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Multicomponent Reactions: Development, Scope,

and Applications

Ajay Chandgude


The research presented in this PhD thesis was performed in the group of Drug Design within the

Groningen Research Institute of Pharmacy at the University of Groningen, The Netherlands.

The author thanks the financial support from the Erasmus Mundus Svaagata.eu Programme of the

European Union and the University of Groningen.

Printing of this thesis was financially supported by the University Library and the Graduate School

of Science, Faculty of Mathematics and Natural Sciences, University of Groningen, The Netherlands.

Cover picture: ‘Cooking‘ Painting by Saurabh Dingare

Design en lay-out: Legatron Electronic Publishing

Printing: Ipskamp Printing, Enschede

ISBN: 978-90-367-9931-7

©Copyright 2017, Ajay Chandgude. All rights reserved. No part of this thesis may be reproduced in

any form or by any means without prior permission of the author


Multicomponent Reactions: Development, Scope,

and Applications

PhD thesis

to obtain the degree of PhD at the

University of Groningen

on the authority of the

Rector Magnificus Prof. E. Sterken

and in accordance with

the decision by the College of Deans.

This thesis will be defended in public on

Monday 19 June 2017 at 11.00 hours

by

Ajay Chandgude

born on 16 November 1988in Dandavadi, India


SupervisorsProf. A.S.S. Dömling

Prof. W.J. Quax

Assessment CommitteeProf. P.H. Elsinga

Prof. C. Hulme

Prof. L. El Kaim


Table of Contents

Chapter 1 Introduction and Scope of the Thesis 7

Chapter 2 The Passerini Reaction: Scope, Chirality, and Applications 29

Chapter 3 An Efficient Passerini Tetrazole Reaction (PT-3CR) 61

Chapter 4 Unconventional Passerini Reactiontowards α-Aminoxy-amides 77

Chapter 5 N-Hydroxyimide Ugi Reaction toward α-Hydrazino-amides 93

Chapter 6 Convergent Three-Component Tetrazole Synthesis 111

Chapter 7 Highly Diastereoselective One Pot Five-Component Reaction toward 133

4-(Tetrazole)-1,3-Oxazinane

Chapter 8 Direct Amination of α-Hydroxy Amides 145

Chapter 9 2-Nitrobenzyl Isocyanide as a Universal Convertible Isocyanide 159

Summary 179

Samenvatting 181

Acknowledgements 185



Chapter 1Introduction and Scope of the Thesis

Part of this thesis was published in:

T. Zarganes - TzitzikasA. L. Chandgude

A. DömlingChem. Record, 2015, 15, 981-996.


Chapter 1

8

Abstract

Multicomponent reactions (MCRs), which are located between 1- and 2-component and

polymerization reactions, provide a number of valuable conceptual and synthetic advantages

over stepwise sequential approaches towards complex and valuable molecules. To address current

limitations in number of MCR and resulting scaffolds the concept of union of MCRs was introduced

two decades ago by Dömling and Ugi and is rapidly advancing apparent by several recently

published work. MCR technology is now widely recognized for its impact on drug discovery projects

and is strongly endorsed by industry in addition to academia. Clearly, novel scaffolds accessible in

few steps including MCR will further enhance the field of applications. Additionally, broad expansion

of MCR applications in fields such as imaging, material science, medical devices, agriculture, or

futuristic applications in stem cell therapy and theragnostics or solar energy and superconductivity

are predicted.


Introduction and Scope of the Thesis

9

1

1. Multicomponent reactions

Reactions in organic chemistry can be classified according to the number of participating starting

materials. There are one-component reactions, two-component reactions, multi-component

reactions (MCR) and polymerizations (Figure 1). An example of a one-component reaction is the

classical Claisen rearrangement.[1] One-component reactions involve one starting material and

if necessary a catalyst and yield one or two products. In a two-component reaction two starting

materials are combined into one product.[2] Reactions involving three and more starting materials are

known as MCRs. Prototypical examples are the Mannich reaction and the Ugi reaction.[3] According

to a generally accepted definition “MCRs are reactions with three and more starting materials where

the majority of the atoms of the starting materials are incorporated into the product”.[4] An important

subgroup of MCRs are so called unions of MCRs where a MCR is combined with a secondary reaction

e.g. MCR in the same flask, even enhancing the diversity and potential usefulness of the reactions.[5]

MCRs bridge one- and two-component reactions with polymerizations, where one or several starting

materials combine repetitively to form a polymer of varying length. The majority of organic textbook

chemistry consist of one- and two-component reactions and polymerizations. Surprisingly, the

wealth of MCRs is not adequately represented in modern teaching of organic chemistry despite the

many contemporary and important applications in chemistry. This small review gives a personalized

glimpse of modern MCR with a focus on higher MCRs and some intriguing recent applications

underscoring the immense potential of navigating the MCR space.[6]

Figure 1. Schematic presentation of different reactions based on number of starting materials.


Chapter 1

10

1.1 Classes of MCRs Many of the classical MCRs are named reactions and all have proven their wide applicability in

chemistry with multiple commercial products on the market (Table 1).

TaniaPhos® for example is a commercial application of the Mannich-3CR reaction. It is a chiral

ligand for a catalyst used in the asymmetric hydrogenations and can be synthesized from the (R)-

Ugi amine in two steps.[7] The (R)-Ugi amine can be synthesized via a Mannich reaction between

ferrocene, dimethyl amine and acetaldehyde (Table 1, entry 1).[8]

α,α-Disubstituted amino acids have attracted increasing attention as unnatural amino acid

analogues due to their applications in peptide-mimetics and in the de novo design of proteins. The

Strecker-3CR was used for the synthesis of ((S)-N-ethoxycarbonyl-α-methylvaline) where 3-methyl-2-

butanone and NaCN were treated with NH4Cl in the presence of MgSO

4 in NH

3/MeOH at 30°C. Further

steps involve the formation of the tartrate salt and the preparation of (S)-2-ethoxycarbonylamino-

2,3-dimethylbutyric acid dicyclohexylamine salt (Table 1, entry 2).[9]

The Passerini reaction affords the fungicidal compound mandipropamid in just 2 steps. The first

step involves the Passerini reaction of an in situ synthesized isocyanide, an aldehyde and a carboxylic

acid to form the α-acyloxycarboxamide. The second step involves the alkylation with propargyl

bromide to yield Micora (Mandipropamid®) (Table 1, entry 3).[10]

Lidocaine (Xylocain®) is a very popular local anesthetic. Its synthesis can be accomplished by

the Ugi-3CR of formaldehyde, diethyl amine and 2,6-dimethyl-phenylisocyanide. This synthesis

comprises an early application of IMCR in production of commercial drugs (Table 1, entry 4).[11]

Prostaglandins have antioxidant and ionophoric activities. The Pauson-Khand 3CR is used as the

key step for the regio- and stereoselective synthesis of prostaglandin B1. The Pauson-Khand reaction

involved a silyl- protected propargyl acetylene, ethylene and octacarbonyl dicobalt as a carbon

monoxide source to afford the 3-tert-butyldimethylsilyloxymethyl-2-substituted-cyclopent-2-en-1-

one at room temperature in good yield (Table 1, entry 5).[12]

p38 MAP kinase is involved in the inflammatory pathway and inhibitors of the p38 MAP kinase

are widely investigated as potential drugs. 1,4,5-trisubstituted imidazoles were synthesized as p38

MAP kinase inhibitors using the van Leussen-3CR of an α-substituted tosylmethyl isocyanide, a

primary amine and and aldehdye in the presence of a base. The reaction has been described on a

500 kg batch scale to provide enough material for phase III clinical trials (Table 1, entry 6).[13]

The Gewald-3CR generally affords bioisosteres of anthranilic acids. 2-Amino-3-carbonyl

thiophene is the starting material for the synthesis of several drugs e.g. Olanzapine (Zyprexa®),

an atypical antipsychotic drug. This thiophene-phenol bioisostere can be easily prepared by the

Gewald-3CR using cyanoacetamides, a-methylene active aldehydes or ketones, and sulfur (Table 1,

entry 7).[14]

The Hantzsch-3CR was used for the synthesis of the calcium channel blocker Nifedipine

(Procardia®). Synthesis of the dihydropyridine derivative involves condensation of a 2-nitro

benzaldehyde with 2 equivalents of methyl acetoacetate and ammonia (Table 1, entry 8).[15]



11

1

Ezetimibe (Zetia®) is a lipid-lowering compound which selectively inhibits the intestinal absorption

of cholesterol. It is synthesised by using the Staudinger-3CR as a key reaction. The imine formed from

p-fluoroaniline and benzyloxybenzaldehyde was treated with methyl 5-chloro-5-oxopentanoate

in the presence of tributylamine and toluene to form the β-lactam ring. This reaction involves the

formation of an intermediate ketene which undergoes a [2+2] cycloaddition reaction with the imine

to form regioselectively the β-lactam ring giving the trans isomer as the major product (Table 1,

entry 9).[16]

Table 1

Name Reaction Reaction Product

1 Mannich 3CR[3a,7]R1

HN

R2 R3

O

R4NR2

R1

R3 R4+ +

R6

OR5

R5

R6

O

FeNMe

2PPh2

TaniaPhos®

Ph2PH

2 Strecker 3CR[9]O

R2R1R3 NH2

+ HCNR2R1

NC NHR3+ N

HCN

O

EtO

((S)-N-Ethoxycarbonyl-a-methylvaline)

3 Passerini 3CR[10]R1 R2

O

R3 OH

OR4 NC R3 O

O R1 R2

O

HN

R4++ O

O

HN

O

O

Cl

Micora

(Mandipropamid®)

4 Ugi 3CR[11]R3

HN

R4+

R1 R2

O+ R5 NC R3 N

R4

NH

OR5

R1 R2

NNH

O

Lidocaine

(Xylocain®)

5Pauson-Khand

3CR[12]

O

R1

Pauson-KhandReaction

R1

H

CO+R2

R2+

O

OH

COOMen

m

PPB1-I n =

7, m = 1

PGB1 n =

6, m = 4

Prostaglandin B1

6 Van Leusen 3CR[13]NNR2

R3R2 NH2

R1

O

H R3 NC

Ts

R1

++

N

N

N

N

F

H2N

NH

P38 MAP

Kinase

Inhibitor


Chapter 1

12

Name Reaction Reaction Product

7 Gewald 3CR[14] EWG CNR1 R2

OS

SR1NH2

R2EWG

+ +N

NH

N

S

N

Olanzapine

(Zyprexa®)

8 Hantzsch 3CR[15]R1

O ONH2

N

R1

++2O

HR2

R2

O O

Nifedipine

(Procardia®)

NH

MeOOC COOMeNO2

9 Staudinger 3CR[16]N

O

R2R1 H

OR2 NH2 Cl

O

R3

R3

R1

++N

O

OBn

F

OH

F

Ezetimibe

(Zetia®)

2. Multicomponent Reaction and Subsequent Transformations

Many MCRs have been described in the past one and a half century and recently many fundamental

advances in finding new MCRs have been made. A strategy to enhance the size and diversity of

current MCR chemical space is the concept of combining a MCR and a subsequent secondary

reaction, examples involve postcondensations or the Ugi-deprotection-cyclization (UDC) strategy.[17] Herein, bifunctional orthogonally protected starting materials are used and cyclizations can

take place in a secondary step upon deprotection of the orthogonal functional groups. Many

different scaffolds have been recently described using this strategy. A recent example of such a

postcondensation strategy is shown in Scheme 1. It is based on a recently discovered variation of the

Ugi reaction of α-amino acids (1), oxo components (2), and isocyanides (3), now including primary

and secondary amines (4) and can afford highly substituted isoindolones (5), pyrolidindiones (6),

di (7), tri (8), and tetra (9)-cyclic scaffolds reminding to alkaloids, quinocarcin and notoamide B. The

MCR is stereoselective as the chiral a-amino acid can be used under stereoretention (Scheme 1).[18]



13

1

Scheme 1. Postcondensation examples involving an Ugi 5C-4CR reaction.

3. Union of Multicomponent Reactions

The term “union of MCR“ was coined by Dömling and Ugi in the publication “The seven component

reaction” performing the one-pot combination of a modified Asinger-4CR[19] and the Ugi-4CR

(Scheme 2).[20]

Scheme 2. “The seven component reaction” (Asinger-Ugi-7CR).

The union of MCRs is a strategy for the rational design of novel MCRs combining two (or more)

different types of MCRs in a one-pot process. The presence of orthogonal reactive groups in the

product of the primary MCR, which is either formed during the primary MCR or present in one of

the inputs, allows the union with the secondary MCR.[21] The union of MCRs is an intriguing concept

to increase even more the complexity and efficiency and provide new scaffold types. Several new

examples have been elaborated recently.


Chapter 1

14

Besides various 5- and 6-CRs, the first example of an eight component reaction, currently the highest

number of different compounds used in a one-pot procedure, was published by the Orru group

in 2009.[22] This 8-CR unifies three different MCRs, with nine new bonds formed, creating highly

complex and structurally versatile drug-like compounds with eleven points of diversity (Scheme 3).

In the first of the three MCRs imidazoline intermediate (19) was formed through a three

component reaction utilizing the sodium salt of glycine (18), which provided the carboxylic acid

handle for the latter Ugi-4CR.[23] The N-(cyanomethyl)amide-intermediate (23) was accessed via a

second three component reaction.[24] Here the authors made use of the difference in reactivity of

the two isocyanides in 2,5-diisocyanopentanamide (20) to produce compound (23) in good yield,

carrying an isocyanide handle for the subsequent MCR. Multicomponent products (19) and (23)

could be formed either in separate reaction vessels (sequential manner) or in a single reaction vessel.

In the case of a one-pot procedure, first the formation of (19) was established, whereafter the second

set of starting materials was added to give intermediate (23). Finally, the reaction mixture was

neutralised to activate the carboxylic acid, and a final set of reagents (i.e. aldehyde and amine) was

added, generating the final product (24) in an impressive 24% yield (85% yield per bond forming

step).

Scheme 3. Combination of three multicomponent reactions leading to an 8CR.

One of the first MCRs combining more than four different components making use of an orthogonal

functionality was reported by Bienayme in 1998.[25] In a modified Bredereck reaction a secondary

amine morpholine (25), N-formylimidazole diethyl acetal (26) and methyl isocyanoacetate (27) were



15

1

reacted to produce the intermediate isocyanide (28) exclusively as the (z)-stereoisomer (Scheme

4). After the subsequent addition of a carboxylic acid (e.g. benzoic acid) and an aldehyde (e.g.

cyclohexane carboxyaldehyde) a Passerini-3CR takes place, resulting in the formation of product

(29) which is a racemic mixture in a fair yield (30%), accounting for an 80% yield per bond forming

step (five new bonds).

Scheme 4. Combination of a Bredereck - Passerini-3CR.

The combination of a Petasis-3CR[26] and an Ugi-4CR (Pt-U-6CR) was recently described by Portlock

and co-workers (Scheme 5).[27] With six new bonds formed and the introduction of six points of

diversity, dipeptide amides (34) could be obtained as 1 : 1 mixtures of racemic diastereomers with

yields ranging from 80–95% per bond forming step. As shown in Scheme 5 amino acid (33), formed

by the Petasis-3CR, serves as the carboxylic acid component in the following Ugi-4CR. Despite the

readily achievable high structural diversity, a solvent change is required for the second MCR to

proceed, hence limiting the applicability of this approach in the rapid preparation of structurally

diverse, drug-like compound libraries. To overcome this drawback, the same authors showed that

this reaction sequence could be translated to a solid support, thus allowing the exploration of a

larger chemical space, though at the cost of one point of diversity as a result of the linkage to a

resin.[28]

Scheme 5. Combination of Petasis-3CR and Ugi-4CR.

Another interesting example of creating complexity and structural diversity by the combination of

two successive MCRs was published recently by Al-Tel and co-workers.[29] By combining the Groebke-

Bienaymé-Blackburn reaction[30] an acid-mediated isocyanide addition to 2-iminopyridines yielding

fused pyridine-imidazoles (38) with a Passerini-3CR or an Ugi-4CR, a 5- or 6CR was developed,

generating structurally diverse (up to ten points of diversity), highly substituted, drug-like heterocyclic

compounds (39) and (40) respectively in an efficient manner (>90% yield per bond forming step).

The formylbenzoic acids (36) react with 2-aminopyridine (35) and isocyanides (37) selectively on

the aldehyde group and the benzoic acid moiety is left intact. Thus the orthogonal reactivity of the

carboxylic acid in the Groebke-Bienayme-Blackburn reaction was used as a functional handle in the

subsequent MCRs i.e. Ugi or Passerini (Scheme 6).


Chapter 1

16

Scheme 6. Combination of the Groebke-Bienaymé-Blackburn-3CR with Ugi-4CR and Passerini-3CR.

4. Recent MCR Applications

Several interesting recent applications of MCR chemistry going beyond simple combinatorial

applications are discussed in the following.

Large scale pharmacophore based virtual screening of MCR libraries: ANCHOR.QUERYTwo decades ago, MCR chemistry was almost generally neglected in pharmaceutical and agrochemical

industry. The knowledge of these reactions was often low and it was generally believed that MCR

scaffolds are associated with useless drug-like properties e.g absorption, distribution, metabolism,

excretion, and toxicity (ADMET). During the times of combinatorial chemisitry, however, MCR offerd

a major technology to produce in a reliable fashion large compound libraries to fill the screening

decks. Now MCR technology is widely recognized for its impact on drug discovery projects and is

strongly endorsed by industry as well as academia.[31] These examples show that pharmaceutical

and agrochemical compounds with preferred ADMET properties and superior activities can be

engineered based on MCR chemistry. The very high compound numbers per scaffold based on MCR

may be regarded as a friend or foe. On the one hand, it can be fortunate to have a MCR product as a

medicinal chemistry starting point, since a fast and efficient SAR elaboration can be accomplished;

on the other hand, the known chemical space based on MCRs is incredibly large and can neither

be screened nor exhaustively synthesized with reasonable efforts. The currently preferred path to

medicinal chemistry starting points in industry, the high-throughput screening (HTS), however,

is an expensive process with rather low efficiency yielding hits often only in low double-digit or

single-digit percentage. Modern postgenomic targets often yield zero hits. The initial hits are often

ineffective to elaborate due to their complex multistep synthesis. Thus, neither the screening even



17

1

of a very small fraction of the chemical space accessible by the classical Ugi-4CR and other scaffolds,

nor the synthesis is possible.

Recent advances in computational chemical space enumeration and screening, however, allow

for an alternative process to efficiently foster a very large chemical space. The free web-, anchor-,

and pharmacophore-based server AnchorQueryTM (anchorquery.ccbb.pitt.edu/), for example, allows

for the screening of a very large virtual MCR library with over a billion members.[32] Anchor.Query

builds on the role deeply buried amino acid side chains or other anchors play in protein-protein

interactions. Based on the efficient and convergent nature of MCR chemistry proposed virtual

screening hits can be instantaneously synthesized and tested. The software was instrumental to

the discovery of multiple potent and selective MCR-based antagonists of the protein–protein

interaction between p53 and MDM2.[33–34] Thus, computational approaches to screen MCR libraries

will likely play a more and more important role in the early drug discovery process in the future. More

and more high-resolution structural information on MCR molecules bound to biological receptors

is available (Scheme 7). With the advent of structure-based design and fragment-based approaches

in drug discovery, access to binding information of MCR molecules to their receptors is becoming

crucial. Once the binding mode of an MCR molecule is defined, hit-to-lead transitions become more

facile and time to market can be shortened and attrition rate in later clinical trials can be potentially

reduced with the knowledge to engineer the physicochemical properties of the target compounds.

Scheme 7. p53 – mdm2 inhibitors synthesized by Ugi-4CR.

Active compounds were reported based on anchoring of a 6-chloro-indole moiety onto Trp23 of p53

in the p53 mdm2 interaction, designed through special computational software AnchorQueryTM and

synthesized through Ugi and other multicomponent chemistry.[35-36] The most potent compounds

are (41) (PDB: 3TJ2), (42) (PDB: 4MDQ), and (43) (PDB: 4MDN) with IC50

values of 400 nM, 1.2 μM, and

600 nM, respectively.

Compounds (41) and (42) mimic three distinct aminoacids of p53 (Phe19, Trp23, and Leu26), but

compound (43) induced an additional hydrophobic pocket on the MDM2 surface and unveiled for

the first time a four-point binding mode (Scheme 7).[37]


Chapter 1

18

Figure 2. The use of ANCHOR.QUERY in structure-based drug discovery. Above: a) The endogenous interaction of p53 in Mdm2 with the hot spot amino acids Phe19, Trp23 and Leu26. b) Pharmacoph-

ore model and screening of a very large virtual library of MCR products allows for the efficient discov-ery of novel and potent scaffolds. c) Three MCR molecules mimicking the p53 interaction with Mdm2.

Figure 3. A potent p53-Mdm2 antagonist comprising of four pharmacophore points based on the Ugi-4CR discovered with AnchorQueryTM technology (PDB ID 4MDN). The AnchorQueryTM

(http://anchorquery.ccbb.pitt.edu/) derived p53-Mdm2 antagonists based on MCR chemistry. The hotspot of the protein protein interaction of p53 (green sticks) on Mdm2 (redish surface) different

ligand areas important for the ligand-protein interaction are projected onto the receptor surface and presented by different colors: isocyanide blue, aldehyde red, amine green and orange. The acid com-

ponent (formic) does not make major contributions but rather points into solvent.



19

1

Besides applications in structure based drug design and medicinal chemistry, MCR chemistry recently

also finds application in the design and synthesis of libraries with unusual 3D and physicochemical

properties for applications in high throughput screening campaigns, such as the European Lead

Factory (https://www.europeanleadfactory.eu/).

Natural ProductsThe use of MCR in natural product synthesis is currently totally underinvestigated however several

recent examples are discussed in the following.

While the Bucherer-Bergs and the related Strecker synthesis are well established methods for

the one-pot synthesis of natural and unnatural amino acids and provide very early examples of

MCR triggered natural product syntheses, the complex antibiotic penicillin was synthesized 50 years

ago in a highly convergent approach by Ivar Ugi using two MCRs, the Asinger reaction and his own

reaction (Scheme 8).[38]

Scheme 8. Penicillin synthesis via the union of Asinger-4CR and Ugi-4CR MCRs.

Although early example of the advantageous use of MCR in the conscious total synthesis of complex

natural products leads the way, its use has been neglected for decades and only recently realized by

a few organic chemists. [39-44]

A novel MCR approach towards Aspergillamide A (54) was discribed by Dömling et al. using

an Ugi-4CR between N-acetylleucin (50), methylamine (51), phenylacetaldehyde (52) and E/Z-3-(2-

isocyanoethen)-indole (53), the natural product was obtained in one step (Scheme 9).[45]

Scheme 9. Synthesis of Aspergillamide A via the Ugi-4CR.

The natural product and proteasome inhibitor Omuralide (59) has been synthesized in a stereo

controlled manner using a intramolecular U-4CR of the ketocarboxylic acid (55) as a key step

(Scheme 10).[46] Herein a novel convertible isocyanide, 1-isocyano-2-(2,2-dimethoxyethyl) benzene


Chapter 1

20

(56) was used, which was introduced independently by two groups. The p-methoxybenzylamine

(57) is used as an ammonia surrogate. The indole acyl of the intermediate (58) resulting from the

convertible isocyanide can be cleaved under very mild conditions to produce the final product.

Scheme 10. Synthesis of Omuralide using an Ugi-4CR as a first step.

Polymers – MaterialsAnother application of MCR chemistry far from being leveraged to its full extent is in materials

science. Precise engineering of macromolecular architectures is of utmost importance for designing

future materials. Like no other technology, MCRs can help to meet this goal. Recently, the synthesis

of sequence-defined macromolecules (64) without the utilization of any protecting group using a

Passerini-3CR has been described (Scheme 11).[47]

Scheme 11. Macromolecule synthesis via the Passerini-3CR.

Another sequence-specific polymer synthesis with biological applications comprises the peptide

nucleic acids (PNAs), which are metabolically stable and can recognize DNA and RNA polymers

which can be accomplished by the Ugi- 4CR (Scheme 12).[48]

Scheme 12. MCR approach to PNA polymers.

Yet another application of MCRs in materials science might underscore the potential opportunities

to uncover. Ugi molecule-modified stationary phases have been recently introduced to efficiently

separate immunoglobulins (Igs).[49] Currently, more than 300 monoclonal antibodies (mAbs) are

moving toward the market. However, the efficient and high-yielding cleaning of the raw fermentation



21

1

brew is still a holy grail in technical antibody processing. Thus, it is estimated that approximately half

of the fermentation yield of mAbs is lost during purification. Ugi-modified stationary phases (70)

(Scheme 13) have been found in this context to be far superior to purification protocols based on

natural Ig-binding proteins, which are expensive to produce, labile, unstable, and exhibit lot-to-lot

variability.

Scheme 13. Ugi-modified stationary phase.

Fluorescent pharmacophores were discovered by the Groebke-Blackburn-Bienaymè MCR (GBB-3CR)

with potential applications as specific imaging probes using a droplet array technique on glass slides.[50] Another group described the discovery of BODIPY dyes for the in vivo imaging of phagocytotic

macrophages and assembled by MCRs.[51]

Synthesis of Macrocycles Macrcocyclic synthetic compounds or natural products structures recently became en-vogue

due to many potential advantages over small molecular weight compounds. Macrocycles can

have improved binding to the receptor and even can target proteins which otherwise are difficult

to handle such as protein protein interactions due to their large and flat surface area. Moreover

some macrocycles show enhanced transport properties due to their cameleon-like behavior in

hydrophobic and hydrophilic environments. This behaviour can be triggered by conformational

changes induced by a shift between intra- and intermolecular hydrogen bondings.

Modular MCR chemistry is very well suitable for the fast and efficient synthesis of many diverse

macrocycles. Pioneers using MCR for the macrocyclization step were Failli and Immer who synthesized

bioactive cyclic hexa-peptides via a Ugi MCR of N-C-terminal unprotected linear hexapeptides.[52] Later many other groups contributed to macrocycle synthesis via MCR. A recent outstanding

example consists the macrocycle synthesis of Yudin[53] involving amphiphilic aziridinoaldehydes (71)

in Ugi-type reactions (Scheme 14).

The macrocycles synthesis is diverse in terms of ring size and starting materials. An interesting

application of the macrocyclization in very small volumes has been recently disclosed.[54]


Chapter 1

22

Scheme 14. Macrocycle synthesis via MCR.

Applications in Pharmaceutical and Agrochemical IndustryOther worthwhile applications of MCRs in medicinal chemistry are in route scouting for shorter,

convergent, and cheaper syntheses. An excellent showcase is the synthesis of the recently approved

HCV protease inhibitor Incivek® (Telaprevir) (75). The complex compound is industrially produced

using a lengthy, highly linear strategy relying on standard peptide chemistry exceeding 20 synthetic

steps. Orru et al. [55a,b] were able to reduce the length and complexity of the synthesis of Incivek®

(Telaprevir) by almost half using a biotransformation and two multicomponent reactions as the key

steps. (Scheme 15) Recently Riva et al. reported on a second MCR approach towards Incivek® with

an enantioselective enzymatic desymmetrization approach. [55c]



23

1

Scheme 15. MCR approach towards Incivek® (Telaprevir).

Another example is the convergent synthesis of the schistosomiasis drug Biltricide® (Praziquantel)

(89) using key Ugi and Pictet-Spengler reactions (Scheme 16).[56] Clearly, more synthetic targets are

out there, which can be potentially accessed in a more convergent and cheaper way using MCR

chemistry, thus potentially benefiting the patient.

Scheme 16. Biltricide® (Praziquantel) synthesis using key Ugi-4CR and Pictet-Spengler reactions.

Clinical candidatesPreterm labor is the major reason for neonatal morbidity and occurs in 10% of all birth worldwide.

Currently, antagonistic derivatives of the neurohypophyseal nonapeptide hormone oxytocin are

used to control preterm labors, however they are associated with the typical disadvantages of


Chapter 1

24

peptide drugs, such as lacking oral bioavailability, short half life time and potential immunogenicity.

The diketopiperazine scaffold (94) has been discovered in a HTS campaign which after further

medicinal chemistry optimization developed to the first clinical class of small molecular weight

oxytocin antagonists Retosiban (96) and Epelsiban (95) currently undergo human clinical trials. The

later is also the first oxytocin antagonist drug developed for the treatment of premature ejaculation

in men (Scheme 17).[57]

Interestingly, they show superior activity for the oxytocin receptor and selectivity toward the

related vasopressin receptors than the peptide-based compounds currently used clinically. Perhaps

against the intuition of many medicinal chemists, the Ugi diketopiperazines are orally bioavailable,

while the currently used peptide derivatives are i.v. only and must be stabilized by the introduction

of terminal protecting groups and unnatural amino acids.

Scheme 17. Oxytocin antagonists produced via the UDC methodology.

Because of the convergent and efficient nature of the MCR chemistry, detailed SAR of the scaffolds

substituents could be performed giving rapid access to all eight stereoisomers of this Ugi DKP

backbone in a landmark paper involving Ugi chemistry.[58]

5. MCR: Quo Vadis?

The immense scaffold diversity coupled with the ease of access of many different compounds

and the resulting straightforward optimisation protocols make MCR chemistry an almost perfect

technology to solve many of modern lifes issues. Whereas MCR has recently found broad acceptance

in general organic and medicinal chemistry, other science and technology domains still do not

appreciate the outstanding opportunities that MCR offers. We predict MCRs to become even more

popular especially if new applications become introduced.



25

1

6. Aim and scope of this thesis

Since the importance of MCRs in the organic and medicinal chemistry is undisputed. To get

biologically important molecules with high molecular diversity and complexity, in this thesis we

developed a new MCR, checked the substrate scope in well-known Ugi and Passerini reaction.

Furthermore, we also described the union of MCR and the applications of MCR towards complex

molecules.

In Chapter 1, the MCR reactions, use in getting molecular diversity and complexity is discussed.

In Chapter 2, we give an overview of recent research about Passerini reaction. Passerini reaction‘s

scope, chirality and applications are discussed.

In Chapter 3, a new efficient method for the Passerini-type three component reaction (PT-

3CR) is presented. The scope of the reaction is investigated with various aldehydes and isocyanides.

Finally, the application of this method to get fused-tetrazole is briefly discussed.

In Chapter 4, the first time use of N-hydroxamic acids as acid isostere in Passerini reaction is

described. The application of this method to get diverse and biologically important a-hydroxy

amides are discussed. Finally, the use of this reaction for the synthesis of oxyamines is discussed

briefly.

In Chapter 5, we describe the successful use of the N-hydroxyimides as an acid isostere in the

U-4CR for a direct route to the synthesis of α-hydrazinoamides. This is the first time that Ugi-4CR

is used for the synthesis of α-hydrazino amides synthesis. Postmodification of this reaction for the

synthesis of diverse molecules also discussed.

In Chapter 6, a novel three component reaction is reported for the synthesis of 1,5-tetrazole

scaffold. The application of this reaction toward 1,5-disubstituted tetrazoles is reported. The

usefulness of this method is also demonstrated in the synthesis of biologically important various

fused tetrazole scaffolds and the marketed drug cilostazol.

Chapter 7 focus on the union of Asinger and Ugi-tetrazole reaction for the synthesis of highly

diastereoselective tetrazole-oxazinane synthesis.

In Chapter 8, the use of Passerini-2CR product for the direct amination reaction towards a-amino

amides is described. The diverse scope of this new amination methods is discussed.

In Chapter 9, a new universal convertible isocyanide is reported. The application of this cleavable

isocyanide in Ugi-reactions and at different cleavage conditions is described.


Chapter 1

26

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Chapter 2The Passerini Reaction:

Scope, Chirality, and Applications

Manuscript in Preparation:

A. L. ChandgudeA. Dömling

2017


Chapter 2

30

Abstract

Passerini reaction is one of the most studied IMCR. It was first reported in 1921. In the last few

decades, the importance of this reaction has been increased tremendously with the lots of

breakthroughs, such as the report of first catalytic enantioselective Passerini reaction, introduction

to polymer science and report of pseudo-four component mechanism. In this review, we focus on

the recent developments in the Passerini reaction that have been reported about scope, chirality,

and applications.


The Passerini Reaction: Scope, Chirality, and Applications

31

2

1. Introduction

Over the last few decades, the research area of isocyanide-based multicomponent reactions (IMCR)

has grown rapidly to become one of the exciting and powerful tools for peptidomimetics synthesis.

The history of IMCR goes back to the first IMCR by Passerini in 1921.[1] Since the landmark publication

of the first IMCR about a century ago, the mechanism, scope, chirality and applications in different

areas has been elevated to the rarefied status of being one of the most studied IMCR.

Passerini reaction named after the discoverer, Italian scientist Mario Torquato Passerini. He was

born on 29, August 1891, in Casellina/Torri (now Scandicci, Florence, Italy). He graduated from the

University of Florence in 1916. In 1920 he joined doctoral studies and in 1921 published the first paper

reporting on the “Reaction of an oxo component, an isocyanide, and an acid component to form

α-acyloxy carboxamide“, which is now known as “Passerini reaction“. He worked as a pharmaceutical

chemistry professor in Siena from 1930 and from 1933 in the university of Florence. After 1937, he

did not continue his work on isocyanide and moved to a characterization of natural products from

the lygustrum japonicum leaves and in helichrysum italicum flowers. He died in 1962 in Florence,

just after his retirement in a previous year.[2]

His discovery of this first isocyanide-based multicomponent reaction made a robust movement

towards the new era of IMCR which was followed by Ivar Ugi. In last decade, this reaction emerging

as powerful MCR in the synthetic world which we can clearly see from the high increase in the

number of articles on Passerini reaction (Figure 1).

Figure 1. A number of publications on Passerini reaction per year (result derived from SciFinder query on “Passerini reaction”).

Many reviews are available from our group and other research groups about the multicomponent

reactions which also cover the Passerini reaction.[3] In 2005, L. Banfi and R. Riva made the exclusive

review about Passerini reaction with a mechanism, scope, and applications.[4] A. Kazemizadeh and

A. Ramazani reviewed the synthetic applications of Passerini reaction.[5] As the remarkable growth of

Passerini reaction articles in last decade, an update to this reach area is much needed. The purpose


Chapter 2

32

of this mini-review is to highlight the growing interest in Passerini reaction about scope, chirality

and it’s applications in the different fields, especially research reported from 2005 to December 2016.

1.1 MechanismM. Passerini first time proposed that this reaction mechanism might involve the zwitterionic

intermediate. An extensive research has been focused on finding the Passerini reaction mechanism,

and different literature has shown the different intermediates, such as hemiacetals, carbocation,

and hydrogen-bonded adducts.[4] The formation of the hydrogen-bonded intermediate is the most

accepted mechanism for this reaction (Scheme 1). It involves the activation of an aldehyde by the

carboxylic acid, followed by addition of an isocyanide to form nitrilium intermediate (A). Which is

trapped by the carboxylate, which undergoes Mumm type rearrangement to form final α-acyloxy

amide product (4).

Scheme 1. The proposed Mechanism for the Passerini-3CR.

In 2011, Maeda et al. used the AFIR method for mechanistic studies of Passerini reaction. They show

that mechanism involves the extra acidic component before the final product formation, so it shows

that Passerini reaction is a pseudo four-component reaction (Scheme 2).[6]

Recently, Ramozzi and Morokuma performed high-level DFT calculations which also support

the four component mechanism (Scheme 3).[7] They found the nitrilium intermediate (B) is stable

in solution and its formation is rate-determining. This step is catalyzed by a second carboxylic acid

molecule followed by Mumm rearrangement to form final product (4).



33

2

Scheme 2. Passerini reaction (pseudo-four component reaction) mechanism based on AFIR method in a gas phase.

Scheme 3. Passerini reaction (pseudo-four component reaction) mechanism based on high-level DFT in solution.


Chapter 2

34

2. Substrate scope

During the last decade, the substrate scope was extensively studied and the new isosteres have

been reported for the acid and aldehyde. The acid isostere use provides the interesting scaffolds and

different new bond formations, such as C-Si, C-P, and C-N.

2.1 Acid isosteres in Passerini ReactionIvar Ugi reported the use of HN

3 and Al(N

3)

3 as first acid isostere in Passerini reaction (PT-3CR) in

1961.[8] This reaction became a model reaction to synthesize α-hydroxy tetrazoles (8) (Scheme 4).

Scheme 4. PT-3CR toward a-hydroxy tetrazole.

Use of HN3 or NaN

3 in PT-3CR has been used by many instants.[4, 9] Zhu also used HN

3 in enantioselective

Passerini reaction (Scheme 5).

Scheme 5. Enantioselective Passerini-type MCR catalyzed by the [(salen)AlIIIMe] complex.

Hulme reported the use of TMSN3

as a safe alternative to NaN3 and HN

3 for the synthesis of cis-

constrained norstatine analogs. Reaction provides the TMS-ether product which was removed

by TBAF treatment.[10] Zinc iodide catalyst use with TMSN3 was also reported in PT-3CR where de-

etherification done by basic conditions Passerini.[11] Our group reported the PT-3CR in the screening

for the X-linked inhibitor of an apoptosis-baculoviral inhibitor of apoptosis protein repeats domain

binder.[12]

A significant drawback of this PT-3CR reaction with TMSN3 is, that, TMS-ether will be the product.

So always require one extra step for de-etherification and also yields will be very low. Recently, we

reported a significant improvement of this method. We reported a sonication accelerated, fast and

catalyst free PT-3CR in methanol: water (1 : 1) solvent system which provided good to excellent

yields (Scheme 6).[13] Sonication gave high conversion and giving high yields and no TMS-ether side

products.



35

2

Scheme 6. Sonication accelerated PT-3CR in an aqueous solvent.

In 2010, Soeta and co-workers reported the O-silylative Passerini reaction for the synthesis of

α-siloxyamides (11) by using silanol (10) as an acid isosteric replacement (Scheme 7).[14]

Scheme 7. Passerini reaction with silanol.

The same group reported O-sulfinative Passerini/oxidation for the synthesis of α-(Sulfonyloxy)amide

derivatives by using one-pot O-sulfinative Passerini/oxidation reaction (Scheme 8).[15] Passerini

reaction carried out with sulfinic acid (12) followed by the addition of an oxidant, mCPBA to provide

corresponding α-(sulfonyloxy)amides (14).

Scheme 8. Passerini reaction with sulfinic acid.

Phosphinic acids (15) use in a one-pot O-phosphinative Passerini/Pudovik reaction has been

reported for the synthesis of a-phosphinyloxy amide (16) (Scheme 9).[16]

Scheme 9. Phosphinic acids in Passerini reaction.


Chapter 2

36

Recently, we reported the use of N-hydroxyimide (17) as an acid isostere to get direct access

α-aminoxy amides (18) (Scheme 10).[17] This sonication-accelerated reaction is compatible with

N-hydroxysuccinimides and phthalimides.

Scheme 10. N-hydroxyimide in Passerini reaction.

El Kaim and co-workers reported Passerini-Smiles reaction for the synthesis O-arylated compounds

just after the report of Ugi-Smiles reaction (Scheme 11).[18] Phenol (19) as acid component works

well in methanol with the key step of the conversion of an irreversible Smiles rearrangement of the

intermediate phenoxyimidate adducts (20).

Scheme 11. Passerini-Smiles reaction.

After the report of Passerini-Smiles reaction, they modified the conditions for better yield and

substrate scope, also for the synthesis of diverse post-condensations reactions.[19]

Paserini reaction with TiCl4

for the synthesis of α-hydroxy amide is well established and used

reaction.[20] The use of water, mineral acid, organic acid and Lewis acid as acid isostere was reviewed

by Banfi et all.[4] The use of mineral acids, such as aqueous hydrochloric acid, hydrobromic acid,

nitric acid, phosphoric acid and sulfuric acid was reported. In Lewis acids, TiCl4, BF

3, AlCl

3, POCl

3 and

combination of Me3SiCl/Zn(OTf )

2 were used to made a-hydroxy amides (21) (Scheme 12). Recently

organic acids were also reported, such as diphenylborinic acid/water,[21] and Boric acid/DMF.[22]

Scheme 12. Acid catalyzed P-2CR.

O-alkylative Passerini reaction of aliphatic alcohols catalyzed by In(OTf )3 was reported to access

α-alkoxy amide products (25) in good yield (Scheme 13).[23] Similar O-alkylative Passerini reaction

catalyzed by AlCl3 was also reported to provide access for functional α-alkoxy-β,γ-enamide

derivatives.[24]



37

2

Scheme 13. O-alkylative Passerini reaction.

2.2 Carbonyl isosteres in Passerini ReactionAcylphosphonates as carbonyl isostere in Passerini reactions was reported. This reaction involves

a phospha-Brook rearrangement to form α-amidophosphates (28). Acylphosphonates are formed

from acyl chlorides (Scheme 14).[25]

Scheme 14. Acylphosphonates as carbonyl isostere in Passerini reaction.

Direct use of alcohols instead of an aldehyde in the Passerini reaction has been reported by Zhu

and co-workers. This reaction worked well by heating O-iodoxybenzoic acid (IBX) at 40°C and then

after oxidation/P-3CR to gave α-acyloxy carboxamide (4) in good-to-excellent yield (Scheme 15).[26]

Scheme 15. Passerini-alcohol IBX-promoted oxidative Passerini reaction.

The same group reported the catalytic aerobic oxidative protocol, a catalytic amount of cupric

chloride, NaNO2, and TEMPO, under an oxygen atmosphere for the same reaction.[27] This oxidative

Passerini reaction with primary alcohols in presence of ferric nitrate and TEMPO and under air also

provide good yields.[28] Recyclable magnetic core-shell nanoparticle supported TEMPO use for the

one-pot oxidative Passerini reaction of primary or secondary alcohols under metal- and halogen-

free reaction conditions have been reported.[29]


Chapter 2

38

Basso and co-workers developed the four-step, one-pot improvement of the alkylative Passerini

reaction (Oxidation-Passerini-Hydrolysis-Alkylation strategy) for the synthesis of alkoxyamide and

also benzoxazepines (32) (Scheme 16).[30]

Scheme 16. Oxidation-Passerini-Hydrolysis-Alkylation towards benzoxazepines.

Recently, the use of isatins (33) in Passerini reaction to form oxindole derivatives (34) in the presence

of molecular sieves,[31] and in solvent-free was reported (Scheme 17).[32]

Scheme 17. Isatins in Passerini reaction.

Passerini reactions with oxetan-3-ones for the efficient synthesis of 3,3-disubstituted oxetanes (37)

has been reported (Scheme 18).[33] Good diastereomeric (dr = 4 : 1) products can be achieved when

the oxetane with bulky cyclohexyl substitution (35) used.

Scheme 18. Passerini reaction with oxetan-3-ones.



39

2

2.3 Isocyanide isosteres in Passerini ReactionGuchhait and co-workers reported the one-pot preparation of isocyanides from amines and used

for the Passerini and other MCRs.[34] The nature and quantities of dehydrating agent and base and

the function of by-products as promoters for post-transformation were crucial for the success of this

reaction. This reaction involves N-formylation of amine by formic acid followed by dehydration by

p-TsCl and DABCO.

Recently our group described a rapid and highly diverse formamide synthesis via a modified

Leuckart-Wallach procedure, with conversion in situ into isocyanides, this one pot protocol can be

used for different IMCRs.[35]

3. Chirality in Passerini reaction

In 2003, our group developed the first enantioselective Passerini three-component reaction. The

development of an enantioselective Passerini three-component reaction remains a significant

challenge. Recently, significant breakthroughs were achieved to get high enantioselectivity by

Schreiber, Zhu, and Tan.

3.1 Enantioselective Passerini three-component reactions Our group reported the use of a stoichiometric amount of a Ti-taddol complex (38) to afford

α-acyloxyamides with moderate enantioselectivity.[36] We screened hundreds of Lewis acid/ligand

combinations in a parallel fashion for stereochemical induction but only able to get 32–42% ee

(Scheme 19).

Scheme 19. Enantioselective Passerini reaction by using Ti-taddol complex.

Schreiber et al. used chiral tridentate Lewis acidic Cu-pybox complex (39) to activate the carbonyl

species and get enantioselective Passerini reaction. However, a good enantioselectivity was

observed only with chelating aldehydes (Scheme 20).[37]


Chapter 2

40

Scheme 20. Cu(II)-pybox-catalyzed enantioselective Passerini reaction.

In 2008, Zhu and co-workers reported the use of stable aluminium salen complex (41) as a chiral

Lewis acid catalyst in the enantioselective Passerini three-component reaction. This reaction

provides the moderate to excellent enantioselectivities (68–>99% ees) with nonchelating aldehydes

carboxylic acids, and isocyanides (Scheme 21).[38]

Scheme 21. Enantioselective Passerini reaction catalyzed by the [(salen)-AlIIICl] complex.

In 2015, Zhang et al. have elegantly demonstrated the use of chiral phosphoric acid (42) in P-3CR

to activate carboxylic acids, aldehyde, and isocyanide aldehyde to get most efficient and highly

enantioselective products. This metal-free Passerini three-component reaction was valid for diverse

substrates such as aromatic aldehydes and the very bulky pivalaldehyde (Scheme 22).[39]



41

2

Scheme 22. Chiral phosphoric acid-catalyzed enantioselective Passerini reaction.

3.2 Enantioselective Passerini-type reactions In last decade few enantioselective Passerini-type reactions have been reported. In 2003, Denmark

reported the first catalytic, enantioselective, Passerini-type reaction. A catalytic system of chiral

bisphosphoramide (44) and SiCl4 provided good to excellent enantioselectivities for a wide range of

aldehydes and isocyanides (Scheme 23).[40]

Scheme 23. Lewis base-catalyzed SiCl4-mediated enantioselective Passerini-type reaction.

Zhu reported the different catalytic systems for the Passerini-type reaction to getting access of

enantioselective 5-aminooxazoles, such as Chiral Salen-Aluminum Complex,[41] [Sn-(R)-Ph-PyBox]

(OTf )2,[42] and Chiral Aluminum-Organophosphate (49) (Scheme 24).[43]


Chapter 2

42

Scheme 24. The enantioselective Passerini-type reaction catalyzed by the [(salen)-AlIIICl] complex.

Zhu and co-workers reported an asymmetric Passerini-tetrazole-3CR (Scheme 25). An aluminium

salen complex (51) was also reported for to get a-hydroxy-tetrazoles (52) in modest to high yields

(45–99%) with enantiomeric excesses (51–97% ees).[44]

Scheme 25. The enantioselective Passerini-type reaction catalyzed by the [(salen)AlIIIMe] complex.

3.3 Diastereoselective Passerini reactionRecently, Banfi et al. reported a Lewis acid catalyzed diastereoselective Passerini reaction of biobased

chiral aldehydes (54) derived from desymmetrized erythritol (53). Good diastereoselectivity was

observed. The P-3CR products used fort he library of polyoxygenated heterocycles (Scheme 26).[45]

Scheme 26. Diastereoselective Passerini reaction of biobased chiral aldehydes.



43

2

Riva and co-workers reported diastereoselective Passerini Reactions on biocatalytically derived

chiral azetidines (58) (Scheme 27).[46]

Scheme 27. Passerini Reaction towards chiral azetidines.

The same author reported the Ugi and Passerini reactions of biocatalytically derived chiral aldehydes

meso-diol (1,2-cyclopentanedimethanol) (59).[47] They reported 6 out of all 8 possible stereoisomers

of peptidomimetic pyrrolidines (60) in good yields and further used this protocol for an efficient

synthesis of antiviral drug telaprevir (Scheme 28).

Scheme 28. Passerini reactions of biocatalytically derived chiral aldehydes.

