCl (pH~2). The product was extracted with EtOAc (3x) then dried

over magnesium sulfate and filtered. The filtrate was concentrated and used without

further purification to give 2-iodo-4-nitrobenzoic acid (4bb) as a yellow solid (0.98 g,

72%). 1H NMR (500 MHz, MeOD): δ 5.04 (1H, br), 7.91-7.93 (1H, d), 8.28-8.29 (1H, d),

8.75 (1H, s) ppm. 13C NMR (500 MHz, MeOD): δ 92.3, 122.5, 130.4, 135.1, 142.6,

148.6, 167.4 ppm.

A representative procedure for iron assisted nitro reduction is described using 4bb

as the substrate (Org. Lett. 2011, 13, 24, 6488-6491):

4-amino-2-iodobenzoic acid, 4bc:

To a two-neck round bottom flask was added a solution NH4Cl (0.547 g, 10.2

mmol, 3 equiv.) in H2O (10 mL) and EtOH (10 mL). To this was added iron powder

(1.14 g, 20.5 mmol, 6 equiv.), and the suspension was warmed to 60 ℃ for 30 minutes.

2-iodo-4-nitrobenzoic acid (4bb) (1g, 3.41 mmol, 1 equiv.) was then added in small

155

portions, and the reaction temperature was elevated to 80 ℃. The reaction was

monitored via TLC, and when the reaction was complete, the mixture was cooled in an

ice bath (0 ℃) and basified with NaOH (5N, pH>7) and filtered to remove the excess

iron powder. The filtrate was evaporated via rotary evaporation, and the residue was

acidified by 6N HCl (pH~3). The mixture was then filtered again and washed with

MeOH/DCM (v/v = 1/1). The filtrate was concentrated to give 4-amino-2-iodobenzoic

acid, 4bc (0.81 g, 90%). 1H NMR (500 MHz, MeOD): δ 6.63-6.65 (1H, d), 7.32 (1H, s),

7.74-7.75 (1H, d) ppm. 13C NMR (500 MHz, MeOD): δ 95.8, 112.5, 120.5, 126.2, 132.7,

152.7, 167.9 ppm.

4-acetamido-2-iodobenzoic acid, 4bd:

4bd was synthesized using the representative procedure for the acetylation as

stated above. By using 4-amino-2-iodobenzoic acid (4bc) as the starting material, 4-

acetamido-2-iodobenzoic acid (4bd) was synthesized in a 90% yield (0.85 g). 1H NMR

(500 MHz, MeOD): δ 2.15 (3H, s), 7.65-7.66 (1H, d), 7.84-7.86 (1H, d), 8.35 (1H, s)

ppm. 13C NMR (500 MHz, MeOD): δ 22.6, 93.7, 118.0, 129.8, 131.3, 131.4, 142.1,

167.7, 170.54 ppm.

4-acetamido-N-butyl-2-iodobenzoic acid, Catalyst 4b:

156

Catalyst 4b was synthesized using the representative procedure for the n-butyl

amidation as stated above by using 4-acetamido-2-iodobenzoic acid (4bd) as the starting

material. Catalyst 4b as a yellow solid (0.53 g, 79%). IR (neat): 3290 (br), 3263 (br),

2928 (s), 2859 (w), 1636 (s), 1589 (m), 1519 (m), 1369 (m), 1300 (w), 1258 (m), 833 (s)

cm-1. 1H NMR (500 MHz, CDCl3): δ 0.93−0.96 (3H, t), 1.40−1.44 (2H, m), 1.60−1.63

(2H, m), 2.07 (3H, s), 3.36-3.40 (2H, t), 6.86 (1H, s, br), 7.00-7.02 (1H, d), 7.29-7.30

(1H, d), 7.75 (1H, s), 9.40 (1H, br) ppm. 13C NMR (500 MHz, CDCl3): δ 13.8, 20.2, 24.4,

31.4, 39.9, 92.2, 119.7, 127.9, 130.7, 137.3, 140.1, 169.7, 169.9 ppm.

General Synthesis of Catalyst 4c:

5-amino-2-iodobenzoic acid, 4cc:

By using 4ca as the substrate, and applying the representative procedure for

diazotization/iodination, followed by the iron assisted nitro reduction, as described above,

gave the product (without purification) 5-amino-2-iodobenzoic acid (4cc) in a 65% yield

(1.87 g) over the two steps. 1H NMR (500 MHz, MeOD): δ 8.01-8.05 (1H, d), 8.29-8.32

(1H, d), 8.57 (1H, s) ppm. 13C NMR (500 MHz, MeOD): δ 101.6, 124.4, 125.7, 137.6,

142.7, 147.8, 166.5 ppm.

5-amino-N-butyl-2-iodobenzamide, 4cd:

NH2

OH

O

NO2

I

OH

O

NO2

4cb

I

OH

O

NH2

Fe powder, NH4ClH2O/EtOH (60ºC)

4cc65% (Over 2 steps)

I

NH

O

NH2

4cd76%


2.) NEt3, Dry DCM

NH2

NaNO2 (0ºC)KI (90ºC)

HCl/H2O

I

NH

O

HN

OCatalyst 4c

84%


4ca

157

By using 4cc as the substrate and applying the representative procedure for the n-

butyl amidation as described above, 5-amino-N-butyl-2-iodobenzamide (4cd) was

synthesized (76%, 0.92 g). 1H NMR (500 MHz, MeOD): δ 0.99-1.05 (3H, m), 1.38-1.47

(2H, m), 1.52-1.67 (2H, m), 3.31-3.51 (2H, m), 7.25 (1H, br), 7.82-7.89 (2H, m), 8.22

(1H, s) ppm. 13C NMR (500 MHz, MeOD): δ 12.8, 19.8, 31.2, 39.5, 93.3, 126.1, 129.9,

135.9, 136.5, 140.1, 166.9 ppm.

5-acetamido-N-butyl-2-iodobenzoic acid, Catalyst 4c:

By using 4cd as the substrate and applying the representative procedure for the

acetylation as described above, Catalyst 4c was synthesized (84%, 0.92 g). IR (neat):

3746 (w), 2955 (w), 2924 (w), 2866 (w), 1670 (s), 1589 (s), 1466 (m), 1385 (w), 829 (m)

cm-1. 1H NMR (500 MHz, CDCl3): δ 0.98−1.00 (3H, t), 1.44−1.50 (2H, m), 1.64−1.68

(2H, m), 2.18 (3H, s), 3.44-3.48 (2H, t), 6.09 (1H, s, br), 7.18-7.20 (1H, d), 7.42-7.43

(1H, d), 7.86 (1H, s), 8.38 (1H, br) ppm. 13C NMR (500 MHz, CDCl3): δ 13.8, 20.2, 24.5,

31.4, 39.9, 92.3, 119.8, 128.2, 130.8, 137.5, 139.9, 169.2, 169.6 ppm.

General Synthesis of Catalyst 4d:

O

O

4db99%

I

H2N

CH3 OH

OI

H2N

NH

O

4dc68%

I

H2N

NH2

NH

OI

NH

O

Catalyst 4d82%

Acetic anhydridepyridine, r.t.1.) NEt3, Dry DCM

SOCl2 (0ºC)

2.) NEt3, Dry DCM

KOH, MeOH/H2O75 ºC

4da

158

A representative procedure for the hydrolysis of methyl esters is illustrated with -

4-amino-3-iodobenzoic acid (4db) (J. Comb. Chem. 2004, 6, 3, 407-413.):

To a 150 mL round bottom flask was added KOH (6.9 mmol, 0.39 g, 1 equiv.)

in 50 mL of MeOH/H2O (v/v = 1/1). To this solution was added 4da (6.9 mmol, 1.9 g,

1 equiv.). The resulting mixture was heated at 75 °C for 20 h. The reaction mixture was

concentrated in vacuo to one-half of its original volume. The residue was acidified

(pH~4) with 1 N HCl. The white precipitate was collected by filtration and then dried

under vacuum to give 4db (99%, 1.78 g) as an off-white powder. 1H NMR (500 MHz,

MeOD): δ 6.77-6.78 (1H, d), 7.76-7.77 (1H, d), 8.27 (1H, s). 13C NMR (150 MHz,

MeOD) δ 80.2, 112.5, 119.8, 130.9, 141.1, 152.6, 167.6 ppm.

4-amino-N-butyl-3-iodobenzamide, 4dc:

By using 4db as the substrate and applying the representative procedure for the n-

butyl amidation as described above, 5-amino-N-butyl-2-iodobenzamide (4dc) was

synthesized (84%, 1.02 g). 1H NMR (500 MHz, CDCl3): δ 0.86-0.87 (3H, m), 1.31 (2H,

m), 1.49-1.50 (2H, m), 3.32 (2H, m), 4.51 (2H, s), 6.47 (1H, br), 6.62-6.64 (1H, d), 7.50-

7.52 (1H, d), 8.04 (1H, s) ppm. 13C NMR (500 MHz, CDCl3): δ 13.8, 20.2, 31.8, 39.8,

82.8, 113.4, 125.6, 128.4, 138.2, 149.7, 166.1 ppm.

4-acetamido-N-butyl-3-iodobenzamide, Catalyst 4d:

By using 4db as the substrate and applying the representative procedure for the

acetylation as described above, Catalyst 4d was synthesized (84%, 1.02 g). IR (neat):

159

3259 (br), 2955 (w), 2924 (w), 1663 (s), 1632 (s), 1516 (s), 1373 (m), 1296 (m), 1038

(m), 883 (w) cm-1. 1H NMR (500 MHz, CDCl3): δ 0.96-0.98 (3H, m), 1.38-1.46 (2H, m),

1.58-1.64 (2H, m), 2.28 (3H, s), 3.43-3.47 (2H, m), 6.33 (1H, br), 7.63 (1H, s), 7.66-7.68

(1H, d), 8.26-8.29 (1H, d) ppm. 13C NMR (500 MHz, CDCl3): δ 13.8, 20.2, 25.0, 31.7,

39.6, 89.3, 120.6, 127.4, 131.8, 138.1, 140.7, 165.4, 168.5 ppm.

General Synthesis of Catalyst 4e (Chem. Eur. J. 2009, 15, 9424 – 9433):

3-amino-5-nitribenzoic Acid, 6p:

In a 100 ml round bottom flask was added 3,5- dinitrobenzoic acid 6o (1 g, 4.7

mmol) and 20 ml glacial acetic acid. This heterogeneous mixture was slowly heated up to

120 °C, and turned to homogeneous as the temperature increased. After the temperature

of solution increased to 120 °C, Fe powder (0.77 g, 13.8 mmol) was added with stirring

(this was added over ten portions within 30 minutes). The reaction mixture was kept at

120 °C for 15 min, and then poured over ice and water, followed by extracted with ethyl

acetate (x3). The organic phase was washed saturated aqueous Na2CO3 (x3) and brine

Scheme 3.17 Synthetic operations to access the aniline amide Catalyst 4e

6o

COOH

NO2O2N

COOH

NH2O2N

Fe PowderGlacial acetic acid (120 ºC)

COOH

IO2N

conc. HClNaNO2, H2O, 0 ºCKI (90 ºC)

6p45%

6q59%

conc. NH4OHMohr’s salt, H2O

COOH

IH2N INH

O NH2

6r68%

pyridine, r.t. INH

OHN

O

6s73%

Catalyst 4e64%

O

O O

O

1.) NEt3, Dry DCM SOCl2, 0 ºC

2.) NEt3, Dry DCM

NH2

160

(x1), dried over sodium sulfate and concentrated in vacuo to give 6p as a yellow powder

(0.39 g, 45%). 1H NMR (500 MHz, MeOD): δ 8.65 (1H, s), 8.72 (1H, s), 8.74 (1H, s)

ppm. 13C NMR (500 MHz, CDCl3): δ 92.9, 123.2, 133.8, 135.5, 143.7, 148.5, 164.5 ppm.

3-iodo-5-nitrobenzoic acid, 6q:

By using 6p as the substrate, and applying the representative procedure for

diazotization/iodination, as described above, the product 6q was synthesized in a 59%

yield (2.6 g). 1H NMR (500 MHz, DMSO): δ 7.49 (1H, s), 8.59-8.61 (1H, s), 8.70 (1H, s)

ppm. 13C NMR (500 MHz, DMSO): δ 93.5, 123.8, 134.4, 135.5, 144.2, 148.4, 164.8

ppm.

3-amino-5-iodobenzoic acid, 6r:

Compound 6q (1.3 g, 4.4 mmol) was dissolved in 20 ml conc. ammonia. To this

solution, (NH4)2Fe(SO4)2 (10.5 g, 26.7 mmol) in 20 ml H2O was added. After refluxing

for 10 min, the mixture was filtered through celite and the solution was cooled down to

ambient temperature. The pH of the solution was adjusted to ~4 with conc. HCl and then

extracted with ethyl acetate (x3). The combined organic layers were washed with brine

(x1), dried over sodium sulfate and evaporated in vacuo to give 6r as a yellow solid (1.2

g, 68%). 1H NMR (500 MHz, MeOD): δ 7.24 (1H, s), 7.29 (1H, s), 7.57 (1H, s) ppm. 13C

NMR (500 MHz, MeOD): δ 61.5, 94.8, 116.2, 127.9, 128.2, 134.2, 151.0 ppm.

161

3-acetamido-5-iodobenzoic acid, 6s:

6s was synthesized using the representative procedure for the acetylation as stated

above. By using 6q as the starting material, 6s was synthesized in a 73% yield (0.85 g).

1H NMR (500 MHz, MeOD): δ 2.01 (3H, s), 8.03 (1H, s), 8.13 (1H, s), 8.30 (1H, s) ppm.

13C NMR (500 MHz, MeOD): δ 23.9, 94.1, 121.1, 133.4, 134.3, 134.7, 141.4, 167.8,

171.9 ppm.

3-acetamido-N-butyl-5-iodobenzamide, Catalyst 4e:

Catalyst 4e was synthesized using the representative procedure for the n-butyl

amidation as stated above by using 6s as the starting material. Catalyst 4e (0.53 g, 64%).

IR (neat): 3279 (br), 2955 (w), 2928 (w), 2866 (w), 1635 (m), 1589 (m), 1535 (s), 1312

(m), 1280 (m), 1258 (m), 867 (m) cm-1. 1H NMR (500 MHz, CDCl3): δ 0.88−0.91 (3H,

t), 1.32−1.37 (2H, m), 1.53−1.57 (2H, m), 2.13 (3H, s), 3.34-3.36 (2H, m), 7.13 (1H, s,

br), 7.68 (1H, s), 7.87 (1H, s), 8.14 (1H, s), 9.50 (1H, br) ppm. 13C NMR (500 MHz,

CDCl3): δ 0.88−0.91 (3H, t), 1.32−1.37 (2H, m), 1.53−1.57 (2H, m), 2.13 (3H, s), 3.34-

3.36 (2H, m), 7.13 (1H, s, br), 7.68 (1H, s), 7.87 (1H, s), 8.14 (1H, s), 9.50 (1H, br) ppm

General Synthesis of Catalyst 4f:

OH

O

NH2

O

4fb87% Catalyst 4f

84%

Acetic anhydridepyridine, r.t. II

NHNH2

NH

OI

NH

O4fa O


2.) NEt3, Dry DCM

NH2

162

2-amino-N-butyl-5-iodobenzamide, 4fb: 4fb was synthesized using the representative procedure for the acetylation as

stated above. By using 4fa as the starting material, 4fb was synthesized in 87% yield

(0.53 g). 1H NMR (500 MHz, MeOD): δ 2.21 (3H, s), 7.85-7.87 (1H, d), 8.36-8.39 (2H,

m) ppm. 13C NMR (500 MHz, MeOD): δ 25.1, 85.9, 119.4, 123.3, 140.9, 142.1, 143.8,

169.9, 171.4 ppm.

