Synthetic Applications of N-H Aziridine Containing

Compounds

by

Shannon Marie Decker

A thesis submitted in conformity with the requirements

for the degree of Master of Science

Department of Chemistry

University of Toronto

© Copyright by Shannon Marie Decker, 2010

ii

Synthetic Applications of N-H Aziridine Containing

Compounds

Shannon Marie Decker

Master of Science

Department of Chemistry

University of Toronto

2010

Abstract

Unprotected N-H aziridine aldehydes are surprisingly stable compounds which can undergo

reactions in the absence of protecting groups. In total, three different transformations were

explored during my Master’s thesis. The conversions include the dissociation of the aziridine

aldehydes, which exist as dimers, and their subsequent re-dimerization in various solvents. The

development of mixed aziridine aldehyde adducts and their attempted modifications will also be

discussed. Finally, the discovery of N-H aziridine compounds containing a 1,3-dicarbonyl

functionality will be discussed, as will their attempted transformations.

iii

Acknowledgments

I would like take the time to personally thank my supervisor, Professor Andrei K. Yudin for his

much appreciated and continued support during my Master’s degree. His desire to explore new

reactions has greatly influenced my desire to attempt reactions that I wouldn’t normally think to

try. I am grateful to Professor Ronald Kluger for taking the time to read my thesis. All of the

members of the Yudin group (past and present) have been a pleasure to work with, but in

particular I would like to single out Mr. Zhi He for all of his insights and thoughtful discussions

we had about chemistry. He has been a tremendous help in showing me how to improve upon

my lab techniques. I also owe many thanks to Mr. Nick Afagh, Mrs. Naila Assem, and Dr.

Vishal Rai for including me in their discussions on their chemistry developments and provided

me with suggestions when my chemistry was not working as hoped. These past twelve months

have been very rewarding due mainly to my involvement with the Yudin group. Lastly, I would

like to thank my family and friends for helping and supporting me during the past year.

iv

Table of Contents

Acknowledgments ........................................................................................................................ iii

Table of Contents .......................................................................................................................... iv

List of Tables .................................................................................................................................. v

List of Figures ............................................................................................................................... vi

List of Schemes .............................................................................................................................vii

List of Abbreviations ................................................................................................................. viii

1 Introduction ............................................................................................................................... 1

2 Results and Discussion .............................................................................................................. 2

2.1 Crossover experiments of aziridine aldehyde dimers..................................................... 4

2.2 Synthesis of mixed aziridine aldehyde adducts and their applications ........................ 7

2.2.1 Development of mixed aziridine aldehyde adducts ................................................. 7

2.2.2 Attempt at the applications of mixed aziridine aldehyde adducts ......................... 17

2.2 Synthesis of N-H aziridines containing a 1,3-dicarbonyl functionality ...................... 21

2.2.1 Development of N-H aziridines containing a 1,3-dicarbonyl functionality .......... 21

2.2.2 Attempt at the applications of N-H aziridine compounds containing a 1,3-

dicarbonyl .............................................................................................................. 24

3 Conclusion ............................................................................................................................... 27

4 Experimental Procedures ....................................................................................................... 28

4.1 Protocols for unprotected aziridine aldehydes.............................................................. 28

4.2 Protocols for mixed aziridine aldehyde adducts ........................................................... 29

4.3 Protocols for 1,3-dicarbonyl compounds ....................................................................... 32

5 References ................................................................................................................................ 35

Appendix I: 1H,

13C, and NOE NMR........................................................................................ 37

v

List of Tables

Table 1.1 Summary of terminology of new compounds ............................................................... 3

Table 1.2 Results of the synthesis of mixed adducts with phenyl aziridine aldehyde in

acetonitrile ..................................................................................................................................... 7

Table 1.3 Results of the synthesis of mixed adducts with leucine aziridine aldehyde in

acetonitrile ..................................................................................................................................... 9

Table 1.4 Results of the catalytic experiment between phenyl aziridine aldehyde and

hydrocinnamaldehyde .................................................................................................................. 10

Table 1.5 Scope of mixed aziridine aldehyde adduct synthesized from phenyl aziridine aldehyde

..................................................................................................................................................... 11

Table 1.6 Scope of mixed aziridine aldehyde adduct synthesized from 4-phenylbutene aziridine

aldehyde ....................................................................................................................................... 13

Table 1.7 Summary of conditions tried to make compound 51 .................................................. 23

Table 1.8 Conditions tried to make compounds 54 and 55 ......................................................... 25

vi

List of Figures

Figure 1.1 Equilibrium of unprotected N-H aziridine aldehydes ................................................. 1