Krishna et al. reported diastereoselective Passerini-Smiles reactions by using chiral aldehydes (61)

(Scheme 29).[48]

Scheme 29. Passerini-Smiles Reaction of chiral aldehydes.


Chapter 2

44

Different chiral aldehydes have been reported to get diastereoselective Passerini reaction.

Szymanski and Ostaszewski reported the enantioconvergent method for the synthesis of chiral

α-amino acids by chiral separation.[49] Enantiomerically enriched α-hydroxyamides converted

into α-aminoamides and further hydrolyzed to give α-amino acids. Krishna and co-workers

reported diastereoselective Passerini reactions by using sugar-derived aldehydes,[50] and 2,3-epoxy

aldehydes,[51] with p-toluenesulfonylmethyl isocyanide (TosMIC). Alcaide and co-workers reported

the diastereoselective β-lactam-triazole hybrids synthesis via Passerini/CuAAC Sequence by using

Azetidine-2,3-diones.[52] and also the synthesis of γ-Lactams and γ-Lactones by using 4-oxoazetidine-

2-carbaldehydes.[53]

Deobald et al. reported asymmetric organocatalytic epoxidation/Passerini-3CR for the synthesis of

α-acyloxy-α,β-epoxy-carboxamides.[54] Bos and Riguet developed one-pot method for the synthesis

of α,γ-substituted Chiral γ-Lactones (68) by sequential enantioselective organocatalytic Michael

addition of boronic acids (66) to 5-hydroxyfuran-2(5H)-one (65) followed by diastereoselective

intramolecular Passerini reaction (Scheme 30).[55]

Scheme 30. Diastereoselective intramolecular Passerini reaction towards γ-Lactones.

4. Applications of Passerini reaction

4.1 Passerini reaction for the Macrocycles/Peptidomimetics synthesisRecently, our group reported the first intramolecular macrocyclization through a Passerini reaction.[56]

We reported the easy and one-pot synthesis of macrocycles of a size of 15−20 (Scheme 31).

Scheme 31. Intramolecular macrocyclization by Passerini reaction.



45

2

Wessjohann expanded the multiple multicomponent macrocyclizations including bifunctional

buildings blocks (MiBs) methodology to Passerini three-component reactions (3CR) fort he synthesis

of bis-R-acyloxy carboxamide macrocycles. Reaction with primary alcohols works well under

oxidative conditions to form products.[57]

Umbreen et al. demonstrated the use of an organocatalytic, direct, asymmetric α-amination

in combination with a Passerini reaction to provide diverse norstatine-based peptidomimetics

(Scheme 32).[58]

Scheme 32. Two-step synthesis of norstatine intermediates.

The Passerini reaction with α-hydrazino acids (77), carbonyl compounds (1) and isocyanides (2) was

reported for the synthesis of hydrazino depsipeptides (78) (Scheme 33).[59]

Scheme 33. Passerini for synthesis of hydrazino depsipeptides


Chapter 2

46

El Kaim group reported the Passerini reaction of alpha,beta-unsaturated aldehydes (79) with formic

acid (80) followed by a reductive Tsuji-Trost reaction affords beta, gamma-unsaturated amides (82)

(Scheme 34).[60] The same group also report the synthesis of α-ketoamides from Passerini adducts of

cinnamaldehyde derivatives under basic microwave conditions.[61]

Scheme 34. Passerini for the synthesis of unsaturated amides.

4.2 Passerini reaction post-modifications for heterocycles synthesis In MCR, use of post-modification reactions for the synthesis of diverse heterocycles is a very important

area. As getting diverse heterocycles within 1 or 2 steps make it very useful and convenient tool. Last

decade the use of Passerini reaction has been also increased to synthesize diverse heterocycles.

Recently, Ponra et al. reported the TiCl4-mediated synthesis of the thiophthalide derivatives via

thio-Passerini reactions (Scheme 35).[62] This reaction involves the formation of a sulfanyl-phthalide

intermediate (84), followed by thiol dealkylation which undergoes forms Mumm 1,5-acyl transfer to

form final product (85).

Scheme 35. Thio-Passerini reactions for the synthesis of thiophthalide derivatives.



47

2

Van der Eycken reported the one-pot synthesis of butenolides (89) using Passerini reaction followed

by a triethylamine-promoted cycloisomerization (Scheme 36).[63]

Scheme 36. One-pot Passerini/cycloisomerization towards butenolides.

El Kaim reported the use of double Smiles rearrangement of Passerini adducts for the synthesis of

benzoxazinones. This reaction involves the cascade of two Smiles rearrangements coupled with

carbon-carbon bond formation (Scheme 37).[64]

Scheme 37. Passerini-Smiles-Smiles sequence for the synthesis of benzoxazinones.


Chapter 2

48

Basso reported the use of azidoalcohol in Passerini reaction. This two step involves first oxidation

by IBX in microwave condition followed azide-alkyne dipolar cycloaddition reaction in MW to form

triazolo-fused dihydrooxazinones (95) (Scheme 38).[65]

Scheme 38. Passerini reaction/dipolar cycloaddition toward triazolo-fused dihydrooxazinones.

Passerini Three-Component Coupling/Staudinger/Aza-Wittig/Isomerization reaction used for the

one-pot synthesis of 2,4,5-trisubstituted oxazoles (97), starting from easily accessible α-azido-

cinnamaldehydes (96), acids (3), isocyanide (2) and triphenylphosphine (Scheme 39).[66]

Scheme 39. Passerini reaction coupling/Staudinger/Aza-Wittig/isomerization reaction towards 2,4,5-trisubstituted oxazoles.

Krasavin and co-workers reported the BF3OEt

2-promoted reaction between o-aminobenzophenones

with aliphatic isocyanides to form 4-aryl-4-hydroxy-3,4-dihydroquinazolines (99). The reaction

involves the initial three-center, two-component Passerini-type reaction followed by skeletal

rearrangement of the 3H-indol-3-ol framework (Scheme 40).[67]

Scheme 40. Passerini type reaction for the synthesis of 3,4-dihydroquinazolin-4-ols.



49

2

Basso and co-workers reported the synthesis of triazolo-fused benzoxazepines and benzoxaze-

pinones via Passerini reactions followed by 1,3-dipolar cycloadditions (Scheme 41).[68]

Scheme 41. Passerini reactions towards triazolo-fused benzoxazepines and benzoxazepinones.

Schwablein and Martens reported the synthesis of alpha,beta-unsaturated lactones (110) by using

the Passerini reaction and ring-closing metathesis (RCM) using a ruthenium catalyst (Scheme 42).[69]

Passerini reaction performed with terminal unsaturated carboxylic acids (108), allyl ketones (107),

and isocyanides (2).

Scheme 42. Synthesis of α,β-unsaturated lactones by Passerini reaction.

Gao et al. reported a three-component bicyclization strategy for the stereoselective synthesis of

pyrano[3,4-c]pyrroles (113) from dialkyl acetylenedicarboxylates (111), 3-aroylacrylic acids (112),

and isocyanides. This reaction involves a sequence of Huisgen 1,3-dipole formation, Passerini-type

reaction, Mumm rearrangement and an oxo-Diels-Alder reaction (Scheme 43).[70]


Chapter 2

50

Scheme 43. Synthesis of pyrano[3,4-c]pyrroles by Passerini reaction.

Polycyclic alkaloid-like scaffold (115) have been prepared by coupling the Passerini and Ugi reactions

with Two Sequential Metal-Catalyzed Cyclization (Scheme 44).[71] It involves an intramolecular Tsuji-

Trost reaction of the isocyanide-derived amide followed by a ring-closing metathesis with moderate

to good diastereoselectivity.

Scheme 44. Passerini/Ugi towards Polycyclic alkaloid-like scaffold.

El Kaim recently reported the Passerini adducts (117) and indoles (118) in FeCl3 catalyzed Friedel-

Crafts-type reaction (Scheme 45).[72]

Scheme 45. Passerini /Friedel-Crafts towards indole derivatives.



51

2

4.3 Passerini reaction-amine-deprotection-acyl-migration strategy (PADAM) First reported in 2000 by Passerini reaction-amine-deprotection-acyl-migration strategy (PADAM),

which was independently described by two group.[73] Three-component Passerini condensation

of N-Boc-a-aminoaldehydes (120), isocyanides (2) and carboxylic acids (3) to form (121), followed

by boc-deprotection/transacylation to complex peptide-like structures containing an a-hydroxy-b-

aminoacid unit (122) (Scheme 46).

Scheme 46. PADAM strategy for α-hydroxy-β-aminoacid synthesis.

Banfi reported the PADAM strategy for the solid-phase preparation of peptidomimetic

compounds.[74] Hulme used PADAM methodology for the synthesis of norstatine isosteres in four

steps which involves the benzimidazole formation. This sequence involves a PADAM sequence

followed by a TFA-mediated microwave-assisted cyclization to form the benzimidazole isostere of

the norstatine scaffold (127) (Scheme 47).[75]

Scheme 47. PADAM for benzimidazole synthesis.


Chapter 2

52

Basso and co-workers reported the PADAM strategy for the synthesis of polyfunctionalised 2(1H)-

Pyrazinones. Passerini reaction with N-Boc amino acids formed β-acylamino-α-hydroxyamides

(130) followed by secondary-alcohol oxidation and then Boc deprotection by TFA which undergoes

spontaneous aromatisation to form 2(1H)-pyrazinones (132) (Scheme 48).[76]

Scheme 48. PADAM strategy towards 2(1H)-pyrazinones.

Gravestock et al. used the PADAM strategy for the synthesis of potential HIV-1 protease inhibitors.[77]

Different branched isocyanides which have been synthesized from l-serine are used to make Passerini

reaction. Furthermore, the homo-PADAM protocol was also used for the stereoselective and

operationally simple synthesis of alpha-oxo- or alpha-hydroxy-gamma-acylaminoamides and

chromanes.[78]



53

2

Faure and co-workers used PADAM strategy as a key step for the synthesis of linear pentapeptide

intermediate (137) in the total synthesis of cyclotheonamide C (138) (Scheme 49).[79]

Scheme 49. Cyclotheonamide C synthesis by PADAM.

4.4 Industrial applications of Passerini reactionIn 2003, Wright et al. reported the first use of IMCRs in the syntheses of polymers, where they

performed ring-opening metathesis polymerization (ROMP) with Ugi-4CR products and norbornenyl

starting materials.[80] The use of IMCRs for direct polymer synthesis via polycondensation was

reported by Meier in 2011 (Scheme 50).[81] They introduced the new approach in polymer science

by combining IMCRs and acyclic diene metathesis (ADMET) polymerization. The Passerini three-

component reaction was used for the synthesis of diverse monomers derived from bio-renewable

ricinoleic acid for acyclic diene metathesis (AD-MET) polymerizations.


Chapter 2

54

Scheme 50. Macromolecule synthesis via the Passerini reaction.

After this report by Meier, multicomponent reactions use in polymer synthesis have been intensively

explored which was also reviewed by him.[82] Kakuchi also reported a brief review about MCR in

polymer.[83] Passerini reaction use in this field has been reported many instants, such as synthetis

of dendrimers,[84] polyamides,[85] acrylate monomers,[86] photo-cleavable polymers,[87] cross-linked

polymers,[88] and highly branched polymers.[89]

4.5 Medicinal/clinical applications of Passerini reaction Passerini reaction has been used for the many bio-active agents and also in some other

pharmaceutical applications. The Passerini 2-CR used for the synthesis of a fungicidal compound,

mandipropamid. This two steps synthesis involves the Passerini reaction to form mandelamide (144)

followed by the alkylation with propargylbromide (145) to yield Micora (mandipropamid) (146).[90]

Trifluoroatrolactamide Library made from one-pot Passerini/hydrolysis reaction sequence was also

screened for the fungicidal activities (Scheme 51).[91]

α-Acylamino-amide-bis (indolyl) methane heterocycles as antibacterial potency were

synthesized by one pot condensation-Ugi/Passerini reactions.[92] Passerini reaction also used in

different pharmaceutical applications like degradable cationic polymer library for gene delivery,[93]

and reduction-sensitive amphiphilic copolymers for drug delivery.[94]

Scheme 51. Passerini reaction towards mandipropamid.



55

2

5. Union of Passerini reaction with other MCRs

Two decades ago Dömling and Ugi introduced the concept of the union of MCRs which gained

attention to get diverse diversity and complexity. Union of Passerini reaction with other MCRs did not

get that much attention as compare to Ugi reaction. Only a few examples have been reported. Long

back, Passerini union with Bredereck reaction was reported by Bienayme (Scheme 52).[95] A modified

Bredereck reaction used to produce the intermediate isocyanide (150) followed by Passerini-3CR to

form final product (151).

Scheme 52. Passerini-3CR union with Bredereck reaction.

Recently, one-pot Biginelli-Passerini tandem reaction was demonstrated for the synthesis of diverse

3,4-dihydropyrimidin-2(1H)-ones via sequential Biginelli and Passerini reactions (Scheme 53).[96]

Scheme 53. Biginelli and Passerini reaction union.


Chapter 2

56

Groebke-Bienayme-Blackburn reaction union with Ugi or Passerini was reported for the synthesis of

drug-like heterocyclic compounds, fused pyridine-imidazoles (160) (Scheme 54).[97]

Scheme 54. Union of Passerini reaction with Groebke-Bienaymé-Blackburn-3CR.

6. Summary and Outlook

Along with this mini-review, we succinctly highlighted the utility of Passerini reaction in the

pharmaceutical and organic industry that has been reported in the last decade. Research momentum

in Passerini reaction in last decade has been more than collectively over history, which is proving

ground for expanding the chemical space for the medicinal and organic chemist. It has become a

powerful and efficient tool in organic chemistry.

The increasing knowledge about the mechanism of Passerini reaction will allow the design

of innovative substrates to afford high molecular diversity and complexity. The isosteres use are

interesting and it will help to get more interesting bond formations like C-Si, C-P, or C-N. The lack

of sufficient examples of Passerini reaction union with other MCR will also take impetus. Recent

advances will offer a bright future for the development of novel scaffolds with chemo-, regio-, and

stereoselective reactions.

A future trend is definitely the application of this reaction in different fields, such as polymer,

agrochemical, explosives and natural products synthesis. This reaction continues to provide

inspiration for better and novel research of making diverse and complex molecules. More

breakthroughs are to be expected in near future.



57

2

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Chapter 3An Efficient Passerini

Tetrazole Reaction (PT-3CR)



Green Chem., 2016, 18, 3718-3721.


Chapter 3

62

Abstract

A sonication accelerated, catalyst free, simple, high yielding and efficient method for the Passerini-

type three component reaction (PT-3CR) has been developed. It comprises the reaction of an

aldehyde/ketone, an isocyanide and a TMS-azide in methanol : water (1 : 1) as the solvent system. The

use of sonication not only accelerated the rate of the reaction but also provided good to excellent

quantitative yields. This reaction is applicable to a broad scope of aldehyde/ketone and isocyanides.


An Efficient Passerini Tetrazole Reaction (PT-3CR)

63

3

Introduction

Tetrazoles scaffolds are extensively used in medicinal chemistry and in industries like agriculture,

explosives, and photography.[1] 1,5-Disubstituted tetrazoles are important ring systems, having

applications as bio-active agents or in drugs like cilostazol, pentylenetetrazole, latamoxef, BMS-

317180 and cis-amide bond isosteres in peptides (Figure 1). This propels the need for efficient

synthetic methods for tetrazoles.[2] Different reactions have been developed for the direct access

to diverse 1,5-disubstituted tetrazoles, but three- and four-component reactions (MCRs) are mostly

preferred due to their convergent, atom-efficient and flexible nature.[3] Multicomponent reactions

are considered ideal syntheses, and that’s why their use in synthetic chemistry is increasing

tremendously.[4]

Figure 1. Some bio-active agents/drugs containing the tetrazole moiety.

In 1921, a three-component reaction between carboxylic acids, oxo components, and isocyanides

for the synthesis of α-acyloxy amide was discovered by Passerini (P-3CR).[5,7c] In 1961, Ugi reported the

synthesis of tetrazoles via a Passerini-type 3CR (PT-3CR) for the first time using HN3 and Al(N

3)

3.[6] Even

though the use of HN3 or NaN

3 in Passerini reaction for the synthesis of tetrazoles was reported, the

highly toxic and explosive nature of HN3 and NaN

3 limit its application.[7] The use of TMSN

3 as a safe

substitute for HN3 was then introduced by Hulme.[8] However the use of TMSN

3 as an azide source in

the PT-3CR resulted in a very low yield, and the TMS-ether was found as a major product. Similarly

protected amino aldehydes in DCM also resulted in generally low yields[9] and the described reaction

times were up to 96 hours.[9a] Reported PT-3CRs are not very suitable for aromatic aldehydes.[7] The


Chapter 3

64

use of different Lewis acids as catalysts, like AlCl3, to activate aldehydes forms an inseparable mixture

of desired product with α-hydroxy-amide, with a maximum yield of 30%.[10] Zhu and co-workers

used TMSN3 as a test reaction component in the asymmetric PT-3CR; nevertheless, they could not

avoid the formation of α-hydroxy-amide.[7b]

To the best of our knowledge, no efficient, diverse and high yielding PT-3CR reaction has yet

been reported. We report herein a sonication-promoted catalyst free, TMSN3-modified PT-3CR using

methanol : water (1 : 1) as solvent with diverse scope and affording good to excellent yields.

Results and Discussion

We started our investigation by using tert-butyl isocyanide, phenylacetaldehyde and TMSN3

as

starting materials (Table 1). We hypothesized that the use of fluoride ion sources like TBAF, CsF and

KF could trigger TMSN3 activation.[11] However, when the reaction was carried out with TBAF with

different solvents like DCM water, or neat, the product was formed only in trace amounts (Table 1,

entries 1–3). Surprisingly, using methanol as a solvent increased the isolated yield to 25%. Carrying

out the reaction with alternative F-sources, such as KF in DCM or CsF in DCM, methanol and water,

resulted only in small amounts of product formation.

The use of Iodine, to trap TMS as TMSI, also failed to improve the reaction yield. 17% product

formed when the reaction was carried out in water without any additive. TBAF in methanol : water

(1 : 1) enhanced the yield up to 63%; however comparable yields were obtained when the reaction

was carried out without TBAF in the same solvent system. Thus we concluded that the use of TBAF

is not fruitful, whereas the solvent system has a major impact.

We foresaw that the accelerating effect of sonication could potentially speed up the reaction

and increases yields. Ultrasound in general[1,2] and also in the context of MCR[12d] is often used in

organic synthesis due to its advantages such as increasing the reaction efficacy while decreasing

waste byproducts, short reaction times, cleaner reactions, easier experimental procedure and

having low energy requirements. Recently, the popularity of sonication-assisted synthesis as a green

synthetic approach has significantly increased and has resulted in a plethora of ‘better’ reactions.[13]

Ultrasound in chemical reactions works via a physical phenomenon called acoustic cavitation, which

forms, expands and collapses gaseous and vaporous cavities in an ultrasound irradiated liquid. The

mechanical effect of cavitation destroys the attractive forces of molecules in the liquid phase and so

accelerates reaction rates by facilitating mass transfer in the microenvironment.[13]



65

3

Table 1. Optimization of reaction conditions.a

Entry Catalyst Solvent Time (h) Product Yield b (%)

1 TBAFc — 12 trace

2 TBAFd DCM 12 trace

3 TBAFc H2O 12 trace

4 TBAFc MeOH 12 25

5 KFe DCM 12 nd

6 CsFf DCM 12 nd

7 CsFf MeOH 12 nd

8 CsFf H2O 12 nd

9 I2

f DCM 12 nd

10 I2

f H2O 12 nd

11 H2O 12 17

12 TBAFc

MeOH : H2O

(1 : ) 12 63

13MeOH : H

2O

(1 : 1) 12 64

14 SonicationMeOH : H2O

(1 : 1) 2 97

15 Sonicationg — 3 31

16 Sonication DCM 2 34

17 Sonication H2O 2 71

aThe reaction was carried out with phenylacetaldehyde (1 mmol), tert-butyl isocyanide (1 mmol), and TMSN3 (1 mmol) at room

temperature. bYield of isolated product. C1 equivalent TBAF. 3H2O. d1 equivalent TBAF in 1M THF. e1 equivalent KF. f1 equivalent CsF.

gReaction carried out at 70°C. nd = not determined

To our delight, the use of sonication not only accelerated the reaction time from 12 to two hours

but provided quantitative yield in methanol : water (1 : 1) as the solvent system, noteworthily

without the necessity of any previously used additive (Table 1, entry 14). We used a simple ultrasonic

cleaning bath which is the most widely available and cheapest source of ultrasonic irradiation.

A recent study has shown that both ultrasonic cleaning bath and ultrasonic probe systems are

efficient in Passerini reaction.[14] The ultrasonic cleaning bath offers further advantages; for example,

the reaction vessel can be put directly into the ultrasonic bath without any adaptation. This is in

contrast to the ultrasonic probe system, which is more expensive and also requires special vessels,

making it inconvenient to use.

Lastly, reactions under sonication in DCM or in neat conditions provided smaller yields, 34% and

31% respectively, and the formation of TMS-ether as a side product was observed. The use of pure

water as the solvent under sonication conditions provided the product in 71% yield. The use of 1


Chapter 3

66

equivalent of TMSN3 avoids the danger of forming hydrazide from excess azide. This catalyst free

reaction does not require any work-up.

With these optimized conditions in hand, we next examined the generality of this PT-3CR by

reacting different aldehydes with different isocyanides (Table 2). Good to excellent yields were

obtained with linear and branched aliphatic aldehydes. Aromatic aldehydes are also compatible

substrates for this process (Table 2, entries 15–22). Electron donating (methoxy) and withdrawing

groups (Cl, Br, NO2) at different positions like ortho, meta and para are valid, providing moderate to

good yields. Paraformaldehyde also reacts when pure water was used as the solvent. Reaction with

one or six equivalent paraformaldehyde in methanol : water system only forms mono-substituted

tetrazole. The reaction of benzyl isocyanide with aliphatic aldehydes gave excellent yields.

Table 2. Substrate scope for the PT-3CR.a

Entry 1 R3 Yieldc (%)

Aldehydes

1 C6H

5 -CH

2-CHO C

6H

5-CH

296 (3a)

2 iPr-CHO (CH3)

3-C 98 (3b)

3 CH3-(CH

2)

2-CHO C

6H

5-CH

280 (3c)

4 C6H

5-CH

2-CHO tOctyl 77 (3d)

5 iPr-CHO CN-CH2-CH

272 (3e)

6 C6H

5-(CH

2)

2-CHO

EtO

EtO

53 (3f)

7 C6H

5-(CH

2)

2-CHO Cy 76 (3g)

8 C6H

5-CH

2-CHO 2-BrC

6H

4-CH

277 (3h)

9 H-CHOd 2-BrC6H

4-CH

242 (3i)

10 iPr-CHO 2-BrC6H

4-CH

280 (3j)

11 C6H

5-(CH

2)

2-CHO (CH

3)

3-C 88 (3k)

12 CH3-CH

2-CHO C

6H

5-CH

291 (3l)

13 (CH3)

2-CH-CH

2-CHO C

6H

5-CH

292 (3m)

14 C6H

5-CH

2-CHO (CH

3)

3-C 97 (3n)

15 C6H

5-CHO (CH

3)

3-C 41 (3o)

16 2,6-(Cl)2C

6H

3-CHO C

6H

5-CH

271 (3p)

20b 2,3-(Cl)2C

6H

3-CHO Cy 73 (3q)

17 2-MeO-5-BrC6H

3-CHO C

6H

5-CH

2-CH

246 (3r)

18 2-BrC6H

4-CHO Cy 60 (3s)

19 2-Cl-3,4-(OCH3)

2C

6H

2-CHO Cy 42 (3t)



67

3

Entry 1 R3 Yieldc (%)

21

CHO

NO2

O

OCy 39 (3u)

22 2,5-(OCH3)

2C

6H

3-CHO Cy 48 (3v)

Ketones

23 cyclohexanone C6H

5-CH

284 (3w)

24 1-benzylpiperidin-4-one C6H

5-CH

246 (3x)

aThe reaction was carried out with 1 mmol 1, 1 mmol 2, 1 mmol TMSN3. bcy = cyclohexyl, octyl = 2-isocy-

ano-2,4,4-trimethylpentane. cYield of isolated product. d6 equivalent of paraformaldehyde in water as solvent and at 60°C. iPr = isopropyl

Isocyanides, easy to deprotect in acidic and basic conditions, are compatible with the developed

methodology (Table 2, entries 2, 4 and 5). The functional group tolerance of the isocyanide (Table 2,

entries 5–6 and 8–10), in this protocol provides multiple opportunities for various further chemical

manipulations. For example, the compatibility of 1,1-diethoxy-2-isocyanoethane as the isocyanide

component could be used in further reactions as aldehyde or halogens functional groups for

coupling reactions.

We also explore the scope of ketones in the developed method (Table 2, entries 23 and

24). Cyclohexanone gives a good yield of 84%. The important building block piperidone is also

compatible with the reaction.

Fused tetrazoles are important scaffolds as it possess a wide spectrum of activity and vast

industrial applications. As functional group bearing isocyanides are compatible in our developed

method, we foresaw a quick and easy access to fused tetrazole. According to our synthetic plan, the

use of functionalized PT-3CR product for post modification would allow an anticipated cyclization

process. (1-(2-Bromobenzyl)-1H-tetrazol-5-yl)methanol (3i), when refluxed with Copper(II) triflate

in the presence of a base, formed 5,11-dihydrobenzo[f]tetrazolo[5,1-c][1,4]oxazepine in 89% yield

(Scheme 1).

Scheme 1. Synthesis of fused tetrazole.


Chapter 3

68

Conclusions

In conclusion, we have developed a novel, efficient, safe and general sonication assisted Passerini

tetrazole reaction (PT-3CR) to access 5-(1-hydroxyalkyl)tetrazoles in good to excellent yield. The herein

described Passerini tetrazole procedure provides multiple advantages over previously described

procedures. The reaction does not use highly toxic and explosive staring materials like HN3, Al(N

3)

3 or

NaN3.

This catalyst-free reaction avoids the use of any dangerous or adverse catalysts such as Al-salen

chiral complex, AlCl3. Sonifications was found to provide superior reaction conditions, resulting in

high conversion and giving high yields of Passerini products and no TMS-ether side product, as often

observed previously. Sonification is also well known to be compatible with upscaling procedures.

The scope of the reaction could be dramatically extended, including aliphatic, aromatic aldehydes

and also ketones. Due to the extended functional group compatibility of the reaction, many new

scaffolds amenable by post-condensation reactions can be foreseen as we have illustrated by the

synthesis of a Cu-mediated fused tetrazole. Altogether, we believe that our procedure is superior to

all previously reported Passerini tetrazole reactions and will be the method of choice for the future.

General Information

Reagents were available from commercial suppliers (Sigma Aldrich, ABCR, Acros and AK Scientific) and

used without any purification unless otherwise noted. Thin layer chromatography was performed

on Fluka precoated silica gel plates (0.20 mm thick, particle size 25 μm). Flash chromatography was

performed on a Teledyne ISCO Combiflash Rf, using RediSep Rf Normal-phase Silica Flash Columns

(Silica Gel 60 Å, 230–400 mesh) and on a Reveleris® X2 Flash Chromatography, using Grace® Reveleris

Silica flash cartridges (12 grams). All ultrasonic irradiation reactions were carried out in a Sonicor “SC”

Ultrasonic Table Top Cleaner with 220/240V, frequency of 50/60 Hz and 25 Amps. Nuclear magnetic

resonance spectra were recorded on a Bruker Avance 500 spectrometer. Chemical shifts for 1H NMR

were reported relative to TMS (δ 0 ppm) and coupling constants were in hertz (Hz). The following

abbreviations were used for spin multiplicity: s = singlet, d = doublet, t = triplet, dt = double triplet,

ddd = doublet of double doublet, and m = multiplet. Chemical shifts for 13C NMR reported in

ppm relative to the solvent peak (CDCl3 δ 77.23 ppm). Mass spectra were measured on a Waters

Investigator Supercritical Fluid Chromatograph with a 3100 MS Detector (ESI) using a solvent system

of methanol and CO2 on a Viridis silica gel column (4.6 × 250 mm, 5 μm particle size) and reported

as (m/z).

Experimental Procedures and Spectral Data

General procedure for the synthesis of tetrazole A 10 ml tube was charged with aldehyde/ketone (1.0 mmol) and isocyanide (1.0 mmol) and

trimethylsilyl azide (1 mmol) in methanol : water (1 : 1) (1 ml). The mixture was sonicated in the water



69

3

bath of an ultrasonic cleaner (220/240V, 25 Amps and frequency of 50/60 Hz) at room temperature

till completion of the reaction (monitored by TLC). The solvent was removed under reduced pressure

and the residue was purified by silica gel flash chromatography using EtOAc–hexane as eluent.

Spectral Data

1-(1-benzyl-1H-tetrazol-5-yl)-2-phenylethanol (3a)

Colourless liquid, mp 79-80°C, yield: 268 mg (96%); 1H NMR (500 MHz, CDCl3)

δ 7.34 – 7.29 (m, 3H), 7.29 – 7.23 (m, 3H), 7.18 (dd, J = 6.6, 2.9, 2H), 7.11 – 7.04

(m, 2H), 5.49 (d, J = 15.1, 1H), 5.37 (d, J = 15.1, 1H), 5.25 – 5.09 (m, 1H), 3.39

(s, 1H), 3.19 (dd, J = 13.8, 5.4, 1H), 3.07 (dd, J = 13.8, 8.3, 1H). 13C NMR (126 MHz, CDCl3) δ 155.9, 135.8,

133.8, 129.6, 129.0, 128.8, 128.7, 128.0, 127.2, 66.2, 51.3, 42.3. MS (ESI) m/z calculated [M+H]+: 281.13;

found [M+H]+: 281.16.

1-(1-(tert-butyl)-1H-tetrazol-5-yl)-2-methylpropan-1-ol (3b)

White solid, mp 126-127°C, yield: 195 mg (98%); 1H NMR (500 MHz, CDCl3) δ 4.71

(dd, J = 10.2, 8.5, 1H), 3.23 (d, J = 10.1, 1H), 2.53 – 2.39 (m, 1H), 1.78 (s, 9H), 1.18 (d,

J = 6.6, 3H), 0.85 (d, J = 6.7, 3H). 13C NMR (126 MHz, CDCl3) δ 156.3, 70.8, 61.6, 34.1, 30.3,

19.5, 18.2. MS (ESI) m/z calculated [M+Na]+: 221.14; found [M+Na]+: 221.18.

1-(1-benzyl-1H-tetrazol-5-yl)butan-1-ol (3c)

Colourless liquid, yield: 186 mg (80%); 1H NMR (500 MHz, CDCl3) δ 7.41 – 7.31

(m, 3H), 7.31 – 7.24 (m, 2H), 5.72 (q, J = 15.1, 2H), 4.99 (t, J = 6.4, 1H), 3.98 (s, 1H),

1.92 – 1.78 (m, 1H), 1.77 – 1.67 (m, 1H), 1.49 – 1.36 (m, 1H), 1.30 – 1.24 (m, 1H), 0.84

(t, J = 7.4, 3H). 13C NMR (126 MHz, CDCl3) δ 156.5, 133.9, 129.0, 128.7, 127.9, 64.7,

51.5, 37.6, 18.4, 13.5. MS (ESI) m/z calculated [M+Na]+: 255.12; found [M+Na]+: 255.08.

2-phenyl-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazol-5-yl)ethanol (3d)

White solid, mp 135-136°C, yield: 232 mg (77%); 1H NMR (500 MHz, CDCl3)

δ 7.27 – 7.22 (m, 2H), 7.21 – 7.16 (m, 3H), 5.38 – 5.20 (m, 1H), 4.09 (d, J = 9.6, 1H),

3.48 (qd, J = 13.4, 7.2, 2H), 1.96 (d, J = 15.2, 1H), 1.81 (d, J = 17.6, 4H), 1.57 (s, 3H),

0.68 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 156.3, 136.2, 129.7, 128.7, 127.1, 67.1, 65.3, 53.8, 43.2, 31.6,

30.5, 30.3, 30.2. MS (ESI) m/z calculated [M+Na]+: 325.20; found [M+Na]+: 325.20.

3-(5-(1-hydroxy-2-methylpropyl)-1H-tetrazol-1-yl)propanenitrile (3e)

Colorless liquid, yield: 140 mg (72%); 1H NMR (500 MHz, CDCl3) δ 4.92 (dt, J = 13.9,

6.9, 2H), 4.77 (dt, J = 13.7, 6.8, 1H), 4.30 (s, 1H), 3.12 (t, J = 6.9, 2H), 2.29 – 2.16 (m, 1H),

1.08 (d, J = 6.7, 3H), 0.91 (d, J = 6.8, 3H). 13C NMR (126 MHz, CDCl3) δ 156.1, 116.3, 70.9,

43.7, 33.8, 18.7, 18.6, 17.8. MS (ESI) m/z calculated [M+Na]+: 218.10; found [M+Na]+:

218.09.


Chapter 3

70

1-(1-(2,2-diethoxyethyl)-1H-tetrazol-5-yl)-3-phenylpropan-1-ol (3f)

Colorless liquid, yield: 170 mg (53%); 1H NMR (500 MHz, CDCl3) δ 7.37 –

7.24 (m, 2H), 7.23 – 7.12 (m, 3H), 5.04 (dd, J = 12.8, 6.4, 1H), 4.82 (t, J = 5.5,

1H), 4.63 (dd, J = 14.2, 5.6, 1H), 4.52 (dd, J = 14.2, 5.4, 1H), 4.08 (d, J = 5.8,

1H), 3.85 – 3.66 (m, 2H), 3.59 – 3.38 (m, 2H), 2.93–2.72 (m, 2H), 2.44 – 2.24

(m, 2H), 1.12 (dt, J = 14.3, 7.0, 6H). 13C NMR (126 MHz, CDCl3) δ 157.0, 140.7, 128.5, 128.5, 126.1, 100.5,

64.3, 64.2, 64.0, 50.0, 36.9, 31.2, 15.0, 15.0. MS (ESI) m/z calculated [M+H]+: 321.18; found [M+H]+:

321.05.

1-(1-cyclohexyl-1H-tetrazol-5-yl)-3-phenylpropan-1-ol (3g)

White solid, mp 104-105°C, yield: 217 mg (76%); 1H NMR (500 MHz, CDCl3)

δ 7.30 – 7.23 (m, 2H), 7.21 – 7.14 (m, 3H), 5.08–4.93 (m, 2H), 4.57 – 4.39

(m, 1H), 2.92–2.80 (m, 1H), 2.79 – 2.68 (m, 1H), 2.41 – 2.26 (m, 1H), 2.26 – 2.10

(m, 1H), 2.05 – 1.82 (m, 6H), 1.71 (d, J = 12.4, 1H), 1.48 – 1.17 (m, 3H). 13C NMR

(126 MHz, CDCl3) δ 155.6, 140.7, 128.6, 128.5, 126.2, 63.7, 58.4, 37.4, 33.0, 31.5, 25.3, 25.2, 24.9. MS (ESI)

m/z calculated [M+H]+: 287.18; found [M+H]+: 287.21.

1-(1-(2-bromobenzyl)-1H-tetrazol-5-yl)-2-phenylethanol (3h)


(dd, J = 7.5, 1.6, 1H), 7.29 – 7.21 (m, 3H), 7.17 (td, J = 7.1, 1.8, 2H), 7.09 (dd, J = 7.5,

1.6, 2H), 6.72 (dd, J = 7.3, 1.9, 1H), 5.49 (d, J = 16.0, 1H), 5.41 (d, J = 16.0, 1H), 5.26

(t, J = 6.7, 1H), 4.05 (s, 1H), 3.26 (dd, J = 13.7, 5.9, 1H), 3.19 (dd, J = 13.7, 7.7, 1H). 13C NMR (126 MHz,

CDCl3) δ 156.2, 135.6, 133.3, 133.1, 130.1, 129.6, 129.1, 128.8, 128.1, 127.3, 122.7, 66.2, 51.1, 42.5. MS

(ESI) m/z calculated [M+H]+: 359.04; found [M+H]+: 359.04.

(1-(2-bromobenzyl)-1H-tetrazol-5-yl)methanol (3i)

White solid, mp 64-65 °C, yield: 112 mg (42%); 1H NMR (500 MHz, CDCl3) δ 7.58 (dd,

J = 7.9, 1.1, 1H), 7.28 (td, J = 7.3, 1.1, 1H), 7.21 (td, J = 7.7, 1.6, 1H), 7.04 (dd, J = 7.7,

1.5, 1H), 5.73 (s, 2H), 5.13 (s, 1H), 4.94 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 154.5, 133.3,

132.7, 130.5, 129.9, 128.2, 123.2, 53.6, 51.4. MS (ESI) m/z calculated [M+H]+: 269.00;

found [M+H]+: 269.00.

1-(1-(2-bromobenzyl)-1H-tetrazol-5-yl)-2-methylpropan-1-ol (3j)


(dd, J = 7.8, 0.9, 1H), 7.24 (dt, J = 7.6, 3.8, 1H), 7.19 (td, J = 7.7, 1.5, 1H), 6.88 (dd,

J = 7.6, 1.1, 1H), 5.79 (s, 2H), 4.89 – 4.73 (m, 1H), 4.67 (d, J = 6.2, 1H), 2.11 (dq, J = 13.6,

6.8, 1H), 1.03 (d, J = 6.7, 3H), 0.77 (d, J = 6.8, 3H). 13C NMR (126 MHz, CDCl3) δ 156.5,

133.5, 133.1, 130.1, 129.2, 128.0, 122.8, 70.3, 51.4, 33.4, 18.7, 18.0. MS (ESI) m/z calculated [M+H]+:

311.04; found [M+H]+: 311.09.



71

3

1-(1-(tert-butyl)-1H-tetrazol-5-yl)-3-phenylpropan-1-ol (3k)

White solid, mp 102-103 °C, yield: 228 mg (88%); 1H NMR (500 MHz, CDCl3) δ 7.32

– 7.26 (m, 2H), 7.20 (d, J = 7.3, 3H), 5.00 (td, J = 9.3, 4.8, 1H), 3.96 (d, J = 9.9, 1H),

3.01 – 2.78 (m, 2H), 2.55 – 2.40 (m, 1H), 2.34 – 2.19 (m, 1H), 1.63 (s, 9H). 13C NMR

(126 MHz, CDCl3) δ 156.5, 140.6, 128.6, 128.5, 126.2, 63.9, 61.7, 38.2, 31.6, 29.9. MS


1-(1-benzyl-1H-tetrazol-5-yl)propan-1-ol (3l)


– 7.22 (m, 5H), 5.73 (d, J = 15.1, 1H), 5.68 (d, J = 15.1, 1H), 4.94 (dd, J = 13.3, 6.3,

1H), 4.84 (d, J = 6.2, 1H), 1.94 – 1.73 (m, 2H), 0.87 (t, J = 7.4, 3H). 13C NMR (126

MHz, CDCl3) δ 156.3, 134.0, 129.0, 128.7, 127.9, 66.3, 51.5, 28.9, 9.6. MS (ESI) m/z

calculated [M+H]+: 219.12; found [M+H]+: 219.10.

1-(1-benzyl-1H-tetrazol-5-yl)-3-methylbutan-1-ol (3m)

White solid, mp 85-86 °C, yield: 226 mg (92%); 1H NMR (500 MHz, CDCl3) δ 7.35 –

7.30 (m, 3H), 7.28 – 7.23 (m, 2H), 5.74 (d, J = 15.2, 1H), 5.67 (d, J = 15.1, 1H), 5.15

– 4.95 (m, 1H), 4.55 (d, J = 6.4, 1H), 1.81 – 1.60 (m, 2H), 1.54 – 1.42 (m, 1H), 0.82

(d, J = 6.6, 3H), 0.77 (d, J = 6.5, 3H). 13C NMR (126 MHz, CDCl3) δ 156.7, 133.9, 129.0,

128.7, 127.9, 63.2, 51.5, 44.3, 24.2, 22.8, 21.6. MS (ESI) m/z calculated [M+Na]+: 269.14; found [M+Na]+:

269.13.

1-(1-(tert-butyl)-1H-tetrazol-5-yl)-2-phenylethanol (3n)


– 7.30 (m, 3H), 7.28 – 7.23 (m, 2H), 5.74 (d, J = 15.2, 1H), 5.67 (d, J = 15.1, 1H), 5.15

– 4.95 (m, 1H), 4.55 (d, J = 6.4, 1H), 1.81 – 1.60 (m, 2H), 1.54 – 1.42 (m, 1H), 0.82 (d,

J = 6.6, 3H), 0.77 (d, J = 6.5, 3H). 13C NMR (126 MHz, CDCl3) δ 156.7, 133.9, 129.0, 128.7, 127.9, 63.2, 51.5,

44.3, 24.2, 22.8, 21.6. MS (ESI) m/z calculated [M+Na]+: 269.14; found [M+Na]+: 269.19.

(1-(tert-butyl)-1H-tetrazol-5-yl)(phenyl)methanol (3o)

White solid, mp 122-123 °C, yield: 95 mg (41%); 1H NMR (500 MHz, CDCl3) δ 7.36 (t,

J = 5.8, 3H), 7.33 – 7.25 (m, 2H), 6.30 (d, J = 7.3, 1H), 4.29 (s, 1H), 1.63 (s, 9H). 13C NMR

(126 MHz, CDCl3) δ 155.8, 139.2, 129.0, 128.9, 127.2, 68.5, 62.1, 29.9. MS (ESI) m/z

calculated [M+Na]+: 255.12; found [M+Na]+: 255.08.

(1-benzyl-1H-tetrazol-5-yl)(2,6-dichlorophenyl)methanol (3p)


– 7.30 (m, 4H), 7.29 (s, 1H), 7.24 (dd, J = 13.1, 6.0, 1H), 7.18 (dd, J = 6.5, 2.8, 2H), 6.63

(d, J = 9.3, 1H), 5.70 (d, J = 4.5, 2H), 3.94 (d, J = 9.4, 1H). 13C NMR (126 MHz, CDCl3)

δ 154.0, 135.2, 133.4, 132.9, 130.9, 129.4, 129.0, 128.7, 127.5, 65.2, 51.8. MS (ESI) m/z



Chapter 3

72

(1-cyclohexyl-1H-tetrazol-5-yl)(2,3-dichlorophenyl)methanol (3q)

White soild, mp 156-157 °C, yield: 238 mg (73%); 1H NMR (500 MHz, CDCl3) δ 7.65

(dd, J = 7.9, 1.3, 1H), 7.50 (dd, J = 8.0, 1.5, 1H), 7.33 (t, J = 7.9, 1H), 6.49 (d, J = 6.2, 1H),

4.72 (d, J = 6.3, 1H), 4.29 (tt, J = 11.4, 3.8, 1H), 1.99 – 1.77 (m, 6H), 1.75 – 1.70 (m, 1H),

1.41 – 1.20 (m, 3H); 13C NMR (126 MHz, CDCl3) δ 153.9, 138.3, 133.6, 130.9, 130.6,

127.9, 126.4, 64.2, 58.6, 32.8, 32.7, 25.3, 25.3, 24.8. MS (ESI) m/z calculated [M+H]+:

327.07; found [M+H]+: 327.03.

(5-bromo-2-methoxyphenyl)(1-phenethyl-1H-tetrazol-5-yl)methanol (3r)

White soild, mp 133-134 °C, yield: 178 mg (46%); 1H NMR (500 MHz, CDCl3)

δ 7.47 – 7.40 (m, 2H), 7.35 – 7.27 (m, 3H), 7.04 (dd, J = 7.6, 1.4, 2H), 6.76 (d,

J = 9.4, 1H), 5.85 (d, J = 7.0, 1H), 4.56 (t, J = 7.5, 2H), 3.86 (d, J = 7.0, 1H), 3.70

(s, 3H), 3.18 – 3.01 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 155.6, 155.3, 136.5,

132.9, 130.5, 129.0, 128.8, 128.1, 127.3, 113.5, 112.8, 63.1, 55.9, 49.2, 36.2. MS (ESI) m/z calculated

[M+H]+: 389.03; found [M+H]+: 389.03.

(2-bromophenyl)(1-cyclohexyl-1H-tetrazol-5-yl)methanol (3s)


(dd, J = 7.8, 1.4, 1H), 7.57 (dd, J = 8.0, 0.8, 1H), 7.40 (t, J = 7.6, 1H), 7.24 (td, J = 7.8,

1.6, 1H), 6.48 (d, J = 6.0, 1H), 4.90 (d, J = 6.0, 1H), 4.25 (tt, J = 11.3, 3.8, 1H), 1.92 – 1.79

(m, 5H), 1.78 – 1.63 (m, 2H), 1.35 – 1.18 (m, 3H); 13C NMR (126 MHz, CDCl3) δ 154.4,

137.5, 133.1, 130.5, 128.8, 128.2, 122.3, 66.0, 58.5, 32.7, 32.7, 25.3, 24.8. MS (ESI) m/z calculated [M+H]+:

337.06; found [M+H]+: 337.05.

(2-chloro-3,4-dimethoxyphenyl)(1-cyclohexyl-1H-tetrazol-5-yl)methanol (3t)


(d, J = 8.7, 1H), 6.89 (d, J = 8.8, 1H), 6.46 (d, J = 6.0, 1H), 4.62 (d, J = 6.1, 1H), 4.25 (tt,

J = 11.5, 3.8, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 1.91 – 1.81 (m, 4H), 1.76 – 1.64 (m, 2H),

1.38 – 1.15 (m, 4H); 13C NMR (126 MHz, CDCl3) δ 154.7, 154.01, 145.5, 128.8, 127.1,

123.5, 110.9, 63.8, 60.7, 58.4, 56.1, 32.7, 32.7, 25.3, 24.8. MS (ESI) m/z calculated

[M+H]+: 353.13; found [M+H]+: 353.05.

(1-cyclohexyl-1H-tetrazol-5-yl)(6-nitrobenzo[d][1,3]dioxol-5-yl)methanol (3u)

Yellow soild, mp 198-199 °C, yield: 135 mg (39%); 1H NMR (500 MHz, CDCl3)

δ 7.63 (s, 1H), 7.45 (s, 1H), 6.67 (d, J = 5.9, 1H), 6.19 (d, J = 11.5, 2H), 4.60 (t,

J = 11.6, 1H), 4.06 (d, J = 5.7, 1H), 2.22 (d, J = 12.3, 1H), 2.15 – 1.94 (m, 5H), 1.78 (d,

J = 12.1, 1H), 1.49 – 1.32 (m, 3H); 13C NMR (126 MHz, CDCl3) δ 153.2, 132.7, 129.8,


found [M+H]+: 348.27.



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3

(1-cyclohexyl-1H-tetrazol-5-yl)(2,5-dimethoxyphenyl)methanol (3v)

White soild, mp 189-190 °C, yield: 152 mg (48%); 1H NMR (500 MHz, CDCl3)

δ 6.93 (d, J = 2.2, 1H), 6.86 (d, J = 3.1, 2H), 6.34 (d, J = 6.5, 1H), 4.35 (tt, J = 11.3,

3.7, 1H), 3.98 (d, J = 6.7, 1H), 3.75 (s, 6H), 1.94 – 1.83 (m, 4H), 1.80 – 1.67 (m, 2H),

1.40 – 1.19 (m, 4H); 13C NMR (126 MHz, CDCl3) δ 154.9, 154.0, 150.5, 127.4, 114.89,


found [M+H]+: 319.22.