2-acetamido-N-butyl-5-iodobenzamide, Catalyst 4f:

Catalyst 4f was synthesized using the representative procedure for the n-butyl

amidation as stated above by using 4fb as the starting material. Catalyst 4f (0.53 g,

64%). IR (neat): 2955 (w), 2932 (w), 2870 (w), 1670 (s), 1589 (s), 1466 (m), 1385 (w),

1339 (w), 1278 (w), 829 (m) cm-1. 1H NMR (500 MHz, CDCl3): δ 0.98−1.01 (3H, t),

1.42−1.50 (2H, m), 1.68−1.74 (2H, m), 2.64 (3H, s), 4.06-4.09 (2H, m), 7.32-7.34 (1H,

d), 7.95-7.97 (1H, d), 8.57 (1H, s) ppm. 13C NMR (500 MHz, CDCl3): δ 13.9, 20.2, 24.4,

31.5, 40.2, 94.1, 118.0, 130.9, 131.2, 136.9, 139.9, 166.6, 169.8 ppm.

General Synthesis of Catalyst 4g:


2.) NEt3, Dry DCMO

O

4gb99%

H2N

I

CH3 OH

OH2N

I

NH

O

4gc74%

H2N

I

KOH, MeOH/H2O75 ºC

NH2

NH

OHN

Catalyst 4g86%


IO

4ga

163

3-amino-4-iodobenzoic acid, 4gb:

Using the representative procedure for the hydrolysis of methyl esters, 4gb was

synthesized (99%, 1.75 g) as an off yellow powder. 1H NMR (500 MHz, MeOD): δ

7.03-7.04 (1H, d), 7.44 (1H, s), 7.71-7.72 (1H, d). 13C NMR (150 MHz, MeOD) δ 88.3,

114.9, 119.2, 131.6, 138.8, 148.3, 168.4 ppm.

3-amino-N-butyl-4-iodobenzamide, 4gc:

By using 4gb as the substrate and applying the representative procedure for the n-

butyl amidation as described above, 5gc was synthesized (74%, 0.98 g). 1H NMR (500

MHz, CDCl3): δ 0.92-0.97 (3H, m), 1.34-1.39 (2H, m), 1.41-1.59 (2H, m), 3.37-3.44 (2H,

m), 4.31 (2H, s), 6.34 (1H, br), 6.74-6.78 (1H, d), 7.21 (1H, s), 7.63-7.66 (1H, d) ppm.

13C NMR (500 MHz, CDCl3): δ 13.8, 20.2, 31.7, 39.8, 87.3, 113.2, 117.2, 136.2, 139.0,

147.2, 167.1 ppm.

3-acetamido-N-butyl-4-iodobenzamide, Catalyst 4g:

By using 4gb as the substrate and applying the representative procedure for the

acetylation as described above, Catalyst 4g was synthesized (86%, 0.82 g). IR (neat):

2955 (w), 2924 (w), 2867 (w), 2465 (br), 2403 (br), 1628 (s), 1558 (m), 1447 (s), 1396

(w), 1280 (m), 1014 (s), 752 (s) cm-1. 1H NMR (500 MHz, MeOD): δ 0.96-0.99 (3H, m),

1.39-1.44 (2H, m), 1.59-1.62 (2H, m), 2.21 (3H, s), 3.35-3.81 (2H, m), 7.39-7.42 (1H, d),

7.88 (1H, s), 7.97-7.99 (1H, d) ppm. 13C NMR (500 MHz, MeOD): δ 12.8, 19.8, 21.9,

31.2, 39.5, 98.9, 125.6, 126.0, 135.5, 139.3, 139.5, 167.4, 170.8 ppm.

164

General Synthesis of Catalyst 4h:

2-amino-N-butyl-4-iodobenzamide, 4hb:

By using 4ha as the substrate and applying the representative procedure for the n-

butyl amidation as described above, 4hb was synthesized (76%, 0.67 g). 1H NMR (500

MHz, CDCl3): δ 0.98-1.01 (3H, m), 1.42-1.47 (2H, m), 1.60-1.65 (2H, m), 3.44-3.48 (2H,

m), 6.24 (1H, br), 7.10-7.11(1H, d), 7.17-7.18 (1H, d), 7.36 (1H, s), 744.-7.46 (1H, m)

ppm. 13C NMR (500 MHz, CDCl3): δ 13.8, 20.2, 31.4, 39.9, 99.3, 114.5, 119.9, 130.3,

131.7, 150.6, 167.5 ppm.

2-acetamido-N-butyl-4-iodobenzamide, Catalyst 4h:

By using 4hb as the substrate and applying the representative procedure for the

acetylation as described above, Catalyst 4h was synthesized (90%, 0.82 g). IR (neat):

3340 (br), 2958 (m), 2870 (w), 1682 (s), 1543 (m), 1501 (s), 1396 (s), 1273 (m), 1153

(w), 775 (w) cm-1. 1H NMR (500 MHz, CDCl3): δ 0.98-1.01 (3H, m), 1.42-1.48 (2H, m),

1.62-1.67 (2H, m), 2.20 (3H, s), 3.44-3.47 (2H, m), 6.39 (1H, br), 7.12-7.14 (1H, d), 7.39

(1H, s), 7.41-7.42 (1H, d), 8.99 (1H, br) ppm. 13C NMR (500 MHz, CDCl3): δ 13.8, 20.2,

25.3, 31.4, 39.9, 99.2, 119.6, 127.4, 130.0, 131.7, 140.1, 168.5, 169.1 ppm.

4ha

NH2

OH

O

I

NH2

NH

O

4hb76%


2.) NEt3, Dry DCM

NH2

NH

NH

O

IICatalyst 4h

90%


O

165

General procedure for azido acid synthesis by diazo transfer330, 342:

Triflyl azide preparation using 7r as an example:

To a round bottom flask was added sodium azide (3.94 g, 6.05 mmol) was added

distilled H2O (15 mL) and DCM (30 mL). This solution was cooled to 0 ℃, and stirred

for 20 minutes. Triflyl anhydride (2.04 mL, 12.1 mmol) was added slowly over 10 min

with stirring continued for 2 h. The mixture was placed in a separatory funnel and the

DCM phase removed. The aqueous portion was extracted with DCM, and the organic

fractions, containing the triflyl azide, were combined and washed with saturated Na2CO3

(x1) and used without further purification.

In a separate round-bottomed flask was added the L-phenylalanine 7q (1.0 g, 6.05

mmol), K2CO3 (1.67 g, 12.1 mmol), Cu(II)SO4 pentahydrate (9.66 mg, 60.5 μmol),

distilled H2O (9 mL) and MeOH (18 mL). The triflyl azide from the previous step was

dissolved in DCM (15 mL) and was added to this separate flask. The mixture was stirred

at ambient temperature and pressure overnight. Subsequently, the organic solvents were

removed under reduced pressure and the aqueous slurry was diluted with H2O (50 mL).

This was acidified to pH 6 with conc. HCl and diluted with 0.25 M, pH 6.2 phosphate

OH

O

NH2


O

N3

7r61% yield

7q

166

buffer (50 mL) and extracted with EtOAc to remove sulfonamide by-product. The

aqueous phase was then acidified to pH 2 with conc. HCl. The product was obtained from

another round of EtOAc extractions. The EtOAc extracts were combined, dried (Na2SO4)

and evaporated to dryness giving 0.71 g of the pale oil (7r) in 61% yield with no need for

further purification.

1H NMR (300 MHz, CDCl3) δ 11.4 (1H, br), 7.31-7.40 (m, 5H), 3.25-3.24 (dd, J = 5.0,

8.8 Hz, 1H), 3.05-3.05 (dd, J = 5.0, 13.9 Hz, 1H) ppm.

13C NMR (100 MHz, CDCl3) δ 174.3, 136.0, 129.3, 128.7, 127.3, 63.1, 37.4 ppm.

The procedure above was used to generate L-phenylglycine (8k) and L-tert-Leucine (8l)

azide derivatives.329

L-phenylglycine azide (8k),Yellow oil, in 75%: 1H NMR (300 MHz, CDCl3) δ

11.9 (1H, br), 7.50-7.46 (m, 5H), 5.13 (s, 1H) ppm.13C NMR (100 MHz, CDCl3) δ 174.9,

133.3, 129.7, 129.3, 127.8, 65.2 ppm.

OH

O

NH2


O

N3

8k75% yield

167

L-tert-Leucine azide (8l), clear oil in 73%: 1H NMR (300 MHz, CDCl3) δ 11.66

(1H, br), 3.75 (s, 1H), 1.08 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 175.6, 71.7, 35.7,

26.5.

N-(2,4-dimethoxybenzyl)propargylamine hydrochloride (7u)329: Propargylamine (2.0 g,

36.2 mmol) and 2,4-dimethoxybenzaldehyde (5.0 g, 30.2 mmol) were dissolved in

anhydrous MeOH (100 mL) and stirred for 2 h. To the resulting clear solution was added

sodium borohydride (2.0 g, 54.0 mmol) in several portions. The suspension was stirred

for 2 h. After dilution with ether (200 mL), 2 M NaOH (40 mL) was added to quench the

reaction. The organic layer was washed with water (x2), brine, and dried over Na2SO4.

After filtration the volatiles were evaporated in vacuo and the sticky residue was

dissolved in methanol (50 mL). To this 12 M HCl (4 mL) was added and the volatiles

were removed under reduced pressure. The residue was dissolved in MeOH/EtOAc (1:4,

80 mL) followed by addition of hexanes (ether can be added to induce crystallization).

The resulting crystals were collected by filtration and dried to give 7u (6.7 g, 92%) as its

HCl salt. 1H NMR (500 MHz, MeOD) δ 7.31-7.30 (1H, d, J = 8 Hz), 6.67 (1H, s), 6.61-

6.60 (1H, d, J = 8 Hz), 4.25 (2H, s), 3.93 (3H, s), 3.90 (d, J = 3 Hz, 2H), 3.85 (3H, s),

OH

O

NH2


O

N3

8l73% yield

168

3.29-3.28 (t, J = 3 Hz, 1H); 13C NMR (100 MHz, MeOD) δ 161.1, 157.8, 132.2, 108.6,

103.9, 97.5, 78.7, 71.9, 57.2, 55.8, 44.7, 35.7.

General procedure for amino acid coupling toward macrocycles329: In a round bottom

flask was added the carboxylic acid component (1.1 eq) and DCM/DMF (4:1) at a

concentration ~0.4 M. To this solution was added DIPEA (2.2 eq). The solution was

cooled to 0ºC and HATU (1 eq) was added. This solution was stirred at 0 ºC for 10

minutes at, and then a solution of the amine component (1 eq) in DMF at a concentration

of ~0.5 M was added. The reactions were reacted at 0 ºC and followed by TLC until

complete. Work-up was accomplished by diluting the reaction mixture with EtOAc

followed by successive washing with 0.5 M KHSO4 (3×) and brine. After drying with

Na2SO4 and filtration, the solvents were removed via rotary evaporation and the residue

was purified by flash chromatography (gradient up to 50:50 EtOAc/Hexanes) or moved

on to the next step without purification.

General procedure for the Fmoc deprotection: In a round bottom flask was added the

Fmoc-protected peptide. This was dissolved in acetonitrile / diethylamine (2:1)

(concentration ~0.1 M) and then stirred for 1 hr, and concentrated under vacuum. The

resulting residue was exchanged with acetonitrile (x3) to remove excess diethylamine and

used directly in the next coupling step.

General procedure for Copper(II) catalyzed macrocyclization via Click reaction331-333:

169

Azido-alkyne 7x (1 equiv) was dissolved in H2O and tert-butanol (2:1) at a concentration

of 1 mM. An aqueous solution of CuSO4∙5H2O (1M, 20 mL) and sodium ascorbate (1 M,

100 mL) were added. After stirring at room temperature for 12 h, water (50 mL) was

added and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined

organic layers were washed with brine (20 mL), dried with Na2SO4, concentrated, and the

residue was purified by flash column chromatography (gradient up to 1:9 MeOH/DCM)

to produce Macrocycle A.