Figure 1.2 X-ray crystal structure of phenyl aziridine aldehyde dimer showing hydrogen

bonding .......................................................................................................................................... 2

Figure 1.3 ESI-MS spectrum for aziridine aldehyde dimer crossover experiment in TFE .......... 5

Figure 1.4 ESI-MS spectrum for aziridine aldehyde dimer crossover experiment in MeOH ...... 6

Figure 1.5 ESI-MS spectrum for aziridine aldehyde dimer crossover experiment in THF .......... 6

Figure 1.6 The two aldehydes which were reacted with phenyl and leucine aziridine aldehydes

..................................................................................................................................................... 10

Figure 1.7 Proposed energy diagram for the synthesis of mixed aziridine aldehyde adducts .... 16

Figure 1.8 NOE between protons in the mixed aziridine aldehyde adducts ............................... 17

Figure 1.9 ESI-MS spectrum for mixed aziridine aldehyde adduct crossover experiment in

acetonitrile ................................................................................................................................... 20

Figure 1.10 ESI-MS spectrum for mixed aziridine aldehyde adduct crossover experiment in

ethyl acetate ................................................................................................................................. 20

Figure 1.11 Three enones tried in the Michael reaction with compound 45 .............................. 26

vii

List of Schemes

Scheme 1.1 Crossover experiment done by R. Hili ...................................................................... 4

Scheme 1.2 Reaction to give the crossover product 6................................................................... 5

Scheme 1.3 R. Hili’s general synthesis of mixed aziridine aldehyde adducts .............................. 7

Scheme 1.4 Synthesis of compound 39 from leucine aziridine aldehyde (4) and

hydrocinnamaldehyde (12) .......................................................................................................... 16

Scheme 1.5 Nucleophilic ring opening of compound 33 ............................................................ 18

Scheme 1.6 Nucleophilic ring opening of compound 20 ............................................................ 18

Scheme 1.7 Crossover reaction of two mixed aziridine aldehyde adducts and the five possible

crossover products ....................................................................................................................... 19

Scheme 1.8 Addition of ethyl diazoacetate (43) to phenyl aziridine aldehyde (1) ..................... 21

Scheme 1.9 Synthesis of an N-H aziridine containing a 1,3-ketoester functionality .................. 21

Scheme 1.10 Alternate synthesis of compound 45 ..................................................................... 22

Scheme 1.11 Initial attempts to expand the scope of 1,3-dicarbonyl compounds ...................... 23

Scheme 1.12 Attempts to expand the scope of the 1,3-dicarbonyl compounds with acetophenone

(50) ............................................................................................................................................... 23

Scheme 1.13 Synthesis of an analogue of compound 45 ............................................................ 24

Scheme 1.14 Michael reaction between compound 45 and acrolein (53) ................................... 25

Scheme 1.15 Proposed synthesis of a seven membered ring via an N-vinyl aziridine ............... 26

Scheme 1.16 The first step towards the synthesis of an N-vinyl aziridine containing a 1,3-

ketoester functionality (60) .......................................................................................................... 27

Scheme 1.17 Attempted synthesis of compound 60 ................................................................... 27

viii

List of Abbreviations 13

C NMR – carbon-13 nuclear magnetic resonance

1H NMR – proton nuclear magnetic resonance

CDCl3 – deuterated chloroform

CH2Cl2 – dichloromethane

CHCl3 – chloroform

d.r. – diastereomeric ratio

DBU – 1,8-Diazabicyclo[5.4.0]undec-7-ene

ESI-MS – electro-spray ionization mass spectrometry

EtOAc – ethyl acetate

HMPA – hexamethylphosphoramide

KHMDS – potassium bis(trimethylsilyl)amide

LDA – lithium diisopropyl amide

LiHMDS – lithium bis(trimethylsilyl)amide

MeCN – acetonitrile

NaH – sodium hydride

NaOMe – sodium methoxide

n-BuLi – n-butyllithium

NOE – nuclear Overhauser effect

rt – room temperature

t-BuOK – potassium t-butoxide

TFE – 2,2,2-trifluoroethanol

THF – tetrahydrofuran

1

1 Introduction

Transformations of N-protected α-amino aldehydes are readily found in the literature,1 as are

transformations of N-protected aziridine aldehydes.2 However, in most cases the nitrogen is a

bystander in the reactions.3 In some cases the nitrogen is deprotected after the aldehyde has been

converted to another functional group,4 and is then incorporated into the final product.