1-(1-benzyl-1H-tetrazol-5-yl)cyclohexanol (3w)

Colorless liquid, yield: 216 mg (84%); 1H NMR (500 MHz, CDCl3) δ 7.32 – 7.26 (m, 3H),

7.25 – 7.21 (m, 2H), 5.83 (s, 2H), 3.84 (s, 1H), 1.98 – 1.87 (m, 2H), 1.85 – 1.76 (m, 2H),

1.76 – 1.53 (m, 5H), 1.36 – 1.21 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 159.6, 134.9, 128.8,

128.3, 127.8, 70.45, 52.2, 37.0, 24.9, 21.1. MS (ESI) m/z calculated [M+H]+: 259.15; found

[M+NH]+: 259.17.

1-benzyl-4-(1-benzyl-1H-tetrazol-5-yl)piperidin-4-ol (3x)

Colourless liquid, yield: 160 mg (46%); 1H NMR (500 MHz, CDCl3) δ 7.36 – 7.26 (m, 7H),

7.25 – 7.18 (m, 3H), 5.82 (s, 2H), 3.52 (s, 2H), 3.40 (s, 1H), 2.79 – 2.59 (m, 2H), 2.43 (td,

J = 11.6, 2.1, 2H), 2.31 – 2.11 (m, 2H), 1.77 (d, J = 12.8, 2H). 13C NMR (126 MHz, CDCl3)

δ 158.8, 138.3, 134.8, 129.0, 128.9, 128.5, 128., 127.6, 127., 68.70, 62., 52., 48., 36.6. MS


Procedure for the synthesis of 5,11-dihydrobenzo[f]tetrazolo[5,1-c][1,4]oxazepine

A 10 ml RBF equipped with a magnetic stirring bar was charged with (1-(2-bromobenzyl)-1H-tetrazol-

5-yl)methanol (0.5 mmol, 134 mg), Copper triflate (20 mol%, 36 mg), N,N’Dimethylethylenediamine

(40 mol%, 21ml), K2CO

3 (4 equivalent, 276 mg) in toluene (2ml) and refluxed overnight. Then the

reaction mixture was added to a 25 ml saturated NaHCO3 solution and extracted in ethyl acetate. The

solvent was removed under reduced pressure and the mixture was purified by flash chromatography

on silica gel (eluent: hexane/EtOAc) to afford the titled compound as a white solid.


Chapter 3

74

5,11-dihydrobenzo[f]tetrazolo[5,1-c][1,4]oxazepine (4)

White solid, yield: 83 mg (89%); 1H NMR (500 MHz, CDCl3) δ 7.46 (td, J = 7.9, 1.4, 1H), 7.43 – 7.38

(m, 1H), 7.30 (d, J = 8.0, 1H), 7.25 (t, J = 7.5, 1H), 5.65 (s, 2H), 5.48 (s, 2H). 13C NMR (126 MHz, CDCl3)

δ 157.7, 152.1, 131.7, 129.3, 127.8, 126.1, 122.2, 67.6, 49.5. MS (ESI) m/z calculated [M+H]+: 189.07;

found [M+Na]+: 189.10.



75

3

References [1] For a review on the importance of tetrazole derivatives, see: (a) C. X. Wei, M. Bian, G. H. Gong, Molecules

2015, 20, 5528–5553; (b) J. Roh, K. Vavrova, A. Hrabalek, Eur. J. Org. Chem. 2012, 6101–6118; (c) P. B. Mohite, V. H. Bhaskar, Int. J. Pharm.Tech. Res. 2011, 3, 1557–1566; (d) L. M. Frija, A. Ismael, M. L. S. Cristiano, Molecules 2010, 15, 3757–3774; (e) L. V. Myznikov, A. Hrabalek, G. I. Koldobskii, Chem. Heterocycl. Compd. 2007, 43, 1–9.

[2] For a review on the synthesis of tetrazole derivatives, see: (a) M. Malik, M. Wani, S. Al-Thabaiti, R. Shiekh, J. Incl. Phenom. Macrocycl. Chem. 2014, 78, 15–37; (b) G. I. Koldobskii, Russ. J. Org. Chem. 2006, 42, 469–486; (c) R. J. Herr, Bioorg. Med. Chem. 2002, 10, 3379–3393; d) V. Y. Zubarev, V. A. Ostrovskii, Chem. Heterocycl. Compd. 2000, 36, 759–774; (e) S. J. Wittenberger, Org. Prep. Proced. Int. 1994, 26, 499–531.

[3] A. Sarvary, A. Maleki, Mol. Divers. 2015, 19, 189–212.

[4] For a general review on the importance of MCR reactions, see: (a) A. Dömling, W. Wang, K. Wang, Chem. Rev. 2012, 112, 3083–3135; (b) T. Zarganes-Tzitzikas, A. L. Chandgude, A. Dömling, Chem. Rec. 2015, 15, 981-996.

[5] (a) M. Passerini, L. Simone, Gazz. Chim. Ital. 1921, 51, 126-129; b) M. Passerini, G. Ragni, Gazz. Chim. Ital. 1931, 61, 964-969.

[6] I. Ugi, R. Meyer, Chem. Ber. 1961, 94, 2229-2233.

[7] (a) T. Sela, A. Vigalok, Adv. Synth. Catal. 2012, 354, 2407–2411; (b) T. Yue, M. X. Wang, D.-X. Wang, J. Zhu, Angew. Chem. Int. Ed. 2008, 47, 9454-9457; (c) L. Banfi, R. Riva, Org. React. 2005, 65, 1-140.

[8] T. Nixey, C. Hulme, Tetrahedron Lett. 2002, 43, 6833-6835.

[9] (a) I. Monfardini, J.-W. Huang, B. Beck, J. F. Cellitti, M. Pellecchia, A. Domling, J. Med. Chem. 2011, 54, 890-900; (b) E. S. Schremmer, K. T. Wanner, Heterocycles 2007, 74, 661-671.

[10] M. Giustiniano, T. Pirali, A. Massarotti, B. Biletta, E. Novellino, P. Campiglia, G. Sorba, G. C. Tron, Synthesis 2010, 4107–4118.

[11] D. Amantini, R. Beleggia, F. Fringuelli, F. Pizzo, L. Vaccaro, J. Org. Chem. 2004, 69, 2896–2898.

[12] (a) R. B. Nasir Baig, R. S. Varma, Chem. Soc. Rev. 2012, 41, 1559–1584; (b) G. Cravotto, P. Cintas, Chem. Soc. Rev. 2006, 35, 180–196; (c) P. Cintas, J. Luche, Green Chem. 1999, 1, 115-125; (d) C. Cui, C. Zhu, X.-J. Du, Z.-P. Wang, Z.-M. Li, W.-G. Zhao, Green Chem. 2012, 14, 3157-3163.

[13] (a) T. J. Mason, Chem. Soc. Rev. 1997, 26, 443–451; (b) R. F. Abdulla, Adrichimica Acta, 1988, 21, 31-42; (c) A. Loupy, J. L. Luche, in Synthetic Organic Sonochemistry, ed. J. L. Luche, Plenum Press, New York, 1998, pp. 107–166; (d) L. H. Thompson and L. K. Doraiswamy, Ind. Eng. Chem. Res., 1999, 38, 1215–1249.

[14] C. Cui, C. Zhu, X.-J. Du, Z.-P. Wang, Z.-M. Li, W.-G. Zhao, Green Chem. 2012, 14, 3157-3163.



Chapter 4Unconventional Passerini Reaction

towards α-Aminoxy-amides

Part of this thesis was published in: A. L. Chandgude

A. Dömling, Org. Lett., 2016, 18, 6396-6399.


Chapter 4

78

Abstract

The Passerini multicomponent reaction (P-3CR) towards the one-step synthesis of α-aminoxy-amide,

by employing for the first time a N-hydroxamic acid component, has been reported. The sonication-

accelerated, catalyst-free, simple, fast, and highly efficient Passerini reaction is used for the synthesis

of diverse α-aminoxy-amides. The reaction is compatible with a vast range of aldehydes, isocyanides,

and N-hydroxamic acids such as N-hydroxysuccinimides and phthalimides. The generated Passerini

products can be easily converted into several follow-up products.


Unconventional Passerini Reaction towards α-Aminoxy-amides

79

4

Introduction

Recently, the design and synthesis of peptidomimetics has gained attention in drug discovery, due

to the potential structural and functional advantages over natural proteins.[1] Modified structures and

functional groups increase the activity, selectivity and bioavailability. Also provide structural rigidity

and stability.[2] Among the peptidomimetics, α-aminoxy-acids stand out as analogs of b-amino

acids. The α-aminoxy-amides can adopt the structure of the secondary eight-membered N-O turn,

which confers extra stability towards enzymatic degradation (Figure 1).[3] These peptidomimetic

foldamers are used as building blocks to construct anion receptors and channels. e.g. to mimic anion

recognition and transport processes.[4]

Figure 1. Model of an eight-membered turn involving α-aminoxy-amide.

Owing to the importance of α-aminoxy-amides, significant effort has been made towards

their design and synthesis. The majority of α-aminoxy-amides synthesis methodologies can be

categorized into two general approaches. The first is coupling between an a-halo acid, ester or amide

with N-hydroxyphthalimide (NHPI) or N-hydroxysuccinimide (NHS)[5] (Scheme 1. Approach A). The

second is the Mitsunobu reaction of a-hydroxy acid, ester or amide with NHPI or NHS[6,7] (Scheme 1.

Approach B). These methods suffer from poor availability of starting materials, hence diversity in the

products, lengthy multistep preparation, long reaction times, low yields, and also use of coupling

reagents which require tedious work-up. Currently there is no known method to directly access

the α-aminoxy-amides from simple starting materials, with high efficiency and scope. Isocyanide-

based multicomponent reactions (IMCRs) have already been proven as a promising strategy for the

synthesis of peptidomimetics.[8] This highly convergent approach provides pronounced diversity

and complexity.[9]

We envisioned the use of N-hydroxamic acid as a novel acid isostere in the Passerini reaction,

which is potentially suitable for the synthesis of α-aminoxy-amides. Surprisingly, the use of carboxylic

acid-isosteres in the Passerini reaction is relatively unexplored,[10] with the exception of hydrogene

azide,[11] nitro-phenol,[12] silanol[13] and phosphinic acid.[14] In the Passerini reaction, the acyl group of

the carboxylic acid acts mechanistically as an electrophile while the OH group works as a nucleophile.

Here we hypothesized that, in the Passerini reaction, the OH group of the hydroxamic acid acts as


Chapter 4

80

the nucleophilic, and the imide-N as the electrophilic species towards the nitrilium intermediate.

Weak hydroxamic acids such as NHS or NHPI (pKa ~7.5) might be able to activate an aldehyde in the

Passerini reaction to allow the attack of the the isocyanide. Further trapping of the resulting nitrilium

intermediate by the hydroxamate affords the final product after the migration of the imide onto the

oxygen atom, originating from the aldehyde (Scheme 1).

Scheme 1. Previous and new synthesis of N-aminoxy amide and a proposed mechanism for P-3CR.


To test the feasibility of hydroxamic acids, we investigated the reaction between isobutyraldehyde

(1.0 equiv), phenylethyl isocyanide (1.0 equiv), and N-hydroxysuccinimide (2.0 equiv) with different

solvents and conditions (Table 1). When the reaction was performed in DCM, a promising 22% yield

of a mixture of the expected product 4a and the free hydroxyl-amide 5 was obtained (Table 1. Entry

1). Use of catalysts such as ZnCl2, PTSA or BF

3.OEt

2 then resulted in only trace product formation



81

4

(Table 1. Entries 2–4). However, the reaction in CH3CN and THF solvents gave desired product in

moderate yields of 58%, after stirring overnight at room temperature (Table 1. Entries 5 and 6).

Water is a known accelerator of the Passerini reaction.[15] However, use of water or a mixture with

methanol as solvent in our case led to hydroxyl amide 5 as the major product. The expected product

4a formed only in a trace amount even after increasing the temperature (Table 1. Entries 7–10).

Increase the temperature in THF solvent reduced the yields slightly to 50%, while in acetonitrile a

considerable yield decrease to 38% was found (Table 1. Entries 11 and 12). Recently we showed

that, sonication greatly increased the efficiency of the Passerini reaction.[16] Applying sonication to

our new reaction led to the α-hydroxy amide 5 as the major product in water and a water/methanol

mixture (Table 1. Entries 14 and 15). Remarkably, use of sonication together with THF as the solvent

increased the yield to an almost quantitative 97%, and moreover the reaction required only 2

hours for completion. An equivalence study of NHS showed that 2 equivalents are necessary to get

maximum yield. An increase or decrease in the NHS equivalents reduced the yield (Table 1. Entries

16–18).

Table 1. Optimization conditions.a

Entry Solvent Temp Condition / catalyst Time (h) Yield (%)c

1 DCM rt 12 22f

2b DCM rt ZnCl2

12 trace

3b DCM rt PTSA 12 trace

4b DCM rt BF3.OEt

212 trace

5 CH3CN rt 12 58

6 THF rt 12 58

7MeOH : H

2O

(1 : 1)rt 12

56f

8 H2O rt 12 trace

9MeOH : H

2O

(1 : 1)60 °C 12 35f

10 H2O 60 °C 12 45f

11 THF 60 °C 12 50

12 CH3CN 60 °C 12 38

13 DCM 60 °C 12 44f

14MeOH : H

2O

(1 : 1)rt sonication 2

76f

15 H2O rt sonication 2 63f


Chapter 4

82

Entry Solvent Temp Condition / catalyst time (h) Yield (%)c

16 THF rt sonication 2 97

17d THF rt sonication 2 82

18e THF rt sonication 2 78aThe reaction was carried out with phenylethyl isocyanide (1.0 mmol), isobutyraldehyde (1.0 mmol) and N-hydroxysuccinimide (2.0 mmol). b10 mol % catalyst used. cYield of isolated product 4a. d1 equivalent NHS used. e3 equivalent NHS used. fTotal yield of 4a and 5 as a mixture.

With these optimized conditions in hand, we then investigated the scope of this novel P-3CR by

reacting different hydroxamic acids, aldehydes, and isocyanides (Scheme 2). NHS gave excellent yields

with benzyl and phenylethyl isocyanides when used with different aldehydes 4a-4c. Furthermore,

we screened the NHPI. An 81% isolated yield obtained from 2 equivalents of NHPI with phenylethyl

isocyanide and isobutylaldehyde, however 1.5 equivalents of NHPI provided the best yield, 89% 4r.

NHPI in 1 and 3 equivalents led to 74 and 63% yields, respectively. NHPI works well with aliphatic

aldehydes such as isobutylaldehyde, cyclohexylcarbaldehyde or even bulky tert-butylaldehyde 4e,

4f, 4i. Aliphatic aromatic aldehydes such as phenylacetaldehyde or phenylethylaldehydes gave

good yields. Aromatic aldehydes also performed well in this reaction giving moderate to good

yields 4k-m. Aromatic aldehydes having electron-donating groups such as tri-methoxy moiety

demonstrated very low reactivity, and their reactions did not produce any of the desired product

4n. Different isocyanides were tested and found to be good substrates for this reaction. Protected

isocyanides like valine ester isocyanide or 1,1-diethoxy-2-isocyanoethane isocyanide 4g, 4o, 4p also

provide moderate to good yields, which potentially allows for further modifications for synthesis of

the diverse scaffolds and more complex peptide mimetics (Figure 1). Products 4g and 4p are formed

as ~1 : 1 mixture of diastereomers. Halogen functionality on an isocyanide could also provide scope

for further coupling reactions in the case of 4i.

In the reaction with HOBt it was found that the product (as confirmed by mass spectroscopy)

is relatively unstable during silica or neutral alumina column chromatography and converts to

α-hydroxy amides 4s. To further investigate the scope of hydroxamic acids, we tested the free NH

hydroxamic acids, but disappointingly they did not form the desired products 4t-4v. These results

show that the nitrogen of the hydroxamic acids should not be acidic to give the product.



83

4

Scheme 2. Substrate scope of the synthesis of α-aminoxy amides from isocyanide, aldehyde and N-hydroxamic acid.a

aReaction conditions: 1.0 mmol 1, 1.0 mmol 2, 2.0 mmol NHS, HOBT, N-hydroxamic acids, 1.5 mmol NHPI 3, and 1 ml THF. nd = not determined.


Chapter 4

84

Scheme 2. (Continued)

Next we used our P-3CR towards the preparation of the oxyamines, which are important

intermediates for the synthesis of peptidomimetics as well as different scaffolds like oxime ethers

and benzofurans.[17] When 2-((1,3-dioxoisoindolin-2-yl)oxy)-3-methyl-N-phenethylbutanamide 4j

was treated with hydrazine for 5 hours at room temperature, it forms the oxy-amine which was

further used for the synthesis of an amide and sulphonamide (Scheme 3). We obtained 71% product

with pivaloyl chloride coupling 6 and 64% with p-TsCl 7.[18]

Scheme 3. Deprotection towards O-hydroxylamines and acylation/sulfonylation.



85

4

Conclusion

In conclusion, we have introduced for the first time N-hydroxamic acids in the Passerini three-

component reaction. We developed a novel, catalyst-free, mild, work-up free, efficient and general

hydroxamic acid based Passerini reaction to gain access to α-aminoxy-amides. This methodology

is applicable to a wide range of isocyanides and aldehydes. Functional group compatibility in this

methodology provides easy access for further modifications. This modified-Passerini reaction has

the ability to expand the scope of substrate for investigation as peptidomimetic design and has the

potential to become a preferred method for the synthesis of complex α-aminoxy amides.


General procedure for the synthesis of α-aminoxy amides A 10 ml tube was charged with aldehyde (1.0 mmol) and isocyanide (1.0 mmol) and NHS/HOBT/N-

hydroxamic acids (2 mmol) or NHPI (1.5 mmol) with THF (1 ml). The mixture was sonicated in the

water bath of an ultrasonic cleaner (frequency of 50/60 Hz, 220/240V, 25 Amps) at room temperature

till completion of the reaction (monitored by TLC). The solvent was removed under reduced pressure


Spectral Data

2-((2,5-dioxopyrrolidin-1-yl)oxy)-3-methyl-N-phenethylbutanamide (4a)

Obtained from 0.5 mmol reaction as a colorless liquid, yield: 154 mg (97%); 1H NMR (500 MHz, CDCl

3) δ 7.33 – 7.24 (m, 2H), 7.19 (t, J = 7.3, 1H), 7.14 (d,

J = 7.2, 2H), 4.16 (d, J = 8.2, 1H), 3.76 – 3.61 (m, 2H), 3.38 (s, 1H), 2.74 (td,

J = 6.8, 2.5, 2H), 2.59 (s, 4H), 2.16 – 1.98 (m, 1H), 1.06 (d, J = 6.6, 3H), 0.97 (d,

J = 6.8, 3H). 13C NMR (126 MHz, CDCl3) δ 170.8, 155.3, 139.8, 129.0, 128.2,

126.1, 72.2, 48.2, 37.2, 32.2, 25.5, 18.5, 18.3. MS (ESI) m/z calculated [M+H]+ : 319.37; found [M+H]+ :

319.28. HRMS (ESI) m/z calculated [M+H]+ : 319.16523; found [M+H]+ : 319.16483.

N-benzyl-2-cyclohexyl-2-((2,5-dioxopyrrolidin-1-yl)oxy)acetamide (4b)

Obtained from 1 mmol reaction as a white solid, yield: 296 mg (86%); 1H NMR

(500 MHz, CDCl3) δ 7.32 – 7.25 (m, 2H), 7.20 (t, J = 7.3, 1H), 7.13 (d, J = 7.5, 2H),

4.64 (s, 2H), 4.36 (br s, 1H), 3.68 (d, J = 4.4, 1H), 2.71 (s, 4H), 2.10 (d, J = 12.4, 1H),

1.90 – 1.60 (m, 5H), 1.33 – 1.20 (m, 2H), 1.20 – 1.12 (m, 1H), 1.12 – 0.96 (m, 2H). 13C NMR (126 MHz, CDCl

3) δ 170.8, 156.7, 139.5, 128.3, 126.7, 126.6, 71.8, 50.4,

41.5, 28.8, 28.5, 26.3, 25.9, 25.7, 25.6. MS (ESI) m/z calculated [M+H]+ : 345.40; found [M+H]+ : 345.30.

HRMS (ESI) m/z calculated [M+H]+ : 345.18088; found [M+H]+ : 345.18024.


Chapter 4

86

N-benzyl-2-((2,5-dioxopyrrolidin-1-yl)oxy)-3-methylbutanamide (4c)

Obtained from 1 mmol reaction as a white viscus liquid, yield: 276 mg (91%); 1H

NMR (500 MHz, CDCl3) δ 7.28 (t, J = 7.5, 2H), 7.19 (t, J = 7.3, 1H), 7.13 (d, J = 7.5,

2H), 4.65 (s, 2H), 4.31 (d, J = 7.9, 1H), 3.87 (s, 1H), 2.71 (s, 4H), 2.25 – 2.07 (m, 1H),

1.10 (d, J = 6.6, 3H), 1.03 (d, J = 6.8, 3H). 13C NMR (126 MHz, CDCl3) δ 170.8, 156.8,

139.5, 128.3, 126.7, 126.6, 72.6, 50.3, 32.3, 25.6, 18.4. MS (ESI) m/z calculated [M+H]+ : 305.34; found

[M+H]+ : 305.23. HRMS (ESI) m/z calculated [M+H]+ : 305.14958; found [M+H]+ : 305.14966.

N-cyclohexyl-2-((1,3-dioxoisoindolin-2-yl)oxy)-4-phenylbutanamide (4d)


3) δ 7.86 (d, J = 3.1, 2H), 7.81 – 7.74 (m, 2H), 7.39 – 7.08

(m, 6H), 4.64 (brs, 1H), 3.44 (brs, 1H), 2.88 (brs, 2H), 2.28 – 2.04 (m, 2H), 1.41 (brs,

5H), 1.09 (brs, 5H). 13C NMR (126 MHz, CDCl3) δ 163.9, 153.6, 141.1, 134.5, 129.4,

128.6, 128.5, 126.1, 123.6, 66.0, 54.7, 36.5, 33.8, 31.2, 25.5, 23.4. MS (ESI) m/z

calculated [M+H]+ : 407.47; found [M+H]+ : 407.30. HRMS (ESI) m/z calculated

[M+H]+ : 407.19653; found [M+H]+ : 407.19626.

N-benzyl-2-cyclohexyl-2-((1,3-dioxoisoindolin-2-yl)oxy)acetamide (4e)


3) δ 7.89 – 7.78 (m, 2H), 7.76 – 7.68 (m, 2H), 7.17 –

7.06 (m, 3H), 6.99 (d, J = 7.2, 2H), 4.65 (s, 2H), 4.51 – 4.41 (m, 1H), 3.64 (d,

J = 6.0, 1H), 2.15 (d, J = 12.4, 1H), 2.01 – 1.87 (m, 2H), 1.84 – 1.75 (m, 2H), 1.68

(d, J = 12.5, 1H), 1.33 – 1.07 (m, 5H). 13C NMR (126 MHz, CDCl3) δ 163.6, 157.2,

139.3, 134.5, 129.3, 128.1, 126.6, 126.4, 123.7, 72.0, 50.3, 41.7, 28.9, 28.5, 26.3, 25.9, 25.8. MS (ESI) m/z

calculated [M+H]+ : 393.45; found [M+H]+ : 393.25. HRMS (ESI) m/z calculated [M+H]+ : 393.18088;

found [M+H]+ : 393.18088.

2-((1,3-dioxoisoindolin-2-yl)oxy)-3,3-dimethyl-N-phenethylbutanamide (4f)

Obtained from 0.5 mmol reaction as a colorless liquid, yield: 119 mg

(63%); 1H NMR (500 MHz, CDCl3) δ 7.87 – 7.82 (m, 2H), 7.81 – 7.74 (m, 2H),

7.15 – 7.06 (m, 3H), 6.99 (d, J = 6.5, 2H), 4.25 (s, 1H), 3.65 – 3.54 (m, 2H),

2.67 – 2.56 (m, 2H), 1.91 (s, 1H), 1.09 (s, 9H). 13C NMR (126 MHz, CDCl3)

δ 163.3, 155.2, 139.5, 134.4, 129.3, 128.9, 128.8, 128.1, 126.0, 123.6, 74.3,

49.4, 37.2, 35.7, 26.0, 25.9. MS (ESI) m/z calculated [M+H]+ : 381.44; found [M+H]+ : 381.28. HRMS (ESI)

m/z calculated [M+H]+ : 381.18088; found [M+H]+ : 381.18069.



87

4

methyl 2-(2-((1,3-dioxoisoindolin-2-yl)oxy)-3-phenylpropanamido)-3-methylbutanoate (4g)

Obtained from 0.5 mmol reaction as a colorless liquid, yield: 150 mg (71%)

as a mixture of diastereomers (1:1.14); 1H NMR (500 MHz, CDCl3) δ 7.93 – 7.86

(m, 4H), 7.83 – 7.75 (m, 4H), 7.38 (t, J = 9.0, 4H), 7.35 – 7.30 (m, 4H), 7.24 (t,

J = 7.5, 2H), 4.82 (s, 1H), 4.70 (t, J = 7.0, 1H), 4.15 (s, 1H), 3.91 (s, 1H), 3.62 (s, 3H),

3.55 (s, 3H), 3.39 – 3.26 (m, 3H), 3.25 – 3.12 (m, 2H), 3.03 (s, 1H), 2.01 – 1.91 (m,

1H), 1.90 – 1.81 (m, 1H), 0.66 (brs, 3H), 0.47 (brs, 6H), 0.36 (brs, 3H). 13C NMR (126 MHz, CDCl3)

δ 171.6, 171.6, 163.5, 163.5, 158.4, 136.1, 136.0, 134.7, 134.5, 129.8, 129.7, 129.7, 129.4, 128.7, 128.6,

127.0, 127.0, 123.8, 123.6, 69.4, 68.9, 64.1, 63.8, 52.0, 51.9, 40.9, 40.2, 31.5, 31.3, 19.2, 19.2. MS (ESI) m/z


found [M+H]+ : 425.17065.

N-benzyl-2-((1,3-dioxoisoindolin-2-yl)oxy)-4-phenylbutanamide (4h)

Obtained from 1 mmol reaction as a colorless liquid, yield: 314 mg (76%); 1H NMR (500 MHz, CDCl

3) δ 8.00 – 7.66 (m, 4H), 7.41 – 7.21 (m, 5H), 7.17 –

7.06 (m, 3H), 6.96 (d, J = 7.0, 2H), 4.72 (d, J = 5.8, 1H), 4.56 (s, 2H), 3.18 (d, J =

4.7, 1H), 3.00 – 2.74 (m, 2H), 2.50 – 2.14 (m, 2H). 13C NMR (126 MHz, CDCl3)

δ 163.5, 157.4, 140.9, 139.1, 134.6, 129.3, 128.6, 128.5, 128.2, 126.5, 126.1,

123.8, 66.6, 50.1, 35.9, 31.1. MS (ESI) m/z calculated [M+H]+ : 415.45; found [M+H]+ : 415.24. HRMS (ESI)


N-(4-chlorobenzyl)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-methylbutanamide (4i)


(90%); 1H NMR (500 MHz, CDCl3) δ 7.86 (dd, J = 5.2, 3.1, 2H), 7.78 (dd,

J = 5.2, 3.1, 2H), 7.10 (d, J = 8.1, 2H), 6.93 (d, J = 8.0, 2H), 4.62 (s, 2H), 4.37 (t,

J = 7.2, 1H), 3.07 (d, J = 5.8, 1H), 2.34 – 2.14 (m, 1H), 1.16 (d, J = 6.6, 3H), 1.09

(d, J = 6.7, 3H). 13C NMR (126 MHz, CDCl3) δ 163.5, 157.4, 137.7, 134.6, 132.2, 129.2, 128.3, 127.9, 123.7,

73.0, 49.7, 32.6, 18.4. MS (ESI) m/z calculated [M+H]+ : 387.83; found [M+H]+ : 387.01. HRMS (ESI) m/z

calculated [M+H]+ : 387.11012; found [M+H]+ : 387.11029.

N-benzyl-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-phenylpropanamide (4j)

Obtained from 4 mmol reaction as a white solid, yield: 1210 mg (76%); 1H NMR

(500 MHz, CDCl3) δ 7.84 (d, J = 3.0, 2H), 7.74 (d, J = 2.8, 2H), 7.37 (d, J = 7.1, 2H),

7.29 (t, J = 7.2, 2H), 7.23 – 7.18 (m, 1H), 7.08 (d, J = 6.8, 3H), 6.85 (d, J = 6.2, 2H),

4.90 (brs, 1H), 4.29 (d, J = 16.1, 1H), 4.08 (d, J = 16.1, 1H), 3.32 (brs, 1H), 3.28 –

3.18 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 163.4, 156.3, 139.0, 135.8, 134.5, 129.8,

129.3, 128.7, 128.1, 127.1, 126.5, 126.4, 123.8, 68.7, 49.9, 41.0. MS (ESI) m/z calculated [M+H]+ : 401.43;

found [M+H]+ : 401.07. HRMS (ESI) m/z calculated [M+H]+ : 401.14958; found [M+H]+ : 401.14911.


Chapter 4

88

2-((1,3-dioxoisoindolin-2-yl)oxy)-N-phenethyl-2-phenylacetamide (4k)

Obtained from 0.5 mmol reaction as a colourless liquid, yield: 98 mg (49%); 1H NMR (500 MHz, CDCl

3) δ 7.84 (d, J = 3.0, 2H), 7.77 (dd, J = 4.6, 3.2, 2H),

7.41 (t, J = 8.1, 2H), 7.36 – 7.31 (m, 2H), 7.07 (brs, 3H), 6.88 (brs, 2H), 5.63

(s, 1H), 3.58 – 3.47 (m, 2H), 2.52 (t, J = 6.7, 2H). 13C NMR (126 MHz, CDCl3)

δ 168.2, 164.7, 138.5, 135.6, 134.5, 133.6, 129.8, 129.0, 128.8, 128.8, 128.7,

128.6, 127.3, 126.6, 123.7, 75.9, 40.3, 35.5. MS (ESI) m/z calculated [M+H]+ : 401.43; found [M+H]+ :


N-benzyl-2-(4-chlorophenyl)-2-((1,3-dioxoisoindolin-2-yl)oxy)acetamide (4l)

Obtained from 0.5 mmol reaction as a white solid, yield: 109 mg (52%); 1H NMR

(500 MHz, CDCl3) δ 7.86 (d, J = 2.8, 2H), 7.79 – 7.76 (m, 2H), 7.60 (d, J = 8.1, 2H),

7.40 (d, J = 8.1, 2H), 7.14 – 7.05 (m, 4H), 6.90 (d, J = 6.1, 2H), 5.79 (s, 1H), 4.57 (d,

J = 15.8, 1H), 4.47 (d, J = 15.9, 1H). 13C NMR (126 MHz, CDCl3) δ 163.4, 156.1,

138.7, 135.8, 135.2, 134.7, 134.5, 129.2, 129.1, 128.2, 127.9, 126.5, 123.9, 69.2, 50.0. MS (ESI) m/z


found [M+H]+ : 421.09506.

N-benzyl-2-((1,3-dioxoisoindolin-2-yl)oxy)-2-(2-nitrophenyl)acetamide (4m)

Obtained from 0.5 mmol reaction as a brown solid, yield: 156 mg (72%); 1H NMR

(500 MHz, CDCl3) δ 8.15 (dd, J = 33.5, 7.7, 2H), 7.87 – 7.68 (m, 7H), 7.55 (t, J = 7.4,

1H), 7.20 – 7.07 (m, 3H), 7.03 (d, J = 6.4, 2H), 6.53 (s, 1H), 4.77 (s, 2H). 13C NMR

(126 MHz, CDCl3) δ 163.2, 154.4, 147.5, 138.9, 134.7, 134.2, 133.6, 129.4, 129.2,

129.1, 128.2, 126.8, 126.6, 125.3, 123.8, 66.1, 50.9. MS (ESI) m/z calculated [M+H]+

: 432.40; found [M+H]+ : 432.13. HRMS (ESI) m/z calculated [M+H]+ : 432.11901;

found [M+H]+ : 432.11879.

N-(2,2-diethoxyethyl)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-methylbutanamide (4o)


3) δ 7.86 (dd, 2H), 7.81 – 7.75 (m, 2H), 4.41 – 4.25

(m, 2H), 3.82 (d, J = 2.2, 1H), 3.73 (dd, J = 12.5, 5.6, 1H), 3.67 – 3.55 (m, 2H), 3.53

– 3.46 (m, 1H), 3.46 – 3.36 (m, 2H), 2.35 – 2.19 (m, 1H), 1.15 – 1.08 (m, 12H). 13C NMR (126 MHz, CDCl

3) δ 163.1, 158.5, 134.4, 129.3, 123.6, 102.0, 72.6, 63.5,





89

4

methyl 2-(2-((1,3-dioxoisoindolin-2-yl)oxy)-3-methylbutanamido)-3-methylbutanoate (4p)


(46%) as a mixture of diastereomers (1:1.05); 1H NMR (500 MHz, CDCl3)

δ 7.92 – 7.84 (m, 4H), 7.78 (dd, J = 5.4, 3.1, 4H), 4.37 (d, J = 4.0, 1H), 4.27 (d,

J = 4.0, 2H), 4.13 (d, J = 8.6, 1H), 3.67 (s, 3H), 3.62 (s, 3H), 3.25 (s, 1H), 3.03 (s,

1H), 2.32 – 2.15 (m, 2H), 2.13 – 2.02 (m, 2H), 1.18 – 1.02 (m, 13H), 0.73 (dd,

J = 15.3, 5.8, 6H), 0.49 (s, 6H). 13C NMR (126 MHz, CDCl3) δ 171.9, 171.9, 171.7, 163.7, 163.6, 163.6, 163.6,

159.5, 134.7, 134.4, 129.4, 129.4, 123.6, 123.6, 73.8, 73.8, 64.6, 64.3, 64.2, 52.0, 51.9, 32.7, 32.7, 31.8, 31.8,

31.5, 31.2, 31.2, 19.3, 19.2, 18.5, 18.5, 18.5, 18.4 . MS (ESI) m/z calculated [M+H]+ : 377.40; found [M+H]+

: 377.37. HRMS (ESI) m/z calculated [M+H]+ : 377.17071; found [M+H]+ : 377.17036.

2-cyclohexyl-2-((1,3-dioxoisoindolin-2-yl)oxy)-N-phenethylacetamide (4q)


3) δ 7.93 – 7.82 (m, 2H), 7.80 – 7.72 (m, 2H), 7.16 –

7.04 (m, 3H), 6.99 (d, J = 6.8, 2H), 4.30 – 4.14 (m, 1H), 3.70 – 3.52 (m, 2H), 2.73

(d, J = 5.3, 1H), 2.69 – 2.53 (m, 2H), 2.09 (d, J = 12.5, 1H), 1.88 – 1.64 (m, 5H),

1.36 – 1.23 (m, 2H), 1.22 – 1.11 (m, 1H), 1.10 – 0.88 (m, 2H). 13C NMR (126

MHz, CDCl3) δ 163.3, 156.1, 139.6, 134.4, 129.2, 128.9, 128.1, 126.0, 123.6, 71.5, 48.8, 41.5, 37.2, 28.9,



2-((1,3-dioxoisoindolin-2-yl)oxy)-3-methyl-N-phenethylbutanamide (4r)

Obtained from 1 mmol reaction as a colorless liquid, yield: 324 mg (89%); 1H

NMR (500 MHz, CDCl3) δ 7.89 – 7.82 (m, 2H), 7.81 – 7.74 (m, 2H), 7.18 – 7.06

(m, 3H), 7.00 (d, J = 6.9, 2H), 4.24 – 4.08 (m, 1H), 3.71 – 3.52 (m, 2H), 2.75 –

2.55 (m, 3H), 2.14 – 1.99 (m, 1H), 1.09 (d, J = 6.5, 3H), 1.00 (d, J = 6.8, 3H). 13C

NMR (126 MHz, CDCl3) δ 163.3, 156.1, 139.6, 134.4, 129.2, 128.9, 128.2, 126.1,



Procedure for the synthesis of O-hydroxylamines and acylation/ sulfonylation

Procedure for the synthesis of N-benzyl-3-phenyl-2-(pivalamidooxy)propanamide (6)1


Chapter 4

90

To a solution of 4j (200 mg, 0.5 mmol) in 5 ml of methanol was added 200 μl of hydrazine hydrate.

This mixture was stirred at room temperature over 5 h, at the end of which the solvent was removed

and dissolved the residue in 15 ml of DCM and washed it with 3% NaHCO3 aqueous solution. The

organic layer was dried over anhydrous MgSO4, and then concentrated to afford colorless oil which

was subjected to the next step without further purification. To the solution of above crude product

in 2 ml of DCM/H2O (3 : 1) was added 207 mg of K

2CO

3 (3 equivalent), and followed by 61 μl of

pivaloyl chloride (0.5 mmol) at 0°C. The resulting mixture was stirred for 12 h, and then 10 ml of

DCM added to it and organic layer was separated and after washed with brine dried over anhydrous

MgSO4. The solvent was removed under reduced pressure and the residue was purified by silica gel

flash chromatography using EtOAc–hexane as eluent to afford 6.

(1: D. W. Zhang, Z. Luo, G. J. Liu and L. H. Weng, Tetrahedron, 2009, 65, 9997-10001.)

N-benzyl-3-phenyl-2-(pivalamidooxy)propanamide (6)

Obtained as a white solid, yield: 126 mg (71%); 1H NMR (500 MHz, CDCl3)

δ 7.34 – 7.30 (m, 4H), 7.29 – 7.27 (m, 2H), 7.26 – 7.23 (m, 3H), 7.21 (d, J =

7.3, 2H), 6.76 (s, 1H), 4.48 (dd, J = 14.7, 6.0, 1H), 4.45 – 4.34 (m, 2H), 3.27 (dd,

J = 13.9, 4.1, 1H), 2.95 (dd, J = 13.9, 8.2, 1H), 1.26 (s, 9H). 13C NMR (126 MHz,

CDCl3) δ 176.0, 172.2, 137.9, 136.6, 132.1, 129.6, 128.9, 128.7, 127.8, 127.6, 127.1, 73.0, 43.2, 40.9, 27.5,

27.1, 27.0. MS (ESI) m/z calculated [M+H]+: 355.44; found [M+H]+: 355.26.

Synthesis of N-benzyl-2-((4-methylphenylsulfonamido)oxy)-3 phenylpropanamide (7)

To a solution of 4j (200 mg, 0.5 mmol) in 5 ml of methanol was added 200 μl of hydrazine hydrate.

This mixture was stirred at room temperature over 5 h, at the end of which the solvent was removed

and dissolved the residue in 15 ml of DCM and washed it with 3% NaHCO3 aqueous solution. The

organic layer was dried over anhydrous MgSO4, and then concentrated to afford colorless oil which

was subjected to the next step without further purification. To the solution of above crude product

in 2 ml of DCM/H2O (3 : 1) was added 207 mg of K

2CO

3 (3 equivalent), and followed by 80 mg of

p-TsCl (0.5 mmol) at 0 °C. The resulting mixture was stirred for 12 h, and then 10 ml of DCM added

to it and organic layer was separated and after washed with brine dried over anhydrous MgSO4.

The solvent was removed under reduced pressure and the residue was purified by silica gel flash

chromatography using EtOAc-hexane as eluent to afford 7.



91

4

N-benzyl-2-((4-methylphenylsulfonamido)oxy)-3-phenylpropanamide (7)

Obtained as a white solid, yield: 135 mg (64%); 1H NMR (500 MHz,

CDCl3) δ 7.78 (d, J = 8.2, 2H), 7.34 (d, J = 8.1, 2H), 7.32 – 7.27 (m, 4H), 7.27

– 7.21 (m, 4H), 7.18 (d, J = 7.1, 2H), 6.87 (brs, 1H), 5.87 (s, 1H), 4.45 (dd,

J = 14.8, 6.1, 1H), 4.41 – 4.31 (m, 2H), 3.24 (dd, J = 13.9, 4.0, 1H), 2.93 (dd,

J = 13.9, 8.2, 1H), 2.44 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 172.6, 144.6,

137.8, 136.8, 133.1, 130.0, 129.6, 128.7, 128.7, 128.4, 128.2, 127.8, 127.5, 127.0, 72.9, 43.1, 40.9, 21.6. MS



Chapter 4

92

References

[1] For a general reviews on the peptidomimetics, a) R. Gopalakrishnan, A. I. Frolov, L. Knerr, W. J. Drury, 3rd, E. Valeur, J. Med. Chem., 2016, 59, 9599; b) A. Grauer, B. Konig, Eur. J. Org. Chem. 2009, 5099-5111; c) T. KieberEmmons, R. Murali, M. I. Greene, Curr. Opin. Biotech. 1997, 8, 435-441.

[2] a) J. Vagner, H. C. Qu, V. J. Hruby, Curr. Opin. Chem. Biol. 2008, 12, 292-296; b) A. S. Ripka, D. H. Rich, Curr. Opin. Chem. Biol. 1998, 2, 441-452; c) A. Giannis, Angew. Chem., Int. Ed. 1993, 32, 1244-1267.

[3] a) F. Chen, B. Ma, Z. C. Yang, G. Lin, D. Yang, Amino Acids 2012, 43, 499-503; b) X. Li, D. Yang, Chem. Commun. 2006, 3367-3379; c) D. J. Hill, M. J. Mio, R. B. Prince, T. S. Hughes, J. S. Moore, Chem. Rev. 2001, 101, 3893-4012; d) D. Yang, B. Li, F. F. Ng, Y. L. Yan, J. Qu, Y. D. Wu, J. Org. Chem. 2001, 66, 7303-7312; e) Y. D. Wu, D. P. Wang, K. W. K. Chan, D. Yang, J. Am. Chem. Soc. 1999, 121, 11189-11196; f ) D. Yang, F. F. Ng, Z. J. Li, Y. D. Wu, K. W. K. Chan, D. P. Wang, J. Am. Chem. Soc. 1996, 118, 9794-9795.

[4] a) X. Li, Y. D. Wu, D. Yang, Acc. Chem. Res., 2008, 41, 1428-1438; b) X. Li, Y. D. Wu, D. Yang, Accounts Chem. Res. 2008, 41, 1428-1438; c) D. Yang, X. Li, Y. Sha, Y. D. Wu, Chem.-Eur. J., 2005, 11, 3005-3009; d) D. Yang, J. Qu, W. Li, Y. H. Zhang, Y. Ren, D. P. Wang, Y. D. Wu, J. Am. Chem. Soc. 2002, 124, 12410-12411.

[5] A. R. Katritzky, I. Avan, S. R. Tala, J. Org. Chem. 2009, 74, 8690-8694.

[6] a) B. Ma, H. Y. Zha, N. Li, D. Yang, G. Lin, Mol. Pharmaceut. 2011, 8, 1073-1082; b) D. Yang, B. Li, F. F. Ng, Y. L. Yan, J. Qu, Y. D. Wu, J. Org. Chem. 2001, 66, 7303-7312.

[7] X. Li, B. Shen, X. Q. Yao, D. Yang, J. Am. Chem. Soc. 2007, 129, 7264-7265.

[8] G. Koopmanschap, E. Ruijter, R. V. A. Orru, Beilstein J. Org. Chem. 2014, 10, 544-598.

[9] a) T. Zarganes-Tzitzikas, A. L. Chandgude, A. Domling, Chem. Rec. 2015, 15, 981-996; b) A. Domling, W. Wang, K. Wang, Chem. Rev., 2012, 112, 3083-3135; c) I. Ugi, B. Werner, A. Domling, Molecules 2003, 8, 53-66; d) A. Domling, I. Ugi, Angew. Chem., Int. Ed. 2000, 39, 3168-3210.

[10] T. Soeta, Y. Ukaji, Chem. Rec. 2014, 14, 101-116.

[11] I. Ugi, R. Meyr, Chem. Ber-Recl. 1961, 94, 2229-2233.

[12] a) L. El Kaim, M. Gizolme, L. Grimaud, J. Oble, J. Org. Chem. 2007, 72, 4169-4180; b) L. El Kaim, M. Gizolme, L. Grimaud, Org. Lett. 2006, 8, 5021-5023.

[13] T. Soeta, Y. Kojima, Y. Ukaji, K. Inomata, Org. Lett. 2010, 12, 4341-4343.

[14] T. Soeta, S. Matsuzaki, Y. Ukaji, Chem.–Eur. J. 2014, 20, 5007-5012.

[15] M. C. Pirrung, K. Das Sarma, J. Am. Chem. Soc. 2004, 126, 444-445.

[16] A. L. Chandgude, A. Domling, Green Chem., 2016, 18, 3718-3721.

[17] a) N. Takeda, O. Miyata, T. Naito, Eur. J. Org. Chem. 2007, 1491-1509; b) S. M. Johnson, H. M. Petrassi, S. K. Palaninathan, N. N. Mohamedmohaideen, H. E. Purkey, C. Nichols, K. P. Chiang, T. Walkup, J. C. Sacchettini, K. B. Sharpless, J. W. Kelly, J. Med. Chem. 2005, 48, 1576-1587; c) O. Miyata, N. Takeda, T. Naito, Org. Lett. 2004, 6, 1761-1763.

[18] D. W. Zhang, Z. Luo, G. J. Liu, L. H. Weng, Tetrahedron, 2009, 65, 9997-10001.


Chapter 5N-Hydroxyimide Ugi Reaction

toward α-Hydrazino-amides


A. L. ChandgudeA. Dömling,

Org. Lett., 2017, 19, 1228–1231


Chapter 5

94

Abstract

The Ugi four-component reaction (U-4CR) with N-hydroxyimides as a novel carboxylic acid isostere

has been reported. This reaction provides straightforward access to α-hydrazino-amides. A broad

range of aldehydes, amines, isocyanides and N-hydroxyimides were employed to give products in

moderate to high yields. This reaction displays N-N bond formation by cyclic imide migration in

the Ugi reaction. Thus, N-hydroxyimide is added as a new acid component in the Ugi reaction and

broadens the scaffold diversity.


N-Hydroxyimide Ugi Reaction toward α-Hydrazino-amides

95

5

Introduction

The Ugi reaction (U-4CR) is a widely used multicomponent reaction (MCR) for the synthesis of bis-

amides and peptidomimetics.[1] This reaction has emerged as a powerful synthetic method for the

organic, pharmaceutical and polymer industries.[2] However, it cannot meet the ever-increasing

need for molecular complexity and diversity in organic and medicinal chemistry. An increasing

demand for novel scaffolds has led to the interest in U-4CR postmodifications and single reactant

replacement (SRR) by isosteres.[3] U-4CR postmodifications are useful for the synthesis of various

heterocycles and peptidic scaffolds.[4] Nevertheless, isostere use in the Ugi reaction is rather limited.[5]

An amine component could be replaced by secondary amines, hydroxylamines and hydrazines. As

with amines, use of acid isosteres in the Ugi reaction is also limited.

In the Ugi reaction, the carboxylic acid plays several prominent structural roles, including

activation of the intermediate imine, the reversible addition to the nitrilium ion and participation

in the irreversible Mumm rearrangement to form the final bis-amide product. Because of carboxylic

acid’s substantial role in the reaction, isosteric replacement by other agents is difficult to accomplish.