170

Oxytosylated propiophenone, 4l

O

OTs

171

N-butyl-2-Iodobenzamide, Catalyst 1

O

NH

I

172


O

NH

I

173


O

NH

I

174

N-butyl-2-Iodo-4,5-dimethoxybenzamide, Catalyst 4

O

NH

H3CO

I

OCH3

175

N-butyl-2-Iodo-5-methoxybenzamide, Catalyst 5

O

NH

I

OCH3

176

N-butyl-2-Iodo-5-methylbenzamide, Catalyst 6

O

NH

I

CH3

177


O

NH

IH3C

178


O

NH

ICH3

179


O

NH

I

H3C

180

N-butyl-3-Iodo-4-methoxybenzamide, 10

O

NH

H3CO

I

181

N-butyl-5-Iodo-2-methoxybenzamide, Catalyst 11

O

NH

I

OCH3

182

N-butyl-5-Iodo-2-methoxy-4-methylbenzamide, Catalyst 12

O

NH

I

OCH3

O

NH

H3C

I

OCH3

183

1-oxo-1-p-tolylpropan-2-yl 4-methylbenzenesulfonate, Product 18

O

OTsH3C

184

1-(4-Methoxyphenyl)-1-oxopropan-2-yl 4-Methylbenzenesulfonate, Product 19

O

OTsH3CO

185

1-(4-Fluorophenyl)-1-oxopropan-2-yl 4-methylbenzenesulfonate, Product 20

O

OTsF

186

1-(4-Chlorophenyl)-1-oxopropan-2-yl 4-Methylbenzenesulfonate, Product 21

O

OTsCl

187

1-(4-Bromophenyl)-1-oxopropan-2-yl 4-Methylbenzenesulfonate, Product 22

O

OTsBr

188

α-Tosyloxyacetophenone, Product 23

O

OTs

189

P=ProductISTD=Internalstandard

190

3-Iodoarene-arene-Z-L-Dap-Amino Methyl Ester, Catalyst 1a

HN

O

ONH

O

O

O

I

191

3-Iodoarene-Z-L-Dab-Amino Methyl Ester, Catalyst 1b

8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm

1.823

1.832

2.199

2.208

2.216

2.225

2.234

3.184

3.192

3.201

3.210

3.687

3.856

3.869

3.881

4.455

4.463

4.473

4.479

4.489

5.142

5.974

7.132

7.147

7.162

7.317

7.326

7.333

7.350

7.517

7.786

7.800

7.814

8.219

0.98

1.05

1.05

3.03

1.05

1.01

2.00

1.01

1.09

5.05

0.92

2.01

1.02

1H, CDCl3TL−−VI−3b�

DCM H−grease

NH

OI

HN

O

O

O

O

180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

32.75

36.07

51.62

52.75

67.39

94.35

126.17

128.14

128.34

128.59

130.22

135.99

136.12

136.34

140.36

156.84

166.01

172.64

13C, CDCl3�TL−VI−3b�

192

3-Iodoarene-Z-L-Lys-Amino Methyl Ester, Catalyst 1c

9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm

1.678

1.698

1.718

1.776

1.800

1.868

1.909

1.933

1.952

3.409

3.431

3.453

3.474

3.497

3.518

3.539

3.562

3.751

4.399

4.420

5.127

5.584

5.609

6.731

7.129

7.155

7.181

7.352

7.744

7.769

7.803

7.830

8.142

2.22

2.04

2.00

3.08

0.99

2.06

0.95

0.97

1.06

5.05

1.05

1.08

1.00

1H, CDCl3�TL−VI−3C�

H−grease

HN

O

ONH

O

O

O

I

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

25.26

30.40

39.42

52.62

53.34

67.18

94.21

126.29

128.13

128.27

128.56

130.22

136.00

136.09

136.45

140.29

156.10

166.08

172.61

13C, CDCl3TL−VI−3C�

H−grease

193

3-Iodoaryl-Z-L-Orn-Amino Methyl Ester, Catalyst 1d

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

22.48

28.68

32.33

39.66

52.51

53.49

67.06

94.22

126.29

128.07

128.22

128.55

130.20

136.00

136.15

136.65

140.23

156.17

166.23

172.89

13C, CDCl3�TL−VI−3D�

9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm

1.454

1.647

1.659

1.672

1.710

1.722

1.738

1.872

2.053

2.090

3.367

3.433

3.441

3.751

4.394

5.035

5.059

5.091

5.115

5.529

5.543

6.514

7.110

7.124

7.140

7.336

7.344

7.357

7.741

7.756

7.795

7.810

8.127

2.15

2.09

2.00

2.04

3.03

0.97

2.02

0.98

0.94

1.02

5.03

0.94

0.97

1.00

1H, CDCl3TL−VI−3D�

NH

OI

HN

O

O

O

O

194

5-Iodo-2-Methoxy-arene-Z-L-Dap-Amino Methyl Ester, Catalyst 2a

5-

9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm

3.396

3.412

3.698

3.880

4.328

4.344

5.077

5.592

5.617

6.673

6.701

7.262

7.307

7.372

7.421

7.638

7.666

7.759

8.427

2.00

3.06

3.10

1.04

2.05

0.93

1.03

5.01

1.09

1.07

1.00

1H, CDCl3TL−VI−4A�

Hexanes

DCM

HN

O

ONH

O

O

O

I

OCH3

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

29.04

39.25

52.38

56.19

66.88

83.67

113.71

123.57

128.02

128.12

128.50

136.31

140.62

141.11

156.05

157.20

163.90

172.92

13C, CDCl3�TL−VI−4A�

DCM Hexanes Hexanes

195

Iodo-2-methoxy-arene-Z-L-Dab-Amino Methyl Ester, Catalyst 2b

9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm

1.823

1.840

1.850

1.858

1.867

2.176

2.185

2.193

2.202

2.211

2.219

3.207

3.216

3.224

3.233

3.676

3.833

3.845

3.858

3.871

3.950

4.470

4.486

4.501

5.134

5.822

5.838

6.722

6.739

7.326

7.333

7.352

7.359

7.683

7.700

8.338

8.464

1.03

1.06

1.03

3.10

1.07

3.10

1.02

2.02

1.19

1.10

5.05

1.13

1.06

1.03

1H, CDCl3TL−VI−4B�

DCM

H−grease

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

32.97

35.74

51.65

52.55

56.06

67.07

83.44

113.70

123.37

128.03

128.23

128.56

136.23

140.62

141.26

156.47

157.50

164.07

172.76

13C, CDCl3�TL−VI−4B�

H−grease

DCM

NH

OI

HN

O

O

O

O

OCH3

196

5-Iodo-2-methoxy-Iodoarene-Z-L-Lys-Amino Methyl Ester, Catalyst 2c

9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm

1.665

1.740

1.754

1.767

1.780

1.944

1.954

1.964

1.970

3.480

3.492

3.769

3.952

4.433

4.443

4.457

5.128

5.458

5.473

6.750

6.767

7.343

7.351

7.372

7.380

7.736

7.741

7.800

8.482

2.25

2.04

2.01

3.07

3.09

1.01

2.09

1.08

1.01

5.00

1.03

1.00

1.00

1H, CDCl3TL−VI−4C�

H−grease

NH

OI

OCH3HN

O

O

O

O

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

25.60

30.10

39.18

52.55

53.67

56.19

67.05

83.77

113.65

123.51

128.10

128.23

128.56

136.19

140.78

141.23

155.91

157.23

163.93

172.6613C, CDCl3�

TL−VI−4C�

197

5-Iodo-2-methoxy-Iodoarene-Z-L-Orn-Amino Methyl Ester, Catalyst 2d

9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm

1.405

1.423

1.446

1.465

1.484

1.612

1.627

1.646

1.668

1.721

1.744

1.759

1.785

1.898

1.913

1.932

3.748

3.934

4.359

4.391

4.418

5.117

5.466

5.481

6.730

6.747

7.358

7.704

7.721

7.774

8.482

2.10

2.13

1.02

1.14

2.04

3.04

3.06

1.03

2.09

1.07

1.04

5.09

1.01

1.01

1.00

1H, CDCl3TL−VI−4D�

DCM

H−grease

NH

OI

HN

O

O

O

O

OCH3

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

22.56

29.08

32.10

39.28

52.43

53.75

56.19

66.97

83.77

113.67

123.61

128.09

128.18

128.54

136.29

140.76

141.16

156.00

157.21

163.93

172.92


198

5-Iodo-2-methoxy-4-mehtyl-Z-L-Dap-Amino Methyl Ester, Catalyst 3a

HN

O

ONH

O

O

O

I

OCH3H3C

199

5-Iodo-2-methoxy-4-mehtyl -Z-L-Dab-Amino Methyl Ester, Catalyst 3b

NH

OI

HN

O

O

O

O

OCH3H3C

200

5-Iodo-2-methoxy-4-methyl -Z-L-Lys-Amino Methyl Ester, Catalyst 3c

9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm

1.600

1.626

1.658

1.680

1.721

1.744

1.769

1.816

1.949

2.464

3.466

3.477

3.761

3.943

4.424

4.434

5.124

5.484

5.498

6.857

7.368

7.788

8.558

2.10

2.03

3.09

2.19

3.08

3.13

1.05

1.99

0.97

1.01

5.06

1.28

1.00

1H, CDCl3TL−VI−5C�

H−grease

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

25.66

28.49

30.08

39.10

52.53

53.70

56.11

67.03

90.66

112.93

120.82

128.10

128.21

128.56

136.21

142.06

146.36

155.92

157.36

163.93

172.69

13C, CDCl3�TL−VI−5C�

HN

O

ONH

O

O

O

I

H3C OCH3

201

5-Iodo-2-methoxy-4-mehtyl -Z-L-Orn-Amino Methyl Ester, Catalyst 3d

9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm

1.186

1.210

1.251

1.650

1.672

1.746

1.771

1.913

2.415

3.422

3.442

3.718

3.900

4.379

4.399

5.088

5.644

5.671

6.815

7.238

7.277

7.321

7.376

7.783

8.504

2.08

2.17

2.09

3.05

2.06

3.09

3.03

1.07

2.04

1.01

1.09

5.04

1.09

1.00

1H, CDCl3�TL−VI−5D�

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

25.69

28.45

29.50

29.92

39.10

52.49

53.73

56.11

66.94

90.56

112.96

120.77

128.03

128.15

128.51

136.23

141.91

146.32

156.00

157.34

163.91

172.72


NH

OI

HN

O

O

O

O

OCH3H3C

202

2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-iodobenzamido)propanoic acid, 6l

203

3-amino-N-butyl-2-iodobenzamide, 4ab

I

NH

OH2N

204

3-acetamido-N-butyl-2-iodobenzamide, Catalyst 4a

I

NH

OHN

O

205

2-iodo-4-nitrobenzoic acid, 4bb

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

92.29

122.53

130.41

135.09

142.59

148.62

167.38

13C, MeOD�TLVI−22�

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm

5.035

7.910

7.927

8.277

8.281

8.293

8.298

8.754

1.80

1.00

1.03

1.01

1H, MeODTLVI−22�

I

OH

O

O2N

206

4-amino-2-iodobenzoic acid, 4bc

9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm

6.625

6.629

6.642

6.646

7.321

7.325

7.736

7.753

1.05

1.00

1.08

1H, MeODTL−VI−23�

H2O

180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

95.84

112.46

120.48

126.22

132.70

152.71

167.99

13C, MeOD�TLVI−23�

I

OH

O

H2N

207

4-acetamido-2-iodobenzoic acid, 4bd

I

OH

O

NH

O

208

4-acetamido-N-butyl-2-iodobenzoic acid, Catalyst 4b

9 8 7 6 5 4 3 2 1 0 ppm

0.926

0.941

0.956

1.398

1.413

1.428

1.442

1.596

1.611

1.626

2.074

3.356

3.369

3.382

3.395

6.863

7.001

7.017

7.286

7.300

7.749

9.399

3.18

2.00

2.12

3.17

2.17

1.01

1.05

1.07

1.01

1.00

1H, CDCl3SP−4−53�

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

13.81

20.24

24.44

31.37

39.99

92.24

119.72

127.99

130.71

137.31

140.09

169.68

169.85

13C, CDCl3�SP−4−53�

I

NH

O

NH

O

209

5-amino-2-iodobenzoic acid, 4cc

9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm

8.009

8.018

8.037

8.047

8.289

8.318

8.568

8.577

1.02

1.02

1.00


H2O

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

101.63

124.44

125.71

137.59

142.72

147.76

166.45

13C, MeOD�TL−VI−10�

I

OH

O

NH2

210

5-amino-N-butyl-2-iodobenzamide, 4cd

I

NH

O

NH2

211

5-acetamido-N-butyl-2-iodobenzoic acid, Catalyst 4c

9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm

0.975

0.989

1.004

1.444

1.458

1.473

1.488

1.502

1.635

1.650

1.665

1.678

2.180

3.436

3.450

3.463

3.476

6.089

7.179

7.195

7.418

7.434

7.864

8.381

3.00

2.17

2.13

2.99

2.06

0.99

0.95

1.09

0.95

1.00

1H, CDCl3TL−VI−45�

I

NH

O

HN O

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

13.79

20.22

24.50

31.41

39.97

92.28

119.77

128.20

130.77

137.53

139.92

169.20

169.61

13C, CDCl3�TL−VI−45�

212

4-amino-3-iodobenzoic acid, 4db

OH

OI

H2N

213

4-amino-N-butyl-3-iodobenzamide, 4dc

NH

OI

H2N

214

4-acetamido-N-butyl-3-iodobenzamide, Catalyst 4d

NH

OI

NH

O

215

3-amino-5-nitrobenzoic acid, 6p (Scheme 3.17)

10 9 8 7 6 5 4 3 2 1 0 ppm

2.005

3.320

3.325

3.331

4.996

8.640

8.645

8.649

8.711

8.718

8.723

8.732

8.737

8.744

1.01

0.96

1.02

SP−4−43 (1H) (MeOD) (300 Bruker)

200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm

92.89

123.20

133.83

135.49

143.69

148.49

164.45

SP−4−43 (13C) (MeOD) (300 Bruker)�

COOH

NH2O2N

216

3-iodo-5-nitrobenzoic acid, 6q (Scheme 3.17)

COOH

IO2N

217

COOH

IH2N

3-amino-5-iodobenzoic acid, 6r (Scheme 3.17)

10 9 8 7 6 5 4 3 2 1 0 ppm

1.228

1.252

1.275

2.027

3.315

3.320

3.325

3.331

3.336

4.075

4.099

4.123

4.147

4.948

5.504

7.242

7.248

7.249

7.254

7.295

7.299

7.301

7.306

7.565

7.569

4.26

0.96

1.01

1.00

SP−4−44 (1H) (MeOD) (300 Bruker)�

200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

14.46

20.87

54.80

61.54

94.82

116.16

127.93

128.23

134.22

151.04

168.77

SP−4−44 (13C) (MeOD) (300 Bruker)�

218

3-acetamido-5-iodobenzoic acid, 6s (Scheme 3.17)

10 9 8 7 6 5 4 3 2 1 0 ppm

1.991

2.013

2.022

2.134

2.144

2.198

2.372

3.303

3.307

3.310

3.313

3.316

4.889

5.494

8.030

8.032

8.035

8.126

8.129

8.132

8.299

8.302

8.306

3.60

0.92

1.05

1.00


210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

23.88

94.13

121.14

133.38

134.30

134.70

141.38

167.81

171.86

13C, MeOD�SP−4−45�

IHN

O NH2

O

219

3-acetamido-N-butyl-5-iodobenzamide, Catalyst 4e (Scheme 3.17)

9 8 7 6 5 4 3 2 1 0 ppm

0.879

0.894

0.908

1.320

1.335

1.350

1.365

1.528

1.543

1.557

1.571

2.128

3.348

3.361

6.130

7.130

7.286

7.676

7.865

8.139

9.500

3.06

2.30

2.16

2.95

2.11

1.00

1.10

1.10

1.07

1.09

1H, CDCl3SP−4−48�

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

13.85

20.23

24.42

31.51

40.20

94.09

118.02

130.96

131.18

136.88

139.92

166.55

169.81

13C, CDCl3�SP−4−48�

INH

OHN

O

220

2-amino-N-butyl-5-iodobenzamide, 4fb

10 9 8 7 6 5 4 3 2 1 0 ppm

2.209

7.850

7.868

8.363

8.373

8.391

3.04

1.00

2.00


210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

25.05

85.88

119.38

123.28

140.92

142.05

143.77

169.85

171.42

13C, MeOD�SP−4−41�

OH

OI

NH

O

221

2-acetamido-N-butyl-5-iodobenzamide, Catalyst 4f

10 9 8 7 6 5 4 3 2 1 0 ppm

0.982

0.996

1.011

1.420

1.435

1.450

1.465

1.480

1.495

1.675

1.692

1.706

1.723

1.737

2.635

4.055

4.071

4.087

7.324

7.342

7.946

7.950

7.963

7.967

8.567

8.570

3.36

2.26

2.15

3.05

2.09

1.00

1.08

1.00

SP−4−42 (1H) (CDCl3) (Fr. 13−21) (500 Bruker)

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

13.73

20.24

23.20

30.63

44.62

90.52

122.20

128.47

135.59

142.84

146.50

154.87

160.56

13C, MeOD�SP−4−42�

NH

OI

NH

O

222

3-amino-4-iodobenzoic acid, 4gb

9 8 7 6 5 4 3 2 1 0 ppm

7.026

7.042

7.435

7.706

7.722

1.04

1.00

1.05


H2O

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

88.27

114.85

119.20

131.63

138.76

148.33

168.43

13C, MeOD�TL−VI−27�

OH

OH2N

I

223

3-amino-N-butyl-4-iodobenzamide, 4gc

9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm

0.916

0.941

0.965

1.335

1.348

1.359

1.371

1.383

1.397

1.422

1.550

1.573

1.590

1.599

3.368

3.392

3.412

3.435

4.307

6.335

6.742

6.749

6.769

6.776

7.208

7.630

7.657

3.02

2.18

1.91

2.05

2.10

0.98

1.03

1.01

1.00

1H, CDCl3�TL−VI−40�

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

13.81

20.16

31.66

39.83

87.27

113.21

117.18

136.15

139.00

147.24

167.07


NH

OH2N

I

224

3-acetamido-N-butyl-4-iodobenzamide, Catalyst 4g

NH

OH2N

I

225

2-amino-N-butyl-4-iodobenzamide, 4hb

NH2

NH

O

I

226

2-acetamido-N-butyl-4-iodobenzamide, Catalyst 4h

11 10 9 8 7 6 5 4 3 2 1 0 ppm

0.979

0.993

1.008

1.421

1.436

1.451

1.466

1.481

1.624

1.638

1.653

1.667

2.200

3.441

3.453

3.455

3.467

6.391

7.124

7.140

7.396

7.399

7.412

7.415

8.995

11.071

3.08

2.11

2.06

3.01

2.04

1.06

1.01

1.09

1.00

0.99


NH

NH

O

I

O

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

13.77

20.18

25.32

31.43

39.92

99.15

119.62

127.43

130.04

131.70

140.12

168.50

169.09


227

7r

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

37.44

63.05

127.31

128.71

129.29

136.02

174.33


EtOAc

EtOAc

EtOAc

EtOAc

12 11 10 9 8 7 6 5 4 3 2 1 0 ppm

3.053

3.064

3.242

3.253

7.306

7.346

7.359

11.411

0.87

0.86

4.11

1.00


EtOAc

EtOAc

EtOAc

OH

O

N3

228

7u

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm

3.285

3.289

3.295

3.848

3.909

3.914

3.926

4.246

6.592

6.596

6.608

6.613

6.662

6.667

7.297

7.314

1.09

3.00

2.06

3.03

2.04

1.09

1.15

1.16

1H, MeODTL−IV−13�

H2O

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

35.731

44.669

55.819

57.201

71.851

78.710

97.526

103.933

108.615

132.191

157.832

161.141

13C, CDCl3/MeODTL−VI−13�

CDCl3

MeOD

OMeMeO

HN

Cl

229

8k

OH

O

N3

230

8l

12 11 10 9 8 7 6 5 4 3 2 1 0 ppm

1.076

3.752

11.659

9.03

1.00

1.01

1H, CDCl3�TL−VI−61�

200 180 160 140 120 100 80 60 40 20 ppm

26.52

35.69

71.66

175.6313C, CDCl3�

TL−VI−61�

OH

O

N3

231

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239

CHAPTER FOUR

IODOARENE-CONTAINING BIODEGRADABLE X-RAY MATERIALS

4.1 INTRODUCTION

Synthetic materials exhibiting contrast imaging properties have become vital to

the field of biomedical imaging. However, polymeric biomaterials typically lack imaging

contrast properties for deep tissue imaging. This chapter details the synthesis and

characterization of a suite of aryl-iodo monomers, which were used to prepare iodinated

polyesters using a pre-functionalization approach. Commercially available 4-iodo-

phenylalanine or 4-iodobenzyl bromide served as the starting materials for the synthesis

of three iodinated monomeric moieties (a modified lactide, morpholine-2,5-dione, and

caprolactone), which under a tin-mediated ring-opening polymerization (ROP), generated

their respective polyesters (PE) or poly(ester amides) (PEA). An increase in X-ray

intensity of all synthesized iodine-containing polymers, in comparison to noniodinated

poly(lactic acid) (PLA), validated their functionality as radio-opaque materials. The

iodinated-poly(lactic acid) (iPLA) material was visualized through varying thicknesses of

chicken tissue, thus demonstrating its potential as a radio-opaque biomaterial (Figure

4.1).