In 1962, Ugi reported the first acid isosteric replacements by inorganic acids, such as hydrazoic acids,

cyanates, thiocyanates etc. (Figure 1).[6] To date, only a few acid isosteres have been reported. For

example, our group reported the thioacetic acid as an isostere.[7] El Kaïm and co-workers reported

the phenol as an acid isostere in the Ugi reaction involving Smiles rearrangement to form an

N-arylamine.[8] Other Ugi-Smiles and similar strategies have been described by El Kaïm (thiophenol),[9]

Charton (squaric acid),[10] and Neo (hydroxycoumarins).[11] Further, Lewis acids and CO2 were used as

acid isoteres in the U-4CR.[5]

As for the related Passerini reaction,[12] organic acid isostere replacement has remained largely

unexplored for the Ugi-4CR as there are only a few examples of isostere use in the Ugi-4CR for the

synthesis of peptidomimetics.[5] Therefore, finding new isosteres in U-4CR for the synthesis of diverse

and complex peptidomimetic derivatives is of high interest.

We hypothesized that N-hydroxyimides could be used as a novel acid isostere in the U-4CR

reaction, which can directly provide the α-hydrazino amides as Ugi reaction products. α-Hydrazino

amides are aza analogues of β-peptides and are of interest for several reasons.[13] These foldamers

exhibit the special hydrazino turn, and the hydrazidic bond is very resistant to protease.[14] Hydrazino

amides are found in many natural products such as linatine, a vitamin B6 antagonist;[15a] negamycine,

an antibiotic;[15b] and matlystatins, antimicrobial compounds.[15c] They also have broad applications

in medicinal chemistry including use as proteasome inhibitors,[16a] antimicrobials,[16b] DNA and RNA

interactors,[16c] (S)-(-)-carbidopa for the treatment of Parkinson’s disease,[17] and as human leukocyte

elastase (HLE) inhibitors.[18]


Chapter 5

96

Figure 1. Previously reported and new acid isoteres in U-4CR.

Hydrazino peptides are mainly synthesized by two methods: first, by using hydrazine derivatives[19]

and, second, by coupling of an amino group with another amine typically employing oxaziridines.[14]

The general use of hydrazine and oxaziridine is limited by unavailability of diverse derivatives and

their highly toxic and unstable nature. Another drawback is that their synthesis is laborious. Therefore,

the development of new methods for the synthesis of this important foldamer is highly desirable.

Herein, we report the successful use of the N-hydroxyimides as an acid isostere in the U-4CR

for a direct route to the synthesis of α-hydrazinoamides. This is the second example of cyclic imide

migration to nitrogen (O N imide transfer) in the Mumm rearrangement to form an N-N bond.

This type of N-O bond breaking and N-N bond formation in a Mumm-type rearrangement has been

recently reported.[20] This reaction illustrates the use of N-hydroxamic acid for N-N bond formation

without phthalimidation.


We started our optimization by using propionaldehyde, benzylamine, cyclohexyl isocyanide, and

N-hydroxyphthalimides (NHPI) as model reactants. Reaction in methanol did not form any desired

product (Table 1, entry 1). In polar aprotic solvents such as THF and CH3CN, only traces of product

were formed. In the polar protic solvent MeOH, the U-3CR product, α-amino-amide, was formed as

a major product; in contrast, it formed only in trace amounts in solvents such as THF and toluene.

This U-3CR product formation might be due to the low acidity of N-hydroxyimide (pKa ~7.5), which

functioned only as a catalyst. This observation led us to try a nonpolar solvent and Lewis acid to

activate N-hydroxyimide for the further optimization. Indeed, nonpolar solvents such as DCE and

toluene allowed moderate product formation of 25% and 20%, respectively, at room temperature.



97

5

Table 1. Solvent screening.a

Entry Solvent Yield (%)b

1 MeOH —

2 THF trace

3 DCE 25

4 CH3CN trace

5 toluene 20aThe reaction was carried out with using propionaldehyde (0.5 mmol), benzylamine (0.5 mmol), cyclohexyl isocyanide (0.5 mmol) and N-hydroxyphthalimide (0.75 mmol) in 1 mL solvent. bYield of isolated product 5a.

Next, we screened various Lewis acids, (Table 2) such as InCl3, I

2, Sc(OTf )

3 etc.

(10 mol %) in DCE as a

solvent. We found that ZnCl2 was the best of the screened Lewis acids (Table 2, entry 3).

Table 2. Catalyst screening.a

Entry Catalystb Yield (%)c

1 I2

22

2 InCl2

10

3 ZnCl2

22

4 Sc(OTf )3

15

5 PTSA trace

6 TBAF trace

7 TMSCl 19

8 AlCl3

17

9 BF3.OEt

2trace

10 Zn(OTf )2

nd

11 ZnI2

nd

12 FeCl3

trace

13 CeCl2

trace

14 BaCl2

trace


Chapter 5

98

Entry Catalystb Yield (%)c

15 GdCl2

trace

16 AuCl3

traceaThe reaction was carried out with using propionaldehyde (0.5 mmol), benzylamine (0.5 mmol), cyclohexyl isocyanide (0.5 mmol), N-hydroxyphthalimide (0.75 mmol) and catalyst (as mentioned in table) in 1 mL DCE. b0.1 equivalent catalyst used cYield of isolated product 5a. nd = not determined

An increase in the temperature failed to improve the product yield (Table 3, entries 1 and 2).

Table 3. Optimization Conditions.a

Entry Solvent Temp Catalyst Time (h) Yield %

1b THF 50 °C I2

12 trace

2b DCE 50 °C ZnCl2

12 ndaThe reaction was carried out with propionaldehyde (1.0 mmol), benzylamine (1.0 mmol), cyclohexyl isocyanide (1.0 mmol) and N-hy-droxyphthalimide (1.5 mmol) in 2 mL of solvent. b10 mol % of catalyst used. nd = not determined

In further solvent screening with ZnCl2, (Table 4), we observed that toluene and xylene gave similar

yields, 51% and 49%, respectively (Table 4, entries 11 and 12). The nature of the solvent played

a critical role in the success of the reaction. Next, we performed a catalyst equivalence study in

toluene as solvent. An increase in the catalyst quantity to 30 mol % gave the best yield of 66% (Table

4, entry 17). However, a further increase in the quantity of ZnCl2 to 50 mol % gave a lower yield, 47%

(Table 4, entry 18). The use of sonication in this reaction did not have any effect on product yield

(Table 4, entries 19 and 20).[12a]

Table 4. Solvent and ZnCl2 equivalence screening.a

Entry Solvent ZnCl2 equiv Yield (%)b

1 MeOH 0.1 —

2 THF 0.1 trace

3 Chloro-benzene 0.1 31

4 TFE 0.1 38

5 DCM 0.1 nd



99

5

Entry Solvent ZnCl2 equiv Yield (%)b

6 CHCl3

0.1 22

7 Dioxane 0.1 trace

8 Acetone 0.1 trace

19 DMSO 0.1 nd

10 CH3CN 0.1 nd

11 toluene 0.1 51

12 xylene 0.1 49

13 DCE 0.1 22

14 DCE 0.01 25

15 DCE 0.5 40

16 DCE 1 24

17 toluene 0.3 66

18 toluene 0.5 47

19c toluene 0.1 43

20c toluene 0.3 50

19 DME 0.3 trace

20 isopropanol 0.3 traceaThe reaction was carried out with using propionaldehyde (0.5 mmol), benzylamine (0.5 mmol), cyclohexyl isocyanide (0.5 mmol), N-hydroxyphthalimide (0.75 mmol) and ZnCl

2 (as mentioned in table) in 1 mL solvent. bYield of isolated product 5a.

cReaction performed in sonication nd = not determined

With these optimized conditions in hand, next we examined the generality of this U-4CR by using

various aldehydes, amines, isocyanides and N-hydroxyimides (Table 5). Aliphatic aldehydes offered

good yields, up to 78% (Table 5, entries 1–3). Aromatic aldehydes are also useful substrates in this

reaction (Table 5, entries 6–9).

Electron-withdrawing and -donating groups in aromatic aldehydes at different positions such

as ortho and para provided moderate to good yields. Amines with protected functional groups like

acetal and halogens were well-tolerated in this reaction, affording moderate to good yields of the

products (Table 5, entries 3, 4, and 6). The acid-protected amino acid b-alanine ester gave only 18%

yield (Table 5, entry 5). Various aliphatic and aromatic isocyanides such as cyclohexyl, phenylethyl,

2-nitrobenzyl, benzyl, 4-methoxyphenyl, and b-cyanoethyl were well-suited within the developed

methodology.


Chapter 5

100

Table 5. Substrate Scope.a

toluene

ZnCl2

rt, 12

h

NR7

R6HONC

R4

N

R2

N

O

NH

R4 R6

R3

R1 R7R3

NH2CHOR2

(30 mol

%)

1 2 3 45

Entry 1 2 3 4 % Yieldb

1 CHO

NH2NC

NHPI 66 (5a)

2CHO NH2 NC

NHPI 74 (5b)

3 CHO

NH2

O O

NC

NHPI 78 (5c)

4 CHOPh

NH2

F

NC

NHPI 58 (5d)

5c CHO

NH2.HCl

O

O NC NHPI 18 (5e)

6

CHONH2

Cl

NC

NHPI 57 (5f)

7

CHO

Cl

NH2NC

NHPI 51 (5g)

8

CHOCl

NH2 NC

NHPI 46 (5h)

9

CHO

OCH3

NH2NC

NHPI 21 (5i)

10CHO

NH2

Cl

NC

NHPI 91 (5j)



101

5

Entry 1 2 3 4 % Yieldb

11CHO

NH2

Cl

NC

NC

NHPI 38 (5k)

12CHO

NH2

Cl

NC

ONHPI 71 (5l)

13CHO

NH2

Cl

NC

NHPI 65 (5m)

aReaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), 3 (1.0 mmol), and 4 (1.5 mmol), ZnCl2 (30 mol %) in toluene (2 mL) at rt for

overnight. bIsolated yield. c1.5 equivalent triethylamine used.

Among N-hydroxyimides, N-hydroxysuccinimides (NHS) also proceeded smoothly similarly to NHPI

and gave 48-59% yield (Scheme 1, 5n-p). However, the reaction with hydroxybenzotriazole (HOBt)

resulted in only trace product formation (Scheme 1, 5q).

Scheme 1. N-Hydroxyimides Scope.

A abroad functional group tolerance in this reaction could be of interest for the postmodification

condensations. Thus, among the vast number of possible post-modification reactions with this

modified U-4CR, we attempted several. Hydrazines are important intermediates for the synthesis

of many heterocycles and scaffolds.[19] The U-4CR product (5d) treatment with hydrazine hydrate


Chapter 5

102

deprotects the NHPI and forms the free hydrazine derivatives 6.[12a] We obtained free hydrazine in a

good yield of 64% after overnight reaction (Scheme 2).

Scheme 2. Deprotection toward Hydrazine Formation

Next, we turned our attention to creating access for pharmaceutically important a-amino-amide

molecules. We converted the U-4CR product (5l) to U-3CR product, α-amino-amides 7 in good yield

(73%). This AlCl3 catalyzed reaction cleave the N-N bond (Scheme 3) to form the final product.[21]

Scheme 3. Deprotection toward α-Amino Amide.

We did not carry out detailed mechanistic studies but envision the following mechanism (Scheme

4). ZnCl2 activates an imine A to allow the nucleophilic addition of isocyanide 3 to form the nitrilium

intermediate C. The hydroxamate nucleophilicly traps the nitrilium intermediate C. Finally this

intermediate D undergoes an irreversible Mumm-like N N migration to form the α-hydrazino-

amide 5.



103

5

Scheme 4. Anticipated mechanism for the Ugi-N-hydroxyimide reaction.

Conclusion

In conclusion, we have reported N-hydroxyimides as novel acid isosteres in the U-4CR toward the

one-step synthesis of α-hydrazinoamides via N-N bond formation. This mild and general reaction

requires catalytic amounts of ZnCl2. This protocol uses readily available N-hydroxy imides, which

replace the toxic and unstable hydrazines/oxaziridine use for the synthesis of α-hydrazinoamides.

The method is applicable for a wide range of aldehydes and amines and has the potential for multiple

post-modifications. Such scaffolds will be useful to fill the screening decks of the European Lead

Factory (ELF).[22] Moreover, as this reaction has significant potential in peptidomimetics synthesis,

studies on post-modification reactions are now in progress.

Experimental Procedures and Spectral Data of α-hydrazino-amides

General procedure for the synthesis of α-hydrazino-amides: A mixture of amine (1 mmol), aldehyde (1 mmol), isocyanide (1 mmol), N-hydroxamic acid

(1.5 mmol) and ZnCl2 (0.3 equivalent) in 2 mL of toluene were stirred for overnight at room

temperature. The solvent was removed under reduced pressure and the residue was purified by

silica gel flash chromatography using EtOAc–hexane as eluent.


Chapter 5

104

Spectral Data

2-(benzyl(1,3-dioxoisoindolin-2-yl)amino)-N-cyclohexylbutanamide (5a)

Obtained from 0.5 mmol reaction as a colorless liquid, yield: 139 mg (66%) ; 1H

NMR (500 MHz, CDCl3) δ 7.88 (dd, J = 4.9, 3.0, 2H), 7.77 (dd, J = 5.4, 3.1, 2H), 7.46

(d, J = 7.4, 2H), 7.33 (t, J = 7.5, 2H), 7.29 – 7.19 (m, 1H), 4.11 (d, J = 12.7, 1H), 3.73

(d, J = 12.7, 1H), 3.70 – 3.63 (m, 1H), 3.25 (s, 1H), 2.03 – 1.81 (m, 3H), 1.51 – 1.32

(m, 5H), 1.17 – 0.97 (m, 8H). 13C NMR (126 MHz, CDCl3) δ 164.1, 153.7, 139.9, 134.3, 129.6, 128.4, 127.1,

123.5, 55.5, 55.0, 51.6, 34.2, 34.0, 26.7, 25.5, 23.4, 23.3, 10.8. MS (ESI) m/z calculated [M+H]+ : 420.22;


2-(allyl(1,3-dioxoisoindolin-2-yl)amino)-N-cyclohexyl-3-methylbutanamide (5b)

Obtained from 1 mmol reaction as a colorless solid, yield: 283 mg (74%); 1H NMR

(500 MHz, CDCl3) δ 7.86 (dd, J = 5.3, 3.1, 2H), 7.77 (dd, J = 5.4, 3.1, 2H), 6.03 – 5.83

(m, 1H), 5.31 (dd, J = 17.2, 0.9, 1H), 5.13 (d, J = 10.3, 1H), 3.58 (dd, J = 14.0, 5.3, 1H),

3.45 – 3.30 (m, 2H), 3.16 (dd, J = 14.0, 6.1, 1H), 2.14 – 1.96 (m, 1H), 1.64 (s, 1H), 1.52

– 1.31 (m, 5H), 1.21 – 1.02 (m, 11H). 13C NMR (126 MHz, CDCl3) δ 164.0, 153.5, 136.9, 134.3, 129.6, 123.4,



2-((2,2-dimethoxyethyl)(1,3-dioxoisoindolin-2-yl)amino)-4-methyl-N-phenethylpentanamide

(5c)


3) δ 7.83 (dd, J = 5.4, 3.1, 2H), 7.76 (dd, J = 5.4, 3.1,

2H), 7.08 (t, J = 6.6, 3H), 6.96 (d, J = 6.0, 2H), 4.50 (t, J = 5.3, 1H), 3.79 (t, J =

7.5, 1H), 3.63 – 3.48 (m, 2H), 3.40 (s, 6H), 3.06 (dd, J = 11.9, 6.0, 1H), 2.62 (t, J =

6.9, 2H), 2.50 (dd, J = 11.9, 4.8, 1H), 1.90 – 1.77 (m, 1H), 1.64 (t, J = 7.2, 2H), 0.95 (d, J = 6.6, 3H), 0.92 (d,

J = 6.6, 3H). 13C NMR (126 MHz, CDCl3) δ 163.3, 157.0, 139.5, 134.3, 129.4, 128.8, 128.1, 126.0, 123.5,



N-cyclohexyl-2-((1,3-dioxoisoindolin-2-yl)(2-fluorobenzyl)amino)-4-phenylbutanamide (5d)


NMR (500 MHz, CDCl3) δ 7.88 (dd, J = 5.4, 3.1, 2H), 7.77 (dd, J = 5.4, 3.1, 2H), 7.56 –

7.47 (m, 1H), 7.30 – 7.21 (m, 6H), 7.18 (t, J = 6.8, 1H), 7.12 (t, J = 7.5, 1H), 7.08 – 7.01

(m, 1H), 4.11 (d, J = 12.9, 1H), 3.81 (d, J = 12.9, 1H), 3.75 (t, J = 7.1, 1H), 3.11 (s, 1H),

2.96 – 2.83 (m, 1H), 2.82 – 2.70 (m, 1H), 2.31 – 2.16 (m, 1H), 2.15 – 2.03 (m, 1H),

1.85 (s, 1H), 1.50 – 1.21 (m, 5H), 1.14 – 0.90 (m, 5H). 13C NMR (126 MHz, CDCl3)

δ 163.9, 162.3, 160.3, 153.8, 141.4, 134.3, 130.7, 130.6, 129.6, 128.8, 128.8, 128.6, 128.4, 126.0, 124.1,

124.1, 123.5, 115.4, 115.3, 55.1, 53.5, 45.3, 45.2, 35.4, 34.1, 33.9, 32.1, 25.4, 23.4. MS (ESI) m/z calculated

[M+H]+ : 514.25; found [M+H]+ : 514.10. HRMS (ESI) m/z calculated [M+H]+ : 514.25005; found [M+H]+

: 514.25055.



105

5

methyl 3-((1-(cyclohexylamino)-1-oxobutan-2-yl)(1,3-dioxoisoindolin-2-yl)amino)propanoate

(5e)

Obtained from 1 mmol reaction as a colorless liquid, yield: 74 mg (18%); 1H NMR

(500 MHz, CDCl3) δ 7.88 (dd, J = 5.3, 3.1, 2H), 7.79 (dd, J = 5.4, 3.1, 2H), 3.73 (s, 3H),

3.69 (t, J = 7.5, 1H), 3.47 (brs, 1H), 3.30 – 3.21 (m, 1H), 2.84 – 2.75 (m, 1H), 2.61 (t,

J = 6.1, 2H), 1.92 – 1.84 (m, 2H), 1.52 – 1.39 (m, 5H), 1.23 – 1.17 (m, 2H), 1.17 – 1.11

(m, 2H), 1.09 (t, J = 7.4, 4H). 13C NMR (126 MHz, CDCl3) δ 173.1, 163.9, 153.5, 134.3, 129.5, 123.4, 56.5,

55.0, 51.7, 43.2, 34.8, 34.1, 34.0, 26.6, 25.5, 23.3, 10.6. MS (ESI) m/z calculated [M+H]+ : 416.21; found


2-((4-chlorobenzyl)(1,3-dioxoisoindolin-2-yl)amino)-N-phenethyl-2-phenylacetamide (5f)

Obtained from 1 mmol reaction as a colorless solid, yield: 298 mg (57%); 1H

NMR (500 MHz, CDCl3) δ 7.87 (brs, 2H), 7.78 (dd, J = 5.4, 3.0, 2H), 7.56 (d, J = 7.6,

2H), 7.42 – 7.34 (m, 4H), 7.33 – 7.26 (m, 3H), 7.11 – 7.02 (m, 3H), 6.85 (dd, J = 7.0,

1.9, 2H), 4.77 (s, 1H), 4.07 (d, J = 13.2, 1H), 3.84 (d, J = 13.2, 1H), 3.33 (t, J = 6.9, 2H),

2.52 (td, J = 6.8, 3.2, 2H), 2.15 (s, 1H). 13C NMR (126 MHz, CDCl3) δ 163.3, 155.8,

139.4, 138.1, 137.2, 134.5, 132.9, 130.0, 129.4, 128.8, 128.6, 128.2, 128.2, 127.5, 126.1, 123.7, 57.9, 50.9,

49.0, 37.1. MS (ESI) m/z calculated [M+H]+ : 524.17; found [M+H]+ : 524.05. HRMS (ESI) m/z calculated

[M+H]+ : 524.17355; found [M+H]+ : 524.17432.

2-(benzyl(1,3-dioxoisoindolin-2-yl)amino)-2-(4-chlorophenyl)-N-cyclohexylacetamide (5g)


NMR (500 MHz, CDCl3) δ 7.88 (d, J = 2.7, 2H), 7.84 – 7.74 (m, 2H), 7.65 (d, J = 8.1,

2H), 7.51 (d, J = 7.4, 2H), 7.41 – 7.32 (m, 4H), 7.27 (t, J = 7.4, 1H), 4.85 (s, 1H), 4.24

(d, J = 13.0, 1H), 3.99 (d, J = 13.0, 1H), 3.17 (s, 1H), 2.25 (s, 1H), 1.51 – 1.20 (m, 5H),

1.17 – 0.93 (m, 5H). 13C NMR (126 MHz, CDCl3) δ 163.9, 152.4, 139.4, 136.6, 134.5,

133.8, 129.5, 129.0, 128.8, 128.6, 128.5, 127.3, 123.6, 56.6, 55.3, 51.6, 34.0, 33.6, 25.4, 23.4, 23.2. MS (ESI)

m/z calculated [M+H]+ : 502.18; found [M+H]+ : 502.06. HRMS (ESI) m/z calculated [M+H]+ : 502.1892;

found [M+H]+ : 502.1893.

2-(benzyl(1,3-dioxoisoindolin-2-yl)amino)-2-(2-chlorophenyl)-N-phenethylacetamide (5h)


NMR (500 MHz, CDCl3) δ 7.97 (dd, J = 7.8, 1.2, 1H), 7.92 – 7.81 (m, 2H), 7.76 (dd,

J = 5.4, 2.8, 2H), 7.43 (d, J = 7.3, 2H), 7.39 – 7.35 (m, 1H), 7.34 – 7.29 (m, 3H),

7.28 – 7.23 (m, 2H), 7.09 – 6.96 (m, 3H), 6.91 – 6.82 (m, 2H), 5.16 (s, 1H), 4.07 (d,

J = 12.7, 1H), 3.88 (d, J = 12.7, 1H), 3.41 – 3.32 (m, 1H), 3.31 – 3.19 (m, 1H), 2.48

(t, J = 6.9, 2H), 2.09 (s, 1H). 13C NMR (126 MHz, CDCl3) δ 163.3, 155.3, 139.4, 139.2, 135.5, 134.5, 133.7,

129.8, 129.6, 129.4, 128.9, 128.8, 128.4, 128.1, 127.8, 127.3, 126.0, 123.7, 55.6, 52.3, 48.9, 36.9. MS (ESI)

m/z calculated [M+H]+ : 524.17; found [M+H]+ : 524.18. HRMS (ESI) m/z calculated [M+H]+ : 524.17355;

found [M+H]+ : 524.17413.


Chapter 5

106

2-((4-chlorobenzyl)(1,3-dioxoisoindolin-2-yl)amino)-N-cyclohexyl-2-(4-methoxyphenyl)aceta-

mide (5i)


NMR (500 MHz, CDCl3) δ 7.88 (d, J = 2.9, 2H), 7.79 (dd, J = 5.4, 3.1, 2H), 7.60 (d,

J = 8.4, 2H), 7.46 (d, J = 8.1, 2H), 7.31 (d, J = 8.2, 2H), 6.94 (d, J = 8.5, 2H), 4.81 (s, 1H),

4.20 (d, J = 13.2, 1H), 3.97 (d, J = 13.2, 1H), 3.81 (s, 3H), 3.19 (s, 1H), 1.50 – 1.30 (m,

4H), 1.28 – 1.20 (m, 1H), 1.17 – 0.92 (m, 5H). 13C NMR (126 MHz, CDCl3) δ 164.0,

159.3, 152.9, 138.3, 134.5, 132.8, 129.9, 129.5, 128.7, 128.5, 123.6, 114.0, 56.9, 55.3,



N-benzyl-2-((4-chlorobenzyl)(1,3-dioxoisoindolin-2-yl)amino)-3-methylbutanamide (5j)


NMR (500 MHz, CDCl3) δ 7.99 – 7.87 (m, 2H), 7.84 – 7.74 (m, 2H), 7.36 (d, J = 8.4,

2H), 7.33 – 7.27 (m, 2H), 7.24 – 7.14 (m, 3H), 7.02 (d, J = 6.9, 2H), 4.40 (q, J = 16.1,

2H), 4.14 (d, J = 13.3, 1H), 3.77 (d, J = 13.3, 1H), 3.43 (d, J = 9.0, 1H), 2.25 – 2.08

(m, 1H), 1.95 (s, 1H), 1.23 (d, J = 6.6, 3H), 1.13 (d, J = 6.7, 3H). 13C NMR (126 MHz, CDCl3) δ 163.9, 163.7,

157.9, 139.2, 138.5, 134.5, 134.5, 132.7, 129.8, 129.4, 128.5, 128.2, 126.6, 126.5, 123.7, 123.6, 60.2, 50.8,



2-((4-chlorobenzyl)(1,3-dioxoisoindolin-2-yl)amino)-N-(2-cyanoethyl)-3-methylbutanamide

(5k)

Obtained from 1 mmol reaction as a white liquid, yield: 166 mg (38%); 1H NMR

(500 MHz, CDCl3) δ 7.96 – 7.84 (m, 2H), 7.84 – 7.73 (m, 2H), 7.39 (d, J = 8.4, 2H),

7.29 (d, J = 8.4, 2H), 4.08 (d, J = 13.4, 1H), 3.77 (d, J = 13.4, 1H), 3.40 – 3.30 (m, 1H),

3.27 – 3.17 (m, 2H), 2.27 (t, J = 6.7, 2H), 2.14 – 1.99 (m, 1H), 1.87 (s, 1H), 1.16 (d,

J = 6.6, 3H), 1.07 (d, J = 6.7, 3H). 13C NMR (126 MHz, CDCl3) δ 163.4, 163.4, 158.9, 138.2, 134.6, 132.8,

129.7, 129.1, 128.6, 123.7, 117.6, 60.6, 50.6, 43.2, 31.5, 20.0, 19.9, 19.5. MS (ESI) m/z calculated [M+H]+

: 439.15; found [M+H]+ : 439.12. HRMS (ESI) m/z calculated [M+H]+ : 439.15314; found [M+H]+ :

439.15314.

2-((4-chlorobenzyl)(1,3-dioxoisoindolin-2-yl)amino)-N-(4-methoxyphenyl)-3-methylbutana-

mide (5l)

Obtained from 1 mmol reaction as a white liquid, yield: 348 mg (71%); 1H

NMR (500 MHz, CDCl3) δ 7.86 (brs, 2H), 7.80 – 7.68 (m, 2H), 7.36 (d, J = 8.4,

2H), 7.31 – 7.19 (m, 2H), 6.78 – 6.68 (m, 2H), 6.64 – 6.53 (m, 2H), 4.14 (d,

J = 12.7, 1H), 3.72 (s, 3H), 3.61 (d, J = 12.7, 1H), 3.24 (d, J = 9.2, 1H), 2.13 – 1.97

(m, 1H), 1.69 (s, 1H), 1.16 (d, J = 6.8, 3H), 1.09 (d, J = 6.6, 3H). 13C NMR (126

MHz, CDCl3) δ 163.0, 158.2, 156.3, 138.6, 137.8, 134.5, 132.6, 129.8, 129.2, 128.4, 123.7, 121.3, 114.2,

61.7, 55.4, 51.1, 31.7, 20.1, 20.0. MS (ESI) m/z calculated [M+H]+ : 492.16; found [M+H]+ : 492.05. HRMS

(ESI) m/z calculated [M+H]+ : 492.16846; found [M+H]+ : 492.16888.



107

5

N-benzhydryl-2-((4-chlorobenzyl)(1,3-dioxoisoindolin-2-yl)amino)-3-methylbutanamide (5m)

Obtained from 1 mmol reaction as a white liquid, yield: 358 mg (65%); 1H NMR

(500 MHz, CDCl3) δ 7.99 – 7.87 (m, 2H), 7.84 – 7.71 (m, 2H), 7.23 – 7.18 (m, 2H),

7.18 – 7.14 (m, 2H), 7.13 – 7.04 (m, 6H), 7.02 – 6.98 (m, 2H), 6.97 – 6.93 (m, 2H),

5.46 (s, 1H), 3.89 (d, J = 13.5, 1H), 3.49 – 3.36 (m, 2H), 2.10 – 1.95 (m, 1H), 1.80

(s, 1H), 1.10 (d, J = 6.6, 3H), 0.81 (d, J = 6.8, 3H). 13C NMR (126 MHz, CDCl3) δ 164.1, 163.9, 158.1, 143.8,

143.8, 138.5, 134.7, 134.7, 132.5, 129.6, 129.6, 128.4, 128.4, 128.3, 126.9, 126.9, 126.8, 126.7, 123.8,



2-(allyl(2,5-dioxopyrrolidin-1-yl)amino)-N-(2-nitrobenzyl)butanamide (5n)


NMR (500 MHz, CDCl3) δ 8.02 – 7.94 (m, 1H), 7.60 (td, J = 7.6, 1.0, 1H), 7.48 – 7.37

(m, 2H), 5.98 – 5.81 (m, 1H), 5.22 (dd, J = 17.2, 1.5, 1H), 5.12 (dd, J = 10.2, 1.2, 1H),

4.92 (s, 2H), 3.80 (t, J = 7.4, 1H), 3.62 – 3.48 (m, 1H), 3.26 (dd, J = 13.8, 6.7, 1H), 2.83

(brd, J = 8.3, 4H), 1.89 (p, J = 7.3, 2H), 1.07 (t, J = 7.5, 3H). 13C NMR (126 MHz, CDCl3) δ 170.2, 158.8, 148.2,

136.3, 134.8, 133.3, 129.4, 127.8, 124.7, 117.0, 55.8, 50.2, 48.7, 26.6, 25.7, 10.5. MS (ESI) m/z calculated


: 375.16647.

2-(benzyl(2,5-dioxopyrrolidin-1-yl)amino)-N-cyclohexylbutanamide (5o)


(500 MHz, CDCl3) δ 7.41 (d, J = 7.2, 2H), 7.31 (t, J = 7.5, 2H), 7.24 (t, J = 7.3, 1H), 4.04

(d, J = 12.7, 1H), 3.68 (d, J = 12.7, 1H), 3.66 – 3.60 (m, 1H), 3.24 (brs, 1H), 2.78 (s, 4H),

1.91 – 1.74 (m, 3H), 1.66 – 1.58 (m, 2H), 1.55 – 1.43 (m, 3H), 1.27 – 1.17 (m, 5H), 1.04


55.1, 51.5, 34.5, 34.2, 26.6, 25.7, 25.6, 23.8, 23.7, 10.7. MS (ESI) m/z calculated [M+H]+ : 372.22; found


2-((4-chlorobenzyl)(2,5-dioxopyrrolidin-1-yl)amino)-N-phenethyl-3-phenylpropanamide (5p)


NMR (500 MHz, CDCl3) δ 7.34 (d, J = 7.2, 2H), 7.32 – 7.25 (m, 4H), 7.24 – 7.18

(m, 4H), 7.17 – 7.10 (m, 2H), 6.93 (d, J = 7.2, 2H), 3.92 (d, J = 13.0, 1H), 3.77 (dd,

J = 9.3, 5.7, 1H), 3.57 (d, J = 13.0, 1H), 3.11 – 2.96 (m, 3H), 2.85 – 2.72 (m, 1H),

2.71 – 2.61 (m, 2H), 2.61 – 2.49 (m, 2H), 2.37 – 2.22 (m, 2H), 1.86 (s, 1H). 13C NMR

(126 MHz, CDCl3) δ 170.4, 154.7, 139.7, 138.1, 136.9, 132.8, 129.8, 129.7, 129.2,

129.1, 128.9, 128.8, 128.8, 128.7, 128.5, 128.5, 128.1, 126.9, 126.5, 126.0, 56.3, 50.5, 48.2, 39.6, 36.8, 25.6.

MS (ESI) m/z calculated [M+H]+ : 490.18; found [M+H]+ : 490.22. HRMS (ESI) m/z calculated [M+H]+ :

490.1892; found [M+H]+ : 490.18924.


Chapter 5

108

Experimental Procedures and Spectral Data for post-modifications

Experimental procedure for the synthesis of N-cyclohexyl-2-(1-(2-fluorobenzyl)hydrazinyl)-

4-phenylbutanamide (6)

To a solution of 5d (80 mg, 0.16 mmol) in 1 mL of methanol was added 64 ml of hydrazine hydrate

(98%). This mixture was stirred at room temperature over 12 h, at the end of which the solvent was

removed. Dissolved the residue in 10 ml of CH2Cl

2 and washed it with 3% NaHCO

3 aqueous solution

(4 ml × 5). The organic layer was dried over anhydrous MgSO4, and solvent was removed under

reduced pressure and the residue was purified by silica gel flash chromatography using EtOAc-

hexane as eluent to afford 39 mg of 6 as white solid.

(Procedure as per ref: A. L. Chandgude, A. Dömling, Org. Lett. 2016, 18, 6396−6399.)

N-cyclohexyl-2-(1-(2-fluorobenzyl)hydrazinyl)-4-phenylbutanamide (6)

Obtained as a white solid, yield: 39 mg (64%); 1H NMR (500 MHz, CDCl3) δ 7.31 – 7.23 (m, 4H), 7.22

– 7.13 (m, 4H), 7.09 (td, J = 7.5, 1.0, 1H), 7.07 – 7.01 (m, 1H), 3.86 – 3.73 (m, 2H), 3.61 (d, J = 12.8, 1H),

3.21 – 3.07 (m, 1H), 2.67 (t, J = 8.0, 2H), 2.15 – 2.00 (m, 1H), 1.98 – 1.78 (m, 3H), 1.78 – 1.67 (m, 2H),

1.66 – 1.46 (m, 2H), 1.45 – 1.31 (m, 2H), 1.28 – 1.12 (m, 3H). 13C NMR (126 MHz, CDCl3) δ 172.6, 162.4,

160.4, 141.2, 130.7, 130.6, 129.3, 129.3, 128.5, 128.4, 126.5, 126.3, 126.1, 124.2, 124.2, 115.6, 115.4, 62.3,

47.5, 46.9, 46.9, 35.6, 33.3, 33.0, 32.4, 25.6, 24.9. MS (ESI) m/z calculated [M+H]+: 384.24; found [M+H]+:

384.31.

Experimental procedure for the synthesis of 2-((4-chlorobenzyl)amino)-N-phenethyl-3-phenyl-

propanamide (7)

To a solution of 5l (100 mg, 0.2 mmol) in 2 mL of 1,2-dichloroethane was added AlCl3 (3 equiv). This

mixture was stirred at room temperature over 48 h, at the end of which the reaction was quenched



109

5

with 10% NaOH under ice cooling, and the aqueous layer was extracted with DCM. The organic

layer was dried over anhydrous MgSO4, and solvent was removed under reduced pressure and the

residue was purified by silica gel flash chromatography using EtOAc–hexane as eluent to afford

57 mg of 10 as white solid.

(Procedure as per ref: Y. Kikugawa, Y. Aoki, T. Sakamoto, J. Org. Chem. 2001, 66, 8612-8615.)

2-((4-chlorobenzyl)amino)-N-phenethyl-3-phenylpropanamide (7)

Obtained as a white solid, yield: 57 mg (73%); 1H NMR (500 MHz, CDCl3) δ 7.34 – 7.17 (m, 8H), 7.17 –

7.07 (m, 6H), 6.79 (d, J = 8.3, 2H), 3.63 – 3.44 (m, 3H), 3.34 (d, J = 13.6, 1H), 3.26 (dd, J = 9.5, 4.2, 1H), 3.17

(dd, J = 13.9, 4.1, 1H), 2.87 – 2.72 (m, 2H), 2.64 (dd, J = 13.8, 9.5, 1H), 1.66 (s, 1H). 13C NMR (126 MHz,

CDCl3) δ 173.2, 138.8, 137.6, 137.4, 132.8, 129.2, 129.1, 129.0, 128.9, 128.9, 128.8, 128.8, 128.7, 128.6,


393.00.


Chapter 5

110

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Chapter 6Convergent Three-Component

Tetrazole Synthesis



Eur. J. Org. Chem., 2016, 2383–2387.


Chapter 6

112

Abstract

A microwave accelerated simple and efficient method for the construction of the 1,5-tetrazole

scaffold was developed. It comprises a multicomponent reaction of an amine, a carboxylic acid

derivative, and an azide source. On the basis of the availabililty of the archetypical starting materials,

this method provided very versatile synthetic access to 1,5-disubstituted tetrazoles. The usefulness

of this method was demonstrated in the synthesis of biologically important fused tetrazole scaffolds

and the marketed drug cilostazol.


Convergent Three-Component Tetrazole Synthesis

113

5

6

Introduction

The tetrazole motif is an important synthetic scaffold that is widely use in medicine, biochemistry,

pharmacology, and materials; for example, this structure is found in explosives, photography and

photoimaging chemicals, rocket propellants, polymers, gas generators, and agrochemicals.[1] The

first tetrazole synthesis was reported in 1885.[2] Since then, a plethora of examples has been reported,

the vast majority of which rely on the use of nitriles, heterocumulenes, amides, thioamides, imidoyl

chlorides, ketones, amines, and alkenes as the starting materials.[3] The increasing importance of

1,5-disubstituted tetrazoles in different applications, including as bio-active agents;[1c] drugs such as

cilostazol pentylenetetrazole, and latamoxef; and cis-amide bond isosteres in peptides, has propelled

the need for efficient synthetic methods. Direct access to diverse 1,5-disubstituted tetrazoles is

mainly possible from amides and thioamides.[4] Other methods include the use of ketones and

oximes with suitable azide sources or amidrazones with N2O

4 or HNO

2.[5] Recently, various methods

were developed for the synthesis of 1,5-disubstituted tetrazoles from amides.[3a] These methods

mainly use chlorinating agents to form imidoyl chlorides, followed by the addition of an azide source

to give the disubstituted tetrazoles. However, the limited availability of diverse amides as starting

material compels an additional step for amide synthesis from carbonyl compounds such as acids

and acetyl chlorides. Moreover, direct amide bond formation from unactivated acids is challenging

and thus, multistep sequential syntheses are often the result.[6] Direct amide formation requires

basic conditions, whereas tetrazole formation is favored in acidic conditions through the formation

of the imidoyl chloride, which make a one-pot synthesis of tetrazoles difficult. Also the one-pot

reaction for the synthesis of tetrazoles from amides is challenging, as hydrogen chloride formed in

the chlorination step can have deleterious effects on acid-sensitive functionalities.[7]

Reported methods for tetrazole formation from amides face major drawbacks, including the use

of an excess amount of toxic, volatile, and highly explosive HN3, long reaction time,[8] racemization

of the product,[9] and the use of Mitsunobu reaction conditions, which require expensive reagents,

long reaction times, and tedious workup procedures and with low yields.[10] The use excess of base

to trap HCl generated in the reaction,[7] in addition to an excess amount NaN3 increases the chances

of toxic hydrazoic acid formation.[11,12]

The SiCl4/NaN

3 combination was reported for the one-step synthesis of tetrazoles from amides,

but the major drawbacks of this method are the requirement of anhydrous and inert conditions, long

reaction time (50 h), and limited reported diversity.[13] Thus, the development of a straightforward,

easy, safe, efficient, fast, diverse, and general method for the formation of tetrazoles form unactivated

carbonyl compounds is warranted. We foresaw that the accelerating effect of microwaves could

potentially lead to a multicomponent reaction (MCR) of tetrazoles among suitable carbonyl

compounds, amines and azide with a chlorinating agent. We hypothesized that, in situ amide

formation from amines and carbonyl compounds followed by imidoyl chloride formation and finally

a tetrazole formation by azide addition would be possible in a one-pot three-component reaction

(3CR). Careful choice of a suitable chlorinating reagent could trigger activation for both amide and

imidoyl chloride formation as the key step of the reaction.


Chapter 6

114


To test this hypothesis, optimization of the reaction was performed with hydrocinnamoyl chloride,

benzylamine, and TMS-azide as starting materials with different chlorinating reagents, solvents,

temperatures, microwave conditions, reaction times. Initially screening was performed at room

temperature and by using conventional heating. We screened different reagents such as HCl,

AlCl3, (COCl)

2, and SOCl

2 at room temperature or heating, and with the use of different solvents,

including CH3CN, DMF, THF, 2,6-lutidine, but we did not get the expected product. The reactions

mostly ended up in amide formation, and even refluxing for 3 days in the presence of excess amount

HCl, the product was not formed. We shifted to POCl3, which is safer alternative to phosgene and

easier to handle than PCl5. Encouragingly, we found a trace product formation with POCl

3 at room

temperature after a long reaction time (3 days) (Table 1). An increase in the temperature led to a

slight enhancement in the reaction conversion, but the reaction still gave the amide as the major

product. The use of a base to reduce the requisite amount of HCl in the reaction did not have

any effect on the reaction. The synthesis of tetrazoles by using nitriles and NaN3 at 220 °C under

microwave conditions is known,[14] and this encouraged us to try microwave conditions at higher

temperature. A reaction at 150 °C gave the product but required 25 minutes to obtain complete

conversion. Increasing the temperature to 180 °C accelerated the reaction to 3 minutes with 100

% conversion. We used 1.5 equivalents of TMS-azide which avoids the danger of forming hydrazide

from excess azide.

Table 1. Optimization of MCR with different reaction conditions.a

Entry Catalyst/Additive Solvent Temp °C Time Yield(%)c

1 HCl CH3CN reflux 3 days nr

2 POCl3

CH3CN rt 3 days trace

3 POCl3

CH3CN 80 1 day 10

4 SOCl2

DCM 80b 20 min nr

5 AlCl3

CH3CN 80b 30 min nr

6(COCl)

2

2,6-lutidine(1.5 eq)DCM 120b 50 min trace

7(COCl)

2

2,6-lutidine(1.5 eq)THF 120b 20 min nr

8(COCl)

2

2,6-lutidine(1.5 eq)DMF 120b 15 min nr

9 POCl3

CH3CN 150b 20 min 70



115

5

6

Entry Catalyst/Additive Solvent Temp °C Time Yield(%)c

10 POCl3

CH3CN 180b 5 min 76

11POCl

3

TEA (2.0 eq)CH

3CN 180b 5 min 75

12POCl

3

TMS-azide(3.0 eq)CH

3CN 180b 5 min 72

aThe reaction was carried out with 1mmol 1, 1 mmol 2, 1.5 mmol TMSN3 and 1 mmol POCl

3. bmicrowave heating cYield of isolated

product, nr = no reaction.

With these optimized conditions at hand, we next examined the generality of this novel 3CR by

treating different carbonyl compounds like acid chlorides, carboxylic acids, and esters with different

amines (Table 2). The majority of the acid chlorides gave complete conversion into the corresponding

tetrazoles under these optimized conditions in good to high yields (Table 2, entries 1–17). Aromatic

and aliphatic acid chloride compounds proved to be equally effective in this reaction. The functional

group tolerance of the acid chloride (e.g., methoxy, nitro and chloro; (Table 2, entries 4–7 and 12–

14) in this protocol provides multiple opportunities for various further chemical manipulations.

The conversions of aromatic and aliphatic carboxylic acids were as effective as those of the acid

chlorides, but these substrates delivered the products in slightly lower yields.

Application of this method to esters was also successful; however, a longer reaction time was

required (25–30 min) for total conversion, and moderate to good yields were provided with aliphatic

and aryl esters. Esters with nitrile and chloro substituents also displayed decent reactivity in this

reaction (Table 2, entries 29–31). Aliphatic and aromatic amine compounds were compatible

substrates for this process. Good conversions were also observed in case of sterically hindered

groups, including 2-chloroaniline, 2-benzyl-aniline, and 2-methylaniline, which provided the product

in good to excellent yields of 91, 80, and 72%, respectively (Table 2, entries 6, 15, and 17). Amine

derivatives containing both electron-withdrawing and donating functionalities such as methoxy,

chloro, and nitrile were equally compatible and afforded the expected adducts. Easily cleavable

groups such as cyanoethyl and benzyl were also compatible with this method, and they readily

give access of 1H-5-tetrazoles (Table 2, entries 2, 11, and 26). Bistetrazoles are also accessible via

our method (Table 2, entries 37–40), and these compounds are highly important in high-energy

nitrogen-rich compounds and in polymerization.[15]


Chapter 6

116

Table 2. Synthesis of tetrazoles from carbonyl compounds, amines and TMS-azide.a

Entry R1 R2b Time (min) Yield(%)c

R-COCl

1 CH2-C

6H

5(CH

2)

2-C

6H

54 68 (3a)

2 (CH2)

2-C

6H

5CH

2-C

6H

53 72 (3b)

3 (CH2)

2-CH

3(CH

2)

2-CH

34 78 (3c)

4 CH2-C

6H

4-p-Cl (CH

2)

2-C

6H

4-p-OCH

35 76 (3d)

5 CH2-C

6H

4-p-Cl (CH

2)

2-C

6H

55 73 (3e)

6 CH2-C

6H

4-p-Cl o-Cl-C

6H

45 91 (3f)

7 CH2-C

6H

4-p-Cl Cy 5 48 (3g)

8 CH2-CH

3CH

2-CH-CH

27 70 (3h)

9 CH2-CH

3(CH

2)

2-C

6H

55 73 (3i)

10 CH2-CH

3Ph 5 86 (3j)

11 (CH2)

2-CH

3(CH

2)

2-CN 10 60 (3k)

12 (CH2)

2-Cl (CH

2)

2-C

6H

55 71 (3l)

13 m-OCH3-C

6H

4Ph 4 72 (3m)

14 p-NO2-C

6H

4m,p-OCH

3-C

6H

37 87 (3n)

15 CH2-C

6H

4-p-Cl o-Bn-C

6H

47 88 (3o)

16 CH2-Cl Ph 5 73 (3p)

17 CH2-Cl o-CH

3-C

6H

45 72 (3q)

R-COOH

18 (CH2)

2-C

6H

5(CH

2)

2-CH

34 92 (3r)

19 (CH2)

2-C

6H

5CH

2-C

6H

54 72 (3s)

20 m,p-OCH3-CH

2C

6H

5 iPr 4 56 (3t)

21 CH2-C

6H

4-p-Cl (CH

2)

2-C

6H

55 63 (3u)

22 2-Naphthyl-CH2

(CH2)

2-CH

35 73 (3v)

23 Ph Ph 5 56 (3w)

24 Ph (CH2)

2-C

6H

55 48 (3x)

25 p-OCH3-C

6H

4p-Cl-C

6H

44 63 (3y)

26 (CH2)

2-CH

3(CH

2)

2-CN 7 62 (3z)

27 (CH2)

2-CH

3(CH

2)

2-C

6H

5 5 71 (3aa)

28 (CH2)

2-CH

3CH

2-CH-CH

23 52 (3ab)

R-COOCH3

29 CH2-CN (CH

2)

2-C

6H

530 67 (3ac)

30 CH2-Cl C

6H

4-o-Cl 30 57 (3ad)

31 CH2-Cl CH

2-C

6H

525 63 (3e)

32 CH2CH

3C

6H

4-o-Cl 25 60 (3af)



117

5

6

Entry R1 R2b Time (min) Yield(%)c

33 (CH2)

2-C

6H

5CH

2-C

6H

525 69 (3ag)

34 (CH2)

2-C

6H

5(CH

2)

2-CH

325 60 (3ah)

35 CH2-C

6H

4-p-Cl CH

2-C

6H

4-p-Cl 25 70 (3ai)

36 Ph CH2-C

6H

530 63 (3aj)

R-COCld (Bistetrazoles)

37 CH2-C

6H

5C

6H

4-o,p-NH

28 60 (3ak)

38 (CH2)

2-C

6H

5NH

2-(CH

2)

3-NH

28 57 (3al)

39 CH2-CH

3NH

2-(CH

2)

3-NH

28 61(3am)

40 CH2-C

6H

4-p-Cl NH

2-(CH

2)

3-NH

28 66 (3an)

aThe reaction was performed with 1 (1mmol), 2 (1 mmol), TMSN3 (1.5 mmol), and POCl

3 (1 mmol). bcy = cyclohexyl, iPr = isopropyl,

Bn = Benzyl. c Yield of isolated product. dAcid chloride (2 equivalents), POCl3 and TMS-N

3 (3 equivalents) were used.

The use of PCl5 in the synthesis of amino acid tetrazoles often results in racemization of the

products, as ketamine formation leads to racemization and careful control over the amount of base

is required.[16] To check the stereochemical retention of our method, we used N-benzyloxycarbonyl

(Cbz)-L-alanine (4) and benzyl amine (5) for the synthesis of the amino acid tetrazole 6 (Scheme 1).

To our delight, the reaction proceeds under full stereoretention, as shown by chiral HPLC on a chiral

stationary phase (see experimental part). Our method, therefore, provides enantiopure product

likely by avoiding the use of a base. This opens the opportunity to introduce chiral tetrazoloamino

acids into peptides.

Scheme 1. Synthesis of amino acid tetrazole.

Next, we tried to access more elaborated fused tetrazole scaffolds. We envisaged a second strategy

by exploiting a MCR for the synthesis of fused tetrazoles. Multicomponent reactions have lately

emerged as a powerful tool in synthesis of biologically important diverse scaffolds. Even though

fused tetrazole possess a wide spectrum of biological activities only very limited access to these

fused tetrazole is currently possible by simple one-pot MCR.[1,17] For example, fused tetrazoles are

accessible via isocyanide-based synthesis of tetrazoles followed by cyclization.[18] Using our highly

flexible and robust methodology, we foresaw a quick and easy access to therapeutically interesting

complex molecular structures.

According to our synthetic plan, the use of functionalized carboxylic acid with amines

bearing additional functional groups would allow an anticipated domino-cyclization process in

one step. The reaction of formamide, which works as an ammonia and formaldehyde surrogate,

and 2-aminobenzoic acid under optimized conditions led to the formation of the tetrazolo[1,5-c]

quinazoline scaffold in moderate yield (Table 3, entry 1).


Chapter 6

118

Biologically important tetrazolo[1,5-a]quinoxaline derivatives[19] were synthesized by using 2-oxoacids

or their sodium salt with o-phenylenediamine, and they generally worked well with complete

reaction conversion with good yields (Table 3, entries 2–4). 4-Methyl-4,5-dihydrotetrazolo[1,5-a]

quinoxaline was formed by the reaction of 2-chloropropanoyl chloride and o-phenylenediamine

(Table 3, entry 5). Tetrazolo[5,1-a]phthalazine (Table 3, entry 6), for example, was reported as an

anticonvulsant.[20] Using our method, the reaction between hydrazine, 2-formylbenzoic acid, and

TMS-azide permitted the construction of tetrazolo[5,1-a]phthalazine in one step in 48% yield. Next,

we attempted the synthesis of 4H-benzo[b]tetrazolo[1,5-d][1,4]oxazine, which is an antidepressant/

anxiolytic agent.[21] Treating 2-aminophenol with 2-chloro acetyl chloride in the presence of TMS-

azide allows the preparation of a tetrazole ring fused to a benzooxazine (Table 3, entry 7).

Pentylenetetrazole (PTZ) is a GABAA

receptor antagonist and prototypical anxiogenic drug

that is used experimentally as a probe to study seizure phenomena.[22] It is typically synthesized

by multi-step method starting with caprolactame to form the imino ether followed by addition of

hydrazine to form hydrazine derivatives, which are further treated with nitrous acid to finally affords

the targets.[23] We hypothesized that PTZ could rapidly be accessed through a three-center, two-

component reaction between commercially available and inexpensive 6-aminohexanoic acid and

TMS-azide. We isolated this compound in a good 76% yield by using our one-pot method after

reaction time of 8 min (Table 3, entry 10).

Table 3. Synthesis of 1,5-fused tetrazole from carboxylic acid derivatives, amine and TMSN3.a

Entry 7 8 Time (min) Yield (%)b Product

1c

COOH

NH2

O

NH210 50 (9a)

N

NN

NN

2 O

CONa NH2

NH2

25 61(9b)

N

N NNN

3COOH

O

NH2

NH2

15 59 (9c)

N

N NNN

4COOH

O

NH2

NH2

15 61 (9d)

N

N NNN

5COOH

Cl

NH2

NH2

15 63 (9e)NH

N NNN



119

5

6

Entry 7 8 Time (min) Yield (%)b Product

6d

COOH

CHO

NH2H2N 10 48 (9f)NN

NNN

7COCl

Cl

NH2

OH7 56 (9g)

O

N NNN

8NH2

COOH8 76 (9h) N

NNN

9NH2COOH 5 67 (9i) N

NNN

aThe reaction was performed with 7 (1 mmol), 8 (1 mmol), and TMSN3 (1.5 mmol). bYield of isolated product. c ormamide used as

solvent. dExcess amount of hydrazine hydrate was used.

Finally, we validated our novel one-pot synthetic pathway towards preparation of the marketed

drug Cilostazol, which targets phosphodiesterase and inhibits platelet aggregation. It is employed

as a direct arterial vasodilator. Notably, this drug is usually synthesized by multistep procedures,

also using toxic and explosive HN3 and PCl

5.[24] Our rapid two-step Cilostazol synthesis involves

the 3CR of 5-chloropentanoic acid chloride 10, cyclohexyl amine 11, and TMS-azide to form the

tetrazole intermediate 12, which was followed by coupling with commercially available 6-hydroxy-

3,4-dihydro-2(1H)-quinolinone 13 (Scheme 2).

First, we performed the reaction of 5-chloropentanoic acid chloride 10, cyclohexyl amine 11,

and TMSN3 with POCl

3 at 180 °C in a microwave to form tetrazole 12, but we observed the formation

of several side products, likely involving nucleophilic substitution reactions. Then, we sequentially

performed amide formation between 10 and 11 in one-pot at room temperature followed by the

addition of POCl3 and TMSN

3 and heated reaction at 120 °C for 10 minutes. Tetrazole 12 could be

isolated in good yields. Coupling of 12 with 13 under microwave heating at 150 °C for 7 minutes

afforded Cilostazol 14 in 89% yield (Scheme 2).


Chapter 6

120

Scheme 2. Two-step synthesis of Cilostazol by our MCR methodology.

Conclusion

In conclusion, we developed a novel, efficient, safe, and general microwave-assisted first-in-class

MCR-based methodology to gain access to diverse and fused tetrazoles in a single step. Multiple

inter- and intramolecular examples pinpoint the versatility of the reaction. Use of TMSN3 in an

almost equimolar ratio makes the process safer than reported protocols. Moreover, the synthetic

utility of this developed methodology was illustrated in the synthesis of biologically active 1,5-fused

tetrazoles, an amino acid tetrazole and the marketed drug Cilostazol.


CAUTION: Great caution should be exercised during addition of compounds as gas evolves. Proper

protective measures like proper shielding and an additional safety screen in the fume hood, safety

glasses, lab coat, gloves, should be used. The reactions described here were run on only 1–5 mmol

scale. Use clean and scratch free microwave vial as during the reaction pressure create (up to 14 bar).

Residual pressure should be relieved before opening the vessel by carefully puncturing the septum

with a needle. Many tetrazole derivatives are known to be explosive. Functional groups known to be

cleavable in acidic conditions like t-butyl or t-octyl (1,1,3,3-tetramethylbutyl) as amine source were

avoided; as these groups may cleave under the reaction conditions and may form the free tetrazole

which are explosive. Also derivatives containing a high number of nitrogens weren’t pursued, as

increasing the nitrogen atoms may lead to an increase in the risk for an explosion.



121

5

6

General procedure for the synthesis of tetrazole: A 20 ml microwave vial equipped with a magnetic stirring bar was charged with carbonyl compound

(1.0 mmol) in CH3CN (5 ml) and amine (1.0 mmol) was added slowly followed by phosphoryl chloride

(1.0 mmol) and trimethylsilyl azide (1.5 equiv) at room temperature. The vial was sealed with a cap

containing a septum and subjected to microwave heating at 180 °C [attention: during irradiation,

pressure develops] till completion of the reaction (monitored by TLC). Then the reaction mixture was

poured into 50 mL of saturated NaHCO3 and extracted 3 times with 25 mL of CH

2Cl

2. The solvent was

removed under reduced pressure and the residue was purified by silica gel flash chromatography

using EtOAc–hexane or DCM:MeOH as eluent. [Caution: Addition of reagents and work-up must be

done in a fumehood.]

Spectral Data

5-benzyl-1-phenethyl-1H-tetrazole (3a)

Black viscous liquid, Yield: 180 mg (68%); 1H NMR (500 MHz, CDCl3) δ 7.36 – 7.22

(m, 6H), 7.04 (d, J = 7.0, 2H), 6.96 – 6.87 (m, 2H), 4.30 (t, J = 7.1, 2H), 3.80 (s, 2H), 2.99 (t,

J = 7.1, 2H); 13C NMR (126 MHz, CDCl3) δ 153.9, 136.4, 133.9, 129.1, 129.0, 128.9, 128.8,

128.7, 128.5, 127.7, 127.4, 48.8, 36.1, 28.9; MS (ESI) m/z calculated [M+H]+: 265.14;

found [M+H]+: 265.18.

1-benzyl-5-phenethyl-1H-tetrazole (3b)

Brown solid, Yield: 190 mg (72%); 1H NMR (500 MHz, CDCl3) δ 7.37 – 7.31 (m, 3H), 7.30

– 7.22 (m, 3H), 7.12 – 7.01 (m, 4H), 5.20 (s, 2H), 3.01 (s, 4H); 13C NMR (126 MHz, CDCl3)

δ 154.5, 139.4, 133.3, 129.3, 129.2, 128.91, 128.8, 128.4, 127.5, 127.4, 126.9, 50.5, 33.4,

25.6; MS (ESI) m/z calculated [M+H]+: 263.14; found [M+H]+: 263.16.

5-phenethyl-1-propyl-1H-tetrazole (3c)

Brown liquid, Yield: 168 mg (78%);1H NMR (500 MHz, CDCl3) δ 7.30 – 7.23 (m, 3H),

7.13 (d, J = 7.2, 2H), 3.93 (t, J = 7.3, 2H), 3.18 (dd, J = 11.3, 4.4, 2H), 3.11 (dd, J = 11.6,

4.5, 2H), 1.78 – 1.71 (m, 2H), 0.86 (t, J = 7.4, 3H); 13C NMR (126 MHz, CDCl3) δ 154.1,

139.5, 128.8, 128.81, 128.6, 128.4, 126.9, 126.4, 48.3, 33.7, 25.6, 22.9, 10.9; MS (ESI)


5-(4-chlorobenzyl)-1-(4-methoxyphenethyl)-1H-tetrazole (3d)

Yellow liquid, Yield: 251 mg (76%); 1H NMR (500 MHz, CDCl3) δ 7.26 (d, J = 8.6,

2H), 6.95 (d, J = 8.3, 2H), 6.85 – 6.73 (m, 4H), 4.29 (t, J = 6.8, 2H), 3.78 (s, 3H), 3.72

(s, 2H), 3.02 (t, J = 6.8, 2H); 13C NMR (126 MHz, CDCl3) δ 158.9, 153.5, 133.6, 132.2,

129.8, 129.7, 129.2, 128.8, 128.2, 114.4, 55.3, 49.1, 35.2, 28.3; MS (ESI) m/z calculated

[M+H]+: 329.11; found [M+H]+: 329.15.


Chapter 6

122

5-(4-chlorobenzyl)-1-phenethyl-1H-tetrazole (3e)

Brown liquid, Yield: 218 mg (73%); 1H NMR (500 MHz, CDCl3) δ 7.36 – 7.14 (m, 5H), 7.00

– 6.87 (m, 4H), 4.33 (t, J = 6.9, 2H), 3.69 (s, 2H), 3.07 (t, J = 6.9, 2H); 13C NMR (126 MHz,

CDCl3) δ 153.6, 136.4, 133.6, 132.2, 129.8, 129.2, 129.1, 129.1, 128.9, 128.7, 127.5, 48.9,

36.1, 28.3; MS (ESI) m/z calculated [M+H]+: 299.10; found [M+H]+: 299.15.

5-(4-chlorobenzyl)-1-(2-chlorophenyl)-1H-tetrazole (3f)

Brown solid, Yield: 279 mg (91 %); 1H NMR (500 MHz, CDCl3) δ 7.33 (m, 3H),

7.24 – 7.19 (m, 3H), 6.98 – 6.91 (m, 2H), 3.58 (s, 2H); 13C NMR (126 MHz, CDCl3)

δ 153.5, 133.7, 133.1, 130.9, 130.3, 129.4, 129.3, 128.3, 127.6, 127.3, 123.5, 38.2;

MS (ESI) m/z calculated [M-H]-: 303.03; found [M-H]-: 303.98.

5-(4-chlorobenzyl)-1-cyclohexyl-1H-tetrazole (3g)

Colorless liquid, Yield: 132 mg (48%); 1H NMR (500 MHz, CDCl3) δ 7.30 (d,

J = 8.3, 2H), 7.15 (d, J = 8.3, 2H), 4.26 (s, 2H), 4.11 – 3.99 (m, 1H), 1.99 – 1.83 (m,

4H), 1.79 – 1.62 (m, 3H), 1.38 – 1.18 (m, 3H); 13C NMR (126 MHz, CDCl3) δ 152.3,

133.6, 132.8, 129.8, 129.3, 129.2, 129.0, 128.8, 128.6, 57.9, 32.6, 28.9, 25.2, 25.1,


1-allyl-5-ethyl-1H-tetrazole (3h)

Colourless liquid, Yield: 96 mg (70%); 1H NMR (500 MHz, CDCl3) δ 6.01 – 5.94 (m, 1H), 5.36

(d, J = 10 Hz, 1H), 5.16 (d, J = 15 Hz, 1H), 4.97 (d, J = 5 Hz, 2H), 2.89 – 2.84 (q, J = 15 Hz,

2H), 1.42 (t, J = 10 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 156.0, 130.1, 119.7, 49.2, 16.8, 11.3

ppm; MS (ESI) m/z calculated [M+H]+: 139.09; found [M+H]+: 139.11.

5-ethyl-1-phenethyl-1H-tetrazole (3i)

Brown liquid, Yield: 147 mg (73 %); 1H NMR (500 MHz, CDCl3) δ 7.39 – 7.18 (m, 3H), 6.98

(d, J = 7.7, 2H), 4.46 (t, J = 6.8, 2H), 3.21 (t, J = 6.8, 2H), 2.35 (q, J = 7.6, 2H), 1.17 (t, J = 7.6,

3H); 13C NMR (126 MHz, CDCl3) δ 156.2, 136.4, 129.0, 128.8, 128.7, 127.4, 48.5, 36.3, 16.4,


5-ethyl-1-phenyl-1H-tetrazole (3j)

Colorless liquid, Yield: 149 mg (86%); 1H NMR (500 MHz, CDCl3) δ 7.68 – 7.56 (m, 3H),

7.52 – 7.41 (m, 2H), 2.93 (q, J = 7.6, 2H), 1.38 (t, J = 7.6, 3H); 13C NMR (126 MHz, CDCl3)

δ 156.1, 133.8, 130.4, 129.9, 124.8, 17.5, 11.6; MS (ESI) m/z calculated [M+H]+: 175.09;

found [M+H]+: 175.10.

3-(5-propyl-1H-tetrazol-1-yl)propanenitrile (3k)

Colorless liquid, Yield: 99 mg (60%); 1H NMR (500 MHz, CDCl3) δ 4.61 (t, J = 6.6, 2H), 3.13

(t, J = 6.6, 2H), 2.90 (t, J = 7.6, 2H), 1.97 – 1.81 (m, 2H), 1.06 (t, J = 7.4, 3H); 13C NMR (126

MHz, CDCl3) δ 155.5, 116.1, 42.4, 24.8, 20.6, 18.7, 13.6; MS (ESI) m/z calculated [M+H]+:

166.10; found [M+H]+: 166.13.



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5-(2-chloroethyl)-1-phenethyl-1H-tetrazole (3l)

Brown liquid, Yield: 167 mg (71%); 1H NMR (500 MHz, CDCl3) δ 7.37 – 7.18 (m, J = 5.1,

1.6, 3H), 7.01 – 6.93 (m, 2H), 4.54 (t, J = 6.7, 2H), 3.66 (t, J = 6.9, 2H), 3.22 (t, J = 6.7, 2H),

2.71 (t, J = 6.9, 2H); 13C NMR (126 MHz, CDCl3) δ 152.5, 136.3, 129.1, 129.0, 128.7, 128.7,

127.5, 48.9, 40.6, 36.3, 26.3; MS (ESI) m/z calculated [M+H]+: 236.08; found [M+H]+:

237.29.

5-(3-methoxyphenyl)-1-phenyl-1H-tetrazole (3m)

Brown liquid, Yield: 182 mg (72%); 1H NMR (500 MHz, CDCl3) δ 7.57 – 7.51 (m, J = 7.8,

3H), 7.41 (d, J = 7.2, 2H), 7.14 (s, 1H), 7.11 – 6.95 (m, 4H), 3.74 (s, 3H); 13C NMR (126 MHz,

CDCl3) δ 159.8, 153.5, 134.6, 130.5, 130.1, 129.9, 128.9, 125.4, 121.1, 117.6, 113.9, 55.4;

MS (ESI) m/z calculated [M+H]+: 253.10; found [M+H]+: 253.18.

1-(3,4-dimethoxyphenyl)-5-(4-nitrophenyl)-1H-tetrazole (3n)

Yellow solid, Yield: 290 mg (87%); 1H NMR (500 MHz, CDCl3) δ 8.28 (d, J = 8.6,

2H), 7.83 (d, J = 8.6, 2H), 6.98 – 6.92 (m, 2H), 6.87 (dd, J = 8.5, 2.2, 1H), 3.98

(s, 3H), 3.88 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 151.9, 151.1, 150.1, 149.3,

129.9, 129.7, 128.9, 126.6, 124.1, 123.7, 118.0, 111.3, 108.7, 56.4, 56.3; MS (ESI)


1-(2-benzylphenyl)-5-(4-chlorobenzyl)-1H-tetrazole (3o)

Yellow liquid, Yield: 318 mg (88%); 1H NMR (500 MHz, CDCl3) δ 7.54 (td, J = 7.6,

1.1, 1H), 7.41 (d, J = 7.6, 1H), 7.34 (td, J = 7.7, 1.2, 1H), 7.24 – 7.11 (m, 5H), 6.90

(dd, J = 7.8, 0.8, 1H), 6.86 (d, J = 8.4, 2H), 6.79 (d, J = 6.6, 2H), 3.62 (s, 2H); 13C

NMR (126 MHz, CDCl3) δ 154.5, 139.1, 138.1, 133.5, 132.4, 132.3, 131.6, 131.4,

130.1, 128.9, 128.7, 128.7, 127.6, 127.4, 126.8, 37.4, 28.3; MS (ESI) m/z calculated [M+H]+: 361.11; found

[M+H]+: 361.20.

5-(chloromethyl)-1-phenyl-1H-tetrazole (3p)

White solid, Yield: 141 mg (73%); 1H NMR (500 MHz, CDCl3) δ 7.68 – 7.47 (m, 5H), 4.83 (s, 2H);

13C NMR (126 MHz, CDCl3) δ 151.6, 133.1, 131.0, 130.1, 124.7, 31.2; MS (ESI) m/z calculated

[M+H]+: 195.04; found [M+H]+: 195.26.

5-(chloromethyl)-1-(o-tolyl)-1H-tetrazole (3q)

White solid, Yield: 150 mg (72%); 1H NMR (500 MHz, CDCl3) δ 7.51 (t, J = 7.6, 1H), 7.42 (d,

J = 7.4, 1H), 7.38 (t, J = 8.0, 1H), 7.28 (d, J = 7.8, 1H), 4.66 (s, 2H), 2.04 (s, 3H); 13C NMR (126

MHz, CDCl3) δ 152.4, 135.5, 131.9, 131.6, 127.3, 126.6, 30.9, 17.3; MS (ESI) m/z calculated

[M+H]+: 209.05; found [M+H]+: 209.26.


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124

5-phenethyl-1-propyl-1H-tetrazole (3r)

Yellow liquid, Yield: 199 mg (92%); 1H NMR (500 MHz, CDCl3) δ 7.28 (dd, J = 12.9, 5.2,

2H), 7.23 (t, J = 7.2, 1H), 7.13 (d, J = 7.2, 2H), 3.93 (t, J = 7.3, 2H), 3.21 – 3.06 (m, 4H),

1.81 – 1.67 (m, 2H), 0.86 (t, J = 7.4, 3H); 13C NMR (126 MHz, CDCl3) δ 154.1, 139.5, 128.8,

128.4, 126.9, 48.3, 33.7, 25.6, 22.9, 10.9; MS (ESI) m/z calculated [M+H]+: 217.14; found

[M+H]+: 217.20.

1-benzyl-5-phenethyl-1H-tetrazole (3s)

Brown solid, Yield: 190 mg (72%); 1H NMR (500 MHz, CDCl3) δ 7.42 – 7.34 (m, 3H), 7.33

– 7.23 (m, 3H), 7.15 – 7.05 (m, 4H), 5.22 (s, 2H), 3.04 (s, 4H); 13C NMR (126 MHz, CDCl3)

δ 154.4, 139.4, 133.3, 129.2, 128.9, 128.8, 128.4, 127.4, 126.9, 50.5, 33.5, 25.6; MS (ESI)


5-(3,4-dimethoxybenzyl)-1-isopropyl-1H-tetrazole (3t)

Brown solid, Yield: 148 mg (56%);1H NMR (500 MHz, CDCl3) δ 6.81 (d, J = 8.2,

1H), 6.71 (d, J = 8.3, 1H), 6.68 (d, J = 1.7, 1H), 4.48 (hept, J = 6.7, 1H), 4.24 (s, 2H),

3.86 (s, 3H), 3.82 (s, 3H), 1.43 (d, J = 6.7, 6H); 13C NMR (126 MHz, CDCl3) δ 152.6,

149.5, 148.5, 126.5, 120.4, 119.4, 111.4, 111.3, 111.1, 110.5, 55.9, 55.9, 50.7, 29.2,


5-(4-chlorobenzyl)-1-phenethyl-1H-tetrazole (3u)

Yellow liquid, Yield: 189 mg (63%); 1H NMR (500 MHz, CDCl3) δ 7.30 – 7.26 (m, 5H),

6.98 – 6.88 (m, 4H), 4.32 (t, J = 6.9, 2H), 3.68 (s, 2H), 3.08 (t, J = 6.9, 2H); 13C NMR (126

MHz, CDCl3) δ 153.5, 136.4, 132.2, 129.8, 129.3, 129.1, 128.7, 127.5, 48.9, 36.1, 28.2; MS


5-(naphthalen-2-ylmethyl)-1-propyl-1H-tetrazole (3v)

Colorless solid, Yield: 184 mg (73%); 1H NMR (500 MHz, CDCl3) δ 7.82 – 7.78

(m, 2H), 7.77 – 7.74 (m, 1H), 7.60 (s, 1H), 7.50 – 7.46 (m, 2H), 7.29 (dd, J = 8.4, 1.7,

1H), 4.43 (s, 2H), 4.07 (t, J = 7.4, 7.2, 2H), 1.78 – 1.67 (m, 2H), 0.79 (t, J = 7.4, 3H); 13C NMR (126 MHz, CDCl

3) δ 153.4, 133.4, 132.6, 131.3, 129.1, 127.8, 127.6, 127.1,


found [M+H]+: 253.22.

1,5-diphenyl-1H-tetrazole (3w)

White solid, Yield: 124 mg (58%); 1H NMR (500 MHz, CDCl3) δ 7.62 – 7.44 (m, 2H), 7.41

– 7.12 (m, 6H), 7.03 – 6.85 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 154.5, 131.3, 130.5,

129.9, 129.0, 129.0, 128.9, 128.4, 125.3; MS (ESI) m/z calculated [M+H]+: 223.09; found

[M+H]+: 223.18.



125

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6

1-phenethyl-5-phenyl-1H-tetrazole (3x)

Yellow viscous liquid, Yield: 120 mg (48%); 1H NMR (500 MHz, CDCl3) δ 7.58 – 7.52

(m, 1H), 7.47 (t, J = 7.6, 2H), 7.32 – 7.28 (m, 3H), 7.26 – 7.20 (m, 2H), 7.01 – 6.92 (m, 2H),

4.63 (t, J = 7.1, 2H), 3.27 (t, J = 7.1, 2H); 13C NMR (126 MHz, CDCl3) δ 154.8, 136.1, 131.1,

129.1, 128.9, 128.9, 128.7, 128.7, 127.3, 49.2, 36.1; MS (ESI) m/z calculated [M+H]+:

251.12; found [M+H]+: 251.23.

1-(4-chlorophenyl)-5-(4-methoxyphenyl)-1H-tetrazole (3y)

Brown soild, Yield: 180 mg (63 %); 1H NMR (500 MHz, CDCl3) δ 7.54 – 7.46 (m,

1H), 7.22 (d, J = 8.6, 2H), 7.09 (dd, J = 19.3, 8.6, 2H), 6.93 (d, J = 8.9, 1H), 6.87 – 6.76

(m, 2H), 3.78 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 162.0, 146.4, 130.5, 130.2, 129.3,

126.6, 122.8, 114.9, 114.6, 114.4, 55.5; MS (ESI) m/z calculated [M+H]+: 287.06;

found [M+H]+: 287.19.

3-(5-propyl-1H-tetrazol-1-yl)propanenitrile (3z)

Colorless liquid, Yield: 103 mg (62%); 1H NMR (500 MHz, CDCl3) δ 4.58 (t, J = 6.6, 2H),

3.12 (t, J = 6.6, 2H), 2.90 (t, J = 7.6, 2H), 1.97 – 1.83 (m, 2H), 1.07 (t, J = 7.4, 3H); 13C NMR

(126 MHz, CDCl3) δ 155.4, 115.9, 42.4, 24.9, 20.7, 18.8, 13.7; MS (ESI) m/z calculated

[M+H]+: 166.10; found [M+H]+: 166.26.

1-phenethyl-5-propyl-1H-tetrazole (3aa)

Colorless liquid, Yield: 153 mg (71%); 1H NMR (500 MHz, CDCl3) δ 7.29 – 7.23

(m, 3H), 7.02 – 6.96 (m, 2H), 4.46 (t, J = 6.9, 2H), 3.21 (t, J = 6.8, 2H), 2.31 (t, J = 7.6,

2H), 1.63 – 1.54 (m, 2H), 0.86 (t, J = 7.4, 3H); 13C NMR (126 MHz, CDCl3) δ 155.1, 136.5,

128.9, 128.7, 127.4, 48.5, 36.2, 24.5, 20.3, 13.6; MS (ESI) m/z calculated [M+H]+: 217.14;

found [M+H]+: 217.23.

1-allyl-5-propyl-1H-tetrazole (3ab)

Yellow liquid, Yield: 79 mg (52%); 1H NMR (500 MHz, CDCl3) δ 6.04 – 5.89 (m, 1H), 5.36 (d,

J = 10.3, 1H), 5.15 (d, J = 17.1, 1H), 4.96 (d, J = 5.6, 2H), 2.81 (t, J = 7.6, 2H), 1.99 – 1.76 (m,

2H), 1.03 (t, J = 7.4, 3H); 13C NMR (126 MHz, CDCl3) δ 154.9, 130.2, 119.6, 49.2, 24.9, 20.4,


2-(1-phenethyl-1H-tetrazol-5-yl)acetonitrile (3ac)

Colorless solid, Yield: 142 mg (67%); 1H NMR (500 MHz, CDCl3) δ 7.37 – 7.28 (m, 3H),

6.96 (dd, J = 6.4, 2.8, 2H), 4.68 (t, J = 6.3, 2H), 3.24 (t, J = 6.4, 2H), 3.14 (s, 2H); 13C NMR

(126 MHz, CDCl3) δ 146.3, 136.2, 129.5, 128.9, 128.0, 112.4, 49.9, 36.4, 12.9; MS (ESI) m/z

calculated [M-H]-: 212.24; found [M-H]-: 212.16.


Chapter 6

126

5-(chloromethyl)-1-(2-chlorophenyl)-1H-tetrazole (3ad)

Yellow solid, Yield: 130 mg (57%); 1H NMR (500 MHz, CDCl3) δ 7.68 (dd, J = 8.0, 1.1, 1H),

7.66 – 7.61 (m, 1H), 7.59 – 7.48 (m, 2H), 4.75 (s, 2H); 13C NMR (126 MHz, CDCl3) δ 152.7,


found [M+H]+: 229.01.

1-benzyl-5-(chloromethyl)-1H-tetrazole (3ae)


7.33 – 7.25 (m, 2H), 5.68 (s, 2H), 4.62 (s, 2H); 13C NMR (126 MHz, CDCl3) δ 151.1, 132.4,

129.4, 129.4, 127.9, 51.7, 31.4; MS (ESI) m/z calculated [M+H]+: 209.05; found [M+H]+:

209.05.

1-(2-chlorophenyl)-5-ethyl-1H-tetrazole (3af)

White solid, Yield: 125 mg (60%); 1H NMR (500 MHz, CDCl3) δ 7.65 (dd, J = 8.1, 1.4,

1H), 7.60 (td, J = 7.8, 1.6, 1H), 7.52 (td, J = 7.7, 1.4, 1H), 7.43 (dd, J = 7.8, 1.6, 1H), 2.78 (q,

J = 7.6, 2H), 1.35 (t, J = 7.6, 3H); 13C NMR (126 MHz, CDCl3) δ 157.3, 132.4, 131.6, 131.5,

130.9, 128.9, 128.2, 17.0, 11.3; MS (ESI) m/z calculated [M+H]+: 209.05; found [M+H]+: 209.11.

1-benzyl-5-phenethyl-1H-tetrazole (3ag)


7.31 – 7.20 (m, 3H), 7.12 – 7.07 (m, 2H), 7.05 (d, J = 7.3, 2H), 5.20 (s, 2H), 3.01 (s, 4H); 13C

NMR (126 MHz, CDCl3) δ 154.5, 139.5, 133.4, 129.2, 128.9, 128.8, 128.4, 127.4, 126.9,

50.5, 33.4, 25.6; MS (ESI) m/z calculated [M+H]+: 265.14; found [M+H]+: 265.21.

5-phenethyl-1-propyl-1H-tetrazole (3ah)


7.25 – 7.20 (m, 1H), 7.13 (d, J = 7.1, 2H), 3.93 (t, J = 7.2, 2H), 3.22 – 3.14 (m, 2H), 3.14 –

3.07 (m, 2H), 1.82 – 1.69 (m, 2H), 0.86 (t, J = 7.4, 3H); 13C NMR (126 MHz, CDCl3) δ 154.1,

128.82, 128.4, 126.9, 48.3, 33.7, 25.6, 22.9, 10.9; MS (ESI) m/z calculated [M+H]+: 217.14;

found [M+H]+: 217.16.

1,5-bis(4-chlorobenzyl)-1H-tetrazole (3ai)

Colorless solid, Yield: 222 mg (70%); 1H NMR (500 MHz, CDCl3) δ 7.32 – 7.21

(m, 4H), 6.98 (d, J = 8.3, 2H), 6.94 (d, J = 8.4, 2H), 5.31 (s, 2H), 4.13 (s, 2H); 13C NMR

(126 MHz, CDCl3) δ 153.2, 135.1, 133.9, 131.8, 131.3, 129.7, 129.4, 129.3, 128.7,

50.3, 28.9; MS (ESI) m/z calculated [M+H]+: 319.19; found [M+H]+: 319.14.



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6

1-benzyl-5-phenyl-1H-tetrazole (3aj)


7.54 – 7.47 (m, 2H), 7.38 – 7.32 (m, 3H), 7.16 (dd, J = 7.1, 2.2, 2H), 5.62 (s, 2H); 13C NMR

(126 MHz, CDCl3) δ 154.7, 133.9, 131.4, 129.2, 129.2, 129.1, 128.9, 128.8, 127.2, 123.8,


1,3-bis(5-benzyl-1H-tetrazol-1-yl)benzene (3ak)

Yellow solid, Yield: 236 mg (60%); 1H NMR (500 MHz, CDCl3) δ 7.65 (t, J = 8.1, 1H),

7.49 (dd, J = 8.1, 2.0, 2H), 7.26 – 7.17 (m, 7H), 7.04 (dd, J = 7.4, 1.4, 4H), 4.27 (s, 4H); 13C NMR (126 MHz, CDCl

3) δ 153.9, 134.7, 133.6, 131.2, 129.1, 128.5, 127.8, 126.7,

121.9, 29.7; MS (ESI) m/z calculated [M+Na]+: 417.17; found [M+Na]+: 417.34.

1,3-bis(5-phenethyl-1H-tetrazol-1-yl)propane (3al)

Yellow solid, Yield: 221 mg (57%); 1H NMR (500 MHz, CDCl3) δ 7.27 – 7.19 (m, 4H),

7.19 – 7.13 (m, 2H), 7.06 (d, J = 7.2, 4H), 3.80 (t, J = 6.6, 4H), 3.20 – 3.04 (m, 8H), 2.00

(p, J = 6.5, 2H); 13C NMR (126 MHz, CDCl3) δ 154.6, 139.2, 128.8, 128.6, 128.5, 126.9,

43.2, 33.7, 28.0, 25.3; MS (ESI) m/z calculated [M+H]+: 389.21; found [M+H]+: 389.35.

1,3-bis(5-ethyl-1H-tetrazol-1-yl)propane (3am)

Colorless solid, Yield: 145 mg (61%); 1H NMR (500 MHz, CDCl3) δ 4.35 (t, J = 6.7, 4H), 2.82

(q, J = 7.6, 4H), 2.57 (p, J = 6.6, 2H), 1.31 (t, J = 7.6, 6H); 13C NMR (126 MHz, CDCl3) δ 156.2,

63.6, 43.5, 28.4, 16.7, 11.2; MS (ESI) m/z calculated [M+H]+: 237.15; found [M+H]+: 237.12.

1,3-bis(5-(4-chlorobenzyl)-1H-tetrazol-1-yl)propane (3an)

Colorless solid, Yield: 283 mg (66%); 1H NMR (500 MHz, CDCl3) δ 7.28 (d, J = 8.4, 4H),

7.09 (d, J = 8.4, 4H), 4.25 (s, 4H), 4.12 (t, J = 6.5, 4H), 2.19 (p, J = 6.5, 2H); 13C NMR

(126 MHz, CDCl3) δ 153.6, 133.9, 131.9, 129.8, 129.5, 43.7, 28.7, 28.2; MS (ESI) m/z



Chapter 6

128

Experiments for Proving Stereochemical Retention

Synthesis of racemic compound: benzyl (1-(1-benzyl-1H-tetrazol-5-yl)ethyl)carbamate

Synthesized according to the general procedure.

benzyl (1-(1-benzyl-1H-tetrazol-5-yl)ethyl)carbamate

White solid, Yield: 225 mg (67%); 1H NMR (500 MHz, CDCl3) δ 7.46 – 7.12 (m, 10H),

6.50 (s, 1H), 5.06 (s, 2H), 4.49 – 4.32 (m, 2H), 4.32 – 4.15 (m, 1H), 1.39 (d, J = 7.0, 3H); 13C

NMR (126 MHz, CDCl3) δ 172.1, 156.0, 137.9, 136.1, 128.7, 128.6, 128.3, 128.1, 127.6,

127.6, 67.1, 50.6, 43.5, 18.6; MS (ESI) m/z calculated [M-H]-: 336.15; found [M-H]-: 336.24. The racemate

was separated on a Reprosil Chiral-OM column as described in the general methods. Enantiomer A,

tR =3.42 min (48%); Enantiomer B, t

R = 3.63 min (52%).

Synthesis of (S)-benzyl (1-(1-benzyl-1H-tetrazol-5-yl)ethyl)carbamate (6)

Synthesized according to the general procedure.

(S)-benzyl (1-(1-benzyl-1H-tetrazol-5-yl)ethyl)carbamate (6)


7.27 – 7.14 (m, 3H), 6.59 (s, 1H), 5.15 – 4.94 (m, 2H), 4.50 – 4.34 (m, 2H), 4.33 – 4.15 (m,

1H); 13C NMR (126 MHz, CDCl3) δ 172.2, 156.0, 137.9, 136.1, 128.7, 128.6, 128.3, 128.1,

127.6, 127.6, 67.1, 50.6, 43.5, 18.7; MS (ESI) m/z calculated [M-H]-: 336.15; found [M-H]-: 336.16. The

enantiomeric excess was determined on a Reprosil Chiral-OM column as described in the general

methods. Enantiomer A, tR =3.43 min (>99.9%); Enantiomer B, t

R = 3.63 min (0%).



129

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Synthesis of Fused Tetrazoles:Synthesized according to the general procedure.

Tetrazolo[1,5-c]quinazoline (9a)

White solid, Yield: 86 mg (50%); 1H NMR (500 MHz, CDCl3) δ 8.32 (d, J = 8.0, 1H), 8.15 (s,

1H), 7.87 – 7.76 (m, 2H), 7.56 (t, J = 7.4, 1H); 13C NMR (126 MHz, CDCl3) δ 163.1, 149.0,

143.4, 135.0, 127.9, 127.4, 126.4, 122.5; MS (ESI) m/z calculated [M+H]+: 172.05; found

[M+H]+: 172.08.

4-benzyltetrazolo[1,5-a]quinoxaline (9b)


7.31 – 7.24 (m, 5H), 7.22 – 7.17 (m, 2H), 4.24 (s, 2H); 13C NMR (126 MHz, CDCl3)

δ 153.4, 136.3, 129.8, 129.6, 129.0, 129.0, 127.9, 127.3, 122.4, 35.9; MS (ESI) m/z


4-methyltetrazolo[1,5-a]quinoxaline (9c)

White solid, Yield: 109 mg (59%); 1H NMR (500 MHz, CDCl3) δ 8.58 (dd, J = 7.5, 1.7, 1H),

8.21 (dd, J = 7.1, 2.1, 1H), 7.89 – 7.79 (m, 2H), 3.13 (s, 3H); 13C NMR (126 MHz, CDCl3)

δ 151.0, 142.8, 136.8, 131.9, 130.3, 129.8, 129.7, 116.3, 21.7; MS (ESI) m/z calculated

[M+H]+: 186.07; found [M+H]+: 186.32.

4-ethyltetrazolo[1,5-a]quinoxaline (9d)

Pale yellow solid, Yield: 121 mg (61%); 1H NMR (500 MHz, CDCl3) δ 8.59 – 8.52 (m, 1H),

8.26 – 8.16 (m, 1H), 7.87 – 7.78 (m, 2H), 3.49 (q, J = 7.5, 2H), 1.58 (t, J = 7.5, 3H); 13C NMR

(126 MHz, CDCl3) δ 155.3, 136.8, 131.7, 130.7, 130.2, 129.9, 129.6, 116.2, 28.6, 11.3. MS


4-methyl-4,5-dihydrotetrazolo[1,5-a]quinoxaline (9e)

Colorless liquid, Yield: 119 mg (63%); 1H NMR (500 MHz, CDCl3) δ 10.73 (s, 1H), 7.72

– 7.57 (m, 2H), 7.36 – 7.23 (m, 2H), 5.06 (q, J = 6.9, 1H), 1.84 (d, J = 6.9, 3H); 13C NMR

(126 MHz, CDCl3) δ 153.2, 138.3, 123.1, 115.3, 55.3, 19.2; MS (ESI) m/z calculated [M+H]+:

188.09; found [M+H]+: 188.13.

Tetrazolo[5,1-a]phthalazine (9f)

White solid, Yield: 82 mg (48%); 1H NMR (500 MHz, CDCl3) δ 8.99 (s, 1H), 8.76 (d, J = 8.0,

1H), 8.19 (d, J = 8.0, 1H), 8.14 (t, J = 7.6, 1H). 13C NMR (126 MHz, CDCl3) δ 149.23, 142.10,

134.88, 132.76, 128.62, 124.83, 124.58, 122.24; MS (ESI) m/z calculated [M+H]+: 172.05;

found [M+H]+: 172.10.


Chapter 6

130

4H-benzo[b]tetrazolo[1,5-d][1,4]oxazine (9g)

Brown solid, Yield: 97 mg (56%); 1H NMR (500 MHz, CDCl3) δ 7.94 (dd, J = 8.0, 1.4, 1H),

7.36 (td, J = 8.0, 1.5, 1H), 7.22 (t, J = 7.8, 1H), 7.18 (dd, J = 8.3, 0.7, 1H), 5.64 (s, 2H); 13C

NMR (126 MHz, CDCl3) δ 145.9, 144.9, 130.0, 123.7, 121.9, 118.1, 117.2, 62.1; MS (ESI) m/z


Procedure for 9h and 9i: A 20 ml microwave vial equipped with a magnetic stirring bar was charged with 6-aminohexanoic

acid or 5-aminopentanoic acid (1.0 mmol) in CH3CN (5 ml) and phosphoryl chloride (1.0 mmol) was

added slowly followed by trimethylsilyl azide (1.5 equiv) at room temperature. The vial was sealed

with a cap containing a septum and subjected to microwave heating at 180 °C till completion of

reaction. [attention: during irradiation, pressure develops] Then the reaction mixture was poured into

50 mL of saturated NaHCO3 and extracted 3 times with 25 mL of CH

2Cl

2. The solvent was removed

under reduced pressure and residue was purified by silica gel flash chromatography using EtOAc–

hexane or DCM:MeOH as eluent t. [Caution: Addition of reagents and work-up must be done behind the

glass-hood.]

6,7,8,9-tetrahydro-5H-tetrazolo[1,5-a]azepine (9h)

Colorless solid, Yield: 105 mg (76%); 1H NMR (500 MHz, CDCl3) δ 4.58 – 4.44 (m, 2H), 3.18

– 3.05 (m, 2H), 2.07 – 1.95 (m, 2H), 1.94 – 1.85 (m, 2H), 1.84 – 1.72 (m, 2H); 13C NMR (126

MHz, CDCl3) δ 156.6, 49.3, 29.8, 27.1, 24.6, 24.2; MS (ESI) m/z calculated [M+H]+: 139.09;

found [M+H]+: 139.11.

5,6,7,8-tetrahydrotetrazolo[1,5-a]pyridine (9i)

Colorless solid, Yield: 88 mg (71%); 1H NMR (500 MHz, CDCl3) δ 4.34 (t, J = 6.1, 2H), 3.00 (t, J

= 6.4, 2H), 2.19 – 2.07 (m, 2H), 2.06 – 1.93 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 151.9, 45.5,




131

5

6

Synthesis of Cilostazol:

Synthesis of 5-(4-chlorobutyl)-1-cyclohexyl-1H-tetrazole (12)

A 20 ml microwave vial equipped with a magnetic stirring bar was charged with 2-(4-chlorophenyl)

acetic acid chloride (1.0 mmol), 2-phenylethanamine (1.0 mmol), and CH3CN (5 ml) and stirred

at room temperature for 30 min followed by the addition of phosphoryl chloride (1.0 mmol) at

room temperature. Trimethylsilyl azide (1.5 equiv) was added in the reaction mixture and subjected

to microwave heating at 120 oC for 10 minute. Then the reaction mixture was added to a 25 ml

saturated NaHCO3 solution and extracted in DCM. The solvent was removed under reduced pressure

and the mixture was purified by flash chromatography on silica gel (eluent: hexane/AcOEt) to afford

the titled compound as a white solid. Yield: 157 mg (65%); 1H NMR (500 MHz, CDCl3) δ 4.23 – 4.05 (m,

1H), 3.62 (t, J = 6.2, 2H), 2.89 (t, J = 7.5, 2H), 2.07 – 1.95 (m, 8H), 1.95 – 1.88 (m, 2H), 1.83 – 1.75 (m, 1H),

1.52 – 1.30 (m, 3H); 13C NMR (126 MHz, CDCl3) δ 153.3, 57.6, 44.2, 32.9, 31.5, 25.3, 24.8, 24.4, 22.5; MS


Synthesis of Cilostazol (14):

5-(4-chlorobutyl)-1-cyclohexyl-1H-tetrazole 13 (0.25 mmol) and 6-hydroxy-3,4-dihydroquinolin-

2(1H)-one (0.275 mmol) were added to DMF (3 ml) in a 20 ml microwave vial followed by KOH (0.75

mmol) and subjected to microwave heating at 150 °C for 7 min. Then reaction mixture was poured

into water and extracted in ethyl acetate. The solvent was removed under reduced pressure and

the mixture was purified by flash chromatography on silica gel (eluent: DCM/MeOH) to afford a

cilostazol 14 as a colorless solid. Yield: 89%; 1H NMR (500 MHz, CDCl3) δ = 7.85 (s, 1H), 7.26 (s, 2H),

6.78 – 6.62 (m, 3H), 4.21 – 4.05 (m, 1H), 3.98 (t, J = 6.0, 2H), 3.49 (d, J = 5.1, 1H), 2.99 – 2.87 (m, 4H), 2.61

(m, 2H), 2.13 – 1.94 (m, 8H), 1.94 – 1.84 (m, 2H), 1.78 (d, J = 12.0, 1H), 1.50 – 1.32 (m, 3H); 13C NMR (126

MHz, CDCl3) δ 170.9, 154.8, 153.5, 130.8, 125.2, 116.0, 114.5, 113.1, 67.6, 57.6, 32.9, 30.6, 28.6, 25.8, 25.3,



Chapter 6

132

References

[1] For a general review on the importance of tetrazole derivatives, see: a) C. X. Wei, M. Bian, G. H. Gong, Molecules 2015, 20, 5528–5553; b) J. Roh, K. Vavrova, A. Hrabalek, Eur. J. Org. Chem. 2012, 6101–6118; c) P. B. Mohite, V. H. Bhaskar, Int. J. Pharm.Tech. Res. 2011, 3, 1557–1566; d) L. M. Frija, A. Ismael, M. L. S. Cristiano, Molecules 2010, 15, 3757–3774; d) L. V. Myznikov, A. Hrabalek, G. I. Koldobskii, Chem. Heterocycl. Compd. (N. Y., NY, U. S.) 2007, 43, 1–9.

[2] J. A. Bladin, Chem. Ber. 1885, 18, 1544–1551.

[3] For a general review on the synthesis of tetrazole derivatives, see: a) A. Sarvary, A. Maleki, Mol. Divers. 2015, 19, 189–212; b) M. Malik, M. Wani, S. Al-Thabaiti, R. Shiekh, J. Incl. Phenom. Macrocycl. Chem. 2014, 78, 15–37; c) G. I. Koldobskii, Russ. J. Org. Chem. 2006, 42, 469–486; d) R. J. Herr, Bioorg. Med. Chem. 2002, 10, 3379–3393; e) V. Y. Zubarev, V. A. Ostrovskii, Chem. Het. Comp. 2000, 36, 759–774; f ) S. J. Wittenberger, Org. Prep. Proced. Int. 1994, 26, 499–531.

[4] S. Lehnhoff, I. Ugi, Heterocycles 1995, 40, 801–808.

[5] A. R. Katritzky, C. Cai, N. K. Meher, Synthesis, 2007, 1204–1208, and references therein.

[6] C. A. G. N. Montalbetti, V. Falque, Tetrahedron 2005, 61, 10827–10852, and references therein.