240

4.2 MEDICAL IMAGING AND X-RAYCONTRAST AGENTS

Medical imaging, a technique that provides structural visualization inside the body, aides

in the study of specific morphological changes within living and nonliving systems.343, 344

One particular imaging modality, X-ray radiography, is frequently used as a diagnostic

tool for noninvasive, in vivo, real-time examinations of three-dimensional opaque objects.

X-ray imaging can be used to monitor response, degradation, and defects of biomedical

devices.345 Concerns over the long-term stability of prolonged or permanent implantable

devices have led to the development of polyester-based materials due to their desirable

properties (i.e. biocompatibility, biodegradability, and facile synthesis).346-351 The

evolution of biodegradable polyester devices, like staples, stents, sutures, and implants,

HO O O O

O

O

I

O

PLA

iP

CL6

1

2 2

4PL

A

iPCL

6

12

24

Iodinated PLA

Non-Iodinated PLA

Ring-Opening Polymerization

X-Ray Enhancement

Synthesized Iodinated Monomers

Iodine-Containing Polyesters

ü Biodegradableü Biocompatibleü Easily accessedü Enhanced X-Ray contrastü Modularity

Polyester Imaging Agents:O

O

O

O

I

Figure 4.1 Utilizing iodinated monomers for X-ray enhancements

241

have had a significant impact on the biomedical field.346, 352, 353 Perhaps the most

noteworthy advantage is their ability to be degraded and excreted from the body,

obviating the need for their removal or surgical revision. This can be vital in major

surgical procedures such as fracture fixation, spinal fixation, and abdominal wall

repair.346, 353 While commercially available polyester devices have seen a considerable

amount of use in the biomedical field, their in vivo performance can be difficult to predict

and evaluate due to the complex biological environment associated with tissues.353, 354

Therefore, the real-time monitoring of these devices is critical in order to understand their

performance and fate in the body. The major drawback of polyester-based devices is that

they lack inherent contrast imaging properties, making it difficult to visualize the area of

interest. Imaging techniques are useful only when the intensity of a signal is sufficient

enough to distinguish the target from surrounding tissues or materials. This issue

becomes even more evident when imaging materials through deep tissue or when

monitoring minor defects in biomaterials.355 Recent advancements have addressed such

problems through the improvement of contrast-enhancing agents, which can enrich the

quality of images.346 Iodine-containing small organic compounds remain at the forefront

as contrast media due to the ability of heavy iodine atoms to highly absorb X-rays. With

this overall strategy in mind, Van Horn, Whitehead, and Alexis have generated

degradable iodine-bearing polyesters by utilizing conjugation strategies356 and oxime

“Click” ligation reactions.357 More recently, this group has conducted a post-

polymerization modification reaction between poly(e-caprolactones) and iodinated

hydroxylamines.358 The modified poly(e-caprolactones) displayed an increase in X-ray

242

contrast when compared to previously reported monoiodinated materials. Our strategy

builds upon these reports, in which we explored the ring-opening polymerization of

mono-iodinated monomers, omitting the need for post-polymerization modification.

Further, in contrast to the previous studies, the strategy employed herein hinges on the

irreversible incorporation of the iodine-containing motif through the formation of key

carbon-carbon bonds. This report details the design, synthesis, and applicability of

iodine-containing monomers for the synthesis of biocompatible polyesters as X-ray

contrast imaging agents.

4.3 DESIGNING BIODEGRADABLE X-RAY CONTRAST AGENTS

We designed four target monomers each bearing a 4-iodobenzyl moiety to impart X-ray

opacity of the resulting polymer materials. Specifically, we designed lactide 4c,

morpholinediones 4e and 4f, and caprolactone 4j (Scheme 4.1). These monomers were

designed with the twin goals of maintaining high reactivity in the tin-catalyzed

polymerization reaction, but also incorporated the aryl-iodo motif by the formation of a

stable, non-reversible carbon-carbon bond. The syntheses of lactide 4c and

morpholinediones 4e and 4f all commenced with commercially available 4-

iodophenylalanine (4a). Lactide 4c was synthesized in two steps.

Diazotization/hydrolysis of 4a to provide the a-hydroxy carboxylic acid 4b was followed

by acylation/substitution with 2-bromopropionyl chloride, thus resulting in 4-iodo-benzyl

lactide 4c (34–43% over two steps). The methyl substituted morpholinedione 4e (42–48%

243

over two steps) and non-substituted derivative 4f (35–41% over two steps) were

synthesized through an acylation/base-induced cyclization sequence employing 2-

bromopropionyl chloride and chloroacetyl chloride, respectively. Lastly, the 4- iodo-

benzyl-caprolactone 4j was assembled in three straightforward steps. First, pyrrolidine

and cyclohexanone were refluxed in toluene to afford enamine 4h in 87–94% yield.

Second, the aryliodo moiety was incorporated via enamine alkylation with 4-iodo-

benzylbromide to provide substituted ketone 4i in 71% yield. The final step supplied the

target 4-iodobenzyl caprolactone 4j in 68% yield by means of a Baeyer-Villiger oxidation

I

O

OHNH2 I

O

OHOH

H2SO4 (0.5 M)NaNO2/H2O, 3 hr

2-bromopropionyl chlorideNEt3, Dry MeCN (0 °C, Argon)

OO

O

O

I4b69-74%

iLA 4c49-58%

I

O

OHNH2

I

O

OHHN

2-bromopropionyl chlorideH2O/Et2O NEt3, DMF

4d iMMD 4e42-48% over 2 steps

O

Br

0 °C-25 °C, 24 hr

NaOH (4.0 M)0 °C-25 °C, 24 hr I HN

O

O

O

I

O

OHNH2

I

O

OHHN

Chloroacetyl chlorideH2O/Et2O NEt3, DMF

4d iMD 4f35-41 % over 2 steps

ONaOH (4.0 M)0 °C-25 °C, 24 hr I HN

O

O

OCl

CHCl3

CHCl3

O

Dry toluene

NNH

Dry tolueneI

Br

I

O

mCPBA, CHCl30 °C-25 °C, 24 hr

O

O I

4h87-94%

4i 71%

iCL 4j68%

Scheme 4.1 The Synthesis of Aryl-Iodinated Biodegradable Monomers

(1)

(2)

(3)

(4)

4a

4a

4a

4g

244

with m-chloroperbenzoic acid. The corresponding polyesters were synthesized using

standard ring-opening polymerization techniques (Scheme 4.2).

To target a predictable ratio of copolymers, a conventional thermal ring-opening

polymerization with tin(II) 2-ethylhexanoate was exploited.346, 359 Isolation of the final

products was carried out by means of precipitation in cold methanol followed by

centrifugation at –9 ˚C for 5 min followed by freeze-drying for 3 days. The polymers

were then stored –20 ˚C before use. The resulting iodinated polyesters were characterized

by 1H NMR and FTIR spectroscopy. An illustrative example of the 1H NMR and FTIR

spectra comparing the iodinated and non-iodinated poly(lactic) acid, along with its

monomeric precursor 4c, can be seen in Figure 4.2. The presence of the 4-iodobenzyl

moiety in monomeric aryl-iodo lactide 4c is readily apparent based on the downfield

resonances at 7.2 and 7.7 ppm, which are still present in the polymerized (iPLA) 1H

OO

O

O

I

Sn(II), Lactic Acid

110 °CHO O O O

O

O

I

O

Iodinated Lactide (iLA 4c) Iodinated Polylactide (iPLA)

Scheme 4.2 Tin-mediated ring opening polymerization

245

NMR spectrum, indicating that the aryl-iodo functionality is stable throughout the ring-

opening process. Additionally, the downfield shift of the alpha proton signal in the PLA

spectra confirm successful polymerization (Figure 4.2 [A]). Furthermore, the FT-IR

spectra displays a peak at 1755 cm-1 that corresponds to the carbonyl stretching frequency

(Figure 4.2 [B]). A peak at 2955 cm-1 , corresponding to sp2 C-H stretches, is apparent in

both iLA and iPLA, and absent in the case of the noniodinated PLA.

Next, the X-ray contrast properties of the synthesized iodinated polyesters were

evaluated using X-ray imaging methodology (recorded in Hounsfield units). Figure 4.3

illustrates that the aryliodo containing polymers have an increased relative X-ray

intensity when compared to unmodified iodine-free PLA (Figure 4.3a). The significance

of substituents on the polymeric backbone can be seen by comparing the substituted and

Figure 1 [A] 1H NMR spectral overlay of (1a) lactide, (1b) aryl-iodo lactide (iLA), (1c) poly(lactic) acid (PLA), and (1d) aryl-iodo poly(lactic) acid (iPLA). [B] FTIR characterization of the aryl-iodo lactide (iLA), poly(lactic) acid (PLA), and the aryl-iodo poly(lactic) acid (iPLA)

Figure 4.2

246

non-substituted morpholinedione polyesters. The polymer of the iodine-containing

modified morpholinedione (iPMMD), which bears an additional methyl-substituent,

contains a lower iodine-weight concentration than the non-substituted iodinated polymer

of morpholinedione (iPMD), and in theory should have a lower X-ray intensity.

However, to our surprise, iPMMD is able to absorb X-rays more efficiently than the non-

methylated analog (iPMD). The iodinated lactide and substituted morpholinedione

polyesters exhibited comparable X-ray intensities, which can be attributed to their similar

chemical structures and molecular weights. The 4-iodobenzylcaprolactone (iCL)

monomer, provided an iodine-containing poly(-e-caprolactone) (iPCL). Unlike

commonly used PLA/PLG polymers, PCL polymers slowly degrade into less acidic, low

molecular weight by-products, preventing the generation of a toxic environment.360

Although the relative X-ray intensity of iPCL was lower than the iPLA and iPMMD

materials, the access to a class of bioresorbable X-ray enhancing polycaprolactones may

be useful for some medical applications.346

247

We selected the iPLA material for further studies based on its strong X-ray

contrasting properties coupled with its relative ease of synthesis from economical, readily

available starting materials. A poly(lactic acid) copolymer iPLA(iLA/LA) which

incorporated a 50:50 ratio of non-iodinated lactic acid to iodinated lactic acid was

generated, and was shown to have a comparable relative X-ray intensity (~2445 HU) to

the fully iodinated PLA (~ 2450 HU). We were motivated by the fact that the copolymer

could achieve similar X-ray intensity as the homopolymer iPLA, yet it bears only half the

amount of iodine possibly due to higher reactivity with non-iodinated LA monomers

resulting in a copolymer with a larger molecular weight than the iPLA homopolymer. To

further investigate the strategy of incorporating non-iodinated subunits into contrast

enhancing polymers, we copolymerized lactide with varying ratios of the iodinated

monomer (Figure 4.3b). As expected, there was a direct correlation between the X-ray

Figure 2 (a) Relative X-ray intensity of iodinated polymers compared to non-iodinated PLA. (b) Relative X-ray intensity of iodinated and non-iodinated PLA copolymer with varying ratios

Figure 4.3

248

intensity and the amount of iodinated monomer used. The resulting intensity values in

Figure 4.3b are consistent with a gradual increase of iLA monomer in the

copolymerization process of poly(lactic) acid. PLA (100% LA), PLA (iLA: LA; 25:75),

PLA (iLA: LA; 50:50), PLA (iLA: LA; 75:25) showed ~ 1800 HU, ~ 6000 HU, ~ 10700,

~ 18550 HU respectively. To validate the successful incorporation of iLA into the

copolymer, we probed the relative X-ray intensity of the copolymerization at 6, 12, and

24-hour time points (Figure 4.4a).

The increase in X-ray intensity over time confirms the effective incorporation of

iLA into the resulting copolymer. Figure 4.4b depicts the generated polymeric pellets

used in the copolymerization time study, taking the noniodinated PLA with low contrast

as a control showing the gradual increase in the intensity over reaction time. persistent

obstacle frequently encountered in medical imaging is the visualization of biomedical

devices through deep tissue. In order to explore the potential of the synthesized polymeric

materials to help overcome this obstacle, in vitro imaging of iPLA powder was performed

through varying thicknesses (i.e. 0, 2, and 5 cm) of chicken tissue. As seen in Figure

4.4c, effective visualization of the iPLA material was observed through 5 cm-thick

chicken tissue, confirming the potential of the polymeric material for deep tissue imaging

applications.

249

Lastly, the weight loss of iPLA was monitored over an eight-day period, giving a

degradation profile as seen in Figure 4.5. The overall decrease of weight percentage

confirms that the aryl-iodo functionality does not disrupt the biodegradability of the

polymer, and the hydrolysis of ester bonds release water soluble monomers and

Figure 3 Quantitative measurements of relative X-ray intensity. (a) Relative X-ray intensity of iodinated poly(lactic) acid (iPLA) synthesized using various reaction times, in comparison to iodinated polycaprolactone (iPCL). (b) Depiction of polymeric pellets (10 mg) composed of poly(lactic) acid (PLA), iodinated polycaprolactone (iPCL), and iodinated poly(lactic) acid (iPLA) copolymers synthesized using 6, 12, and 24 hours reaction times. (c) In vitro imaging of iPLA powder through different depth of chicken tissue.

Figure 4.4

250

oligomers.361 As described in Figure 4.5, the degradation rate profile of iPLA gradually

decreases with time until nearly 70% of its weight is lost after eight days.

4.4 CONCLUSIONS

A series of monomers bearing a 4-iodoobenzyl moiety (i.e. lactides, morpholines

and caprolactones) were synthesized leveraging straightforward transformations to

Figure 4 Degradation of iPLA pellets over time (days) which was incubated into PBS (pH 7.4) at 37 oC

Figure 4.5 Degradation of iPLA pellets over time (days) which was incubated into PBS (pH 7.4) at ℃ 37 .

251

prepare biomaterials with X-ray contrast properties. Unlike post-polymerization

functionalization methodology of biomaterials such as polyesters, it incorporates the

critical iodine atom into each monomeric unit, therefore maximizing iodine content

within the resulting polymer. The modified polyesters were evaluated as viable contrast

X-ray imaging agents, with emphasis on their potential use in deep tissue imaging. The

iodine-containing polyesters that exhibited the highest

X-ray intensities were the modified iodo-morpholinedione polymer (iPMMD) and the

iodopoly(lactic) acid (iPLA). Lastly, we probed the degradation profile of iPLA, and

confirmed that the covalently bound iodine does not perturb the biodegradability of the

polyester. Iodine containing X-ray contrast agents have demonstrated clinical relevance

within the field of medical imaging. Iodinated polymeric contrast-enhancing materials,

being biodegradable, and therefore less toxic, have the potential to further improve

medical imaging capabilities. This work demonstrates a highly concise and easily

modified strategy to synthesize biodegradable and biocompatible X-ray visible materials.

4.5 FUTURE WORK

Another potential application is to use polymers prepared from related functional

monomers as nanoparticle drug carriers.362-365 Polyester-based nanoparticles can serve as

a vehicle for drug delivery as they can supply therapeutic agents in a controlled manner,

and biodegrade from the body after the drug is released.365, 366 Furthermore, polyesters

are tunable scaffolds, in which many properties (i.e. thermal transitions, mechanical

strength, degradability, crystallinity) can be tailored for various applications.366

252

In this respect, our polyester-based monomers can be functionalized with drug

conjugates, including chemotherapeutics (e.g. doxorubicin and O6-benzylguanine) and

antimicrobial agents (e.g. chlorinated hydantoins) (Figure 4.6). As shown in Figure 4.6,

functionalizing a polyester (i.e. lactide or caprolactone) with a carboxylic acid moiety,

allows for an amine drug to be easily appended the side-chain of the polyester through a

conventional amidation reaction. With the drug is attached, the polyester can be

polymerized by means of tin-mediated ring-opening polymerization (ROP), thereby

creating a drug delivery platform. Due to their biocompatible and biodegradable nature,

polyester drug delivery platforms can reduce toxicity and minimize patient adverse

effects, while also potentially elevating drug loading and therapeutic efficiency.366 Such

an application has the ability to advance the field of medicine and improve upon the

current treatment options.