[7] L. J. Kennedy, Tetrahedron Lett. 2010, 51, 2010–2013.

[8] a) B. C. H. May, A. D. Abell, J. Chem. Soc., Perkin. Trans. 1 2002, 1, 172–178; b) A. D. Abell, G. J. Foulds, J. Chem. Soc., Perkin. Trans. 1 1997, 1, 2475–2482.

[9] K. L. Yu, R. L. Johnson, J. Org. Chem. 1987, 52, 2051–2059.

[10] a) G. M. Schroeder, S. Marshall, H. Wan, A. V. Purandare, Tetrahedron Lett. 2010, 51, 1404–1406; b) A. S. Hernandez, P. T. W. Cheng, C. M. Musial, S. G. Swartz, R. J. George, G. Grover, D. Slusarchyk, R. K. Seethala, M. Smith, K. Dickinson, L. Giupponi, D. A. Longhi, N. Flynn, B. J. Murphy, D. A. Gordon, S. A. Biller, J. A. Robl, J. A. Tino, Bioorg. Med. Chem. Lett. 2007, 17, 5928–5933; c) C. M. Athanassopoulos, T. Garnelis, D. Vahliotis, D. Papaioannou, Org. Lett. 2005, 7, 561–564; d) J. V. Duncia, M. E. Pierce, J. B. Santella, III. J. Org. Chem. 1991, 56, 2395–2400.

[11] G. S. Jedhe, D. Paul, R. G. Gonnade, M. K. Santra, E. Hamel, T. L. Nguyen, G. J. Sanjayan, Bioorg. Med. Chem. Lett. 2013, 23, 4680–4684.

[12] B. J. Al-Hourani, S. K. Sharma, J. Y. Mane, J. Tuszynski, V. Baracos, T. Kniess, M. Suresh, J. Pietzsch, F. Wuest, Bioorg. Med. Chem. Lett. 2011, 21, 1823–1826.

[13] a) B. J. Al-Hourani, S. K. Sharma, M. Suresh, F. Wuest, Bioorg. Med. Chem. Lett. 2012, 22, 2235–2238; b) S. E. Morozova, K. A. Esikov, T. N. Dmitrieva, A. A. Malin, V. A. Ostrovskii, Russ. J. Org. Chem. 2004, 40, 443–445; c) K. A. Esikov, S. E. Morozova, A. A. Malin, V. A. Ostrovskii, Russ. J. Org. Chem. 2002, 38, 1370–1373; d) K. A. Esikov, V. Y. Zubarev, A. A. Malin, V. A. Ostrovskii, Chem. Heterocycl. Compd. (N. Y., NY, U. S.) 2000, 36, 878–878.

[14] a) B. Gutmann, J. P. Roduit, D. Roberge, C. O. Kappe, Angew. Chem. Int. Ed. Engl., 2010, 49, 7101–7105; Angew. Chem. 2010, 122, 7255–7259; b) M. Alterman, A. Hallberg, J. Org. Chem. 2000, 65, 7984–7989.

[15] R. P. Singh, R. D. Verma, D. T. Meshri, J. M. Shreeve, Angew. Chem. Int. Ed. Engl. 2006, 45, 3584–3601; Angew. Chem. 2006, 118, 3664–3682.

[16] J. Zabrocki, J. B. Dunbar Jr., K. W. Marshall, M. V. Toth, G. R. Marshall, J. Org. Chem. 1992, 57, 202–209.

[17] For a general review on the importance of MCR reactions, see: A. Dömling, W. Wang, K. Wang, Chem. Rev. 2012, 112, 3083–3135.

[18] A. Maleki, A. Sarvary, RSC Adv. 2015, 5, 60938–60955.

[19] S.Wagle, A. V. Adhikari, N. S. Kumari, Eur. J. Med. Chem. 2009, 44, 1135–1143.

[20] a) L. Zhang, L. P. Guan, X. Y. Sun, C. X. Wei, K. Y. Chai, Z. S. Quan, Chem. Biol. Drug Des. 2009, 73, 313–319. b) X. Y. Sun, C. X. Wei, X. Q. Deng, Z. G. Sun, Z. S. Quan, Pharmacol. Rep. 2010, 62, 273–277.

[21] S. M. Bromidge, R. Arban, B. Bertani, S. Bison, M. Borriello, P. Cavanni, G. D. Forno, R. Di-Fabio, D. Donati, S. Fontana, M. Gianotti, L. J. Gordon, E. Granci, C. P. Leslie, L. Moccia, A. Pasquarello, I. Sartori, A. Sava, J. M. Watson, A. Worby, L. Zonzini and V. Zucchelli, J. Med. Chem. 2010, 53, 5827–5843.

[22] M. E. Jung, H. Lal, M. B. Gatch, Neurosci. Biobehav. Rev. 2002, 26, 429–439.

[23] R. Stolle, Chem. Ber. 1930, 63, 1032–1037.

[24] M. Baumann, I. R. Baxendale, S. V. Ley, N. Nikbin, Beilstein J. Org. Chem. 2011, 7, 442–495, and references therein.


Chapter 7Highly Diastereoselective One Pot

Five-Component Reaction toward

4-(Tetrazole)-1,3-Oxazinane

Manuscript Submitted:

Ajay L. ChandgudeDaniele Narducci

Katarzyna KurpiewskaJustyna Kalinowska-Tłuścik

Alexander Dömling2017


Chapter 7

134

Abstract

A highly diastereoselective one pot five-component reaction toward the synthesis of 4-(tetrazole)-

1,3-oxazinane has been reported. The sonication-accelerated, catalyst-free, simple, general and highly

time efficient, Asinger-Ugi-tetrazole reaction was used for the synthesis of diverse 4-(tetrazole)-1,3-

oxazinanes. The reaction exhibit excellent diastereoselectivity and broad substrate scope.


Highly Diastereoselective One Pot Five-Component Reaction toward 4-(Tetrazole)-1,3-Oxazinane

135

5

7

Introduction

Oxazines motif attained significant attention due to their widespread availability in natural products,

such as aragupetrosine, bujeine, pagicerine, quimbeline, and upenamide. The oxazines scaffold is

present in many pharmacologically active agents[1] and drugs, such as pranlukast, dirithromycin,

and dolutegravir. It is also used as intermediate for the synthesis drugs like oxacephem antibiotics.[2]

The tetrazole is a highly important synthetic scaffold for a wide range of areas and applications.

It is extensively used in the medicinal and organic chemistry, also in industries such as explosives,

agrochemicals, materials, and polymers.[3] Their use as a carboxylic acid isostere and cis-amide

bond isostere in peptides have many advantages, such as extra lipophilicity, metabolic stability,

and hydrogen bonding to increase potency.[4] On the other hand, heterocycles are important in

drug design and present in half of the top 200 drugs.[5] Thus, recently the use of heterocycle linked

tetrazole scaffolds getting major consideration as a privileged core structure for the development

of a drug candidate. This combination is an effective strategy to balance drug-like properties.

Owning the importance of heterocycles linked tetrazoles resulted into reports of many examples

of bioactive agents, such as pyridine-tetrazole, Akt1 and Akt2 dual inhibitors;[6] pyrazole-tetrazole,

antileishmanials[7] or as cardiotonic agents;[8] pyridine-tetrazole, antibacterial;[9] piperazines-

tetrazole, type 2 diabetes;[10] isoxazole-tetrazole, for AMPA receptors;[11] and also for ionotropic

glutamate receptors.[12] Moreover, in non-medical applications, use of cyclic ketimines-tetrazoles as

organocatalysts,[13] and pyridine-tetrazoles in lanthanide-based applications[14] are also well known.

Strategies for the synthesis of heterocycle-tetrazole can be categorized into three types. First, the

coupling of heterocycle with tetrazole (Figure 1, A).[15] Second, synthesis of cyano-heterocycle

followed by the tetrazole formation (Figure 1 B).[7] Third, tetrazole synthesis followed by post-

condensation reaction toward heterocycle formation (Figure 1 C).[16] These methods mainly involve

more than two steps, harsh coupling conditions, and also the synthesis of starting material for the

coupling is tedious.

Here we are reporting the first example of oxazine-tetrazole motif synthesis by using one-pot

five-component reaction. The oxazine-tetrazole scaffold is accessible in one pot, time efficiently

with high diastereoselectivity and diversity.


Chapter 7

136

Figure 1. Heterocycle-tetrazole synthesis.


We envisioned the use of Asinger-Ugi-tetrazole union for the first time to synthesize an oxazines-

tetrazole scaffold. We start our optimization by using isobutyraldehyde, ammonium hydroxide,

3-hydroxypivalaldehyde, benzyl isocyanide and TMSN3. The reaction in methanol at room

temperature resulted in only trace product formation (Table 1, Entry 1). Union of Asinger reaction

with other MCR is known to be low yielding.[17] Therefore we move our attention towards the use of

sonication as a use of sonication in MCR is known to be effective.[18] Further optimization was carried

out with sonication at room temperature.

First, we optimized the ammonia source. We screened different ammonia sources, like NH4OH,

NH4Cl, and NH

4OAc. NH

4OH in 1.5 equivalent was found to be the best. When the reaction was

performed in MeOH, a promising 51% yield was obtained (Table 1, Entry 2). Next, we move our

attention towards solvent screening. Use of MeOH:H2O solvent systems, such as 3:1, 1:1 or 1:3 resulted

in less product formation, like 21%, 17%, and 15% respectively (Table 1. Entries 3–5). However, EtOH

solvent gave desired product in trace amount. When water used as a solvent, the reaction did not

proceed further which is due to water insolubility of reactants (Table 1, Entry 7). Use of dioxane and

THF provide the almost similar yield of 30% (Table 1, Entries 8–9). TFE and DCM offered a lower yield.

Toluene turned out to be the best solvent with 60% yield (Table 1, Entry 13). However, an attempt to

make the protocol greener by using toluene:water solvent system resulted in a lower than 25% yield

(Table 1, Entries 14–16). While xylene did not ameliorate the reaction yield.



137

5

7

Table 1. Optimization of reaction conditions.a

Entry Solvent Time (h) Yield%b

1c MeOH 12 trace

2 MeOH 2 51

3 MeOH : H2O (3 : 1) 4 21

4 MeOH : H2O (1 : 1) 4 17

5 MeOH : H2O (1 : 3) 6 15

6 EtOH 2 nd

7 H2O 7 nr

8 dioxane 2 32

9 THF 2 29

10 TFE 3 16

11 DCM 3 17

12 MeCN 3 33

13 toluene 2 60

14 toluene : H2O (1 : 1) 4 11

15 toluene : H2O (3 : 1) 3 19

16 toluene : H2O (4 : 1) 2 25

17 p-xylene 4 15aThe reaction was carried out with isobutyraldehyde (1 mmol), ammonium hydroxide (1.5 mmol), 3-hydroxypivalaldehyde (1 mmol), benzyl isocyanide (1.2 mmol) and TMSN

3 (1.2 mmol) in 0.5 ml solvent. bYield of isolated product. CWithout sonication at

room temperature. nd- not determined. nr- no reaction.

With optimized conditions in hand, next, we tested the scope and limitations of this reaction by

reacting various aldehydes and isocyanides (Table 2). Different linear and branched aliphatic

aldehydes such as isobutyraldehyde, propanal, butyraldehyde, and valeraldehyde provide moderate

to good yields of 21% to 60% (Table 2, Entries 2–7). Good to excellent yield were obtained with

aliphatic-aromatic aldehydes like benzyl and phenylacetaldehyde. Benzaldehyde and 2-chloro

benzaldehyde are valid substrates in this reaction with providing moderate yields of 35% and 45%

respectively (Table 2, Entries 12 and 13). However, the reaction with ketone resulted in only trace

product formation. It is important to mention that, the preformation of imine from aldehyde and

ammonium hydroxide is needed to get high yield which normally requires 30 minutes to 1 hour.

The slow addition of 3-hydroxypivalaldehyde over 30 min also help to get a clean reaction. After the

addition of isocyanide and TMSN3, reaction completes within 2–4 hours.

Further, we screened different isocyanides. Aliphatic isocyanides like tert-octyl isocyanide and

cyclohexyl isocyanide worked well (Table 2, Entries 3 and 9). Aromatic isocyanides like benzyl and


Chapter 7

138

phenylethyl isocyanide with different aldehydes, product yields were good. The glycine isocyanide

provides the excellent yield of 83% (Table 2, Entry 11). While the functional group protected

isocyanide, diethoxy-acetaldehyde also compatible in this reaction, which is interesting for further

postmodification condensation or for the union with other MCR (Table 2, Entry 6). Also, a tolerance

of a 2-bromo benzyl isocyanide is interesting for the postmodification reaction (Table 2, Entry 4).

In all examples a higher diastereoselectivity was observed. Aliphatic, aromatic aldehydes and

also all isocyanides show more than 90:10 diastereoselectivity. However with benzyl isocyanide and

2-bromo benzylisocyanides low diastereoselectivity observed.

Table 2. Substrate scope.a

Entry R1-CHO R

2-NC Yieldb (%) dr

1 CHONC

(1a) 60 78 : 22

2 CHONC

(1b) 51 91 : 09

3 CHO NC(1c) 56 90 : 10

4 CHONC

Br(1d) 47 88 : 12

5CHO NC

(1e) 38 90 : 10

6CHO

O

NCO(1f) 55 91 : 09

7

CHO NC (1g) 25 90 : 10

8CHO NC

(1h) 34 96 : 04

9

CHO NC

(1i) 48 94 : 06

10

CHO NC(1j) 50 90 : 10



139

5

7

Entry R1-CHO R

2-NC Yieldb (%) dr

11

CHO

O

ONC

(1k) 83 91 : 09

12

CHO NC(1l) 35 94 : 06

13

CHO

Cl

NC(1m)45 92 : 08

14

ONC

(1n) trace —

aThe reaction was carried out with isobutyraldehyde (1 mmol), ammonium hydroxide (1.5 mmol), 3-hydroxypivalaldehyde (1 mmol), benzyl isocyanide (1.2 mmol) and TMSN

3 (1.2 mmol) in 0.5 ml solvent. bYield of isolated product.

The structures has been confirmed by NMR, MS (low and high resolution) and also by X-ray

crystallography.

Figure 2. X-ray structures of 1b and 1c.

Conclusion

In conclusion, we have developed a highly diastereoselective one-pot five component reaction

toward oxazinane-tetrazoles synthesis. This sonication-assisted, novel, and general reaction

have many advances, such as high time efficiency, catalyst-free, diverse scope, and excellent

diastereoselectivity. Moreover, due to diverse substrate compatibility, this reaction has become


Chapter 7

140

significant potential for postcondensation to get more complex and diverse oxazine-tetrazole

structures. Studies towards this area are now in progress.


General procedure for the synthesis of 4-(tetrazole)-1,3-oxazinane:

A 10 mL tube was loaded with an aldehyde (1 mmol) and amonium hydroxyde 30% (1.5 mmol)

in toluene (0.5 ml) and the mixture was sonicated for one hour in the water bath of an ultrasonic

cleaner (220/240V, 25 Amps and frequency of 50/60 Hz). 3-hydroxy-2,2-dimethylpropanal (1 mmol)

was added dropwise over 15 minutes and sonicated for 30 minutes. Isocyanide (1.2 mmol) and

TMS-N3 (1.2 mmol) was added to the reaction. The resulting reaction mixture was sonicated till the

completion of the reaction (monitored by TLC). The solvent was removed under reduced pressure


Spectral Data

5,5-dimethyl-2-phenethyl-4-(1-phenethyl-1H-tetrazol-5-yl)-1,3-oxazinane (1a)

Obtained from 0.5 mmol reaction as a white crystal, yield: 190 mg (60%); as 78:22

diastereomeric mixture: 1H NMR (major+minor diastereomer, 500 MHz, CDCl3)

δ 7.40 – 7.31 (m, 5H), 7.22 – 7.15 (m, 3H), 5.82 (d, J = 15.4, 1H), 5.70 (d, J = 3.6, 2H),

5.52 (d, J = 15.4, 1H), 3.80 (d, J = 14.2, 2H), 3.62 (d, J = 11.3, 1H), 3.34 (d, J = 11.3,

1H), 3.23 (d, J = 8.5, 1H), 1.98 – 1.77 (m, 2H), 1.77 – 1.68 (m, 1H), 1.35 (s, 3H), 0.98 (dd, J = 6.8, 4.1, 6H),

0.85 (d, J = 6.6, 2H), 0.70 (s, 3H), 0.34 (d, J = 6.7, 2H). 13C NMR (major+minor diastereomer, 126 MHz,

CDCl3) δ 153.2, 133.7, 129.1, 129.1, 128.9, 128.8, 127.7, 127.5, 92.9, 79.2, 58.5, 57.8, 51.4, 51.3, 32.7, 32.0,



2-isopropyl-4-(1-phenethyl-1H-tetrazol-5-yl)-1,3-oxazinane (1b)

Obtained from 1 mmol reaction as a yellow liquid, yield: 168 mg (51%); as 91:09

diastereomeric mixture: 1H NMR (major diastereomer, 500 MHz, CDCl3) δ 7.33 – 7.25

(m, 3H), 7.04 (d, J = 6.7, 2H), 4.89 – 4.75 (m, 1H), 4.68 – 4.55 (m, 1H), 3.71 (dd, J = 12.0,

5.1, 1H), 3.57 (d, J = 11.3, 1H), 3.28 – 3.19 (m, 4H), 1.85 – 1.71 (m, 2H), 1.24 (s, 3H),

0.97 (dd, J = 6.8, 4.6, 6H), 0.67 (s, 3H). 13C NMR (major diastereomer, 126 MHz, CDCl3)

δ 153.3, 137.0, 129.1, 128.8, 127.3, 92.8, 79.0, 58.0, 49.4, 36.3, 32.7, 22.4, 18.1, 17.9, 17.6. MS (ESI) m/z


found [M+H]+ : 330.22867.



141

5

7

2-isopropyl-5,5-dimethyl-4-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazol-5-yl)-1,3-oxazinane (1c)

Obtained from 0.5 mmol reaction as a colorless crystal, yield: 95 mg (56%); as 90:10

diastereomeric mixture: 1H NMR (major diastereomer, 500 MHz, CDCl3) δ 4.30 (d,

J = 12.8, 1H), 3.88 (dd, J = 12.8, 5.4, 1H), 3.72 (d, J = 11.2, 1H), 3.48 (d, J = 11.2, 1H),

1.95 – 1.80 (m, 9H), 1.53 (s, 3H), 0.96 (dd, J = 8.2, 6.9, 6H), 0.80 (s, 9H), 0.73 (s, 3H). 13C

NMR (major diastereomer, 126 MHz, CDCl3) δ 153.4, 93.2, 80.3, 65.5, 59.1, 53.7, 33.9, 32.8, 31.7, 31.5,



4-(1-(2-bromobenzyl)-1H-tetrazol-5-yl)-2-isopropyl-5,5-dimethyl-1,3-oxazinane (1d)

Obtained from 1 mmol reaction as a colorless liquid, yield: 185 mg (47%); as 88:12

diastereomeric mixture: 1H NMR (major diastereomer, 500 MHz, CDCl3) δ 7.63 (d,

J = 7.9, 1H), 7.32 – 7.26 (m, 1H), 7.25 – 7.18 (m, 1H), 6.84 (d, J = 7.6, 1H), 5.89 (d,

J = 16.1, 1H), 5.67 (d, J = 16.1, 1H), 3.94 (d, J = 12.2, 1H), 3.84 (dd, J = 12.0, 5.1,

1H), 3.64 (d, J = 11.3, 1H), 3.41 (d, J = 11.3, 1H), 1.87 (t, J = 12.3, 1H), 1.81 – 1.73 (m, 1H), 1.36 (s, 3H),

0.94 – 0.88 (m, 6H), 0.74 (s, 3H). 13C NMR (major diastereomer, 126 MHz, CDCl3) δ 153.7, 133.5, 133.1,



: 394.12332.

2-ethyl-5,5-dimethyl-4-(1-phenethyl-1H-tetrazol-5-yl)-1,3-oxazinane (1e)

Obtained from 1 mmol reaction as a pale yellow solid, yield: 120 mg 38%); as 90:10


(m, 3H), 7.10 – 7.02 (m, 2H), 4.83 – 4.71 (m, 1H), 4.65 – 4.56 (m, 1H), 3.94 – 3.86 (m,

1H), 3.57 (d, J = 11.3, 1H), 3.34 (d, J = 12.5, 1H), 3.30 – 3.21 (m, 3H), 1.77 (t, J = 12.4,

1H), 1.69 – 1.57 (m, 2H), 1.24 (s, 3H), 0.98 (t, J = 7.5, 3H), 0.67 (s, 3H). 13C NMR (major

diastereomer, 126 MHz, CDCl3) δ 154.4, 129.1, 129.0, 128.8, 127.4, 89.7, 78.9, 58.0, 49.4, 36.4, 28.4, 22.5,

18.2, 9.3. MS (ESI) m/z calculated [M+H]+ : 316.42; found [M+H]+ : 316.07. HRMS (ESI) m/z calculated

[M+H]+ : 316.21319; found [M+H]+ : 316.21283.

4-(1-(2,2-diethoxyethyl)-1H-tetrazol-5-yl)-5,5-dimethyl-2-propyl-1,3-oxazinane (1f)

Obtained from 1 mmol reaction as a colorless solid, yield: 187 mg (55%); as 91:09

diastereomeric mixture: 1H NMR (major diastereomer, 500 MHz, CDCl3) δ 4.83 (t,

J = 5.6, 1H), 4.70 (dd, J = 14.1, 5.7, 1H), 4.41 (dd, J = 14.1, 5.5, 1H), 4.27 (s, 1H), 4.21

– 4.11 (m, 1H), 3.82 – 3.70 (m, 2H), 3.66 (d, J = 11.3, 1H), 3.53 – 3.41 (m, 3H), 2.06 (s,

1H), 1.70 – 1.51 (m, 2H), 1.49 – 1.40 (m, 2H), 1.27 (s, 3H), 1.19 – 1.12 (m, 6H), 0.92

(t, J = 7.4, 3H), 0.84 (s, 3H). 13C NMR (major diastereomer, 126 MHz, CDCl3) δ 154.3, 101.3, 88.4, 78.9,

64.7, 64.6, 57.7, 50.3, 37.5, 33.0, 22.7, 18.5, 18.1, 15.2, 15.1, 13.9. MS (ESI) m/z calculated [M+H]+ : 342.46;



Chapter 7

142

2-isobutyl-5,5-dimethyl-4-(1-phenethyl-1H-tetrazol-5-yl)-1,3-oxazinane (1g)

Obtained from 0.5 mmol reaction as a white solid, yield: 43 mg (25%); as 90:10


(m, 3H), 7.10 – 6.99 (m, 2H), 4.76 (dt, J = 13.8, 7.7, 1H), 4.66 – 4.56 (m, 1H), 4.01 (brs,

1H), 3.56 (d, J = 11.3, 1H), 3.33 (d, J = 8.6, 1H), 3.30 – 3.18 (m, 3H), 1.85 – 1.73 (m,

2H), 1.70 – 1.59 (m, 1H), 1.56 – 1.47 (m, 1H), 1.44 – 1.34 (m, 1H), 1.24 (s, 3H), 0.93

(dd, J = 6.6, 4.2, 6H), 0.67 (s, 3H). 13C NMR (major diastereomer, 126 MHz, CDCl3) δ 153.2, 136.9, 129.1,



: 344.24417.

2-benzyl-5,5-dimethyl-4-(1-phenethyl-1H-tetrazol-5-yl)-1,3-oxazinane (1h)


diastereomeric mixture: 1H NMR (major diastereomer, 500 MHz, CDCl3) δ 7.34

– 7.29 (m, 2H), 7.26 – 7.19 (m, 6H), 6.89 (dd, J = 7.0, 2.3, 2H), 4.71 – 4.59 (m, 1H),

4.53 – 4.44 (m, 1H), 4.21 – 4.09 (m, 1H), 3.56 (d, J = 11.4, 1H), 3.22 (d, J = 11.4, 1H),

3.17 – 3.07 (m, 3H), 2.94 (dd, J = 13.9, 5.0, 1H), 2.84 (dd, J = 13.9, 5.8, 1H), 1.75 (t,

J = 12.4, 1H), 1.19 (s, 3H), 0.66 (s, 3H). 13C NMR (major diastereomer, 126 MHz, CDCl3) δ 153.1, 137.0,

136.6, 129.7, 129.0, 128.8, 128.4, 127.5, 126.8, 89.0, 79.0, 58.0, 49.4, 41.8, 36.3, 22.5, 18.1. MS (ESI) m/z


found [M+H]+ : 378.22894.

(E)-4-(1-cyclohexyl-1H-tetrazol-5-yl)-5,5-dimethyl-2-styryl-1,3-oxazinane (1i)



(m, 2H), 7.22 – 7.15 (m, 3H), 4.35 – 4.23 (m, 1H), 4.19 – 4.07 (m, 1H), 3.95 (d, J = 12.5, 1H),

3.73 (d, J = 11.4, 1H), 3.52 (d, J = 11.4, 1H), 2.76 (t, J = 7.8, 2H), 2.30 – 2.11 (m, 2H), 2.03 –

1.89 (m, 7H), 1.44 – 1.33 (m, 3H), 1.29 (s, 3H), 0.77 (s, 3H). 13C NMR (major diastereomer,

126 MHz, CDCl3) δ 152.10, 141.37, 128.48, 128.42, 125.96, 87.79, 87.64, 78.75, 58.14,

36.72, 33.14, 30.99, 25.38, 24.85, 22.78, 18.77, 18.64. MS (ESI) m/z calculated [M+H]+ : 370.50; found


5,5-dimethyl-2-phenethyl-4-(1-phenethyl-1H-tetrazol-5-yl)-1,3-oxazinane (1j)

Obtained from 1 mmol reaction as a yellow solid, yield: 196 mg (50%); as 90:10

diastereomeric mixture: 1H NMR (major diastereomer, 500 MHz, CDCl3) δ 7.33 (t,

J = 7.4, 2H), 7.27 – 7.19 (m, 7H), 6.99 (dd, J = 7.3, 1.9, 2H), 4.75 (dt, J = 13.8, 7.6, 1H),

4.67 – 4.53 (m, 1H), 4.01 – 3.89 (m, 1H), 3.66 – 3.55 (m, 1H), 3.31 – 3.21 (m, 4H),

2.77 (t, J = 7.8, 2H), 2.07 – 1.93 (m, 1H), 1.93 – 1.79 (m, 2H), 1.27 (s, 3H), 0.66 (s, 3H). 13C NMR (major diastereomer, 126 MHz, CDCl

3) δ 153.2, 141.3, 136.9, 129.1, 128.8,



: 392.24426.



143

5

7

methyl 2-(5-(5,5-dimethyl-2-phenethyl-1,3-oxazinan-4-yl)-1H-tetrazol-1-yl)acetate (1k)


diastereomeric mixture: 1H NMR (major diastereomer, 500 MHz, CDCl3) δ 7.33 –

7.28 (m, 2H), 7.23 – 7.17 (m, 3H), 5.37 (d, J = 17.3, 1H), 5.25 (d, J = 17.4, 1H), 4.09 (t,

J = 5.6, 1H), 3.97 (s, 1H), 3.78 (s, 3H), 3.68 (d, J = 11.5, 1H), 3.46 (d, J = 11.5, 1H),

2.73 (t, J = 7.8, 2H), 2.17 (s, 1H), 2.02 – 1.91 (m, 1H), 1.90 – 1.79 (m, 2H), 1.38 (s,

3H), 1.03 (s, 3H). 13C NMR (major diastereomer, 126 MHz, CDCl3) δ 166.4, 153.6,



: 360.20306.

5,5-dimethyl-4-(1-phenethyl-1H-tetrazol-5-yl)-2-phenyl-1,3-oxazinane (1l)



(m, 2H), 7.40 – 7.34 (m, 3H), 7.30 – 7.26 (m, 3H), 7.06 – 7.01 (m, 2H), 5.02 (d, J = 12.0,

1H), 4.93 – 4.80 (m, 1H), 4.72 – 4.63 (m, 1H), 4.61 – 4.58 (m, 0H), 3.75 (d, J = 11.4, 1H),

3.52 (d, J = 12.1, 1H), 3.46 (d, J = 11.4, 1H), 3.26 (t, J = 7.0, 2H), 2.11 – 1.95 (m, 1H),

1.33 (s, 3H), 0.74 (s, 3H). 13C NMR (major diastereomer, 126 MHz, CDCl3) δ 153.1, 139.2, 136.9, 129.1,



: 364.21304.

2-(2-chlorophenyl)-5,5-dimethyl-4-(1-phenethyl-1H-tetrazol-5-yl)-1,3-oxazinane (1m)

Obtained from 1 mmol reaction as a yellow liquid yield: 179 mg (45%); as 92:08

diastereomeric mixture: 1H NMR (major diastereomer, 500 MHz, CDCl3) δ 7.68 –

7.60 (m, 1H), 7.42 – 7.37 (m, 1H), 7.33 – 7.28 (m, 2H), 7.24 – 7.19 (m, 3H), 6.97 (dd,

J = 7.2, 2.1, 2H), 5.33 (d, J = 12.0, 1H), 5.05 – 4.93 (m, 1H), 4.81 – 4.70 (m, 1H), 3.72

(d, J = 11.4, 1H), 3.39 (dd, J = 18.6, 11.9, 2H), 3.31 – 3.13 (m, 2H), 1.66 (t, J = 12.2,

1H), 1.41 (s, 3H), 0.78 (s, 3H). 13C NMR (major diastereomer, 126 MHz, CDCl3) δ 152.9, 137.1, 136.7,

132.4, 129.8, 129.6, 129.0, 127.3, 127.3, 127.0, 86.3, 79.5, 58.3, 49.5, 36.5, 32.3, 22.3, 18.2. MS (ESI) m/z


found [M+H]+ : 398.1741.


Chapter 7

144

References

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[2] C. Borel, L. S. Hegedus, J. Krebs, Y. Satoh, J. Am. Chem. Soc. 1987, 109, 1101-1105.

[3] (a) L. M. T. Frija, A. Ismael, M. L. S. Cristiano, Molecules 2010, 15, 3757-3774; (b) A. L. Chandgude, A. Domling, Eur. J. Org. Chem. 2016, 2383-2387; (c) V. Y. Zubarev, V. A. Ostrovskii, Chem. Heterocycl. Compd. 2000, 36, 759-774; (d) S. J. Wittenberger, Org. Prep. Proc. Int. 1994, 26, 499-531; (e) A. Sarvary, A. Maleki, Mol. Divers. 2015, 19, 189-212.

[4] (a) C. X. Wei, M. Bian, G. H. Gong, Molecules 2015, 20, 5528-5553; (b) J. Roh, K. Vavrova, A. Hrabalek, Eur. J. Org. Chem. 2012, 6101-6118; (c) L. V. Myznikov, A. Hrabalek, G. I. Koldobskii, Chem. Heterocycl. Compd. 2007, 43, 1-9; (d) R. J. Herr, Bioorg. Med. Chem. 2002, 10, 3379-3393.

[5] N. A. McGrath, M. Brichacek, J. T. Njardarson, J. Chem. Educ. 2010, 87, 1348-1349.

[6] Z. Zhao, W. H. Leister, R. G. Robinson, S. F. Barnett, D. Defeo-Jones, R. E. Jones, G. D. Hartman, J. R. Huff, H. E. Huber, M. E. Duggan, C. W. Lindsley, Bioorg. Med. Chem. Lett. 2005, 15, 905-909.

[7] J. V. Faria, M. S. dos Santos, A. M. R. Bernardino, K. M. Becker, G. M. C. Machado, R. F. Rodrigues, M. M. Canto-Cavalheiro, L. L. Leon, Bioorg. Med. Chem. Lett. 2013, 23, 6310-6312.

[8] L.-M. Duan, H.-Y. Yu, Y.-L. Li, C.-J. Jia, Bioorg. Med. Chem. 2015, 23, 6111-6117.

[9] Y. W. Jo, W. B. Im, J. K. Rhee, M. J. Shim, W. B. Kim, E. C. Choi, Bioorg. Med. Chem. 2004, 12, 5909-5915.

[10] T. Yoshida, F. Akahoshi, H. Sakashita, H. Kitajima, M. Nakamura, S. Sonda, M. Takeuchi, Y. Tanaka, N. Ueda, S. Sekiguchi, T. Ishige, K. Shima, M. Nabeno, Y. Abe, J. Anabuki, A. Soejima, K. Yoshida, Y. Takashina, S. Ishii, S. Kiuchi, S. Fukuda, R. Tsutsumiuchi, K. Kosaka, T. Murozono, Y. Nakamaru, H. Utsumi, N. Masutomi, H. Kishida, I. Miyaguchi, Y. Hayashi, Bioorg. Med. Chem. 2012, 20, 5705-5719.

[11] S. B. Vogensen, R. P. Clausen, J. R. Greenwood, T. N. Johansen, D. S. Pickering, B. Nielsen, B. Ebert, P. Krogsgaard-Larsen, J. Med. Chem. 2005, 48, 3438-3442.

[12] A. A. Jensen, T. Christesen, U. Bolcho, J. R. Greenwood, G. Postorino, S. B. Vogensen, T. N. Johansen, J. Egebjerg, H. Brauner-Osborne, R. P. Clausen, J. Med. Chem. 2007, 50, 4177-4185.

[13] O. I. Shmatova, V. G. Nenajdenko, J. Org. Chem. 2013, 78, 9214-9222.

[14] M. Giraud, E. S. Andreiadis, A. S. Fisyuk, R. Demadrille, D. Imbert, M. Mazzanti, Inorg. Chem. 2008, 47, 3952-3954.

[15] (a) Q. Tang, R. Gianatassio, Tetrahedron Lett. 2010, 51, 3473-3476; (b) I. Becker, J. Heterocycl. Chem. 2008, 45, 1005-1022.

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Chapter 8Direct Amination of α-Hydroxy Amides



Asian J. Org. Chem., 2017. DOI: 10.1002/ajoc.201700277


Chapter 8

146

Abstract

The TiCl4-mediated reaction for the direct amination of a-hydroxy amide has been developed. This

simple, general, additive/base/ligand-free reaction is mediated by economical TiCl4. The reaction

runs under mild condition. This highly efficient C-N bond formation protocol is valid for diverse

amines, including primary, secondary, heterocyclic and even primary amide and indole.


Direct Amination of α-Hydroxy Amides

147

5

8

Introduction

α-Amino amides are very important molecules, that are widely used in organic and medicinal

chemistry. They are present in many drugs, such as Leukotriene D4, Safinamide, Lidoderm, Altace,

Indinavir, Vyvanse, and in all aminopenicillins. They are also present in many natural products, such as

canthiumine, coelichelin,[1] zorbamycin,[2] guadinomine B,[3] myrianthine B,[4] abyssenine,[5] paliurine

E,[5] and mucronine J.[6] Moreover, a-amino amides are used as a building block to synthesize different

molecules and scaffolds like hydantoins.[7] Recently, the use of α-amino amides as organocatalyst for

various asymmetric reactions has proven to be an extremely valuable approach due to their easy

structural modification and straight forward access.[8]

Tremendous progress has been achieved in the use of C-N bond formation for the direct

amination reactions.[9] Recently more efforts have been focused on the direct amination of alcohol

by using transition metals or Lewis acids (Scheme 1 Method A).[9,10] These protocols improved the

waste balance and are a powerful tool for the C-N bond formation. This approach is also strongly

preferred in industry and more research in this field is desirable.[11]

Despite good progress in this field, the scope of alcohol and amine is largely restricted.

Moreover, these approaches are not valid for a more complex structure like α-hydroxy amide and

also for inactivated amines where reaction typically proceeds with poor yield. Direct amination

of the α-hydroxy amide is more challenging than the alcohol, as amide group could hinder the

coordination sites on the catalyst to resist direct amination. So finding a new method for the

direct amination of α-hydroxy amide to get access to highly important a-amino amide remains an

important challenge.

Conversely, to the best of our knowledge, there is only one report by Beller and co-workers

for the direct amination of α-hydroxy amide (Scheme 1 Method B).[12] They used the ruthenium-

catalyzed “borrowing-hydrogen” process for the direct amination. This protocol is simple and green,

but it involves the use of costly catalyst and ligands. Moreover, high reaction temperature with

limited substrate scope were major disadvantages.

Here we are reporting the TiCl4-assisted, general, economical, base/ligand-free, a relatively

mild method for the direct amination of α-hydroxy amides (Scheme 1 Method C). The method is

distinguished by its wide scope, which includes amines such as primary, secondary, heterocyclic,

and even indole and primary amide.


Chapter 8

148

Scheme 1. Previous and New Methods for Amination.


We started our optimization with screening different Lewis acids, as Lewis acid activated reactions

are well developed for the direct amination of alcohol which is used in catalytic and stoichiometric

amounts.[9,10] We sought to examine the possibility of these economical and non-toxic Lewis acids for

direct amination of a-hydroxy amides. We evaluated different Lewis acids, such as InCl3, ZnCl

2, ZrCl

4,

GdCl2, Sc(OTf )

3, TiCl

4, and FeCl

3 in a catalytic amount at room temperature in DCE solvent, however

only with TiCl4 the trace target product formation observed. Next, we increased the temperature

and catalyst amount of TiCl4. Ultimately, we found that increasing the temperature to 100 °C, and

a stoichiometric amount of TiCl4, product formation slightly improved. Then we screened different

solvents with 1 equivalent of TiCl4 at 100 °C (Table 1). In DCE, a low amount of desired amination

product 3a was observed together with a significant amount of starting material (Table 1, entry

1). The reaction did not go to completion even after 3 days. With further solvent screening, the

coupling product yield improved remarkably up to 62% in solvents, such as dioxane, toluene, and

THF (Table 1, entries 2–4). The reaction in methanol did not proceed at all. In DCM less product yield

(53%) was observed. Further improvement was realized when acetonitrile was used as a solvent,

which gave an excellent 85% yield (Table 1, entry 7). The reaction did not go for completion with

xylene and DMF even after 3 days.

Aiming to get a higher yield, we turned our attention toward the use of different additives,[9,10]

such as bases, KOH and triethylamine or drying agents, molecular sieves and MgSO4. With this

additive, the rate of reaction became slow and did not finish even with longer reaction times and



149

5

8

starting materials remained in substantial amount ~50-60%. Next, we performed equivalence

studies of the amine morpholine and we found that 1 and 2 equivalent amount of morpholine

formed only 23% and 42% product respectively. When the TiCl4 equivalent was reduced to 20 mol %

it did not form any product. However, at 50 mol % product was formed, but the conversion remain

incomplete even after 3 days and 130 °C temperature. In conclusion, optimal conditions for this

reaction are 100 °C with 1 equivalent of TiCl4 in acetonitrile as solvent.

Table 1. Optimization Conditions.a

Entry Solvent Additive / Equivalence Yield (%)b

1 DCE <5

2 dioxane 65

3 toluene 59

4 THF 62

5 MeOH <5

6 DCM 53

7 CH3CN 85

8 xylene 42

9 DMF <5

10 CH3CN Et

3N <5

11 CH3CN mol. sieve 30

12 CH3CN KOH <5

13 CH3CN MgSO

4<5

14 CH3CN (1 equiv) 2 23

15 CH3CN (2 equiv) 2 42

16 CH3CN (0.2 equiv) TiCl

4nr

17 CH3CN (0.5 equiv) TiCl

439

aThe reaction was carried out with a-hydroxy amide 1 (1.0 mmol), morpholine (4.0 mmol), TiCl4 (1 mmol) and 4 mL

CH3CN solvent. bYield of isolated product 3a. nr = no reaction.

With these optimized conditions in hand, we examined scope and limitations of this TiCl4-mediated

amination reaction (Table 2). Alkylamines like allylamine, cyclohexylamine, and benzylamine were

effectively worked in this method to form a product in good yield 68%, 76% and 83% respectively.

Arylamines worked well (3e and 3f). Electron-donating and electron-withdrawing substituents

on the arylamines are compatible with the reaction, leading to the desired products in good to

moderate yield (3g and 3h). Further, we expanded the scope of the reaction to the heterocyclic


Chapter 8

150

amine. Heteroaryl molecules are very important in drugs, as these molecules are present in almost

half of the top 200 drugs.[13] Heterocyclic amine like pyrimidine, benzothiazole and benzimidazoles

are known to be inactivated amines, however, can be used in this protocol providing good yields of

58%, 84% and 69% (3i–3k).

Next, we screened different secondary amines, including cyclic amines like piperidine and

thiomorpholine 1,1-dioxide. They also proved to be good substrates in this reaction. The reaction

with indole also works with 36% isolated product. The low yield was due incomplete conversion,

even though the reaction continued for 3 days and increase in temperature to 130 °C and increased

the TiCl4 quantity to 1.5 or 3 equivalent. The method also worked for a primary amide, butyramide,

to form bis-amide product (3p), however, in low 15% yield, while recovering mostly starting material.

Finally, we extended the scope of reaction with differentially substituted a-hydroxy amides. As

expected, other α-hydroxy amides derivatives also show similar results. Aliphatic, aromatic and the

heterocycle thiophene also worked well. The product of thiophene substituted α-hydroxy amide

with morpholine 3q was produced in 70% yield. Aliphatic derivatives (3r and 3s) formed moderate

yields of 62% and 59% as the reaction remained incomplete.

Previously TiCl4-assisted substitution reactions were reported to proceed through a carbocation

mechanism.[14] Others described TiCl4 catalyzed nucleophilic substitutions of alcohol which proceed

via carbon cation formation followed by nucleophile attack.[14a,15] Studies on detail mechanism of

direct amination of a-hydroxy amides are now going on.



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8

Table 2. Scope of Direct Amination of a-hydroxy amides with Amines.a

aThe reaction was carried out with a-hydroxy amide (1.0 mmol), amine (4.0 mmol) and TiCl4 (1 mmol) in 4 mL CH

3CN. bYield of

isolated product 3.


Chapter 8

152

Conclusions

In summary, we developed a TiCl4-facilitated, ligand/additive-free, a relatively mild reaction for the

direct amination of α-hydroxy amides. Under the optimized reaction conditions, a broad range of

amines including primary, secondary, heterocycles, and even primary amides and indoles were

found to participate in this transformation, providing moderate to high yields. Different derivatives

on a-hydroxy amides like aliphatic, aromatic or heterocycle like thiophene also worked well.


General procedure for the synthesis of α-amino amides In a glass pressure tube (10 mL), morpholine (4 mmol, 351 ml) and N-(tert-butyl)-2-hydroxy-

2-phenylacetamide (1 mmol, 207 mg) was added in acetonitrile (4 ml). Then TiCl4 [1 M in DCM]

(1 mmol, 1 ml) was added under nitrogen and the resulting mixture was stirred at 100 °C till completion

of the reaction (monitored by TLC). After cooling down to room temperature, the reaction mixture

was poured into the saturated solution of a NaHCO3. The aqueous layer was extracted with ethyl

acetate and washed with brine. The organic layer was dried over anhydrous MgSO4, and the solvent

was removed under reduced pressure. The residue was purified by silica gel flash chromatography

using EtOAc-hexane as eluent.

Spectral Data

N-(tert-butyl)-2-morpholino-2-phenylacetamide (3a)

Obtained from 1 mmol reaction as a white solid, mp 140−142 °C; yield: 234 mg

(85%); 1H NMR (500 MHz, CDCl3) δ 7.36 – 7.28 (m, 5H), 6.97 (s, 1H), 3.74 – 3.66

(m, 5H), 2.48 – 2.35 (m, 4H), 1.35 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 170.0, 135.8,

128.7, 128.6, 128.2, 77.0, 67.1, 52.2, 50.7, 28.7. HRMS (ESI) m/z calculated [M+H]+ :

277.19105; found [M+H]+ : 277.19089.

2-(allylamino)-N-(tert-butyl)-2-phenylacetamide (3b)


(500 MHz, CDCl3) δ 7.35 – 7.30 (m, 4H), 7.30 – 7.27 (m, 1H), 7.13 (s, 1H), 5.94 – 5.80

(m, 1H), 5.25 – 5.16 (m, 1H), 5.13 (dd, J = 10.3, 1.2, 1H), 4.05 (s, 1H), 3.25 – 3.18 (m,

2H), 1.34 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 171.2, 139.8, 135.9, 128.8, 128.0, 127.2,

116.5, 74.2, 67.5, 50.9, 28.7. HRMS (ESI) m/z calculated [M+H]+ : 247.18049; found [M+H]+ : 247.18031.



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8

N-(tert-butyl)-2-(cyclohexylamino)-2-phenylacetamide (3c)


(76%); 1H NMR (500 MHz, CDCl3) δ 7.54 (s, 1H), 7.38 – 7.30 (m, 4H), 7.30 – 7.23 (m,

1H), 4.15 (s, 1H), 2.50 – 2.37 (m, 1H), 1.99 – 1.84 (m, 2H), 1.79 – 1.68 (m, 2H), 1.67 –

1.58 (m, 1H), 1.57 – 1.45 (m, 1H), 1.38 (s, 9H), 1.28 – 1.21 (m, 2H), 1.20 – 1.00 (m, 3H). 13C NMR (126 MHz, CDCl

3) δ 172.2, 140.9, 128.8, 127.7, 127.1, 66.0, 56.5, 50.5, 34.3, 33.7, 28.7, 25.9, 25.1,


2-(benzylamino)-N-(tert-butyl)-2-phenylacetamide (3d)

Obtained from 1 mmol reaction as a white solid, mp 90−92 °C; yield: 246 mg (83%); 1H NMR (500 MHz, CDCl

3) δ 7.37 – 7.26 (m, 9H), 7.16 (s, 1H), 4.09 (s, 1H), 3.75 (d,

J = 2.6, 2H), 1.99 (s, 1H), 1.33 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 171.1, 139.8, 139.5,

128.8, 128.6, 128.2, 128.0, 127.4, 127.3, 67.8, 52.7, 50.7, 28.8, 28.7, 28.7. HRMS (ESI)


N-(tert-butyl)-2-phenyl-2-(phenylamino)acetamide (3e)

Obtained from 0.5 mmol reaction as a white solid, mp 102−104 °C; yield: 100 mg

(71%); 1H NMR (500 MHz, CDCl3) δ 7.44 – 7.35 (m, 4H), 7.35 – 7.29 (m, 1H), 7.18

(t, J = 7.9, 2H), 6.80 (t, J = 7.3, 1H), 6.63 (d, J = 7.7, 2H), 6.52 (s, 1H), 4.60 (d, J = 1.7,

1H), 4.50 (s, 1H), 1.31 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 170.2, 146.8, 139.3, 129.3,

129.2, 128.5, 127.3, 119.1, 113.9, 64.9, 51.2, 28.6. HRMS (ESI) m/z calculated [M+H]+ : 283.18049; found

[M+H]+ : 283.1803.

N-(tert-butyl)-2-phenyl-2-(p-tolylamino)acetamide (3f)



– 7.29 (m, 1H), 6.99 (d, J = 8.2, 2H), 6.68 (s, 1H), 6.55 (d, J = 8.4, 2H), 4.55 (d, J =

1.5, 1H), 4.30 (s, 1H), 2.24 (s, 3H), 1.32 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 170.5,

144.6, 139.4, 129.8, 129.2, 128.4, 127.4, 114.0, 65.4, 51.1, 28.6, 20.5. HRMS (ESI) m/z


N-(tert-butyl)-2-((3,4-dimethoxyphenyl)amino)-2-phenylacetamide (3g)

Obtained from 0.5 mmol reaction as a brown solid, mp 110−111 °C; yield: 126

mg (74%); 1H NMR (500 MHz, CDCl3) δ 7.44 – 7.40 (m, 2H), 7.39 – 7.35 (m, 2H),

7.35 – 7.29 (m, 1H), 6.72 (d, J = 8.6, 1H), 6.66 (s, 1H), 6.26 (d, J = 2.6, 1H), 6.14

(dd, J = 8.5, 2.6, 1H), 4.55 (s, 1H), 4.27 (s, 1H), 3.80 (s, 6H), 1.32 (s, 9H). 13C NMR

(126 MHz, CDCl3) δ 170.4, 149.8, 142.5, 141.5, 139.4, 129.2, 128.4, 127.3, 112.8,

104.7, 99.6, 65.6, 56.5, 55.7, 51.1, 28.6. HRMS (ESI) m/z calculated [M+H]+ : 343.20162; found [M+H]+

: 343.20105.


Chapter 8

154

N-(tert-butyl)-2-((4-chlorophenyl)amino)-2-phenylacetamide (3h)

Obtained from 1 mmol reaction as a brown solid, mp 184−186 °C; yield: 129

mg (41%); 1H NMR (500 MHz, CDCl3) δ 7.48 – 7.33 (m, 5H), 7.13 (d, J = 8.8, 2H),

6.55 (d, J = 8.8, 2H), 6.32 (s, 1H), 4.74 (s, 1H), 4.60 (s, 1H), 1.33 (s, 9H). 13C NMR

(126 MHz, CDCl3) δ 169.8, 145.2, 138.9, 129.3, 129.1, 128.6, 127.2, 123.5, 114.9,

64.4, 51.4, 28.5. HRMS (ESI) m/z calculated [M+H]+ : 317.14152; found [M+H]+

: 317.14148.

N-(tert-butyl)-2-phenyl-2-(pyrimidin-2-ylamino)acetamide (3i)


(58%); 1H NMR (500 MHz, CDCl3) δ 8.18 (d, J = 4.8, 2H), 7.52 – 7.42 (m, 2H), 7.38 –

7.24 (m, 3H), 6.65 (d, J = 6.1, 1H), 6.53 (t, J = 4.8, 1H), 5.93 (s, 1H), 5.39 (d, J = 6.3,

1H), 1.29 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 169.9, 161.5, 158.0, 138.9, 128.9, 128.1,

127.5, 111.6, 60.3, 51.4, 28.6. HRMS (ESI) m/z calculated [M+H]+ : 285.17099; found

[M+H]+ : 285.17081.

N-(tert-butyl)-2-((6-chlorobenzo[d]thiazol-2-yl)amino)-2-phenylacetamide (3j)

Obtained from 0.5 mmol reaction as a brown viscous liquid, yield: 156 mg

(84%); 1H NMR (500 MHz, CDCl3) δ 7.51 – 7.45 (m, 1H), 7.44 (d, J = 2.1, 1H),

7.38 – 7.27 (m, 3H), 7.27 – 7.20 (m, 2H), 7.16 (dd, J = 8.6, 2.1, 1H), 5.85 (s, 1H),

5.44 (s, 1H), 1.27 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 168.9, 165.8, 150.7,

137.9, 132.2, 129.1, 128.6, 127.5, 126.9, 126.2, 120.4, 119.6, 62.1, 51.9, 28.5.


((1H-benzo[d]imidazol-2-yl)amino)-N-(tert-butyl)-2-phenylacetamide (3k)

Obtained from 0.5 mmol reaction as a white solid, mp >200 °C; yield: 111 mg

(69%); 1H NMR (500 MHz, DMSO) δ 10.42 (s, 1H), 8.10 (s, 1H), 7.49 (d, J = 7.5, 2H),

7.32 (t, J = 7.6, 2H), 7.24 (t, J = 7.3, 1H), 7.13 (d, J = 8.9, 3H), 6.85 (br s, 2H), 5.62 (d,

J = 8.9, 1H), 1.23 (s, 9H). 13C NMR (126 MHz, DMSO) δ 170.3, 154.7, 140.9, 134.0,

128.6, 127.6, 127.1, 120.4, 119.0, 115.2, 109.4, 59.4, 50.8, 28.9. HRMS (ESI) m/z


N-(tert-butyl)-2-(dipropylamino)-2-phenylacetamide (3l)

Obtained from 1 mmol reaction as a gray solid, mp 64−66 °C; yield: 131 mg (45%); 1H NMR (500 MHz, CDCl

3) δ 7.42 (s, 1H), 7.33 – 7.26 (m, 3H), 7.26 – 7.22 (m, 2H), 4.15

(s, 1H), 2.51 – 2.38 (m, 2H), 2.30 – 2.15 (m, 2H), 1.55 – 1.40 (m, 4H), 1.37 (s, 9H), 0.84


52.4, 50.5, 28.7, 20.2, 11.8. HRMS (ESI) m/z calculated [M+H]+ : 291.24309; found

[M+H]+ : 291.24295.



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N-(tert-butyl)-2-phenyl-2-(piperidin-1-yl)acetamide (3m)

Obtained from 0.5 mmol reaction as a brown solid, mp 78−80 °C; yield: 70 mg

(51%); 1H NMR (500 MHz, CDCl3) δ 7.35 – 7.31 (m, 2H), 7.30 – 7.25 (m, 4H), 3.73 (s,

1H), 2.34 (br s, 4H), 1.64 – 1.53 (m, 4H), 1.48 – 1.41 (m, 2H), 1.38 (s, 9H). 13C NMR

(126 MHz, CDCl3) δ 171.0, 136.4, 129.0, 128.3, 127.7, 52.7, 50.5, 44.9, 28.7, 26.4, 24.3.


N-(tert-butyl)-2-(1,1-dioxidothiomorpholino)-2-phenylacetamide (3n)

Obtained from 0.5 mmol reaction as a white solid, mp >200 °C; yield: 86 mg (53%); 1H NMR (500 MHz, CDCl

3) δ 7.41 – 7.33 (m, 3H), 7.33 – 7.29 (m, 2H), 6.48 (s, 1H), 4.00

(s, 1H), 3.15 – 2.86 (m, 8H), 1.34 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 169.2, 135.4,

129.0, 128.7, 128.5, 74.1, 51.5, 51.2, 49.0, 28.7. HRMS (ESI) m/z calculated [M+H]+ :

325.15804; found [M+H]+ : 325.15796.

N-(tert-butyl)-2-(1H-indol-1-yl)-2-phenylacetamide (3o)

Obtained from 0.5 mmol reaction as a gray solid, mp >200 °C; yield: 55 mg (36%); 1H NMR (500 MHz, CDCl

3) δ 8.35 (s, 1H), 7.44 (d, J = 8.0, 1H), 7.36 – 7.27 (m, 5H), 7.25

– 7.21 (m, 1H), 7.20 – 7.14 (m, 1H), 7.07 (t, J = 7.2, 1H), 6.85 (d, J = 2.2, 1H), 5.68 (s, 1H),

5.00 (s, 1H), 1.30 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 171.6, 139.9, 136.5, 128.6, 128.5,

127.0, 126.6, 123.8, 122.4, 119.8, 119.1, 115.1, 111.4, 52.0, 51.4, 28.6. HRMS (ESI) m/z


N-(2-(tert-butylamino)-2-oxo-1-phenylethyl)butyramide (3p)



– 7.26 (m, 1H), 6.97 (d, J = 7.1, 1H), 5.94 (s, 1H), 5.48 (d, J = 7.2, 1H), 2.20 (td,

J = 7.4, 2.3, 2H), 1.68 – 1.61 (m, 2H), 1.28 (s, 10H), 0.90 (t, J = 7.4, 3H). 13C NMR (126

MHz, CDCl3) δ 172.4, 169.3, 138.8, 128.9, 128.0, 127.1, 56.9, 51.7, 38.4, 28.5, 19.0, 13.7. HRMS (ESI) m/z


N-cyclohexyl-2-morpholino-2-(thiophen-2-yl)acetamide (3q)

Obtained from 0.5 mmol reaction as a brown solid, mp 154−156 °C; yield: 108

mg (70%); 1H NMR (500 MHz, CDCl3) δ 7.27 (d, J = 6.4, 1H), 7.03 (d, J = 3.4, 1H), 6.95

(dd, J = 5.1, 3.5, 2H), 4.08 (s, 1H), 3.87 – 3.76 (m, 1H), 3.71 (t, J = 4.5, 4H), 2.55 – 2.36

(m, 4H), 1.96 – 1.86 (m, 2H), 1.75 – 1.68 (m, 2H), 1.66 – 1.56 (m, 1H), 1.47 – 1.32

(m, 2H), 1.28 – 1.19 (m, 3H). 13C NMR (126 MHz, CDCl3) δ 169.0, 138.2, 128.3, 126.6,

126.1, 71.2, 67.0, 51.9, 47.6, 33.1, 32.8, 25.5, 24.7, 24.7. HRMS (ESI) m/z calculated [M+H]+ : 309.16313;

found [M+H]+ : 309.16296.


Chapter 8

156

N-benzyl-2-(cyclopentylamino)butanamide (3r)

Obtained from 0.5 mmol reaction as a yellow solid, mp 80−82 °C; yield: 81 mg

(62%); 1H NMR (500 MHz, CDCl3) δ 7.73 (s, 1H), 7.35 – 7.31 (m, 2H), 7.30 – 7.23 (m,

3H), 4.51 – 4.41 (m, 2H), 3.09 (dd, J = 7.7, 4.6, 1H), 3.02 (p, J = 6.5, 1H), 1.88 – 1.78

(m, 2H), 1.76 – 1.67 (m, 1H), 1.66 – 1.55 (m, 3H), 1.55 – 1.43 (m, 2H), 1.32 – 1.20

(m, 3H), 0.96 (t, J = 7.5, 3H). 13C NMR (126 MHz, CDCl3) δ 175.0, 138.7, 128.6, 127.6, 127.3, 63.0, 59.5,

43.0, 33.2, 33.1, 27.0, 23.6, 23.6, 10.4. HRMS (ESI) m/z calculated [M+H]+ : 261.19614; found [M+H]+ :

261.19595.

3-methyl-N-phenethyl-2-((4-phenoxyphenyl)amino)butanamide (3s)

Obtained from 0.5 mmol reaction as a dark brown solid, mp >200 °C;

yield: 115 mg (59%); 1H NMR (500 MHz, CDCl3) δ 7.31 – 7.25 (m, 2H),

7.25 – 7.15 (m, 3H), 7.09 – 7.00 (m, 3H), 6.96 – 6.88 (m, 4H), 6.82 (t, J

= 5.8, 1H), 6.60 – 6.51 (m, 2H), 3.74 (d, J = 3.0, 1H), 3.68 – 3.59 (m, 1H),

3.55 – 3.37 (m, 2H), 2.85 – 2.64 (m, 2H), 2.43 – 2.27 (m, 1H), 1.03 (d,

J = 7.0, 3H), 0.94 (d, J = 6.9, 3H). 13C NMR (126 MHz, CDCl3) δ 172.5,

158.6, 149.1, 143.8, 138.7, 129.6, 128.7, 128.6, 126.4, 122.3, 121.1, 117.4,

114.7, 65.5, 40.2, 35.9, 31.1, 19.8, 17.6. HRMS (ESI) m/z calculated [M+H]+

: 389.22235; found [M+H]+ : 389.22229.



157

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References

[1] F. Barona-Gomez, S. Lautru, F.-X. Francou, P. Leblond, J.-L. Pernodet, G. L. Challis, Microbiology 2006, 152, 3355-3366.

[2] L. Y. Wang, B. S. Yun, N. P. George, E. Wendt-Pienkowski, U. Galm, T. J. Oh, J. M. Coughlin, G. D. Zhang, M. F. Tao, B. Shen, J.Nat. Prod. 2007, 70, 402-406.

[3] T. C. Holmes, A. E. May, K. Zaleta-Riyera, J. G. Ruby, P. Skewes-Cox, M. A. Fischbach, J. L. DeRisi, M. Iwatsuki, S. Omura, C. Khosla, J.Am. Chem. Soc. 2012, 134, 17797-17806.

[4] J. Marchand, X. Monseur, M. Pais, Ann. Pharm. Fr. 1968, 26, 771-778.

[5] M. Toumi, V. Rincheval, A. Young, D. Gergeres, E. Turos, F. Couty, B. Mignotte, G. Evano, Eur. J. Org. Chem. 2009, 3368-3386.

[6] C. Auvin, F. Lezenven, A. Blond, I. AugevenBour, J. L. Pousset, B. Bodo, J. Camara, J. Nat. Prod. 1996, 59, 676-678.

[7] a) S. M. Dumbris, D. J. Diaz, L. McElwee-White, J. Org. Chem. 2009, 74, 8862-8865; b) W. L. Scott, Z. N. Zhou, J. G. Martynow, M. J. O’Donnell, Org. Lett. 2009, 11, 3558-3561; c) J. H. Rowley, S. C. Yau, B. M. Kariuki, A. R. Kennedy, N. C. O. Tomkinson, Org. Biomol. Chem. 2013, 11, 2198-2205.

[8] a) Z. Chai, G. Zhao, Catal. Sci. Technol. 2012, 2, 29-41; b) L. W. Xu, J. Luo, Y. X. Lu, Chem. Commun. 2009, 1807-1821.

[9] J. Bariwal, E. Van der Eycken, Chem. Soc. Rev. 2013, 42, 9283-9303.

[10] a) E. Emer, R. Sinisi, M. G. Capdevila, D. Petruzziello, F. De Vincentiis, P. G. Cozzi, Eur. J. Org. Chem. 2011, 647-666; b) A. Baeza, C. Najera, Synthesis-Stuttgart 2014, 46, 25-34; c) Q. Yang, Q. F. Wang, Z. K. Yu, Chem Soc Rev 2015, 44, 2305-2329; d) T. D. Nixon, M. K. Whittlesey, J. M. J. Williams, Dalton Trans. 2009, 753-762.

[11] D. J. C. Constable, P. J. Dunn, J. D. Hayler, G. R. Humphrey, J. L. Leazer, R. J. Linderman, K. Lorenz, J. Manley, B. A. Pearlman, A. Wells, A. Zaks, T. Y. Zhang, Green Chem. 2007, 9, 411-420.

[12] M. Zhang, S. Imm, S. Bahn, H. Neumann, M. Beller, Angew. Chem. Int. Edit. 2011, 50, 11197-11201; Angew. Chem. 2011, 123, 11393–11397.

[13] N. A. McGrath, M. Brichacek, J. T. Njardarson, J. Chem. Educ. 2010, 87, 1348-1349.

[14] a) C. Y. Tsai, R. Sung, B. R. Zhuang, K. S. Sung, Tetrahedron 2010, 66, 6869-6872; b) M. L. Yao, T. R. Quick, Z. Z. Wu, M. P. Quinn, G. W. Kabalka, Org. Lett. 2009, 11, 2647-2649; c) G. V. Karunakar, M. Periasamy, J. Org. Chem. 2006, 71, 7463-7466; d) K. Ohta, E. Koketsu, Y. Nagase, N. Takahashi, H. Watanabe, M. Yoshimatsu, Chem. Pharm. Bull. 2011, 59, 1133-1140; e) G. V. Karunakar, M. Periasamy, Tetrahedron Lett. 2006, 47, 3549-3552; f ) Y. Masuyama, M. Hayashi, N. Suzuki, Eur. J. Org. Chem. 2013, 2914-2921.

[15] a) Y. Miyake, S. Uemura, Y. Nishibayashi, Chemcatchem 2009, 1, 342-356; b) R. R. Naredla, D. A. Klumpp, Chem. Rev. 2013, 113, 6905-6948; c) A. Hassner, R. Fibiger, D. Andisik, J. Org. Chem. 1984, 49, 4237-4244; d) J. Y. Chen, L. Dang, Q. Li, Y. Ye, S. M. Fu, W. Zeng, Synlett 2012, 595-600; e) R. Mahrwald, S. Quint, Tetrahedron Letters 2001, 42, 1655-1656; f ) A. Bartels, R. Mahrwald, S. Quint, Tetrahedron Lett. 1999, 40, 5989-5990.



Chapter 92-Nitrobenzyl Isocyanide as

a Universal Convertible Isocyanide


A. L. ChandgudeJ. Li

A. DömlingAsian J. Org. Chem., 2017. DOI: 10.1002/ajoc.201700177


Chapter 9

160

Abstract

2-Nitrobenzyl isocyanide is reported as a universal convertible isocyanide with extensive applicability

in both Ugi-4CR and Ugi-tetrazole reactions. The cleavage of this isocyanide from 17 examples in

both acidic and basic conditions is presented. Additionally, this isocyanide has various handling and

synthetic advantages, such as easy to prepare, odorless, stable and easy to handle as a solid.


2-Nitrobenzyl Isocyanide as a Universal Convertible Isocyanide

161

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Introduction

Multicomponent reactions are considered as ideal reactions due to a wide range of advantages, such

as simplicity, high efficiency, green nature, and time efficacy.[1] Isocyanide-based multicomponent

reaction (IMCR) is a promising synthetic methodology for the synthesis of peptidomimetics and

peptides which find broad applications in pharmaceutical and organic industries.[2] The Ugi reaction

is the most extensively studied and widely used IMCR which directly accesses bis-amides or more

complex structures by means of substrate modification and post-condensations.[3,4]

However, IMCR has several drawbacks, for instance, the commercial availability of a rather few

number of isocyanides and their notorious stench which makes handling unpleasant. Moreover,

isocyanide stability and synthesis are always key concerns. One of the solutions to these problems

is the use of so-called convertible isocyanides which can be easily transformed to other functional

groups such as acids, esters or amides. This consequently circumvents the use of specific isocyanides

to gain similar molecular diversity and complexity. Earlier in 1963, Ugi and Rosendahl reported the

first convertible isocyanide, cyclohexenyl isocyanide, which later on was also called Armstrong

isocyanide.[5] Subsequently, a plenty of convertible isocyanides have been reported in Ugi-4CR[6]

or Ugi-T4CR,[7] which are cleavable under acidic condition, basic condition or in some case require

multistep methods. The use of these convertible isocyanides became a considerable step in the

synthesis of peptidomimetics and natural products.

Despite the increasing popularity of using convertible isocyanides for further molecular

modification, these isocyanides suffer from major disadvantages, such as lengthy synthesis

procedures, instability, incompatibility with more delicate substrates, laborious workup and multistep

cleavage. Furthermore, these isocyanides are only applicable in one type of reactions either Ugi-

4CR or Ugi-tetrazole reactions (Ugi-T-4-CR). Thus, the development of a “truly universal convertible

isocyanide” which could be applicable in both Ugi-4CR and Ugi-T-4-CR and also cleavable under

more than one conditions remains a significant challenge.

Herein, we are reporting the 2-nitrobenzyl isocyanide as a truly universal convertible isocyanide

which is applicable not only in Ugi-4CR but also in Ugi-tetrazole reactions, and also cleavable under

both acidic and basic conditions.

The 2-nitro benzyl group is prevalent in a variety of synthetic transformations mainly due to

its photocleavable nature.[8] It is also used in the preparation of polymers[9] and natural products.[1c,10] Nonetheless, the use of 2-nitrobenzyl isocyanide as a convertible isocyanide has not been

sufficiently explored with the exception of only one example as photocleavable isocyanide (sunlight

for 5 days) in polymers.[11]


Chapter 9

162

Figure 1. Convertible isocyanides


We envisioned the use of this isocyanide as an extensively practical convertible isocyanide in both

acidic and basic conditions.[12] At first, the Ugi-tetrazole reaction product was chosen as the model

substrate to verify this hypothesis. Recently, our group reported a basic condition (LiOH in THF:H2O)

for the cleavage of β-cyanoethyl isocyanide.[7a] Therefore, we start our optimization by using similar

condition and attempted to cleave the 2-nitro benzyl group from the Ugi-tetrazole product (Table

1). Unfortunately, the reaction did not show any product formation under this condition (Table

1, entry 1). The farther increase in the temperature even to reflux for overnight did not show any

effect on reaction and the starting material still remained intact. Meanwhile, change in the solvent

to acetonitrile was also ineffective which indicated that LiOH is not applicable for this isocyanide

cleavage (Table 1, entry 4). Next, we screened different bases and different conditions. The reaction

with NaOH in toluene did not form any product, but trace product formation occurred in acetonitrile

while starting material remained intact in the acetonitrile-water system.



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Table 1. Optimization of reaction conditions.

Entry Base Equiv Solvent Temp Time (°C) Yield (%)a

1 LiOH 2 THF : H2O rt 12 —

2 LiOH 2 THF : H2O 60 12 —

3 LiOH 2 THF : H2O reflux 12 —

4 LiOH 2 CH3CN rt 48 —

5 NaOH 2 Toluene rt 12 —

6 NaOH 2 CH3CN rt 12 trace

7 NaOH 2 CH3CN : H

2O rt 12 —

8 NaOH 2 THF rt 12 nd

9b NaOH >10 CH3CN rt 12 32

10b NaOH 8 MeOH reflux 12 69

11b NaOH >10 MeOH : H2O reflux 6 90

12 KOtBu 1 CH3CN rt 12 nd

13 KOtBu 2 CH3CN rt 48 nd

14 KOtBu 4 CH3CN rt 12 63

15 KOtBu 4 THF rt 12 84aYield of isolated product 2a. b20% NaOH used. n.d. = not deter-mined.

Remarkably, the increase of NaOH equivalence to 20% efficiently promoted the reaction with a

promising reaction conversion. From the further evaluation, we found that the 20% aqueous NaOH

in refluxing MeOH:water solution gave an excellent yield of 90% (Table 1, entry 11). Aiming for milder

conditions instead of refluxing, we next screened KOtBu in different solvents. To our delight, superior

conditions were found in acetonitrile. With only 4 equivalent of KOtBu at room temperature, we

obtained a 63% yield (Table 1, entry 14). The reaction worked best in THF with an 84% yield (Table

1, entry 15).

With these optimized conditions in hand, we next examined the scope of this convertible

isocyanide in various Ugi-tetrazole products (Table 2). This isocyanide performed moderate to

good in the Ugi-tetrazole reactions and was compatible with diverse substrates under optimized

condition. The aliphatic butyl amine substrate gave a moderate deprotection yield, 45% (Table

2, entry 1b). Aromatic amines with electron withdrawing and electron donating functionalities

provided excellent yields (Table 2, entries 1c–1e). Secondary amines and cyclic heterocycles gave

moderate to good yield ranging from 62% to 69% (Table 2, entries 1f–1h). Heterocycles, such as

2-amino pyridine and indole, also worked well (Table 2, entries 1i–1j).


Chapter 9

164

Different aldehydes were also compatible with this protocol. Aliphatic aldehydes, such as

phenylacetaldehyde, butyraldehyde, and isobutyraldehyde, worked well with 84%, 91%, and

99% yields respectively. Aromatic aldehyde with electron withdrawing and electron donating

functionalities resulted in moderate to good yields (Table 2, entries 1b, 1f, 1g, and 1j). Ketones, for

example, cyclohexanone and acetone afforded 55% and 99% yields respectively (Table 1, entries 1e

and 1i).

Table 2. Yields of the Ugi Products (1) and Deprotected 5-Substituted 1H-Tetrazoles.a

Entry Amine Aldehyde / ketone 1 2 yieldb

a NH2

CHO53 84

b NH2

CHO86 45

ccNH2

CHO 30 91

dNH2

Cl

Cl

CHO41 99

eNH2

O

O O40 99

f NHCHO

Cl30 69

g NHOCHO

81 62

hNHN

CHO58 63

i N

NH2 O55 55

j

NH2

NH

CHOO

OO

60 84

aThe reaction was carried out using aldehyde (1.0 mmol), amine (1.0 mmol), isocyanide (1.0 mmol) and TMS-azide (1 mmol) in 1 mL MeOH. bYield of isolated product 1 and 2. cThe Ugi-tetrazole reaction require 24 h.



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We next sought to cleave this 2-nitorbenzyl group from Ugi-4CR products. When the Ugi-4CR

product was treated with the optimized condition, no cleavage was detected. Nevertheless, the use

of NaOH in place of KOtBu to cleave the 2-nitrobenzyl group was successful. A 38% yield (4a) was

obtained with 5 equivalent of NaOH at 60 °C. However, the yield did not improve even when the

reaction was refluxed in 20% NaOH.

Scheme 1. Substrate Scope of Deprotection from a Ugi-4CR Products.a

aDeprotection carried out in 4 N HCl in dioxane and methanol as solvent. bDeprotection with 1 N HCl and H2O:methanol (3 : 1)

as a solvent.

Afterward, we attempted to achieve one step transformation of this convertible isocyanide to acid

or ester from Ugi-4CR products under acidic conditions. After different temperature conditions

screening, we observed that cleavage in acid worked best with 1 N HCl under reflux condition and

provided free acids in 51% and 62% yields (Scheme 1, entries 4a and 4b). Here aliphatic and aromatic

substituents on Ugi-4CR products displayed comparable results. Furthermore, with the purpose of

one step acidic esterification, 4 N HCl in dioxane was used and the desired product was obtained

in good yields (Scheme 1, entries 4c–4g). Under acidic esterification conditions, we observed that

aromatic substitution on the a-carbon afford the ester product in a good yield of 70% (Scheme 1,


Chapter 9

166

entry 4c). Aromatic amines enclosing Ugi-4CR products also performed well with 70% and 87%

yields. Benzoic acid in Ugi-4CR product is also valid with 76% yield (Scheme 1, entry 4f).

Conclusion

In conclusion, the current findings add to a growing body of literature on the developments of

convertible isocyanides. This isocyanide could be called as a true universal convertible isocyanide

owing to its application in more than one reaction types and methods. Many advantages appeared

in this isocyanide such as easy synthesis, odorless, good yields during Ugi-reactions and also in

deprotection steps. We believe that this isocyanide will provide a good choice in multicomponent

reactions as a convertible isocyanide.


General procedure for the synthesis of 2-nitrobenzyl isocyanide (gm scale): 2-Nitrobenzaldehyde (199 mmol, 30 g), formamide (240 mmol, 95 mL) and formic acid (160 mmol,

60 mL) were transferred into 500 mL round bottle flask. The round bottle flask was placed in an oil

bath and the reaction mixture was heated at 180 °C for 5 hours. After cooling down, extractions with

DCM (3x200 ml) followed. The organic layer was separated, washed with water, dried with MgSO4,

filtered and concentrated in vacuo. Flash chromatography on silica gel eluted with hexane-EtOAc

(1 : 2) afforded the corresponding formamide as a brown solid (18.86 g, 105 mmol, 53%).

To a solution of N-(2-nitrobenzyl)formamide (18.1 g, 100 mmol) in DCM (200 mL) was added Et3N

(400 mmol, 4.0 equiv, 55.7 mL). The mixture was cooled to -5 °C at which POCl3 (100 mmol, 1.0 equiv,

9.3 mL) was added dropwise over 60 minutes maintaining the temperature below 0 °C. After the

addition, the reaction was stirred at room temperature for 4 hours. A saturated solution of Na2CO

3

was added carefully. The organic layer was separated. The water layer was extracted with DCM. The

combined organic layers were washed with water, dried over MgSO4, and concentrated in vacuo.

The crude product was purified by filtration over silica (DCM) and after evaporation of the solvent

obtained as a pale yellow solid (14.07 g, 87 mmol, 87 %).

Spectral Data

N-(2-nitrobenzyl)formamide1

Obtained from 199 mmol reaction as brown solid, yield: 18.86 g (53%); mixture of

rotamers is observed, major rotamer is given. 1H NMR (500 MHz, Chloroform-d)

δ 8.24 (s, 1H), 8.07 (dd, J = 8.3, 1.3 Hz, 1H), 7.69 – 7.60 (m, 2H), 7.51 – 7.46 (m, 1H),

6.70 (s, 1H), 4.72 (d, J = 6.6 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 161.3, 148.3, 134.3, 133.1, 132.3, 129.0,

125.2, 39.8.



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1-(isocyanomethyl)-2-nitrobenzene2

Obtained from 100 mmol reaction as pale yellow solid, yield: 14.07 g (87%); mixture of

rotamers is observed, major rotamer is given. 1H NMR (500 MHz, Chloroform-d) δ 8.21

(dd, J = 8.2, 1.3 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.78 (td, J = 7.7, 1.3 Hz, 1H), 7.62 – 7.54 (m,

1H), 5.15 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 160.2, 146.5, 134.8, 129.5, 128.7, 125.6, 44.2.

General procedure for the synthesis of Ugi-Tetrazole products: A solution of aldehyde or ketone (1.0 equiv) and amine (1.0 equiv) in MeOH was stirred at room

temperature for 30 minutes. Subsequently, isocyanide (1.0 equiv) and TMS azide (1.0 equiv) were

added and the reaction was stirred at room temperature overnight. The solvent was removed under

reduced pressure and the residue was purified by silica gel flash chromatography using EtOAc–

hexane as eluent.

N-benzyl-1-(1-(2-nitrobenzyl)-1H-tetrazol-5-yl)-2-phenylethan-1-amine (1a)

Obtained from 5 mmol reaction as yellow oil, yield: 1100 mg (53%); 1H

NMR (500 MHz, Chloroform-d) δ 8.14 – 8.07 (m, 1H), 7.49 – 7.44 (m, 2H),

7.25 – 7.18 (m, 6H), 7.06 – 7.00 (m, 2H), 7.00 – 6.95 (m, 2H), 6.64 – 6.55 (m,

1H), 5.65 (d, J = 16.9 Hz, 1H), 5.49 (d, J = 16.8 Hz, 1H), 4.29 (t, J = 7.5 Hz,

1H), 3.61 (d, J = 13.4 Hz, 1H), 3.41 (d, J = 13.4 Hz, 1H), 3.11 – 3.05 (m, 2H),

1.97 (brs, 1H). 13C NMR (126 MHz, CDCl3) δ 156.7, 147.3, 138.4, 136.1, 134.2,

129.8, 129.4, 129.2, 129.0, 129.0, 128.5, 127.9, 127.4, 127.4, 125.4, 54.4, 51.3, 47.6, 41.0. MS (ESI) m/z


N-((1-(2-nitrobenzyl)-1H-tetrazol-5-yl)(phenyl)methyl)butan-1-amine (1b)

Obtained from 2 mmol reaction as yellow oil, yield: 632 mg (86%); 1H NMR

(500 MHz, Chloroform-d) δ 8.09 (dd, J = 8.2, 1.4 Hz, 1H), 7.43 (td, J = 7.8, 1.4

Hz, 1H), 7.36 – 7.32 (m, 1H), 7.27 – 7.19 (m, 2H), 7.18 – 7.12 (m, 3H), 6.34 (dd,

J = 7.9, 1.3 Hz, 1H), 6.06 (d, J = 17.2 Hz, 1H), 5.95 (d, J = 17.2 Hz, 1H), 5.33 (s,

1H), 2.60 – 2.51 (m, 1H), 2.46 – 2.39 (m, 1H), 1.94 (brs, 1H), 1.46 – 1.35 (m,

2H), 1.32 – 1.21 (m, 2H), 0.84 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 156.4, 147.0, 137.2, 134.0,


[M+H]+: 367.43; found [M+H]+: 367.23.

N-(1-(1-(2-nitrobenzyl)-1H-tetrazol-5-yl)butyl)aniline (1c)

Obtained from 2 mmol reaction as yellow oil, yield: 210 mg (30%); 1H

NMR (500 MHz, Chloroform-d) δ 8.05 (dd, J = 8.2, 1.3 Hz, 1H), 7.37 (td,

J = 7.8, 1.4 Hz, 1H), 7.30 – 7.26 (m, 1H), 6.98 (t, J = 7.9 Hz, 2H), 6.65 (t,

J = 7.3 Hz, 1H), 6.50 (dd, J = 7.9, 1.3 Hz, 1H), 6.38 (d, J = 7.7 Hz, 2H), 6.06

(d, J = 6.9 Hz, 2H), 4.97 – 4.88 (m, 1H), 4.29 (d, J = 5.6 Hz, 1H), 2.01 – 1.84

(m, 2H), 1.53 – 1.42 (m, 1H), 1.41 – 1.28 (m, 1H), 0.90 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ

157.1, 147.0, 145.9, 134.1, 129.9, 129.3, 129.2, 128.8, 125.2, 119.0, 113.2, 49.7, 48.6, 36.3, 19.2, 13.6. MS



Chapter 9

168

2,4-dichloro-N-(2-methyl-1-(1-(2-nitrobenzyl)-1H-tetrazol-5-yl)propyl)aniline (1d)

Obtained from 2 mmol reaction as yellow solid, yield: 337 mg (41%); 1H NMR (500 MHz, Chloroform-d) δ 7.99 (d, J = 8.2 Hz, 1H), 7.60 – 7.56

(m, 2H), 7.48 – 7.41 (m, 1H), 7.33 – 7.28 (m, 1H), 7.25 (dd, J = 2.4, 1.0 Hz,

1H), 6.89 (dd, J = 8.6, 2.4 Hz, 1H), 6.29 (d, J = 8.7 Hz, 1H), 4.69 (d, J = 6.9

Hz, 1H), 4.64 (d, J = 6.1 Hz, 1H), 3.56 (t, J = 4.6 Hz, 1H), 2.40 – 2.27 (m,

1H), 1.02 (d, J = 6.9 Hz, 3H), 0.99 (d, J = 6.8 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 172.3, 148.1, 141.7,

133.9, 133.2, 132.3, 128.9, 128.8, 127.8, 125.1, 123.1, 120.3, 112. 9, 65.0, 41.2, 31.2, 19.6, 17.8. MS (ESI)


3,4-dimethoxy-N-(1-(1-(2-nitrobenzyl)-1H-tetrazol-5-yl)cyclohexyl)aniline (1e)

Obtained from 2 mmol reaction as a yellow oil, yield: 352 mg (40%); 1H NMR (500 MHz, Chloroform-d) δ 7.99 – 7.93 (m, 1H), 7.43 – 7.35

(m, 2H), 6.87 – 6.82 (m, 1H), 6.46 (d, J = 8.6 Hz, 1H), 6.17 (s, 2H), 5.79

(d, J = 2.7 Hz, 1H), 5.60 (dd, J = 8.5, 2.7 Hz, 1H), 3.93 (s, 1H), 3.73 (s, 3H),

3.65 (s, 3H), 2.17 – 2.05 (m, 4H), 1.70 – 1.60 (m, 3H), 1.56 – 1.44 (m, 2H),

1.43 – 1.30 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 159.9, 149.5, 147.7, 142.5, 137.8, 133.6, 130.0, 129.3,

128.9, 124.9, 112.4, 106.1, 100.6, 56.3, 55.5, 54.4, 48.6, 34.0, 24.8, 21.0. MS (ESI) m/z calculated [M+Na]+:

461.48; found [M+Na]+: 461.17.

1-((4-chlorophenyl)(1-(2-nitrobenzyl)-1H-tetrazol-5-yl)methyl)piperidine (1f)

Obtained from 2 mmol reaction as yellow oil, yield: 251 mg (30%); 1H NMR

(500 MHz, Chloroform-d) δ 8.18 (dd, J = 8.2, 1.3 Hz, 1H), 7.55 – 7.47 (m, 1H),

7.42 (td, J = 7.7, 1.3 Hz, 1H), 7.24 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.5 Hz, 2H), 6.43

(d, J = 7.8 Hz, 1H), 6.20 (d, J = 17.3 Hz, 1H), 6.15 (d, J = 17.2 Hz, 1H), 4.96 (s, 1H),

2.48 – 2.35 (m, 2H), 2.26 – 2.16 (m, 2H), 1.53 – 1.41 (m, 4H), 1.41 – 1.31 (m, 2H). 13C NMR (126 MHz, CDCl

3) δ 155.0, 147.0, 134.3, 134.2, 132.1, 130.3, 129.9, 129.2, 128.6, 128.3, 125.4,

64.8, 52.0, 48.3, 25.8, 23.9. MS (ESI) m/z calculated [M+H]+: 413.89; found [M+H]+: 413.10.

4-(naphthalen-1-yl(1-(2-nitrobenzyl)-1H-tetrazol-5-yl)methyl)morpholine (1g)

Obtained from 2 mmol reaction as yellow solid, yield: 694 mg (81%); 1H NMR

(500 MHz, Chloroform-d) δ 8.34 (d, J = 8.5 Hz, 1H), 7.97 (dd, J = 8.3, 1.4 Hz, 1H),

7.68 (dd, J = 8.1, 1.4 Hz, 1H), 7.57 – 7.51 (m, 2H), 7.51 – 7.45 (m, 1H), 7.45 – 7.40

(m, 1H), 7.27 – 7.21 (m, 1H), 7.13 (t, J = 7.7 Hz, 1H), 6.91 (td, J = 7.6, 1.3 Hz, 1H),

6.01 (d, J = 17.3 Hz, 1H), 5.85 (d, J = 17.3 Hz, 1H), 5.77 (dd, J = 7.9, 1.3 Hz, 1H),

5.71 (s, 1H), 3.77 – 3.65 (m, 4H), 2.74 – 2.64 (m, 2H), 2.52 – 2.40 (m, 2H). 13C

NMR (126 MHz, CDCl3) δ 154.6, 146.3, 133.8, 133.6, 131.2, 129.5, 129.4, 129.1, 128.8, 128.7, 127.4, 127.0,

126.7, 126.1, 125.1, 124.6, 123.0, 77.4, 66.8, 52.2, 48.5. MS (ESI) m/z calculated [M+H]+: 431.47; found

[M+H]+: 431.12.



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1-benzyl-4-(1-(1-(2-nitrobenzyl)-1H-tetrazol-5-yl)-2-phenylethyl)piperazine (1h)

Obtained from 2 mmol reaction as yellow solid, yield: 560 mg (58%); 1H NMR (500 MHz, Chloroform-d) δ 8.11 (dd, J = 8.2, 1.3 Hz, 1H), 7.43

(td, J = 7.8, 1.3 Hz, 1H), 7.34 – 7.29 (m, 3H), 7.26 – 7.25 (m, 2H), 7.24

(brs, 1H), 7.18 – 7.13 (m, 3H), 7.10 (dd, J = 7.5, 2.0 Hz, 2H), 6.34 (dd,

J = 7.9, 1.3 Hz, 1H), 5.82 (d, J = 17.3 Hz, 1H), 5.75 (d, J = 17.2 Hz, 1H),

3.97 (dd, J = 10.6, 3.4 Hz, 1H), 3.48 (dd, J = 13.3, 10.5 Hz, 1H), 3.41 (s,

2H), 3.23 (dd, J = 13.2, 3.4 Hz, 1H), 2.63 (d, J = 8.4 Hz, 2H), 2.56 (p, J = 4.6, 4.1 Hz, 2H), 2.26 (s, 4H). 13C

NMR (126 MHz, CDCl3) δ 154.5, 147.1, 137.8, 134.3, 129.9, 129.4, 129.2, 129.1, 128.6, 128.3, 128.3, 127.2,

126.6, 125.3, 62.9, 61.8, 52.8, 47.4, 32.7. MS (ESI) m/z calculated [M+H]+: 484.58; found [M+H]+: 484.17.

N-(2-(1-(2-nitrobenzyl)-1H-tetrazol-5-yl)propan-2-yl)pyridin-2-amine (1i)

Obtained from 2 mmol reaction as yellow solid, yield: 372 mg (55%); 1H

NMR (500 MHz, Chloroform-d) δ 8.01 – 7.95 (m, 1H), 7.73 (dd, J = 5.1, 1.8

Hz, 1H), 7.36 – 7.33 (m, 2H), 7.23 – 7.15 (m, 1H), 6.74 – 6.67 (m, 1H), 6.47 (dd,

J = 7.2, 5.0 Hz, 1H), 6.33 (d, J = 8.3 Hz, 1H), 6.10 (s, 2H), 5.44 (s, 1H), 1.83 (s, 6H). 13C NMR (126 MHz, CDCl

3) δ 160.3, 156.3, 147.3, 137.1, 133.6, 130.0, 129.4,

128.8, 124.9, 114.2, 109.5, 51.42, 48.7, 27.9. MS (ESI) m/z calculated [M+H]+: 340.37; found [M+H]+:

340.20.

2-(1H-indol-3-yl)-N-((1-(2-nitrobenzyl)-1H-tetrazol-5-yl)(3,4,5-trimethoxyphenyl)methyl)ethan-

1-amine (1j)

Obtained from 2 mmol reaction as yellow oil, yield: 648 mg (60%); 1H NMR (500 MHz, Chloroform-d) δ 8.63 (d, J = 2.4 Hz, 1H), 8.03 (dd,

J = 8.2, 1.4 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.34 – 7.29 (m, 2H), 7.23

(td, J = 7.6, 1.4 Hz, 1H), 7.15 – 7.09 (m, 1H), 7.06 – 7.01 (m, 1H), 6.97

(d, J = 2.3 Hz, 1H), 6.27 (s, 2H), 6.20 (dd, J = 7.8, 1.3 Hz, 1H), 6.01 (d, J

= 17.4 Hz, 1H), 5.83 (d, J = 17.5 Hz, 1H), 5.20 (s, 1H), 3.68 (s, 3H), 3.55

(s, 6H), 2.95 – 2.71 (m, 4H). 13C NMR (126 MHz, CDCl3) δ 156.4, 153.4, 146.7, 137.4, 136.4, 133.8, 132.5,

129.9, 129.0, 127.8, 127.3, 125.1, 122.5, 122.0, 119.3, 118.5, 112.8, 111.4, 103.6, 77.5, 60.7, 57.6, 55.9,

48.1, 47. 9, 25.4. MS (ESI) m/z calculated [M+H]+: 544.58; found [M+H]+: 544.21.

General procedure for the synthesis of 1H-Tetrazoles: To a solution of protected tetrazole (around 100 mg) in THF (2mL) was added KOtBu (4.0 equiv).

The resulting suspension was stirred at room temperature for overnight. The solvent was removed

under reduced pressure and water (2 mL) was added. The solution was cooled to 0 °C and acidified

to pH 4–5 with HCl (1 N). Additional EtOAc (5 mL) was added and the organic layer was separated.

The water layer was extracted with EtOAc (5 mL × 5). The combined organic layers were dried over

MgSO4. The solvent was removed under reduced pressure and the residue was purified by silica gel

flash chromatography using MeOH–DCM as eluent.


Chapter 9

170

N-benzyl-2-phenyl-1-(1H-tetrazol-5-yl)ethan-1-amine (2a)

Obtained from 0.27 mmol reaction as yellow solid, yield: 63 mg (84%); 1H NMR

(500 MHz, Methanol-d4) δ 7.35 – 7.31 (m, 3H), 7.30 – 7.26 (m, 2H), 7.09 – 7.04

(m, 3H), 6.90 (d, J = 7.0 Hz, 2H), 4.70 (dd, J = 10.5, 4.8 Hz, 1H), 3.99 (d, J = 13.0 Hz,

1H), 3.81 (d, J = 12.9 Hz, 1H), 3.42 – 3.30 (m, 2H). 13C NMR (126 MHz, DMSO) δ

157.8, 137.4, 129.6, 129.4, 128.8, 128.6, 128.2, 126.9, 57.3, 54.7, 49.8. MS (ESI) m/z


N-(phenyl(1H-tetrazol-5-yl)methyl)butan-1-amine (2b)

Obtained from 0.33 mmol reaction as brown oil, yield: 34 mg (45%); 1H NMR

(500 MHz, Methanol-d4) δ 7.64 – 7.58 (m, 2H), 7.52 – 7.44 (m, 3H), 5.78 (s, 1H),

3.04 – 2.88 (m, 2H), 1.77 – 1.64 (m, 2H), 1.40 – 1.34 (m, 2H), 0.94 (t, J = 7.4 Hz,

3H). 13C NMR (126 MHz, MeOD) δ 156.6, 132.5, 127.9, 127.3, 127.0, 57.0, 44.6,

26.0, 17.9, 10.9. MS (ESI) m/z calculated [M+H]+: 232.30; found [M+H]+: 232.14.

N-(1-(1H-tetrazol-5-yl)butyl)aniline (2c)

Obtained from 0.31 mmol reaction as brown oil, yield: 61 mg (91%); 1H NMR (500

MHz, Chloroform-d) δ 7.02 (t, J = 7.7 Hz, 2H), 6.65 (t, J = 7.3 Hz, 1H), 6.50 (d, J =

8.0 Hz, 2H), 5.01 (t, J = 7.0 Hz, 1H), 1.99 – 1.85 (m, 2H), 1.45 – 1.32 (m, 2H), 0.88 (t,

J = 7.3 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 160.3, 146.0, 129.4, 118.7, 113.3, 49.2,


2,4-dichloro-N-(2-methyl-1-(1H-tetrazol-5-yl)propyl)aniline (2d)


(500 MHz, Chloroform-d) δ 7.15 (d, J = 2.4 Hz, 1H), 6.94 (dd, J = 8.7, 2.4 Hz, 1H),

6.41 (d, J = 8.8 Hz, 1H), 5.03 (s, 1H), 4.78 (d, J = 6.6 Hz, 1H), 2.48 – 2.37 (m, 1H),

1.12 (d, J = 6.7 Hz, 3H), 0.96 (d, J = 6.8 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 158.6,


found [M+H]+: 286.08.

N-(1-(1H-tetrazol-5-yl)cyclohexyl)-3,4-dimethoxyaniline (2e)

Obtained from 0.26 mmol reaction as a a brown oil, yield: 78 mg (99%); 1H NMR

(500 MHz, Methanol-d4) δ 7.76 (s, 1H), 6.53 (d, J = 8.6 Hz, 1H), 5.91 (d, J = 2.6 Hz,

1H), 5.79 (dd, J = 8.5, 2.6 Hz, 1H), 3.55 (s, 3H), 3.48 (s, 3H), 2.13 (t, J = 10.6 Hz, 2H),

2.05 – 1.93 (m, 2H), 1.60 (dd, J = 9.2, 4.5 Hz, 2H), 1.42 (d, J = 7.8 Hz, 1H), 1.39 –

1.28 (m, 3H). 13C NMR (126 MHz, MeOD) δ 160.4, 148.0, 142.0, 135.0, 111.2, 107.9, 101.7, 54.2, 54.1, 53.2,

53.1, 32.9, 23.2, 19.6. MS (ESI) m/z calculated [M+H]+: 304.37; found [M+H]+: 304.22.



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1-((4-chlorophenyl)(1H-tetrazol-5-yl)methyl)piperidine (2f)

Obtained from 0.24 mmol reaction as yellow solid, yield: 46 mg (69%); 1H NMR

(500 MHz, Methanol-d4) δ 7.66 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 5.69 (s,

1H), 3.11 (brs, 2H), 3.00 (brs, 2H), 1.84 – 1.73 (m, 4H), 1.58 (brs, 2H). 13C NMR (126

MHz, MeOD) δ 155.6, 134.1, 129.9, 129.8, 127.4, 64.2, 50.5, 21.3, 20.0. MS (ESI)


4-(naphthalen-1-yl(1H-tetrazol-5-yl)methyl)morpholine (2g)


MHz, Chloroform-d) δ 8.43 (d, J = 7.1 Hz, 1H), 7.86 – 7.76 (m, 2H), 7.73 (d, J = 8.1 Hz,

1H), 7.46 – 7.39 (m, 2H), 7.32 (t, J = 7.7 Hz, 1H), 6.26 (s, 1H), 5.86 (s, 1H), 3.69 – 3.57 (m,

4H), 2.74 – 2.60 (m, 2H), 2.53 – 2.40 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 157.9, 134.0,

131.7, 131.3, 129.4, 129.0, 126.9, 126.9, 126.1, 125.4, 123.2, 66.5, 62.5, 52.0, 50.8, 29.7.

MS (ESI) m/z calculated [M+H]+: 296.35; found [M+H]+: 296.22.