OO

Amine Drug

OAmine Drug

O

OO

O

O

NNO

O NH2

Cl

Drug Delivery Monomer Platforms

Figure 4.6 Biomedical monomers as drug delivery platforms

Chlorinated Hydantoin

H2N N

NNH

NO

H2NO

OH

O

O

O

OH

OH

OHO

HO

O

O6-BenzylguanineDoxorubicin

Cl

Anticancer Drug Target Anticancer Drug Target

Antimicrobial Drug Target

Targets for Drug Delivery

Caprolactone Drug Delivery Platform

Lactide Drug Delivery Platform

253

4.6 Experimental Section

Materials: All reagents and chemicals were obtained from commercial sources and used

without further purification unless stated otherwise. Water was purified on a Millipore

Direct-Q S Water Purification System. Acetonitrile was dried by refluxing over

phosphorous pentoxide (P2O5) and distilling under nitrogen prior to use. Lactic acid,

synthesized monomers, and Na2SO4 were vacuum-dried overnight in the reaction vessel

before use. All isolated products were purified by flash column chromatography using

silica gel SDS 60 C.C. 40−63 μm. All known compounds and starting materials had 1H

NMR and 13C NMR spectra consistent with previous literature reports. 1H and 13C NMR

spectra were recorded at ambient temperature on a 500 MHz NMR spectrometer

(Bruker). Proton and carbon chemical shifts were reported in parts per million (ppm)

downfield from tetramethylsilane (TMS) with reference to the deuterated solvent as the

internal standard (i.e., δ 7.26 ppm for 1H NMR, 77 ppm for 13C NMR in CDCl3). Data are

presented as follows: chemical shift, integration, multiplicity (s = singlet, d = doublet, t =

triplet, q = quartet, br = broad, m = multiplet), and coupling constants (J, in Hertz).

Infrared (IR) spectra, reported in cm−1, were collected using a Shimadzu IRAffinity-1S

Fourier transform spectrophotometer. Bands are characterized as strong (s), medium (m),

weak (w), and broad (br). Melting points were recorded on a DigiMelt MPA160

apparatus.

A Tingle 325MVET X-ray machine was used to perform the X-ray imaging (51 kVp,

300 mA, and 5 millisecond exposure time). Due to its lack of radio-opaque properties and

frequent use in biomedical applications, PLA was chosen as the control. All X-ray

254

images were processed, and image intensities quantified using ImageJ (NIH) normalized

to unmodified polymer.

Synthesis:

α-hydroxy-4-iodo-benzenepropionic acid (2); Typical Procedure[19]

To a flame dried round bottom flask equipped with a stir bar was added 4-Iodo-L-

phenylalanine (17.2 mmol, 5.0 g, 1.0 equiv) and 0.5 M H2SO4 (34.4 mmol, 2.0 equiv).

The reaction was stirred for 10 minutes or until the solution was homogeneous. The

solution was cooled to 0 ºC and a solution of sodium nitrite (7.1 g, 103 mmol, 6.0 equiv)

in H2O (50 mL) was added dropwise. The reaction was stirred at 0 ºC for an additional 4

h, and then allowed to warm to room temperature. The resulting solution was stirred at

room temperature for 24 hours (monitored completion by TLC). The reaction mixture

was extracted with diethyl ether (3 x 50 mL), and the organic phases were combined and

washed with brine (50 mL) and dried over anhydrous sodium sulfate. The drying agent

was filtered off, and the filtrate was concentrated in vacuo. The crude product was

recrystallized from hexane-diethyl ether to give α-hydroxy-4-iodo-benzenepropionic acid

as a yellowish white solid (74%, 3.7 g).

1H NMR (500 MHz, DMSO-d6): δ 2.75 (dd, 1H, 1J = 13.92 , 2J = 4.32 Hz), 2.93 (dd, 1H,

1J = 13.7 , 2J = 8.3 Hz), 4.16 (dd, 1H, 1J = 7.9 , 2J = 4.4 Hz),7.06 (d, 2H, 1J = 7.8 Hz),

7.62 (d, 2H, 1J = 7.8 Hz) ppm.

13C NMR (125 MHz, DMSO-d6): δ 64.9, 70.6, 91.9, 131.9, 136.7, 137.9, 174.9 ppm.

255

(3S)-3-(4-iodobenzyl)-6-methyl-1,4-dioxane-2,5-dione (3); Typical Procedure[20]

To a flame dried round bottom flask equipped with a stir bar and under argon was added

α-hydroxy-4-iodo-benzenepropionic acid (5.1 mmol, 1.5 g, 1.0 equiv), triethylamine

(0.79 mL, 5.6 mmol, 1.1 equiv), and dry MeCN (25 mL) while under argon. This

solution was cooled to 0 ºC, followed by the dropwise addition of 2-bromopropionyl

chloride (0.57 mL, 5.6 mmol, 1.1 equiv). The mixture was stirred for 30 min.

Triethylamine (0.79 mL, 5.6 mmol, 1.1 equiv) was added and the reaction was stirred at

70 ºC for 3-5 h. The reaction was cooled to room temperature, quenched with 1M HCl

(25 mL) and extracted with EtOAc (3 x 25 mL). The combined organic phases were

washed with H2O (25 mL), brine (25 mL), and dried over anhydrous sodium sulfate. The

drying agent was filtered off, and the filtrate was concentrated in vacuo. The crude

product was purified by column chromatography (gradient 70:30 hexanes:EtOAc) as a

yellow oil, which solidified upon storage in the freezer (M.p. 121-122 ºC, 58 %, 1.03 g).

Rf = 0.26 (70:30 hexanes:EtOAc)

1H NMR (500 MHz, CDCl3): δ 1.60 (d, 3H, 1J = 6.7 Hz), 3.19 (dd, 1H, 1J = 14.8 , 2J =

7.5 Hz ), 3.40 (dd, 1H, 1J = 14.9, 2J = 4.0 Hz ) 4.96 (q, 1H 1J = 6.7 Hz), 5.06 (dd, 1H, 1J

= 3.9 , 2J = 7.7 Hz), 7.08 (d, 1J = 8.3 Hz), 7.66 (d, 1J = 8.3 Hz) ppm.

13C NMR (125 MHz, CDCl3): δ 15.9, 35.7, 72.5, 76.1, 93.1, 131.9, 134.2, 137.8, 166.0,

166.7 ppm.

IR (neat): 2995 (w), 2932 (w), 1769 (s), 1738 (s), 1485 (w), 1250 (s) cm−1.

256

(S)-2-((R)-2-bromopropanamido)-3-(4-iodophenyl)propionic acid (4); Typical

Procedure[21-23]

To a flame dried round bottom flask, equipped with a stir bar was added 4-Iodo-

L-phenylalanine (6.9 mmol, 2.0 g, 1.0 equiv), and 20 mL H2O:Et2O (1:1 (V/V)). To this

solution was added 4 M NaOH (8 mL) and stirred until all solids dissolved; this solution

was then cooled to 0 ºC. In a separate flame dried vial was added 2-bromopropionyl

chloride (0.76 mL, 7.6 mmol, 1.1 equiv) and 4 M NaOH (8 mL). The vial solution was

added (dropwise) to the round bottom flask while maintaining a temperature of 0 ºC and a

pH of 11 throughout the addition (4 M NaOH added to maintain pH via dropping funnel)

. After completion of the reaction (monitored by TLC), the reaction was warmed to room

temperature and the ether layer was separated in a separatory funnel. The aqueous layer

was acidified with concentrated HCl to pH of 1, and extracted with ethyl acetate (4 x 25

mL). The combined organic phases were washed with brine and dried over anhydrous

sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated in

vacuo. The white, solid crude product was placed under high vacuum and used in next

step without further purification.

(3S,6S)-3-(4-iodobenzyl)-6-methylmorpholine-2,5-dione (5); Typical Procedure[21-24]

To a flame dried round bottom flask equipped with a stir bar was added crude (S)-2-((R)-

2-bromopropanamido)-3-(4-iodophenyl)propionic acid (6.8 mmol, 2.9 g, 1 equiv) and

DMF (25-30 mL) followed by triethylamine (1.04 mL, 7.5 mmol, 1.1 equiv). The

mixture was heated to 90 ºC for 12 h under N2. When reaction was completed

257

(monitored by TLC), the mixture was allowed to stand overnight in the freezer. The

crystallized salt and DMF/TEA were filtered, and the filtrate was concentrated in vacuo.

Residual DMF was removed by adding toluene to the sample, followed by rotary

evaporation (repeated 4 times). Further purification was performed by recrystallizing in

chloroform and cold Et2O to furnish a white solid (M.p. 147-148 ºC, 1.12 g, 48 % over 2

steps).

1H NMR (500 MHz, DMSO-d6): δ 1.13 (d, 3H, 1J = 6.9 Hz), 3.02 (d, 2H, 1J = 5.1 Hz),

4.67 (t, 1H, 1J = 5.0 Hz ), 4.99 (q, 1H, 1J = 6.8 Hz), 7.09 (d, 2H, 1J = 8.1 Hz), 7.68 (d,

2H, 1J = 8.2 Hz) ppm.

13C NMR (125 MHz, CDCl3): δ 16.8, 36.1, 54.2, 74.6, 93.3, 132.7, 136.5, 137.4, 168.5,

168.6 ppm.

IR (neat): 3202 (br), 1747 (s), 1694 (s), 1483 (w), 1375 (m), 1315 (m) cm−1.

(S)-2-(2-chloroacetamido)-3-(4-iodophenyl)propionic acid (6)[21-24]

Following the typical procedure of 4 was obtained by using chloroacetyl chloride in place

of 2-bromopropionyl chloride. The yellow colored crude product was used in next step

without further purification.

(S)-3-(4-iodobenzyl)morpholine-2,5-dione (7)[21-24]

Following the typical procedure of 5, but using 6 as the starting material, the product was

obtained as an off-white solid. (M.p. - ºC, 1.12 g, 41 % over 2 steps).

258

1H NMR (500 MHz, DMSO-d6): δ 1.13 (d, 3H, 1J = 6.90 Hz), 3.02 (d, 2H, 1J = 5.10 Hz),

4.67 (t, 1H, 1J = 4.98 Hz ), 4.99 (q, 1H, 1J = 6.84 Hz), 7.09 (d, 2H, 1J = 8.10 Hz), 7.68

(d, 2H, 1J = 8.15 Hz) ppm.

13C NMR (125 MHz, CDCl3): δ 16.8, 36.1, 54.2, 74.6, 93.3, 132.7, 136.5, 137.4, 168.5,

168.6 ppm.

1-Cyclohexenylpyrrolidine (9); Typical Procedure[25]

While under N2, a flame dried round bottom flask equipped with a stir bar and dean stark

trap (with activated 4 Å molecular sieves) was charged with cyclohexanone (4.22 mL,

40.8 mmol, 1 equiv), dry toluene (20 mL), and pyrrolidine (6.02 mL, 73.4 mmol, 1.8

equiv). The mixture was refluxed under N2 for 5-7 h. The solvent and excess pyrrolidine

were removed in vacuo. The crude product was used without further purification to afford

the colorless product. (5.8 g, 94%).

1H NMR (500 MHz, CDCl3): δ 1.38-1.43 (m, 2H), 1.52-1.55 (m, 2H), 1.66-1.68 (m, 4H),

1.95-1.96 (m, 2H), 2.02-2.03 (m, 2H), 2.84-2.85 (m, 4H), 4.10-4.16 (m, 1H) ppm.

13C NMR (125 MHz, CDCl3, with traces of toluene present): δ 22.9, 23.3, 24.5, 26.9,

27.4, 47.2, 93.3, 142.9 ppm.

2-(4-iodobenzyl)cyclohexan-1-one (10); Typical Procedure[26]

While under N2, a flame dried round bottom flask equipped with a stir bar was charged

with 4-iodobenzyl bromide (4.9 g , 16.5 mmol, 1 equiv) and dry toluene (30 mL). When

homogeneous solution formed, the flask was charged with 1-cyclohexenylpyrrolidine

259

(2.5 g, 16.5 mmol , 1 equiv). The mixture was refluxed under N2 for 18 h. H2O (30 mL)

was added and the solution was heated for an additional hour. The solvent was

evaporated under vacuum, and the residue was extracted with diethyl ether. The ether

phase was washed consecutively with 5% HCl, 5% NaHCO3 solution, and water, then

dried, and evaporated. The residue was purified via silica gel chromatography eluted with

hexanes/ethyl acetate (9:1) to provide a white solid (3.7 g, 71 %).

1H NMR (500 MHz, CDCl3): δ 1.15-3.02 (m, 11H), 6.79 (d, 2H, 1J = 8.3 Hz), 7.42 (d,

2H, 1J = 8.3 Hz) ppm.

13C NMR (125 MHz, CDCl3): δ 25.1, 27.9, 33.5, 35.1, 42.1, 52.0, 91.2, 131.4, 137.2,

140.1, 211.4 ppm.

7-(4-iodobenzyl)oxepan-2-one (11); Typical Procedure[27. 28]

While under N2, a flame dried round bottom flask equipped with a stir bar was charged

with 2-(4-iodobenzyl)cyclohexan-1-one (1.5 g, 4.8 mmol, 1 equiv) and CHCl3 (50 mL).

The solution was cooled to 0 ºC, and to this solution was added mCPBA (77% reagent)

(14.3 mmol, 3 equiv). The mixture was stirred at room temperature for 2-3 d (monitored

by TLC), and the reaction mixture was quenched with an sat. Na2S2O3 aqueous solution.

The aqueous layer was extracted with CHCl3 (x3). The combined organic layer was

washed with sat. NaHCO3 aqueous solution and brine. The organic layers were dried

over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via silica gel

chromatography eluted with a gradient of hexanes:ethyl acetate (2:8) to provide a

colorless oil (1.07 g, 68%). Rf = 0.69 (1:9 hexanes:EtOAc)

260

1H NMR (500 MHz, CDCl3): δ 1.33-2.78 (m, 10H), 4.28-4.3 (m, 1H), 6.85 (d, 2H, 1J =

8.1 Hz), 7.40 (d, 2H, 1J = 8.2 Hz) ppm.

13C NMR (125 MHz, CDCl3): δ 22.9, 28.3, 33.8, 34.9, 42.1, 80.7, 92.2, 131.7, 136.9,

137.6, 175.2 ppm.

IR (neat): 2924 (w), 2857 (w), 1726 (s), 1483 (w), 1173 (m), 1007 (w) cm−1.

Example Procedure for Conventional Ring-Opening Polymerization: Polymers were synthesized using ring opening polymerization with lactic acid as the

initiator and tin (II) 2-ethylhexanoate as the catalyst. Prior to use, the monomer, lactic

acid, sodium sulfate, and stir bar were vacuum-dried overnight in the reaction vessel. The

reaction vessel was equipped with a reflux condenser, and the reagents were dissolved in

anhydrous toluene while under a nitrogen atmosphere. When the reaction reached 120 ºC,

tin(II) 2-ethylhexanoate was added, and the reaction was allowed to stir at this

temperature for 24 h. The resulting polymer was partitioned between chloroform and

water, and the chloroform phase was collected (3x). The chloroform phases were

combined and dried over MgSO4. The filtrate was collected and the desired polymer

precipitated out by using cold methanol.

261

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263

264

265

266

267

268

4.7 REFERENCES

343. Alikacem, N.; Stroman, P. W.; Marois, Y.; Jakubiec, B.; Roy, R.; Guidoin, R., Noninvasive follow-up of tissue encapsulation of foreign materials - Are magnetic resonance imaging and spectroscopy breakthroughs? Asaio Journal 1995, 41, M617-M624. 344. Ehlerding, E. B.; Grodzinski, P.; Cai, W. B.; Liu, C. H., Big Potential from Small Agents: Nanoparticles for Imaging-Based Companion Diagnostics. ACS Nano 2018, 12, 2106-2121. 345. Hemonnot, C. Y. J.; Koster, S., Imaging of Biological Materials and Cells by X-ray Scattering and Diffraction. ACS Nano 2017, 11, 8542-8559. 346. Attia, M. F.; Brummel, B. R.; Lex, T. R.; Van Horn, B. A.; Whitehead, D. C.; Alexis, F., Recent Advances in Polyesters for Biomedical Imaging. Adv. Healthc. Mater. 2018, 7. 347. Nottelet, B.; Darcos, V.; Coudane, J., Aliphatic polyesters for medical imaging and theranostic applications. Eur. J. Pharm. Biopharm. 2015, 97, 350-370. 348. El Habnouni, S.; Darcos, V.; Coudane, J., Synthesis and Ring Opening Polymerization of a New Functional Lactone, alpha-Iodo-epsilon-caprolactone: A Novel Route to Functionalized Aliphatic Polyesters. Macromol. Rapid Commun. 2009, 30, 165-169. 349. Benabdillah, K. M.; Coudane, J.; Boustta, M.; Engel, R.; Vert, M., Synthesis and characterization of novel degradable polyesters derived from D-gluconic and glycolic acids. Macromolecules 1999, 32, 8774-8780. 350. Samuel, R.; Girard, E.; Chagnon, G.; Dejean, S.; Favier, D.; Coudane, J.; Nottelet, B., Radiopaque poly(epsilon-caprolactone) as additive for X-ray imaging of temporary implantable medical devices. RSC Adv. 2015, 5, 84125-84133. 351. Attia, M. F.; Brummel, B. R.; Lex, T. R.; Van Horn, B. A.; Whitehead, D. C.; Alexis, F., Recent Advances in Polyesters for Biomedical Imaging. Adv. Healthcare Mater. 2018, 7. 352. Boase, N. R. B.; Blakey, I.; Thurecht, K. J., Molecular imaging with polymers. Polym. Chem. 2012, 3, 1384-1389. 353. He, W.; Feng, Y.; Ma, Z. W.; Ramakrishna, S.; Mahapatro, A.; Kulshrestha, A. S., Polymers for Tissue Engineering. Polymers For Biomedical Applications 2008, 977, 310-335. 354. Francis, R.; Kumar, D. S., Biomedical Applications of Polymeric Materials and Composites. 1st ed. Wiley-VCH,2016; p 1 online resource (400 pages). 355. Helmchen, F.; Denk, W., Deep tissue two-photon microscopy. Nature Methods 2005, 2, 932-940. 356. Olsen, T. R.; Davis, L. L.; Nicolau, S. E.; Duncan, C. C.; Whitehead, D. C.; Horn, B. A.; Alexis, F., Non-invasive deep tissue imaging of iodine modified poly(caprolactone-co-1-4-oxepan-1,5-dione) using X-ray. Acta Biomaterialia 2015, 20, 94-103.

269

357. Nicolau, S. E.; Davis, L. L.; Duncan, C. C.; Olsen, T. R.; Alexis, F.; Whitehead,D. C.; Van Horn, B. A., Oxime functionalization strategy for iodinated poly(epsilon-caprolactone) X-ray opaque materials. J. Polym. Sci. A 2015, 53, 2421-2430.358. Van Horn, B. A.; Davis, L. L.; Nicolau, S. E.; Burry, E. E.; Bailey, V. O.; Guerra,F. D.; Alexis, F.; Whitehead, D. C., Synthesis and conjugation of a triiodohydroxylaminefor the preparation of highly X-ray opaque poly(epsilon-caprolactone) materials. J.Polym. Sci. A 2017, 55, 787-793.359. Dechy-Cabaret, O.; Martin-Vaca, B.; Bourissou, D., Controlled ring-openingpolymerization of lactide and glycolide. Chem. Rev. 2004, 104, 6147-6176.360. Benoit, M. A.; Baras, B.; Gillard, J., Preparation and characterization of protein-loaded poly(epsilon-caprolactone) microparticles for oral vaccine delivery. Int. J. Pharm.1999, 184, 73-84.361. Wilbur, D. S. Iodinated borane cage molecules as X-ray contrast media. 1996.362. Andronescu, E.; Grumezescu, A. M., Nanostructures for oral medicine. In Microand nano technologies series Elsevier,: Amsterdam, 2017; p 1 online resource.363. Janib, S. M.; Moses, A. S.; MacKay, J. A., Imaging and drug delivery usingtheranostic nanoparticles. Adv. Drug Delivery Rev. 2010, 62, 1052-1063.364. Bikiaris, D.; Karavelidis, V.; Karavas, E., Novel Biodegradable Polyesters.Synthesis and Application as Drug Carriers for the Preparation of Raloxifene HCl LoadedNanoparticles. Molecules 2009, 14, 2410-2430.365.Shalgunov, V.; Zaytseva-Zotova, D.; Zintchenko, A.; Levada, T.; Shilov, Y.;Andreyev, D.; Dzhumashev, D.; Metelkin, E.; Urusova, A.; Demin, O.; McDonnell, K.;Troiano, G.; Zale, S.; Safarova, E., Comprehensive study of the drug delivery propertiesof poly(L-lactide)-poly (ethylene glycol) nanoparticles in rats and tumor-bearing mice. JControl Release. 2017, 261, 31-42.366. Washington, K. E.; Kularatne, R. N.; Karmegam, V.; Biewer, M. C.; Stefan, M.C., Recent advances in aliphatic polyesters for drug delivery applications. WileyInterdiscip. Rev. Nanomed. Nanobiotechnol. 2017, 9.

270

CHAPTER FIVE

SYNTHESIS OF DIAZACYCLOBUTENES VIA A FORMAL [2 + 2] CYCLOADDITION

5.1 PREFACE

This abridged chapter describes a formal [2 + 2] cycloaddition between electron-rich

alkynes and triazolinediones to generate rather unexplored chemical moieties known as

diazacyclobutenes. The research described in this chapter was conducted in collaboration

with a fellow colleague, Chandima J. Narangoda (Clemson University, advisor: Dr.

Daniel C. Whitehead) and will therefore only be described briefly. For a more detailed

account, the reader is encouraged to read the current and future published peer reviewed

articles that the Whitehead group publishes.367, 368

5.2 INTRODUCTION

The field of organic chemistry perpetually challenges and motivates scientists to design,

develop and implement new synthetic methodologies in order to construct target

compounds. One common chemical moiety that chemists continually aspire to create are

cyclic frameworks. Cyclic compounds, which contain at least one connected series of

atoms that form a ring, have proven to be important in all aspects of life. In particular,

cyclic species have found significance as biologically and pharmaceutically relevant

compounds (i.e. agrochemicals, medicines, dyes, optical materials etc.).369 One

important synthetic strategy to assemble cyclized products has been the use of

271

cycloaddition reactions.369, 370 Cycloadditions allow for two or more new bond

formations to manifest from a single manipulation. Cycloadditions have been utilized by

chemists to create various cyclic moieties, including nitrogen containing heterocyclic

compounds.

Diazacyclobutenes are a unique class of nitrogen-containing heterocycles

containing two nitrogen atoms and a carbon-carbon double bond constrained within a

four-membered ring (Scheme 5.1, 5d).

This scaffold has gained some attention in the scientific community due to their apparent

non-aromatic character, even though they formally obey Hückel’s (4n+2) rule of

aromaticity.371-381 Nevertheless, the diazacyclobutene motif has been relatively

inaccessible due to the limited number of synthetic methodologies reported in the

literature. In fact, the known synthetic routes to generate diazacyclobutenes have been

R1 YR2R1

1.) nBuLi, THF, -78 ℃2.) S8, -78 ℃, 1 h3.) R2X, THF, 0 ℃, 4 h

Condition A

Y = S or Se1.) nBuLi, THF, -78 ℃3.) R2-Y-Y-R2, THF, -78 ℃ to rt, 1 h

Condition Bor

N N

N OO

MeCN, reflux, 24 h5a 5b

5c

Scheme 5.1 General synthetic route toward diazacyclobutenes

N N

N OO

5dYR1 R2

272

rather ineffective, and consequently, less than 10 total examples of this molecular

scaffold have been disclosed (Figure 5.2).373, 378-381

Our group has recently designed a convenient [2 + 2] cycloaddition between

electron-rich alkynes (5a) and a triazolinedione derivative (5c, 4-phenyl-1,2,4-

triazoline-3,5-dione or PTAD) to construct diazacyclobutene derivatives (5d, Scheme

5.1).367 It should be noted that sulfide and selenide alkynes were employed due to their

electron donating ability, thereby creating a more electron rich alkyne.

The production of the diazacyclobutenes began with the synthesis of sulfur-

and/or selenium-containing alkynes (5b). These alkynes were synthesized by means of an

n-butyl lithium (nBuLi)-assisted deprotonation of a terminal alkyne (5a), producing a

lithium acetylide, which can supply the targeted alkyne (5b) with use of elemental sulfur

(Condition A) or an appropriate dialkyl sulfide or selenide (Condition B).367, 382, 383

With optimized reaction conditions, the generated alkynyl sulfides or selenides (5b)

underwent the desired cycloaddition upon refluxing in the presence of acetonitrile

(MeCN) and PTAD (5c), thus furnishing the diazacyclobutene adduct (5d).367

N NArO2S

NRR

5e51-77% (1 step)

7 examples(Effenberger, 1966)

N N

5f5% (3 steps)

t1/2 (20 ℃) = 6.9 h(Warrener, 1972)

OOO

OCH3H3C

N N

N OO

R

5g21-26% (1 step)

2 examples(Greene, 1984)

N N

N OO

CH3

5h11% (2 steps)(Breton, 2001)

Figure 5.1 Historical examples of diazacyclobutene motifs

Ar Ar

273

To investigate this methodology, an assortment of alkynyl sulfides and selenides

were synthesized and treated with PTAD to create a small library of diazacyclobutene

derivatives (Figure 5.2). By using sulfur phenylacetylene derivatives, we first varied the

substituent located on the sulfur/selenium atom (R2). The carbon chain length was

altered, and shorter, as well as longer alkyl chains, supplied the corresponding product in

moderate to good yields (Figure 5.2, 5i-5n, 7789% yields). A benzyl (5o) and aryl (5p)

functional group residing on the sulfur atom provided diazacyclobutene derivatives in 62

and 85% yields, respectively. Compound 5p was also produced in an 81% yield when

carried out at a 6 mmol scale. Next, we modified the R1 substituent with an aryl moiety.

Arenes that contain either a para-positioned electron donating (5q–5s) or electron

withdrawing (5t and 5u) group yielded products with good efficiency (74–92%). When

the R1 and R2 substituents were both alkyl groups (5v–5x), the transformation was also

successful, ranging from moderate to good yields (56–94%). Finally, selenide alkynes

were used in the [2 + 2] cycloaddition, and proceeded to give good diazacyclobutene

yields (5y and 5z, 80 and 93%).

274

N N

N OO

5i (89% yield) 5j (84%, yield) 5k (80% yield) 5l (77% yield)

5m (78%, yield) 5n (81% yield) 5o (62% yield) 5p (85% yield)(81% yield, 6 mmol scale)

5q (92% yield) 5r (77% yield) 5s (74% yield) 5t (85% yield)

5u (83% yield) 5v (61% yield) 5w (56% yield) 5x (94% yield)

5y (80% yield) 5z (93% yield)

Figure 5.2 Substrate scope in a [2 + 2] cycloaddition to diazacyclobutene motifs

R1 YR2

Y = S or Se

N N

N OO

MeCN, reflux, 24 h5b (1.3 eq.)

5c (1 eq.)

5i-5z (56-94% yield)

S Me

N N

N OO

S Et

N N

N OO

S nPr

N N

N OO

S nBu

N N

N OO

S nC5H11

N N

N OO

S nC8H17

N N

N OO

S Bn

N N

N OO

S Ph

N N

N OO

S Me

N N

N OO

S Et

N N

N OO

S Me

N N

N OO

S Me

N N

N OO

S Me

N N

N OO

nBu S Me

N N

N OO

S nBu

N N

N OO

S CH3

N N

N OO

Se

N N

N OO

Se

Me H3C H3CO

CF3

nBu

Cl

N N

N OO

YR1 R2

Me

275

The previous work demonstrated a simple, yet efficient protocol that involves a formal [2

+ 2] cycloaddition between electron rich alkynes and PTAD to generate

diazacyclobutenes. This chemistry has been extended to synthesize another rarely

accessible molecular scaffold, 2-imidothioimidates (Scheme 5.2, 5ac).368

A reaction between sulfide or selenide alkynes (5b) with open-chain

azodicarboxylates (5aa) form a [2 + 2] cycloadduct (5ab), which quickly experiences a

4p conrotatory cycloreversion to provide N,N-dicarbamoyl 2-iminothioimidates (Scheme

5.2, 5ac). The substrate scope involving the use of diethyl azodicarboxylate (DEAD,

5ad) and sulfide/selenide alkynes (5b) is shown in Figure 5.3; it should be noted that

although it is not described in this text, we have been successful with employing other

azodicarboxylates using this strategy, and the reader is directed to our publication for

further details.368 Next, the alkyl chain (R2) situated on the sulfur/selenium atom was

explored. Shorter (5ae-5ah) and longer (5ai-5aj) alkyl chains supplied the desired 2-

imidothioimidates in good to great yields (73–99%). By using aryl and benzyl moieties

at the R2 position, phenyl (5ak) and benzyl (5al) substituted N,N-dicarbamoyl 2-

iminothioimidates could be produced in good yields (77 and 83%, respectively). Further

N N CO2R3R3O2C

MeCN (reflux)24 h

R1 YR2

N

N

O

O R3

R1Y R2N N

R1 Y R2

OO

OR3R3O 4π conrotatory

cycloreversion

40 - 99% yield

5bY = S, Se

O

OR3

Scheme 5.2 General synthetic route toward N,N-dicarbamoyl 2-iminothioimidates

5ab5ac

5aa

276

studies involved substituting arenes at the R1 position of the alkyne, while maintaining a

methyl sulfide motif (5am-5aq). Electron donating groups in the para-position of the

arene were highly effective using these reaction conditions (5am and 5an), however

withdrawing donating groups in the aryl para-position gave mediocre yields (5ao and

5ap). Modifying R1 with alkyl substituents such as n-butyl gave lower yields (40% for

5aq and 45% for 5ar), while a cyclopropyl substituent gave a moderate yield of 77%

(5as). Finally, selenide 2-imidothioimidate derivatives could be produced using this

protocol, and supplied products in good yields (76% for 5at and 73% for 5au).

The work discussed herein demonstrates the high synthetic potential for sulfur

and selenium-containing alkynes to undergo a [2 + 2] cycloaddition with both cyclic (i.e.

PTAD) or acyclic (i.e. DEAD) azodicarboxylates to create novel chemical moieties. The

rarely accessible diazacyclobutene and 2-imidimidates motifs were synthesized in a

simple, facile manner with moderate to good yields. These protocols have the ability to

enrich the synthetic applications of cycloadditions and provide new strategies for

obtaining unique molecular scaffolds.

277

N

N

O

OEt

PhS

CH3

5ae (74% yield)

N

N

O

OEt

PhS

Et

5af (99% yield)(99% yield, 5 mmol scale)

N

N

O

OEt

PhSnPr

5ag (73% yield)

N

N

O

OEt

PhSnBu

5ah (83% yield)

N

N

O

OEt

PhSnC5H11

5ai (80% yield)

N

N

O

OEt

PhSnC8H17

5aj (73% yield)

N

N

O

OEt

PhS

Ph

5ak (77% yield)

N

N

O

OEt

SCH3

5am (88% yield)

N

N

O

OEt

SCH3

5an (95% yield)

MeO

N

N

O

OEt

SCH3

5ao (47% yield)

Cl

N

N

O

OEt

SCH3

5ap (69% yield)

CF3

N

N

O

OEt

nBuS

CH3

5aq (40% yield)

N

N

O

OEt

nBuSnBu

5ar (45% yield)

N

N

O

OEt

S

5as (77% yield)

N

N

O

OEt

PhSe

5at (76% yield)

N

N

O

OEt

PhS

Bn

5al (83% yield)

N N CO2EtEtO2C

MeCN, 24 h, refluxR1 Y

R2

N

N

O

OEt

R1Y R2

CH3CH3

5bY = S, Se(1.3 equiv)

5ad (1 equiv)

5acY = S, Se

O

OEt

O

OEt O

OEt

O

OEt

O O

O

O

OOEt Et

EtO

OEt

O

OEt

O

OEt

O

OEt

O

OEt

O

OEt

O

OEt

O

OEt

O

OEt

O

OEt N

N

O

OEt

PhSe

5au (73% yield)

Bn

O

OEt

Figure 5.3 Substrate scope of 2-imidothioimidates

278

5.3 FUTURE WORK

Ongoing research involves the use of alternative electron rich alkynes such as

ynols (5aw) and ynamides (5aab) to expand the developed synthetic methodologies

(Scheme 5.3). These can be realized by using established synthetic procedures. For

instance, a Corey Fuchs reaction, followed by a copper-catalyzed coupling of

dibromoalkenes with phenols can afford oxygen containing alkynes (Figure 5.3, eq. 1,

5aw). The ynol ethers could be subjected to our reaction conditions, with cyclized and

1.) NaH, DMSO, 70 °C2.)