1-benzyl-4-(2-phenyl-1-(1H-tetrazol-5-yl)ethyl)piperazine (2h)


(500 MHz, Chloroform-d) δ 7.32 – 7.27 (m, 5H), 7.16 – 7.11 (m, 2H), 7.09 (d,

J = 6.8 Hz, 3H), 4.42 (t, J = 7.6 Hz, 1H), 3.98 – 3.82 (m, 2H), 3.39 (dd, J = 13.7,

8.4 Hz, 1H), 3.26 (dd, J = 13.7, 6.9 Hz, 1H), 2.87 (brs, 6H), 2.70 – 2.48 (m, 2H). 13C

NMR (126 MHz, CDCl3) δ 157.9, 138.7, 130.6, 129.2, 129.1, 128.9, 128.1, 126.1,

61.6, 61.3, 52.3, 37.5. MS (ESI) m/z calculated [M+H]+: 349.45; found [M+H]+:

349.27.

N-(2-(1H-tetrazol-5-yl)propan-2-yl)pyridin-2-amine (2i)


MHz, Chloroform-d) δ 8.06 – 7.96 (m, 1H), 7.50 – 7.41 (m, 1H), 7.06 (s, 1H), 6.72 – 6.64

(m, 1H), 6.48 (d, J = 8.6 Hz, 1H), 1.87 (s, 6H). 13C NMR (126 MHz, CDCl3) δ 162.5, 155.5,

143.7, 139.6, 113.8, 111.6, 51.6, 50.7, 27.9. MS (ESI) m/z calculated [M+H]+: 205.24;

found [M+H]+: 205.17.

N-((1H-tetrazol-5-yl)(3,4,5-trimethoxyphenyl)methyl)-2-(1H-indol-3-yl)ethan-1-amine (2j)

Obtained from 0.44 mmol reaction as brown solid, yield: 58 mg

(84%); 1H NMR (500 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.83 (s, 1H), 7.43

(d, J = 7.8 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.17 (d, J = 1.9 Hz, 1H), 7.07

(t, J = 7.3 Hz, 1H), 7.01 (s, 2H), 6.96 (t, J = 7.4 Hz, 1H), 5.74 (s, 1H), 3.85

(s, 1H), 3.75 (s, 6H), 3.64 (s, 3H), 3.15 – 3.04 (m, 2H), 3.04 – 2.91 (m, 2H). 13C NMR (126 MHz, DMSO) δ 153.3, 152.8, 138.0, 136.7, 131.7, 127.1,


[M+H]+: 409.46; found [M+H]+: 409.13.


Chapter 9

172

General procedure for the synthesis of Ugi-4CR products:

A solution of aldehyde (1.0 equiv) and amine (1.0 equiv) in MeOH was stirred at room temperature for

30 minutes. Subsequently, isocyanide (1.0 equiv) and acid (1.0 equiv) were added and the reaction

was stirred at room temperature overnight. The solvent was removed under reduced pressure and

the residue was purified by silica gel flash chromatography using EtOAc–hexane as eluent.

2-(N-benzylacetamido)-4-methyl-N-(2-nitrobenzyl)pentanamide (3a)

Obtained from 1 mmol reaction as colorless oil, yield: 360 mg (91%); 1H

NMR (500 MHz, Chloroform-d) δ 8.02 (dd, J = 8.1, 1.3 Hz, 1H), 7.58 (td, J

= 7.5, 1.3 Hz, 1H), 7.53 (dd, J = 7.8, 1.6 Hz, 1H), 7.49 – 7.42 (m, 1H), 7.36

(t, J = 6.4 Hz, 1H), 7.32 – 7.21 (m, 3H), 7.19 – 7.13 (m, 2H), 5.11 – 5.02 (m,

1H), 4.62 (d, J = 6.2 Hz, 2H), 4.57 (s, 2H), 2.06 (s, 3H), 1.87 – 1.80 (m, 1H), 1.51 – 1.40 (m, 2H), 0.89 – 0.79

(m, 6H). 13C NMR (126 MHz, CDCl3) δ 173.0, 171.2, 148.3, 137.3, 133.7, 131.4, 128.7, 128.5, 127.3, 126.1,


398.48.

3-methyl-N-(2-nitrosobenzyl)-2-(N-propylacetamido)butanamide (3b)


NMR (500 MHz, Chloroform-d) δ 8.03 (dd, J = 8.1, 1.3 Hz, 1H), 7.61 – 7.54

(m, 2H), 7.46 – 7.42 (m, 1H), 4.68 (d, J = 6.2 Hz, 2H), 4.17 (s, 1H), 3.25 – 3.12

(m, 2H), 2.55 – 2.43 (m, 1H), 2.13 (s, 3H), 1.47 – 1.37 (m, 2H), 0.93 (d, J = 6.5

Hz, 3H), 0.87 – 0.76 (m, 6H). 13C NMR (126 MHz, CDCl3) δ 172.3, 171.5, 148.3, 133.5, 131.3, 128.4, 125.0,


3-methyl-N-(2-nitrobenzyl)-2-(N-phenethylacetamido)butanamide (3c)

Obtained from 5 mmol reaction as colorless oil, yield: 1158 mg

(58%); 1H NMR (500 MHz, Chloroform-d) δ 7.99 (dd, J = 8.2, 1.3 Hz,

1H), 7.72 (s, 1H), 7.60 (dd, J = 7.8, 1.5 Hz, 1H), 7.54 (td, J = 7.5, 1.4 Hz,

1H), 7.42 – 7.35 (m, 1H), 7.30 – 7.23 (m, 2H), 7.23 – 7.17 (m, 1H), 7.14 –

7.09 (m, 2H), 4.73 (d, J = 6.2 Hz, 2H), 4.41 (brs, 1H), 3.49 – 3.43 (m, 2H), 2.69 – 2.59 (m, 2H), 2.53 – 2.43

(m, 1H), 2.11 (s, 3H), 0.96 (d, J = 6.5 Hz, 3H), 0.81 (d, J = 6.6 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 172.2,

171.3, 148.3, 138.1, 133.6, 133.6, 131.4, 128.7, 128.5, 126.7, 125.0, 41.1, 35.5, 26.4, 21.8, 19.8, 18.8. MS




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2-(N-benzylacetamido)-N-(2-nitrobenzyl)-2-phenylacetamide (3d)


NMR (500 MHz, Chloroform-d) δ 8.03 (dd, J = 8.2, 1.3 Hz, 1H), 7.70 (d, J

= 7.8 Hz, 1H), 7.62 (td, J = 7.6, 1.3 Hz, 1H), 7.48 – 7.41 (m, 1H), 7.31 – 7.27

(m, 2H), 7.25 – 7.20 (m, 3H), 7.20 – 7.12 (m, 3H), 7.00 (d, J = 6.5 Hz, 2H),

6.47 (t, J = 6.4 Hz, 1H), 5.83 (s, 1H), 4.76 – 4.65 (m, 3H), 4.49 (d, J = 17.6 Hz,

1H), 2.10 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 172.5, 170.0, 148.1, 137.2, 134.6, 134.1, 133.5, 131.7, 129.8,

128.9, 128.8, 128.54, 128.4, 128.4, 127.1, 126.1, 125.1, 63.3, 50.9, 41.5, 22.4. MS (ESI) m/z calculated

[M+H]+: 418.47; found [M+H]+: 418.20.

2-(N-(4-chlorobenzyl)acetamido)-3-methyl-N-(2-nitrobenzyl)butanamide (3e)

Obtained from 1 mmol reaction as colorless oil, yield: 400 mg

(96%); 1H NMR (500 MHz, Chloroform-d) δ 8.03 (dd, J = 8.1, 1.3 Hz,

1H), 7.60 (s, 1H), 7.55 (td, J = 7.5, 1.3 Hz, 1H), 7.52 – 7.43 (m, 2H), 7.13

(d, J = 8.4 Hz, 2H), 6.98 (d, J = 8.3 Hz, 2H), 4.74 (d, J = 17.3 Hz, 1H),

4.62 (d, J = 6.3 Hz, 1H), 4.59 (dd, J = 6.2, 3.7 Hz, 2H), 4.50 (d, J = 17.4 Hz, 1H), 2.43 – 2.29 (m, 1H), 1.97

(s, 3H), 0.90 (d, J = 6.5 Hz, 3H), 0.84 (d, J = 6.7 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 172.9, 170.3, 148.4,

135.9, 133.7, 133.4, 132.8, 131.9, 128.7, 128.6, 127.4, 125.0, 40.9, 27.4, 22.4, 19.6, 19.0. MS (ESI) m/z


N-benzyl-N-(4-methyl-1-((2-nitrobenzyl)amino)-1-oxopentan-2-yl)benzamide (3f)


NMR (500 MHz, Chloroform-d) δ 8.03 (dd, J = 8.2, 1.3 Hz, 1H), 7.78 (brs, 1H),

7.55 (t, J = 7.5 Hz, 1H), 7.49 (dd, J = 7.7, 1.5 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H),

7.40 – 7.33 (m, 5H), 7.14 (brs, 3H), 7.00 (brs, 1H), 4.84 (s, 1H), 4.65 – 4.48 (m,

3H), 4.45 (dd, J = 15.3, 6.1 Hz, 1H), 1.90 (brs, 2H), 1.65 (brs, 1H), 0.93 (brs,

6H). 13C NMR (126 MHz, CDCl3) δ 173.9, 171.2, 148.4, 136.1, 133.8, 131.4,


[M+H]+: 460.55; found [M+H]+: 460.23.

General procedure for the synthesis of Hydrolysis of Ugi-4CR product under basic condition:

To a solution of compound 3a (114 mg) in MeOH (3mL) was added 1N NaOH (5.0 equiv, 1.4 mL). The

resulting suspension was stirred at reflux for 6h. The reaction was concentrated to dryness and water

(2 mL) was added. The water layer was cooled to 0 °C and acidified to pH 1 with HCl (1 N). Additional

EtOAc (5 mL) was added and the organic layer was separated. The water layer was extracted with

EtOAc (5 mL × 3). The combined organic layers were dried over MgSO4. The solvent was removed

under reduced pressure and the residue was purified by silica gel flash chromatography using

MeOH–DCM as eluent.


Chapter 9

174

N-acetyl-N-benzylleucine (4a)

Obtained from 0.3 mmol reaction as colorless oil, yield: 30 mg (38%); Two

rotamers were present on NMR timescale (R1 : R2 = 1: 0.2 ). 1H NMR (500 MHz,

Chloroform-d) δ 7.37 (t, J = 7.4 Hz, 2H), 7.31 (t, J = 7.3 Hz, 0.8H), 7.27 (d, J = 5.9 Hz,

3H), 7.22 – 7.18 (m, 0.2H), 4.99 (d, J = 15.4 Hz, 0.2H), 4.67 (d, J = 17.0 Hz, 1H), 4.50

(d, J = 17.0 Hz, 2H), 4.42 (s, 0.2H), 4.21 (d, J = 15.5 Hz, 0.2H), 2.27 (s, 0.6H), 2.18 (s, 3H), 2.03 – 1.91 (m,

1H), 1.77 – 1.67 (m, 0.2H), 1.63 – 1.47 (m, 2H), 1.40 – 1.31 (m, 0.4H), 0.90 – 0.84 (m, 3.6H), 0.75 (d, J = 6.2

Hz, 3H), 0.60 (d, J = 6.6 Hz, 0.6H). 13C NMR (126 MHz, CDCl3) δ 174.6, 173.6, 136.2, 129.0, 128.3, 127.9,


264.15.

General procedure for the synthesis of Hydrolysis of Ugi-4CR products under acidic

condition:

To a solution of protected Ugi-4CR product (around 100 mg) in MeOH was added 1N HCl (5.0 equiv).

The resulting suspension was stirred at reflux for 6h. The reaction was concentrated to dryness and

1N NaOH (2 mL) was added. The water layer was extracted with DCM (5 mL). The water layer was

cooled to 0 °C and acidified to pH 1 with HCl (1 N). Additional EtOAc (5 mL) was added and the

organic layer was separated. The water layer was extracted with EtOAc (5 mL × 3). The combined

organic layers were dried over MgSO4. The solvent was removed under reduced pressure to get our

product.

N-acetyl-N-benzylleucine (4a) THIS IS THE SAME AS ABOVE


rotamers were present on NMR timescale (R1 : R2 = 1: 0.2 ). 1H NMR (500 MHz,

Chloroform-d) δ 7.37 (t, J = 7.4 Hz, 2H), 7.31 (t, J = 7.3 Hz, 0.8H), 7.27 (d, J = 5.9 Hz,

3H), 7.22 – 7.18 (m, 0.2H), 4.99 (d, J = 15.4 Hz, 0.2H), 4.67 (d, J = 17.0 Hz, 1H), 4.50

(d, J = 17.0 Hz, 2H), 4.42 (s, 0.2H), 4.21 (d, J = 15.5 Hz, 0.2H), 2.27 (s, 0.6H), 2.18 (s, 3H), 2.03 – 1.91 (m, 1H),

1.77 – 1.67 (m, 0.2H), 1.63 – 1.47 (m, 2H), 1.40 – 1.31 (m, 0.4H), 0.90 – 0.84 (m, 3.6H), 0.75 (d, J = 6.2 Hz,

3H), 0.60 (d, J = 6.6 Hz, 0.6H). 13C NMR (126 MHz, CDCl3) δ 174.6, 173.6, 136.2, 129.0, 128.3, 127.9, 126.8,


N-acetyl-N-propylvaline (4b)

Obtained from 0.47 mmol reaction as colorless oil, yield: 59 mg (62%); 1H NMR

(500 MHz, Chloroform-d) δ 10.42 (s, 1H), 3.56 (d, J = 10.8 Hz, 1H), 3.48 – 3.38 (m,

1H), 3.20 – 3.07 (m, 1H), 2.77 – 2.64 (m, 1H), 2.21 (s, 3H), 1.76 – 1.60 (m, 2H), 1.04 (d,

J = 6.5 Hz, 3H), 0.96 – 0.89 (m, 6H). 13C NMR (126 MHz, CDCl3) δ 174.6, 171.6, 74.0, 55.2, 26.6, 22.4, 22.0,




175

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General procedure for the esterification under acidic condition:

To a solution of Ugi-4CR product (around 100 mg) in DCM (2mL) was added 4N HCl in dioxane (5.0

equiv. around 0.25 mL) and 1mL MeOH . The resulting suspension was stirred at reflux for 2–6h.

The solvent was removed under reduced pressure and the residue was purified by silica gel flash

chromatography using EtOAc–hexane as eluent.

methyl N-acetyl-N-phenethylvalinate (4c)


rotamers were present on NMR timescale (R1 : R2 = 1: 1 ). 1H NMR (500 MHz,

Chloroform-d) δ 7.37 – 7.31 (m, 3H), 7.30 – 7.27 (m, 5H), 7.25 – 7.22 (m, 2H),

4.71 (d, J = 10.5 Hz, 1H), 3.90 (d, J = 10.9 Hz, 1H), 3.78 (s, 3H), 3.77 (s, 3H), 3.75 –

3.64 (m, 1H), 3.58 – 3.46 (m, 2H), 3.33 – 3.21 (m, 1H), 3.00 (td, J = 12.1, 5.2 Hz, 1H), 2.93 – 2.75 (m, 2H),

2.60 (td, J = 12.0, 4.7 Hz, 1H), 2.45 – 2.30 (m, 2H), 2.25 (s, 3H), 2.21 (s, 3H), 1.05 (d, J = 6.5 Hz, 3H), 1.01

(d, J = 6.5 Hz, 3H), 0.92 (d, J = 6.7 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 171.8,

171.1, 139.5, 138.2, 128.9, 128.8, 128.6, 128.4, 126.8, 126.3, 66.9, 62.1, 52.2, 51.9, 48.5, 45.0, 36.0, 34.0,

29.7, 27.8, 27.7, 22.5, 21.5, 20.2, 19.7, 18.8, 18.8. MS (ESI) m/z calculated [M+H]+: 278.36; found [M+H]+:

278.20.

methyl 2-(N-benzylacetamido)-2-phenylacetate (4d)

Obtained from 0.22 mmol reaction as colorless oil, yield: 50 mg (77%); 1H NMR

(500 MHz, Chloroform-d) δ 7.23 (brs, 5H), 7.21 – 7.12 (m, 3H), 6.97 (d, J = 7.0 Hz,

2H), 6.00 (s, 1H), 4.64 (d, J = 17.7 Hz, 1H), 4.43 (d, J = 17.7 Hz, 1H), 3.73 (s, 3H),

2.10 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 172.5, 171.1, 137.3, 134.0, 129.8, 128.7,

128.6, 128.4, 127.0, 126.0, 62.1, 52.4, 50.1, 22.3. MS (ESI) m/z calculated [M+H]+:

298.35; found [M+H]+: 298.17.

methyl N-acetyl-N-(4-chlorobenzyl)valinate (4e)


rotamers were present on NMR timescale (R1 : R2 = 1 : 1 ). 1H NMR (500

MHz, Chloroform-d) δ 7.31 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.5 Hz, 2H), 7.15 (d,

J = 8.5 Hz, 2H), 7.10 (d, J = 8.2 Hz, 2H), 4.94 (d, J = 10.4 Hz, 1H), 4.88 (d, J =

15.4 Hz, 1H), 4.62 (d, J = 17.7 Hz, 1H), 4.57 (d, J = 17.7 Hz, 1H), 4.23 (d, J = 15.4 Hz, 1H), 3.94 (d, J = 10.9

Hz, 1H), 3.47 (s, 3H), 3.39 (s, 3H), 2.39 – 2.31 (m, 1H), 2.29 (s, 3H), 2.28 – 2.24 (m, 1H), 2.06 (s, 3H), 0.98

(d, J = 2.8 Hz, 3H), 0.96 (d, J = 2.8 Hz, 3H), 0.89 (d, J = 6.8 Hz, 3H), 0.84 (d, J = 6.8 Hz, 3H). 13C NMR (126

MHz, CDCl3) δ 172.0, 171.8, 171.0, 170.1, 136.4, 135.7, 133.1, 132.6, 129.2, 128.9, 128.2, 127.2, 67.0, 61.6,

51.9, 51.7, 48.4, 44.9, 27.9, 27.5, 22.4, 22.0, 19.9, 19.7, 18.7, 18.7. MS (ESI) m/z calculated [M+H]+: 298.78;

found [M+H]+: 298.11.


Chapter 9

176

methyl N-benzoyl-N-benzylleucinate (4f)


rotamers were present on NMR timescale (R1: R2=1: 0.7). 1H NMR (500 MHz,

Chloroform-d) δ 7.48 (brs, 3.4H), 7.40 (brs, 6.8H), 7.31 (t, J = 7.4 Hz, 4H), 7.28 – 7.19

(m, 2.8H), 4.91 – 4.33 (m, 5.1H), 3.64 (brs, 2.1H), 3.52 (brs, 3H), 2.11 (brs, 0.7H), 1.66

(brs, 3H), 1.35 (brs, 1.4H), 0.84 (d, J = 48.5 Hz, 4.2H), 0.56 (d, J = 22.1 Hz, 6H). 13C

NMR (126 MHz, CDCl3) δ 173.3, 171.6, 138.1, 136.2, 129.7, 128.6, 128.4, 128.0, 127.8,

127.1, 126.7, 60.1, 56.7, 53.1, 52.2, 46.5, 38.5, 25.4, 24.3, 22.4, 21.8. MS (ESI) m/z calculated [M+H]+:

340.44; found [M+H]+: 340.20.

methyl N-acetyl-N-benzylleucinate (4g)

Obtained from 0.23 mmol reaction as a colorless liquid, yield: 56 mg (87%);Two

rotamers were present on NMRtimescale (R1: R2=1: 0.33). 1H NMR (500 MHz,

Chloroform-d) δ 7.35 (t, J = 7.5 Hz, 2H), 7.32 – 7.24 (m, 3H), 4.98 – 4.92 (m, 1H),

4.69 – 4.62 (m, 1.33H), 4.51 (d, J = 17.6 Hz, 1H), 4.43 – 4.38 (m, 0.33H), 3.60 (s, 3H),

3.49 (s, 1H), 2.27 (s, 1H), 2.12 (s, 3H), 1.87 – 1.79 (m, 1H), 1.79 – 1.74 (m, 0.33H), 1.69 – 1.61 (m, 0.33H),

1.59 – 1.49 (m, 2H), 1.45 – 1.38 (m, 0.33H), 0.89 (dd, J = 6.5, 3.0 Hz, 4H), 0.78 (d, J = 6.3 Hz, 3H), 0.71 (d,

J = 6.6 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 172.2, 171.4, 138.1, 137.1, 128.7, 128.2, 128.0, 127.5, 127.0,

126.5, 58.9, 55.8, 52.2, 52.0, 50.6, 46.4, 38.4, 25.2, 24.5, 22.5, 22.5, 22.3, 22.2, 22.2, 22.0. MS (ESI) m/z




177

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References

[1] (a) A. Domling, I. Ugi, Angew. Chem. Int. Ed. 2000, 39, 3168; (b) J. E. Biggs-Houck, A. Younai, J. T. Shaw, Curr. Opin. Chem. Biol. 2010, 14, 371; (c) B. Ganem, Accounts Chem. Res. 2009, 42, 463.

[2] (a) A. Domling, Chem. Rev. 2006, 106, 17; (b) A. Domling, W. Wang, K. Wang, Chem. Rev. 2012, 112, 3083; (c) I. Akritopoulou-Zanze, Curr. Opin. Chem. Biol. 2008, 12, 324; (d) T. Zarganes-Tzitzikas, A. L. Chandgude, A. Domling, Chem. Rec. 2015, 15, 981.

[3] I. Ugi, A. Domling, W. Horl, Endeavour 1994, 18, 115.

[4] [G. Koopmanschap, E. Ruijter, R. V. A. Orru, Beilstein J. Org. Chem. 2014, 10, 544.

[5] I. Ugi, F. K. Rosendahl, Liebigs Ann. Chem. 1963, 666, 65.

[6] (a) O. Kreye, B. Westermann, L. A. Wessjohann, Synlett 2007, 3188; (b) C. B. Gilley, Y. J. Kobayashi, Org. Chem. 2008, 73, 4198; (c) G. van der Heijden, J. A. W. Jong, E. Ruijter, R. V. A. Orru, Org. Lett. 2016, 18, 984; (d) R. J. Linderman, S. Binet, S. R. Petrich, J. Org. Chem. 1999, 64, 336; (e) T. Lindhorst, H. Bock, I. Ugi, Tetrahedron 1999, 55, 7411; (f ) W. Maison, I. Schlemminger, O. Westerhoff, J. Martens, Bioorg. Med. Chem. Lett. 1999, 9, 581; (g) M. C. Pirrung, S. Ghorai, J. Am. Chem. Soc. 2006, 128, 11772; (h) M. C. Pirrung, S. Ghorai, T. R. Ibarra-Rivera, J. Org. Chem. 2009, 74, 4110; (i) L. A. Wessjohann, M. C. Morejon, G. M. Ojeda, C. R. B. Rhoden, D. G. Rivera, J. Org. Chem. 2016, 81, 6535; (j) C. B. Gilley, M. J. Buller, Y. Kobayashi, Org. Lett. 2007, 9, 3631; (k) R. A. W. Neves, S. Stark, M. C. Morejon, B. Westermann, L. A. Wessjohann, Tetrahedron Lett. 2012, 53, 5360.

[7] (a) E. Kroon, K. Kurpiewska, J. Kalinowska-Tluscik, A. Domling, Org. Lett. 2016, 18, 4762; (b) A. R. Katritzky, Y. X. Chen, K. Yannakopoulou, P. Lue, Tetrahedron Lett. 1989, 30, 6657; (c) A. Domling, B. Beck, M. Magnin-Lachaux, Tetrahedron Lett. 2006, 47, 4289; (d) M. Tukulula, S. Little, J. Gut, P. J. Rosenthal, B. J. Wan, S. G. Franzblau, K. Chibale, Eur. J. Med. Chem. 2012, 57, 259.

[8] P. Klan, T. Solomek, C. G. Bochet, A. Blanc, R. Givens, M. Rubina, V. Popik, A. Kostikov, J. Wirz, Chem. Rev. 2013, 113, 119.

[9] H. Zhao, E. S. Sterner, E. B. Coughlin, P. Theato, Macromolecules 2012, 45, 1723.

[10] (a) K. S. Sung, F. L. Chen, P. C. Huang, Synlett 2006, 2667; (b) A. Isidro-Llobet, M. Alvarez, F. Albericio, Chem. Rev. 2009, 109, 2455; (c) M. J. Hansen, W. A. Velema, M. M. Lerch, W. Szymanski, B. L. Feringa, Chem. Soc. Rev. 2015, 44, 3358.

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[12] Y. V. Il’ichev, M. A. Schworer, J. Wirz, J. Am. Chem. Soc. 2004, 126, 4581.



Summary

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5

Summary

Multi-component reaction (MCR) is a promising synthetic methodology for the rapid and easy

access to scaffold with a great diversity and so MCRs find broad applications in pharmaceutical and

organic industries. MCRs are considered as ideal reactions due to a wide range of advantages, such

as simplicity, high efficiency, green nature, and time efficacy. The finding of new MCRs and their

applications to fill chemical space has become an increasingly active area of research.

The research in this thesis is focused on the development of new MCRs and their applications

towards generation of biologically important molecules with vast diversity and complexity.

In Chapter 1, we give an overview of modern MCRs with a focus on higher MCRs and some

intriguing recent applications underscoring the immense potential of navigating the chemical

space. Furthermore, the MCRs impact on both drug discovery projects and organic industry are

discussed.

In Chapter 2, we give an overview of the latest literature covering the Passerini reaction,

especially focusing on scope, chirality and applications in diverse areas.

In Chapter 3, we describe the new most efficient protocol for the Passerini tetrazole reaction.

The scope of the reaction is investigated with various aldehydes and isocyanides.

In Chapter 4, for the first time N-hydroxamic acid is introduced as an acid isostere in the Passerini

multicomponent reaction (P-3CR) towards the one step synthesis of α-aminoxy amide. This

sonication-accelerated, catalyst-free, simple, fast and highly efficient Passerini reaction is used for

the synthesis of diverse α-aminoxy-amides.

In Chapter 5, we describe the successful use of the N-hydroxyimides as an acid isostere in the U-4CR

for a direct route to the synthesis of α-hydrazinoamides. This is the first example of cyclic imide

migration to nitrogen (O N imide transfer) in the Mumm rearrangement to form an N-N bond.


Summary

180

In Chapter 6, we describe the novel microwave accelerated three-component reaction between

an amine, a carboxylic acid derivative and an azide source for the construction of the 1,5-tetrazole

scaffold. The applications of this method is demonstrated in the synthesis of biologically important

fused tetrazole scaffolds and the marketed drug cilostazol.

Chapter 7, is about the union of MCR. We first time used the Asinger-Ugi-tetrazole union for the

synthesis of highly diastereoselective 4-(tetrazole)-1,3-oxazinanes. The reaction exhibit excellent

diastereoselectivity and broad substrate scope.

In Chapter 8, we describe the new TiCl4-mediated reaction for the direct amination of Passerini-2CR

product. This simple, general, additive/base/ligand-free reaction is mediated by economical TiCl4.

The validity of this C-N bond formation protocol with diverse amines is discussed.

In Chapter 9, we introduced the universal convertible isocyanide in the Ugi-4CR and also in Ugi-

tetrazole reaction. The application of this 2-nitro benzyl isocyanide in different reactions and

conditions is described.


Samenvatting

181

5

SamenvattingMulti-component reacties (MCR) is een veelbelovende synthese methode voor snelle en eenvoudige

toegang tot een grote diversiteit aan structuren en geeft MCR’s een grote toepasbaarheid in de

farmaceutische en organische industrie. MCR’s worden beschouwd als ideale reacties, vanwege hun

grote aantal voordelen, waaronder simpliciteit, hoge efficiëntie, groene aard en tijds efficiëntie. Het

vinden van nieuwe MCR’s en zijn toepassingen om ‘chemical space’ te benutten is een groeiend

onderzoekgebied geworden.

Het onderzoek in dit proefschrift is gericht op de ontwikkeling van nieuwe MCR’s en de

toepassing daarvan, op belangrijke biologisch actieve verbindingen, met grote diversiteit en

complexiteit.

In hoofdstuk 1 wordt een overzicht gegeven van de moderne MCR’s, met nadruk op veel

toegepaste MCR’s en een aantal interessante recente toepassingen die de immense potentie van

MCR’s in het uitdiepen van de ‘chemical space’ benadrukken. Bovendien wordt de impact van MCR’s

op zowel medicijn onderzoek als organische chemie besproken.

In hoofdstuk 2 is een overzicht gemaakt van recente literatuur die de Passerini reactie omvat,

waarin de focus ligt op scope, chiraliteit en toepassingen in diverse vakgebieden.

In hoofdstuk 3 beschrijven we een nieuwe, meest efficiënte methode voor de Passerini tetrazole

reactie. Het bereik van de reactie wordt onderzocht aan de hand van verschillende aldehydes en

isocyanides.

In hoofdstuk 4 wordt voor het eerst N-hydroxamic zuur geïntroduceerd als een zuur isosteer in

de Passerini multi-component reactie (P-3CR) ten behoeve van de één stap reactie van α-aminoxy

amide. Deze ultrasoon-geaccelereerde, katalysator vrije, simpele, snelle en zeer efficiënte Passerini

reactie wordt gebruikt om verschillende α-aminoxy-amides mee te synthetiseren.


Summary

182

In hoofdstuk 5 beschrijven we hoe N-hydroxyimides succesvol worden toegepast als zuur isosteren

in de U-4CR om rechtstreeks α-hydrazinoamides te synthetiseren. Het is het eerste voorbeeld van

cyclisch imide migratie naar stikstof (O N imide overdracht) in de ‘Mumm rearrangement’ om een

N-N binding te vormen.

In hoofdstuk 6 is een nieuwe magnetron versnelde drie-component reactie tussen een amine,

carbonzuur derivaat en een azide bron beschreven voor de samenstelling van het 1,5-tetrazool

scaffold. De toepassingen van deze methode worden gedemonstreerd in de synthese van biologisch

relevante gefuseerde tetrazool scaffolden en het op de markt gebrachte medicijn cilostazol.

Hoofdstuk 7 gaat over de vereniging van MCR. We gebruiken voor het eerst de Asinger-Ugi-tetrazole

vereniging om de zeer diastereoselectieve 4-(tetrazole)-1,3-oxazinanes te synthetiseren. De reactie

laat een uitstekende diastereoselectiviteit en brede substraat scope zien.


Summary

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In hoofdstuk 8 wordt de nieuwe TiCl4-gestuurde reactie voor de directe aminatie van Passerini-

2CR producten beschreven. Deze eenvoudige, algemene, additief/base/ligand vrije reactie wordt

gestuurd door het goedkope reagens TiCl4. De waarde van deze C-N binding vorming methode

wordt besproken met diverse amines.

In hoofdstuk 9 introduceren we het universeel omzetbare isocyanide in de Ugi-4CR alsook de Ugi-

tetrazool reactie. De toepassing van 2-nitro benzyl isocyanide bij verschillende reacties en condities

is in dit hoofdstuk beschreven.



Acknowledgements

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AcknowledgementsGratitude cannot be expressed in words. However, I would like to convey my sincere thanks to

everyone who helped me during these four years, for both professional and personal reasons.

Firstly, I would like to express my sincere gratitude to my supervisor Prof. Alexander Dömling for

providing me an opportunity to join your research group as a Ph.D. student. For your continuous

support to my Ph.D. study with your guidance, time, patience, motivation, immense knowledge, and

your smile, which helped me in all the time of research and writing of this thesis. Your ability to work

with students is exceptional. I feel truly grateful to you for being the person you are with us in the

lab and outside as well. You are very generous, kind, funny and relax person. I learned a lot from you

and I have to say that, you are an inspiration for me.

You have been a fantastic supervisor providing me freedom to design and execute my own ideas

in chemistry project, that guided me to grow as an independent researcher. Thanks for making me

a better researcher, problem solver, and boosting my confidence on a whole other level. It has been

a pleasure for me benefiting from your great work ethics, fine mind, your integrity, and knowledge.

Your advice on my personal front as well as on career path have been invaluable.

I still remember the first time we met in your office. After a discussion about projects, you told me

that, in these four years focus on not only professional but also on personal growth. This thing really

helps me throughout these 4 years, and which was much needed for me. And that’s why in these

four years very good things happen with me, like selection in Lindau Nobel laureates Meeting 2015,

or getting prestigious travel grants or awards. I participated in social groups like GISA (Groningen

Indian Student Association) or volunteer in UMCG conference to build-up social confidence. Also,

even my magic tricks which I showed you at dinner at Charry’s apartment or in famelab and even

at MCR symposium. These things really gives me the confidence in public speaking. Thank you very

much for everything.

Next, I would like to thank my co-promotor, Prof. W. J. Quax. Thank you for your suggestions and

guidance during the Ph.D. evaluation each year and more especially during my thesis submission.

Due to your help, I am able to get my defence date even before my contract finish.

I would like to acknowledge the members of the assessment Committee, Prof. P.H. Elsinga, Prof.

C. Hulme and Prof. L. El Kaim, for their time and effort invested in reading and evaluating my thesis

and valuable comments and suggestions.

I would like to convey my regards to Dr. Matthew Groves, Assistant Professor at the Drug

Design Group. Thank you so much for your guidance and useful advice for the caspase project. You

understand every student’s problems and try to solve it on a personal level. You spend plenty of time

with students to share ideas, instructions and introduce scholars to science. Thank you very much for

everything!

Thanks to all collaborators of the Caspase project, Prof. Spanu, and his research group, Prof. Maria,

and other all collaborators from Italy. From RUG, Prof. Elsinga, Dr. Amalia, and Prof. Gosens.

My sincere gratitude to our Lab Manager, Andre Boltjes, who was always there to help us. I

really appreciate your kind and pragmatic nature. Thanks for all the support during this journey. Also

translating my thesis summary in Dutch.


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Jolanda for helps me with administrative issues and information. Thank you Jolanda!

Chary, thank you very much for being as my friend and as a brother with whom I can share any

good or bad moments without any hesitation. You have always been eager to discussion with an

open mind. Whenever anything happens, the first thing I think of is telling you. That’s the sign of an

awesome friend. I got one friend who will be always there for me. Thanks for serving as a mentor to last

2 years. For sharing your ideas and expertise about research and successful experience for projects.

Your understanding of problems, teaching excellence, and interpersonal skills all contributed to a

successful last 2 years of my Ph.D. You are nothing but a just fabulous guy and so compassionate.

Best wishes for your future!

Next, I would like to thank a person who always there to help, from computational chemistry

at the beginning of my Ph.D. to the each and every aspect of thesis and defence process without

vacillating at all. My co-author of my first Ph.D. paper and best friend Tryfonas! I always wonder about

your helping and kind nature with everyone. I wish you an excellent future. You are the best. I’m so

very glad I’m friends with you.

I like to thank my another paranymph, Santosh. For your suggestions and comments during

paper writing. Discussions with you help me to see the both sides of each aspect. Thank you for

always being my best supporter.

I would also like to acknowledge the European Union Erasmus program Svaagata.eu project,

and providing me 3 year Ph.D. scholarship, without this, it was not possible to join Ph.D. Thank you

very much to the University of Groningen for proving me last year scholarship.

Thanks to Anita Veltmaat, for being a Dutch parent for me since last four years. For your concern

about every minute thing, for nice dinners at your home and for nice coffee meetings. Letting us

know more about Dutch culture, cuisine and lot more. You really a great person with big heart.

Thanks to my Erasmus family, Sumit, Hemant, and Ann for sharing information and being

friends since last 4 years. Thanks for Akansha and Anurag. I will always remember our first year Diwali

celebration in Melkweg!

Sumit, I have lots of memories from even before coming to Netherlands. I still remember that

you and Hemant came to receiving me on Groningen train station. The first year in Melkweg, our

cycle trips, countless dinners and GISA events or city center visits and also Rome trip. Wish you best

of luck for your Ph.D. and future.

Hemant, my another buddy, be always there for everything. Thank you very much for being

there for me every time, from receiving from the train station of the first day to even for helping in

booking my Ph.D. defence dinner party. Also for numerous dinners, GISA, and Czech visit. Best of luck

for your future!

Thanks to my Ph.D. colleagues, Eman and former office mate Natalia, for discussions and

information about credit courses, project progress and the plan for the Ph.D. thesis. Best wishes for

your thesis and defense! Eman, I will always remember our long discussion about thesis plans and

your homemade sweet sweets!

My Friend, research project partner & Co-Author Jingyao, it is a nice experience to work with you

and I really enjoyed this opportunity. Also, I am glad to work with you on ongoing projects. My best

wishes are always with you.


Acknowledgements

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Indian friends from our lab, Bhupendra, Pravin, Shrinidhi, Naveen, it was a great time with you guys

in Groningen. Vishwanath, Saif, and Saravanan, I will always remember our weekend parties and

delicious food. Thanks for truckloads of good times.

Thanks to Dinos for lab help and being partner for memorable Lindau Nobel laureates Meeting.

Thanks, Edwin and Ting for valuable suggestions and information gave me time to time. Thank you

for all the good times we shared in and out of the lab.

Our lab mates and also scholars visiting from all over the world, Yuanze, Fandi, Robin, Shabnam,

Silvia, Arianna, Paola, Samat, Maxx (Irish), Ariana, Evo, Michel, Leni, Ewa, Max, Fanny, Keas, Roberto I

and II, Harmen, Perry, Juliana, and Erico. Thanks to our biology lab colleagues Sergey, Atlio, Fernando,

Ameena and Kai.

My office mate, Qian and Markella, hope we had a nice time in office. Best wishes to both of you!

Arianna, thanks for being nice talkative officemate, sharing snacks and being always volunteer for

my magic tricks. Also for planning barbecue. Gita, thank you very much for tons of memories.

My students, Iris, Daniele, Luke, and Soraya. It was nice learning and fun experience with you

guys. I have enjoyed every moment of teaching you, it was a fabulous experience. I hope you also

feel the same. I wish best of luck for your future!

I would like to thank the people from the group of Prof. Dekker, and first-year labmates, Nick,

Marilena, and Martijn. Also thanks to Hannah and Thea.

Thanks to my Marathi friends, Milind, Sneha, Amol, Pallavi, Yoshita, and Nilesh, it was a great time

with you guys in Groningen.

My first-year room partners, Arthur and Peps and also neighbor Summer (Zhang), thank you

guys for being starting my first year with joy and happiness.

Our GISA 2015 team, that was wonderful one year and learned a lot about organizational skills

which extended my Indian friend circle. Thank you to all guys Nilesh, Jasmine, Soma, Amuly, Ketan

and Ashish.

Thanks to my NIPER friends in Europe, Tushar Satav, Somnath, Suresh, Rahul, Bakmukund, Abhijit,

Uma, and Gaurav for all information and friendship. Thanks Tushar for Paris and Belgium visit and

Somnath for Geneva visit.

I am grateful to my master degree supervisor from NIPER, Prof. S. Guchhait without his

encouragement, I would not have opted for Ph.D. research.

Thanks to Saurabh and Aishwarya for drawing such a nice painting for the thesis cover.

Last but not least, I would like to say something about my family. Dear Aaie and Nana, I am proud

to say that I am also now a doctor (of course, not physician doctor), and your wish come true that

both sons are doctors now. Your support and encouragements helped me in all the stages of my

journey. You always kept me focused and taught to stay positive in any situation which helps me

throughout these years staying far away from home in master and in Ph.D.

Thanks to my siblings, Dr. Atul, Rani and Tai and their families to continued support, also to Jyoti

vahini, and cute princes Anannya. My cousin Ajit and his family. Even though I was far away from all

of you, but it never feels that ways when we have chat.


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My best friend and beloved wife Sai, dear you were the best thing happened to me in my Ph.D. I

appreciate your support and understanding each and every moment and making my path more

feasible. You have brought a lot of happiness, good luck, and harmony in my life.

Lavakarach Bhetua Saglynna!!!

Ajay Chandgude

May 22, 2017


About the author

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Ajay L. Chandgude

Address: University of Groningen, Drug Design

Groningen Research Institute of Pharmacy,

Antonius Deusinglaan 1, Room: 3211-469,

9713 AV Groningen, Netherlands

Telephone: (+31)-687251843 or (+31)-50-3635541

Email: [email protected]

Education

PhD in Drug Design-Department of Pharmacy July 2013-June 2017

University of Groningen, The Netherlands

Supervisor: Prof. Alexander Domling

Thesis: “Multicomponent Reactions: Development, Scope, and Applications”.

Master Degree - M. Tech. (Pharm.) in Pharmaceutical Technology (Bulk Drugs) June 2010-June

2012

National Institute of Pharmaceutical Education and Research, Mohali, Punjab, India

8.38 CGPA (CGPA on ten point scale)

Supervisor: Dr. Sankar K. Guchhait

Thesis: “Development of multicomponent reactions for the synthesis of Imidazoheterocycles:

preparation of Zolpidem”.

Bachelor Degree - B. Pharmacy August 2006- May 2010

University of Pune, Pune.

S.V.P.M’s College of Pharmacy, Malegaon (B.K.), Tal-Baramati, Dist-Pune, Maharashtra, India

First class with 65.12%

12th (HSC), 2006, First class with 74.67% 10th (SSC), 2004, Distinction with 79.86%

Publications

1. A. L. Chandgude, A. Dömling, Direct amination of alpha-hydroxy amide, Asian J. Org. Chem.

2017, DOI: 10.1002/ajoc.201700277.

2. A. L. Chandgude, J. Li, A. Dömling, 2-Nitrobenzyl Isocyanide as a Universal Convertible

Isocyanide Asian J. Org. Chem. 2017, DOI: 10.1002/ajoc.201700177.

3. A. L. Chandgude, A. Dömling, N-Hydroxyimide Ugi Reaction toward α-Hydrazino Amides

Org. Lett., 2017, 19, 1228–1231

4. A. L. Chandgude, A. Dömling, Unconventional Passerini Reaction toward α-Aminoxy-amides

Org. Lett., 2016, 18, 6396–6399.


Appendix

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5. A. L. Chandgude, A. Dömling, An efficient Passerini tetrazole reaction (PT-3CR) Green Chem.

2016, 18, 3718-3721.

6. A. L. Chandgude, A. Dömling, Convergent Three‐Component Tetrazole Synthesis Eur. J. Org.

Chem. 2016, 2383-2387.

7. T. Zarganes-Tzitzikas, A. L. Chandgude, A. Dömling, Multicomponent Reactions, Union of

MCRs and Beyond (Review) Chem. Record, 2015, 15, 981-996.

8. S. K. Guchhait, A. L. Chandgude, G Priyadarshani, CuSO4–glucose for in situ generation of

controlled Cu (I)–Cu (II) bicatalysts: multicomponent reaction of heterocyclic azine and

aldehyde with alkyne, and cycloisomerization toward synthesis of N-fused imidazoles J.

Org. Chem. 2012, 77, 4438-4444.

Manuscripts under Review/Preparation

1. A. L. Chandgude, …. A. Dömling, MCR towards oxazinane-tetrazole synthesis, in Review.

2. A. L. Chandgude, A Dömling, The Passerini Reaction-Scope, Chirality and Applications, In

preparation.

3. A. L. Chandgude, A. Dömling, MCR towards the synthesis of indoles, in preparation.

Patent

Potent non-covalent inhibitors of caspase-1, Patent will be file soon.

Awards/Scholarships/Grants

1. Erasmus Mundus PhD scholarship from the European commission (2013-2016).

2. PhD Scholarship from University of Groningen (2016-2017).

3. Travel grant from Volkswagen Foundation, “Aging: Cellular Mechanisms and Therapeutic

Opportunities, a Herrenhausen Symposium”, September 2015, Hanover, Germany.

4. Selection in the “65th Lindau Nobel Laureates Meeting, June 2015”, Lindau, Germany.

5. Travel Grant from Konstanz Research School Chemical Biology, University of Konstanz for the

Autumn School “Chemical Biology” October 2015, Konstanz, Germany.

6. The Alzheimer’s Drug Discovery Foundation (ADDF) “Young Investigator Scholarship”, 16th

International Conference on Alzheimer’s Drug Discovery on October 2015, Jersey City, NJ. (did

not accepted).

7. SCI Travel Bursary Award, “9th RSC / SCI symposium on Proteinase Inhibitor Design” April 2015;

Basel, Switzerland.

8. Awarded NIPER fellowship by ministry of Chemicals and Fertilizers, Government of India

during Master degree, 2010 2012.

9. Qualified Graduate Aptitude Test of Pharmacy GPAT–2010.

10. Qualified Graduate Aptitude Test in Engineering (GATE) 2010, in Biotechnology; and GATE

2009, in Pharmaceutical Sciences, conducted by Council for Technical Education, Govt. of India.


About the author

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Conferences / Presentations

Oral presentations:

1. Medicinal Chemistry and Bioanalysis – Mini Symposium, Groningen, The Netherlands: News

from Passerini Reaction. March 2017.

2. Medicinal Chemistry and Bioanalysis seminars, Groningen, The Netherlands: Potent non-

covalent inhibitors of caspase-1. June 2015.

3. 9th RSC/SCI symposium on Proteinase Inhibitor Design, Basel, Switzerland: Potent non-covalent

inhibitors of caspase-1. April 2015.

Poster presentations:

1. Autumn School Chemical Biology, Symposium, Konstanz, Germany. A. Chandgude. et al.

Potent non-covalent inhibitors of caspase-1. October 2015

2. Aging: Cellular Mechanisms and Therapeutic Opportunities, a Herrenhausen Symposium,

Hannover, Germany. A. Chandgude. et al. Potent and selective inflammasome inhibitors for

healthy aging. September 2015.

3. 9th RSC / SCI symposium on Proteinase Inhibitor Design, Basel, Switzerland. A. Chandgude. et

al. Potent non-covalent inhibitors of caspase-1. April 2015.

4. FIGON Dutch Medicines Days, Ede, The Netherlands. A. Chandgude. et al. Potent non-covalent

inhibitors of caspase-1. October 2014.

5. MCB2014; Joining forces in pharmaceutical analysis and medicinal chemistry conference,

Groningen, The Netherlands. A. Chandgude. et al. Discovery and Design of Noncovalent Small

Molecule Inhibitors of Cysteine Protease Caspase-1. August 2014.

Supervision / Mentor Experience

Project Supervisor and thesis advisor to 2 master degree Students (6 and 9 months projects) and 2

bachelor students (2 and 9 months projects)

Assisted organic chemistry bachelor degree practical 2015 (3 Weeks course)

Extracurricular activities

Participant in “Fame Lab 2017 local heat”, Groningen.

Contestant “ESN’s Got Talent Show Groningen, 2017” as Magician (Card Magic).

Event manager of “Groningen Indian Student Association (GISA)”, Groningen, 2015.

Volunteer and sessions coordinator at the “GSMS PhD Development Conference” Groningen,

The Netherlands, June 2015.

Invited speaker as young researcher in “India Event, April 2015” at University of Groningen.

General Course on Intellectual Property” 2012 “from WIPO Worldwide Academy.

Runner up in “Play competition” (role played: Actor and director) at S.V.P.M’s College of

Pharmacy, Malegaon, 2008.


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Personal Information

Nationality: Indian Date of birth: November 16th 1988

Languages English, Hindi, Marathi (Mother Tongue).

Documents

University of Groningen Multicomponent reactions ......Ajay Chandgude 510585-L-sub01-bw-Ajay Processed on: 30-5-2017 PDF page: 2 The research presented in this PhD thesis was performed