R3

HN R2

Cl

Cl R1

1.) CBr4, PPh3 Dry DCM, 0 °C2.) R2-OH, K3PO4, 2,2-bipyridine, CuI, Toluene, 110 °C3.) tBuOK, 1,4-dioxane, RT

Ynol ethers5aw

R1 H

O R1 O

Ynamides5aab

R1 NR3

R2

N N

R1 O

N OO

R2

NN N

O

O

EtO

O

N

ON

R1

OOEt

Dry MeCN (Reflux 24 hours)


EtO

O

N N

O

OEt

(5c, PTAD)

(5ad, DEAD)R2

N N

R1 N

N OO

R2

NN N

O

O

EtO

O

N

NN

R1

OOEt



EtO

O

N N

O

OEt

(5c, PTAD)

R2

R3

R3

R2

(1)

(2)

(3)

(4)

Scheme 5.3 Synthesis of oxygen and nitrogen derived diazacyclobutenes and 2-imidoimidates

5av

5ax

5ay

5az

5aac

5aad

(5ad, DEAD)

5aaa

279

open-chain azodicarboxylates, to afford oxygen-containing diazacyclobutenes and 2-

imidimidates (Figure 5.3, eq. 1, 5ax, eq. 2, 5ay).384-387 Similarly, nitrogen-containing

alkynes, called ynamides (5aab), can be synthesized from commercially available, cheap,

vinyl dichlorides (5aaa).388, 389 These are relatively unexplored chemical scaffolds, and

thus have the potential to be useful in many areas of science, including medicinal and

synthetic chemistry.

280

5.4 REFERENCES

367. Narangoda, C. J.; Lex, T. R.; Moore, M. A.; McMillen, C. D.; Kitaygorodskiy,A.; Jackson, J. E.; Whitehead, D. C., Accessing the Rare Diazacyclobutene Motif. Org.Lett. 2018, 20, 8009-8013.368. Narangoda, C. J.; Kakeshpour, T.; Lex, T. R.; Redden, B. K.; Moore, M. A.;Frank, E. M.; McMillen, C. D.; Wiskur, S. L.; Kitaygorodskiy, A.; Jackson, J. E.;Whitehead, D. C., A cycloaddition/electrocyclic ring opening sequence between alkynylsulfides and azodicarboxylates to provide N,N-dicarbamoyl 2-iminothioimidates. (Justaccepted DOI:10.1021/acs.joc.9b01515) 2019.369. Nishiwaki, N., Methods and applications of cycloaddition reactions in organicsyntheses. John Wiley & Sons: Hoboken, New Jersey, 2014; p xii, 659 pages.370. Quadrelli, P., Modern applications of cycloaddition chemistry. Elsevier,:Amsterdam, 2019; p 1 online resource.371. Hassner, A., Small ring heterocycles. Wiley: New York ; Chichester, 1983.372. Vol'pin, M. E., Non-benzenoid aromatic compounds and the concept ofaromaticity. Russ. Chem. Rev. 1960, 29, 129-160.373. Warrener, R. N.; Nunn, E. E.; Paddon-Row, M. N., Aust. J. Chem. 1979, 32,2659-2674.374. Budzelaar, P. H. M.; Cremer, D.; Wallasch, M.; Würthwein, E.-U.; Schleyer, P.;R., v., DIOXETENES AND DIAZETINES - NONAROMATIC 6-PI-SYSTEMS IN 4-MEMBERED RINGS. J.Am. Chem. Soc. 1987, 109, 6290-6299.375. Mo, O.; Ya ́ ń ̃ez, M.; Elguero, J., J. Mol. Struct.: THEOCHEM 1989, 201, 17-37.376. Bachrach, S. M.; Liu, M., J. Org. Chem. 1992, 57, 2040-2047.377. Breton, G. W.; Martin, K. L., Are 1,2-dihydrodiazetes aromatic? An experimentaland computational investigation. J. Org. Chem. 2002, 67, 6699-6704.378. Effenberger, F.; Maier, R., CYCLOADDITION OF AZOSULFONES ANDSULFONYLIMINES. Angew. Chem., Int. Ed. Engl. 1966, 5, 416-417.379. Nunn, E. E.; Warrener, R. N., J. Chem. Soc., Chem. Commun. 1972, 818-819.380. Cheng, C.-C.; Greene, F. D.; Blount, J. F., REACTION OFTRIAZOLINEDIONES WITH ACETYLENES - ELECTROPHILIC ADDITION. J.Org. Chem. 1984, 49, 2917-2922.381. Breton, G. W.; Shugart, J. H.; Hughey, C. A.; Perala, S. M.; Hicks, A. D.,Synthesis of Delta(1)-1,2-diazetines via a Diels-Alder cycloaddition approach. Org. Lett.2001, 3, 3185-3187.382. Alcaide, B.; Almendros, P.; Aparicio, B.; Lazaro-Milla, C.; Luna, A.; Faza, O. N.,Gold-Photoredox-Cocatalyzed Tandem Oxycyclization/Coupling Sequence of Allenolsand Diazonium Salts with Visible Light Mediation. Adv. Synth. Catal. 2017, 359, 2789-2800.383. Lang, H.; Keller, H.; Imhof, W.; Martin, S., SYNTHESIS ANDCOORDINATION ABILITY OF SELENOALKYNES R-SE-CC-R'. Chem. Ber. 1990,123, 417-422.

281

384. Jouvin, K.; Bayle, A.; Legrand, F.; Evano, G., Copper-Catalyzed Coupling of 1,1-Dibromo-1-alkenes with Phenols: A General, Modular, and Efficient Synthesis of YnolEthers, Bromo Enol Ethers, and Ketene Acetals. Org. Lett. 2012, 14, 1652-1655.385. Rao, M. L. N.; Dasgupta, P., A concise route to functionalized benzofuransdirectly from gem-dibromoalkenes and phenols. RSC Adv. 2015, 5, 65462-65470.386. Rao, M. L. N.; Jadhav, D. N.; Dasgupta, P., Pd-Catalyzed Domino Synthesis ofInternal Alkynes Using Triarylbismuths as Multicoupling Organometallic Nucleophiles.Org. Lett. 2010, 12, 2048-2051.387. Cao, W.; Chen, P.; Wang, L.; Wen, H.; Liu, Y.; Wang, W. S.; Tang, Y., A HighlyRegio- and Stereoselective Syntheses of alpha-Halo Enamides, Vinyl Thioethers, andVinyl Ethers with Aqueous Hydrogen Halide in Two-Phase Systems. Org. Lett. 2018, 20,4507-4511.388. Alcaide, B.; Almendros, P.; Lazaro-Milla, C., Regioselective Synthesis ofHeteroatom-Functionalized Cyclobutene-triflones and Cyclobutenones. Adv. Synth.Catal. 2017, 359, 2630-2639.389. Tu, Y. L.; Zeng, X. Z.; Wang, H.; Zhao, J. F., A Robust One-Step Approach toYnamides. Org. Lett. 2018, 20, 280-283.

282

5.5 EXPERIMENTAL

General Information:

All reagents were purchased from commercial sources and used without

purification. THF and acetonitrile were dried prior to use over sodium/benzophenone and

phosphorous pentoxide, respectively. 1H and 13C NMR spectra were collected on Bruker

Avance 300 MHz, 500 MHz and JOEL Eclipse 500 MHz NMR spectrometers using

CDCl3. Chemical shifts are reported in parts per million (ppm). Spectra are referenced to

residual solvent peaks. Infrared spectroscopy data were collected using a Shimadzu

IRAffinity-1S instrument (with MIRacle 10 single reflection ATR accessory) operating

over the range of 400 to 4000 cm-1 . Flash silica gel (40-63 µm) was used for column

chromatography. All known compounds were characterized by 1H and 13C NMR and are

in complete agreement with samples reported elsewhere. All new compounds were

characterized by 1H and 13C NMR, ATR-FTIR, HRMS, XRD, and melting point (where

appropriate). TGA analysis was performed using TGA instrument SDT Q600 V20.9

Build 20 over the range of 200 – 800 ˚C, with a ramp rate of 20 ˚C/min under a flow of

nitrogen (100 mL/min).

5b

283

Condition A:

In a flame dried 2-neck round bottom flask was added a stir bar and a solution of

the terminal alkyne (1 equiv) in THF (5 mL for 1 mmol of alkyne) under argon

atmosphere. A septum was placed over the round bottom inlets and the solution was

cooled to -78 ˚C. A solution of n-BuLi (1.1 equiv., 1.6 M in hexane) was added. The

reaction solution was stirred for 30 min, and 1 equiv. of finely ground sulfur powder was

added by briefly removing one of the septa and then replacing it. The resulting mixture

was stirred for 1 hour at -78 ˚C. The resulting mixture was allowed to gradually warm to

0 ˚C until the sulfur was completely consumed, thus producing the lithium alkynyl

thiolate (red color). The corresponding alkyl halide (5.0 mmol, 1 equiv.) was then added

in a dropwise fashion. After 4 h the reaction mixture was quenched with saturated

aqueous NH4Cl (5 mL for 1 mmol of alkyne). The reaction mixture was then poured into

a separatory funnel, and the aqueous layer was extracted with diethyl ether (3 x 5 mL for

1 mmol of alkyne). The combined ether extracts were washed with saturated aqueous

brine (5 mL for 1 mmol of alkyne). The organic layer was then dried over Na2SO4,

decanted, and the solvent was evaporated by rotary evaporation. The crude residue was

then purified by flash chromatography (silica gel, hexane) to afford the desired alkynyl

sulfide.

Condition B:

To a flame dried round bottom flask, equipped with a magnetic stir bar and a

septum, was added a solution of the terminal alkyne (1 equiv.) dissolved in THF (1 mL

284

for 1 mmol of alkyne). The solution was then cooled to -78 ˚C and n-BuLi (1.1 equiv.,

1.6 M in hexane) was added dropwise. This solution was stirred for 10 min after which

dimethyl disulfide (1.2 equiv.) was added at -78 ˚C. The solution was then allowed to

warm to room temperature and stirred for 1 h. The reaction mixture was quenched with

saturated aqueous NH4Cl (5 mL for 1 mmol of alkyne) and extracted with ethyl acetate (3

x 5 mL for 1 mmol of alkyne). The combined organic layers were dried over Na2SO4,

decanted, and concentrated by rotary evaporation. The crude mixture was purified by

flash chromatography (silica gel, hexanes) to yield the desired alkynyl sulfide.

General procedure for the synthesis of diazacyclobutenes:

To a flame dried round bottom flask equipped with a stir bar was added a solution

of 4-phenyl1,2,4-triazoline-3,5-dione (PTAD) (1 equiv.) in dry acetonitrile (5 mL for 1

mmol of PTAD). To this stirring solution was added dropwise a solution of alkynyl

sulfide or alkynyl selenide (1.3 equiv.) in dry acetonitrile (5 mL for 1.3 mmol of alkynyl

substrate). Then the round bottom flask was attached to a water-cooled condenser and the

mixture was refluxed for 24 hours. The resultant mixture was concentrated under reduced

pressure and purified via flash chromatography with hexane and ethyl acetate (gradient

from 100% hexane to 80:20 hexane/ethyl acetate) to afford the corresponding

diazacyclobutene.

285

Characterization of alkynyl sulfides and selenides:

286

287

288

289

Characterization of diazacyclobutenes:

5i

5j

5k

290

5l

5m

5n

291

5l

5m

5n

5o

5p

5q

292

5r

5s

293

5t

5u

294

5v

5w

5x

295

5y

5z

296

1H NMR spectra and 13C NMR spectra for Alkynyl sulfides and selenides

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

General Procedure for the synthesis of N,N-dicarbamoyl 2-iminothioimidates

To a flame-dried round bottom flask equipped with a water-cooled condenser and a

stir bar was added a solution of azodicarboxylate (1 mmol,1 equiv.) and 5 mL of dry

acetonitrile under nitrogen. To this stirring solution was added dropwise a solution of

alkynyl sulfide (1.3mmol, 1.3 equiv.) in 5 mL of dry acetonitrile. The mixture was then

refluxed for 24 hours. The resultant mixture was concentrated under reduced pressure

and purified via flash chromatography with hexanes and ethyl acetate (100% hexanes to

80:20 hexanes/ethyl acetate) to afford the corresponding α-imidothioimidate product.

Characterization data for N,N-dicarbamoyl 2-iminothioimidates

5ae Colorless liquid; Yield: 74% (239 mg); IR (neat): 2981 (w), 2931 (w), 1716 (s), 1627 (m), 1577 (m), 1446 (m), 1365 (m), 1207 (s), 1091 (m), 1033 (m), 864 (w), 690 (m) cm-

1;1H-NMR (300 MHz, CDCl3) δ = 7.83 (d, J = 6.6 Hz, 2H), 7.52 (t, J = 7.4 Hz, 1H), 7.42 (t, J = 7.3 Hz, 2H), 4.27 (q, J = 7.1 Hz, 2H), 4.08 (q, J = 6.8 Hz, 2H), 2.47 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H), 1.15 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ = 175.6, 166.2, 160.8, 159.2, 133.0, 132.4, 128.7, 128.7, 63.0 (2C), 14.3, 14.1, 14.0; HRMS (ESI+): Calcd for C15H19N2O4S, [M+H]+323.1066 Found m/z 323.1087.

333

5af Colorless liquid; Yield: 99% (334 mg); ; IR (neat): 2981 (w), 2931 (w), 2870 (w), 1716 (s), 1627 (m), 1577 (m), 1446 (m), 1365 (m), 1207 (s), 1091 (m), 1033 (m), 864 (m), 690 (m) cm-1;1H-NMR (300 MHz, CDCl3) δ = 7.76 (d, J = 6.5 Hz, 2H), 7.44 (t, J = 7.3 Hz, 1H), 7.34 (t, J = 7.4 Hz, 2H), 4.19 (q, J = 7.1 Hz, 2H), 3.99 (q, J = 6.9 Hz, 2H), 3.02 (q, J = 7.3 Hz, 2H), 1.23 (t, J = 7.3 Hz, 6H), 1.05 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ = 174.6, 166.0, 160.4, 158.8, 132.7, 132.1, 128.5, 128.4, 62.6 (2C), 25.6, 13.8, 13.5, 12.9; HRMS (ESI+): Calcd for C16H21N2O4S, [M+H]+ 337.1222 Found m/z 337.1242. 5ag Colorless liquid; Yield: 73% (256 mg); IR (neat): 2970 (w), 2931 (w), 1716 (s), 1627 (m), 1577(m), 1446 (w), 1365 (m), 1284 (w), 1207 (s), 1091 (m), 1033 (m), 864 (w), 729 (m), 690 (m)cm-1;1H-NMR (300 MHz, CDCl3) δ = 7.82 (d, J = 7.1 Hz, 2H), 7.52 (t, J = 7.3 Hz, 1H), 7.42 (t, J = 7.3 Hz, 2H), 4.27 (q, J = 7.1 Hz, 2H), 4.06 (q, J = 7.1 Hz, 2H), 3.07 (q, J = 7.2 Hz, 2H), 1.69 (sextet, J = 7.3 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H), 1.13 (t, J = 7.1 Hz, 3H), 0.98 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ = 175.0, 166.5, 160.7, 159.1, 132.9, 132.5, 128.8, 128.6, 62.9 (2C), 33.3, 21.5, 14.1, 13.8, 13.2;HRMS (ESI+): Calcd for C17H23N2O4S, [M+H]+ 351.1379 Found m/z 351.1398. 5ah Colorless liquid; Yield: 83% (303 mg); IR (neat) : 2958 (w), 2931 (w), 2870 (w), 1716 (s), 1627 (m), 1577 (m), 1446 (m), 1365 (m), 1207 (s), 1091 (m), 1033 (m), 864 (w), 783

334

(m), 729 (m), 690 (m) cm-1;1H-NMR (300 MHz, CDCl3) δ = 7.79 (d, J = 7.2 Hz, 2H), 7.48 (t, J = 7.3 Hz, 1H), 7.38 (t, J = 7.5 Hz, 2H), 4.24 (q, J = 7.1 Hz, 2H), 4.03 (q, J = 7.1 Hz, 2H), 3.06 (t, J = 7.3 Hz, 2H), 1.60 (p, J = 7.3 Hz, 2H), 1.5-1.2 (m, 5H), 1.10 (t, J = 7.1 Hz, 3H), 0.86 (t, J = 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ = 174.7, 166.3, 160.6, 159.0, 132.8, 132.5, 128.7, 128.5, 62.8 (2C), 31.1, 29.9, 21.7, 14.0, 13.7, 13.2; HRMS (ESI+): Calcd for C18H25N2O4S, [M+H]+ 365.1535 Found m/z 365.1556. 5ai Colorless liquid; Yield: 80% (303 mg); IR (neat): 2954 (w), 2931 (w), 2858 (w), 1720 (s), 1627 (m), 1577 (m), 1446 (m), 1365 (m), 1280 (w), 1207 (s), 1091 (m), 1033 (m), 783 (m), 729 (m), 690 (m) cm-1;1H-NMR (300 MHz, CDCl3) δ = 7.76 (d, J = 6.54 Hz, 2H), 7.44 (t, J = 7.3 Hz, 1H), 7.34 (t, J = 7.5 Hz, 2H), 4.20 (q, J = 7.1 Hz, 2H), 4.00 (q, J = 6.90 Hz, 2H), 3.02 (t, J = 7.2 Hz, 2H), 1.58 (p, J = 7.0 Hz, 2H), 1.4-1.15(m, 7H), 1.05 (t, J = 7.1 Hz, 3H), 0.79 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ = 174.6, 166.1, 160.4, 158.8, 132.7, 132.2, 128.5, 128.3, 62.6 (2C), 31.1, 30.4, 27.4, 21.7, 13.8, 13.5, 13.4; HRMS (ESI+): Calcd for C19H27N2O4S, [M+H]+ 379.1692 Found m/z 379.1710. 5aj Light yellow liquid; Yield: 73% (307 mg); IR (neat): 2924 (m), 2854 (w), 1720 (s), 1627 (m), 1577 (m), 1446 (m), 1365 (m), 1207 (s), 1091 (m), 1033 (m), 910 (m), 783 (m), 729 (m), 688 (m) cm-1;1H-NMR (300 MHz, CDCl3) δ = 7.77 (d, J = 6.63 Hz, 2H), 7.45 (t, J = 7.3 Hz, 1H), 7.36 (t, J = 7.4 Hz, 2H), 4.21 (q, J = 7.1 Hz, 2H), 4.00 (q, J = 7.0 Hz, 2H), 3.03 (t, J = 7.2 Hz, 2H), 1.59 (p, J = 7.1 Hz, 2H), 1.4-1.12 (m, 13H), 1.07 (t, J = 7.1 Hz, 3H), 0.79 (t, J = 6.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ = 175.0, 166.4, 160.7, 159.1, 132.9, 132.5, 128.8, 128.6,62.9, 62.8, 31.6, 31.5, 28.9, 28.8, 28.6, 27.9, 22.4, 14.1, 13.9, 13.8; HRMS (ESI+): Calcd for C22H33N2O4S, [M+H]+ 421.2161 Found m/z 421.2161.

335

5ak Light yellow solid; Yield: 77% (296 mg); Mp: 70-71˚C;IR (neat) : 2981 (w), 1724 (s), 1712 (s), 1631 (m), 1612 (m), 1577 (w), 1477 (m), 1442 (m), 1207 (s), 1095 (w), 1022 (m), 968 (m), 860 (w), 752 (s), 686 (s) cm-1; 1H-NMR (300 MHz, CDCl3) δ = 7.54 (d, J = 7.4 Hz, 2H), 7.50-7.20 (m, 6H), 7.15 (t, J = 7.5 Hz, 2H), 4.38 (q, J = 7.1 Hz, 2H), 4.28 (broad q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ = 173.9, 165.5, 161.3, 159.6, 135.8, 133.2, 132.5, 130.3, 129.0, 128.4, 128.2, 126.1, 63.23, 63.16, 14.2, 14.1; HRMS (ESI+): Calcd for C20H21N2O4S, [M+H]+ 385.1222 Found m/z 385.1240. 5al Colorless liquid; Yield: 83% (330 mg); IR (neat):2978 (w), 1716 (s), 1627 (w), 1577 (m), 1492 (w), 1450 (w), 1207 (s), 1087 (m), 1026 (m), 910 (w), 729 (w), 690 (w) cm-1; 1H-NMR (300 MHz, CDCl3) δ = 7.81 (d, J = 6.2 Hz, 2H), 7.51 (t, J = 7.0 Hz, 1H), 7.40 (t, J = 7.7 Hz, 2H), 7.35-7.16 (m, 5H), 4.34 (s, 2H), 4.23 (q, J = 7.1 Hz, 2H), 4.10 (q, J = 7.1 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H), 1.15 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ = 174.2, 165.9, 160.6, 158.9, 134.6, 132.9, 132.3, 130.4, 129.1, 128.7, 128.5, 127.7, 62.88, 62.86,35.8, 14.0, 13.7; HRMS (ESI+): Calcd for C21H23N2O4S, [M+H]+ 399.1379 Found m/z 399.1391.

336

5am Colorless liquid; Yield: 88% (296 mg); IR (neat):2978 (w), 2927 (w), 1716 (s), 1627 (m), 1600 (m), 1462 (w), 1446 (w), 1411 (w), 1388 (w), 1365 (m), 1292 (m), 1207 (s), 1180 (m), 1091 (s), 1033 (s), 914 (m), 821 (w), 775 (w), 729 (s) cm-1; 1H-NMR (300 MHz, CDCl3) δ = 7.71 (d, J = 7.26 Hz, 2H), 7.21 (d, J = 7.9 Hz, 2H), 4.24 (q, J = 7.1 Hz, 2H), 4.07 (q, J = 6.74 Hz, 2H), 2.44 (s, 3H), 2.35 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H), 1.14 (t, J = 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ = 175.7, 166.0, 160.8, 159.1, 144.0, 129.6, 129.3, 128.7, 62.79, 62.77, 21.5, 14.2, 14.0, 13.7; HRMS (ESI+): Calcd for C16H21N2O4S, [M+H]+ 337.1222 Found m/z 337.1241.

5an Colorless liquid; Yield: 95% (335 mg); IR (neat): 2978 (w), 2931 (w), 2839 (w), 1716 (s), 1593 (s), 1570 (w), 1508 (m), 1462 (w), 1442 (w), 1207 (s), 1168 (s), 1091 (m), 1026 (s), 910 (m), 840 (m), 729 (s)cm-1; 1H-NMR (300 MHz, CDCl3) δ = 7.77 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.9 Hz, 2H), 4.22 (q, J = 7.1 Hz, 2H), 4.06 (q, J = 7.0 Hz, 2H), 3.79 (s, 3H), 2.42 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H), 1.13 (t, J = 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ = 175.6, 165.3, 163.6, 160.9, 159.1, 130.9, 124.7, 114.0, 62.8, 62.7, 55.3, 14.1, 14.0, 13.7; HRMS (ESI+): Calcd for C16H21N2O5S, [M+H]+353.1171 Found m/z 353.1185.

337

5ao Colorless liquid; Yield: 47% (168 mg); IR (neat): 2978 (w), 2927 (w), 1716 (s), 1627 (m), 1589 (m), 1400 (w), 1365 (w), 1207 (s), 1087 (s), 1029 (s), 864 (w), 783 (w), 725 (m) cm-1;1H-NMR (300 MHz, CDCl3) δ = 7.77 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.6 Hz, 2H), 4.26 (q, J = 7.1 Hz, 2H), 4.10 (q, J = 7.1 Hz, 2H), 2.47 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ = 175.4, 165.4, 160.6, 159.0, 139.5, 130.9, 130.0, 129.0, 63.1(2C), 14.3, 14.1, 13.8; HRMS (ESI+): Calcd for C15H18ClN2O4S, [M+H]+ 357.0676 Found m/z 357.0686.

5ap Colorless liquid; Yield: 69% (270 mg); IR (neat): 2981 (w), 1724 (s), 1631 (w), 1577 (w), 1411 (w), 1323 (s), 1211 (s), 1168 (m), 1126 (m), 1064 (s), 1033 (w), 1014 (w), 848 (m), 771 (w), 748 (w)cm-1; 1H-NMR (300 MHz, CDCl3) δ = 7.95 (d, J = 7.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 4.27 (q, J = 7.1 Hz, 2H), 4.09 (q, J = 6.9 Hz, 2H), 2.49 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ = 175.5, 165.5, 160.4, 159.1, 135.8, 134.3 (q, 2JCF = 32.8 Hz), 129.1, 125.7 (q, 3JCF = 3.7 Hz), 123.5 (q, 1JCF = 272.7 Hz), 63.33, 63.25, 14.3, 14.1, 13.9; HRMS (ESI+): Calcd for C16H18F3N2O4S, [M+H]+ 391.0939 Found m/z 391.0963. 5aq Light yellow liquid; Yield: 40% (121 mg) ; IR (neat): 2958 (w), 2931 (w), 1716 (s), 1662 (w), 1608 (w), 1500 (w), 1465 (w), 1365 (w), 1215 (s), 1095 (w), 1033 (m), 948 (w), 914 (w), 732 (m) cm-1;1H-NMR (300 MHz, CDCl3) δ = 4.4-4.1 (m, 4H), 2.48 (t, J = 7.8 Hz, 2H), 2.41 (s, 3H), 1.56 (p, J = 7.6 Hz, 2H), 1.40-1.23 (m, 8H), 0.86 (t, J = 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ = 171.2, 161.7, 160.6, 159.7, 62.9, 62.8, 27.8, 23.3, 15.1,

338

14.1, 14.0, 13.7, 13.5; HRMS (ESI+): Calcd for C13H22N2O4SNa, [M+Na]+ 325.1198 Found m/z 325.1210.

5ar Light yellow liquid; Yield: 45% (155 mg); IR (neat): 2958 (w), 2931 (w), 2870 (w), 1724 (s), 1662 (w), 1604 (m), 1462 (w), 1365 (w), 1215 (s), 1095 (w), 1037 (m), 948 (w), 914 (w), 779 (w), 732 (w)cm-1;1H-NMR (300 MHz, CDCl3) δ = 4.19 (m, 4H), 2.99 (t, J = 7.3 Hz, 2H), 2.47 (t, J = 7.6 Hz, 2H), 1.7-1.48 (m, 4H), 1.48-1.22 (m, 10H), 1.00-0.80 (m, 6H); 13C NMR (75 MHz, CDCl3) δ = 171.4, 161.0, 160.5, 159.8, 62.8, 62.7, 30.6, 30.0, 29.5, 27.7, 22.3, 21.8, 14.1, 14.0, 13.4, 13.3; HRMS (ESI+): Calcd for C16H29N2O4S, [M+H]+ 345.1848 Found m/z 345.1862.

5as Colorless liquid; Yield: 77% (220 mg); IR (neat): 2981 (w), 2931 (w), 1716 (s), 1651 (m), 1583 (m), 1444 (w), 1382 (w), 1365 (m), 1219 (s), 1193 (s), 1028 (s), 995 (m), 862 (m), 775 (m) 731 (m) cm-1; 1H-NMR (300 MHz, CDCl3) δ = 4.25 (q, J = 7.1 Hz, 2H), 4.21 (q, J = 7.1 Hz, 2H), 2.45 (s, 3H), 2.10–1.70 (m, 1H), 1.33 (t, J = 6.3 Hz, 3H), 1.28 (t, J = 6.3 Hz, 3H) 1.26–1.05 (m, 4H); 13C{1H} NMR (75 MHz, CDCl3) δ = 176.1, 175.0, 160.6, 159.3, 63.0, 62.7, 17.2, 13.9 (3C), 12.4 (2C); HRMS (ESI+ -TOF): Calcd for C12H19N2O4S, [M+H]+ 287.1066 Found m/z 287.1069.

339

5at Light yellow liquid; Yield: 76% (280 mg); IR (neat): 2981 (w), 2935 (w), 1716 (s), 1597 (s), 1573 (w), 1446 (w), 1369 (w), 1330 (w), 1292 (w), 1211 (s), 1095 (w), 1026 (m), 898 (w), 864 (w), 771 (w), 732 (w), 690 (m), 528 (w) cm-1; 1H-NMR (300 MHz, CDCl3) δ = 7.88 (d, J = 7.4 Hz, 2H), 7.60-7.47 (m, 1H), 7.47-7.30 (m, 2H), 4.23 (q, J = 6.9 Hz, 2H), 2.19 (s, 3H), 1.45 (m, 6H); 13C NMR (75 MHz, CDCl3) δ =179.9, 165.0, 160.8, 160.4, 133.1, 132.3, 128.7, 128.5, 63.1, 62.8, 14.0, 13.9, 8.3;HRMS (ESI+): Calcd for C15H19N2O4Se, [M+H]+ 371.0510 Found m/z 371.0528.

5au Light yellow liquid; Yield: 73% (361 mg); IR (neat): 2981 (w), 2931 (w), 1716 (s), 1689 (m), 1627 (m), 1577 (w), 1554 (w), 1494 (m), 1448 (m) 1365 (m), 1207 (s), 1180 (s), 1093 (m), 1024 (s), 970 (w), 904 (m), 732 (m), 694 (s) cm-1; 1H-NMR (300 MHz, CDCl3) δ = 7.96 (d, J = 6.6 Hz, 2H), 7.70-7.00 (m, 8H), 4.32 (q, J = 7.1 Hz, 2H), 4.27– 4.15 (m, 4H), 1.33 (t, J = 7.1 Hz, 3H), 1.30 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ = 179.0, 165.3, 161.0, 160.2, 135.1, 133.1, 132.1, 129.0, 128.7, 128.6, 128.5, 127.3, 63.2, 62.9, 32.3, 14.0, 13.8; HRMS (ESI+ -TOF): Calcd for C21H23N2O4Se, [M+H]+ 447.0824 Found m/z 447.0830.

340

1H NMR spectra and 13C NMR spectra for Alkynyl sulfides and selenides

341

1H NMR and 13C NMR spectra for N,N-dicarbamoyl 2-iminothioimidates

1H-NMR (300 MHz, CDCl3)

13C-NMR (75 MHz, CDCl3)

N

N

O

OEt

PhSCH3

5aeO

OEt

342



N

N

O

OEt

PhSEt

5afO

OEt

343



N

N

O

OEt

PhSnPr

5agO

OEt

344



N

N

O

OEt

PhSnBu

5ah

O

OEt

345

N

N

O

OEt

PhSnC5H11

5ai

O

OEt



346



N

N

O

OEt

PhSnC8H17

5ajO

OEt

347



N

N

O

OEt

PhSPh

5akO

OEt

348



N

N

O

OEt

PhSBn

5alO

OEt

349

N

N

O

OEt

SCH3

5am

O

OEt



350

N

N

O

OEt

SCH3

5an

MeO

O

OEt



351

N

N

O

OEt

SCH3

5ao

Cl

O

OEt



352

N

N

O

OEt

SCH3

5ap

CF3

O

OEt



353

N

N

O

OEt

nBuSCH3

5aq

O

OEt



354

N

N

O

OEt

nBuSnBu

5ar

O

OEt



355

N

N

O

OEt

S

5as

CH3

O

OEt



356

N

N

O

OEt

PhSe

5at

CH3

O

OEt



357

N

N

O

OEt

PhSe

5au

Bn

O

OEt



Documents

Developing Iodoarene Derivatives for Useful Oxidative