5

Recently developed unprotected N-H aziridine aldehydes have been involved in a range of

transformations that do not require the aziridine nitrogen to be protected at any stage of the

reaction.6 In some of the examples the aziridine nitrogen is incorporated into a cyclic product

6a,c

whereas other examples allow the nitrogen to be free for a subsequent reaction.6b,d

The aziridine aldehydes exist as a dimeric species as shown below (Figure 1.1). There is an

equilibrium between the dimer and the monomer, with the equilibrium lying heavily to the

dimer. As seen below, these species interconvert via a half-open dimer, and kinetic studies done

in the Yudin group indicate that the half-open dimer, or a similar compound, is the species that

reacts in solution.6b

Figure 1.1 Equilibrium of unprotected N-H aziridine aldehydes

The dimeric species is believed to be very stable due to hydrogen bonding between the alcohol

and the free aziridine nitrogen. This bonding was first observed in an X-ray crystal structure

obtained by R. Hili and can be seen clearly in Figure 1.2.6a

2

Figure 1.2 X-ray crystal structure of phenyl aziridine aldehyde dimer showing hydrogen bonding6a

As the chemistry community is interested in utilizing reactions which minimize waste and use

fewer steps7 it is necessary to develop more reactions which meet this need. An ideal place to

start is to develop reactions which do not require protecting groups. These groups are wasteful,

as they are not incorporated into the final product, and at least two steps are required to add and

then remove the group.7a

This thesis will be focused on transformations of aziridine aldehydes

and their derivatives without the use of any protecting groups.

2 Results and Discussion

This thesis describes three transformations which were tried on the aziridine aldehydes

originally developed in the Yudin group by Dr. Ryan Hili6a

and another aziridine aldehyde

developed by Mr. Zhi He6d

. Applications of the last two transformations will also be discussed.

Before these modifications are discussed it is important to know the terminology used to discuss

the new compounds which have been discovered and developed. Table 1.1 summarizes all of the

terminology which will be used in this thesis.

3

Table 1.1 Summary of terminology of new compounds

Terminology Description Compound Structure

phenyl aziridine

aldehyde -

TBDMSO aziridine

aldehyde -

leucine aziridine

aldehyde -

4-phenylbutene

aziridine aldehyde -

crossover product

compound composed of one half

of one aziridine aldehyde and

another half of a different

aziridine aldehyde

N

O

OH

R2

NH

R1

From aziridine

aldehyde 1

From aziridine

aldehyde 2

4

mixed aziridine

aldehyde adduct

compound formed upon the

addition of an aldehyde to an

aziridine aldehyde

N

R1 O

R2

OH

From aziridine

aldehyde

From aldehyde

N-H aziridine

containing a 1,3-

dicarbonyl

functionality

Where dicarbonyl can be either

‘ketoester’ or ‘diketone’

N-H aziridine

containing a 1,3-

ketoester with a diazo

functionality

-

2.1 Crossover experiments of aziridine aldehyde dimers

Studies which were initially done by R. Hili during his PhD involved the crossover between two

different aziridine aldehyde dimers. His experiment was set up as follows: mix a 1:1 mole ratio

of phenyl aziridine aldehyde (1) with TBDMSO aziridine aldehyde (2) at room temperature and

let it stir for a few days (Scheme 1.1). Interestingly, the only solvent in which a crossover

product (3) was observed was 2,2,2-trifluoroethanol (TFE).8

Scheme 1.1 Crossover experiment done by R. Hili8

5

An attempt to explore the ability of other aziridine aldehyde dimers to dissociate and re-

dimerize in various solvents brought about the next reaction. Upon mixing equal equivalents of

leucine aziridine aldehyde (4) and 4-phenylbutene aziridine aldehyde (5) in seven different

solvents of ranging polarity and letting it stir overnight at room temperature results were

obtained (Scheme 1.2) using electro-spray ionization mass spectrometry (ESI-MS). The desired

product was a compound which was made from one monomer of the leucine aziridine aldehyde

and one monomer of the 4-phenylbutene aziridine aldehyde (6).

Scheme 1.2 Reaction to give the crossover product 6

The seven solvents which were screened were: acetonitrile, dichloromethane, 2,2,2-

trifluoroethanol (Figure 1.3), methanol (Figure 1.4), tetrahydrofuran (Figure 1.5), toluene, and

ethyl acetate. Of these seven solvents the crossover product (6) was observed by ESI-MS in just

two of the solvents, 2,2,2-trifluoroethanol and methanol.

Figure 1.3 ESI-MS spectrum for aziridine aldehyde dimer crossover experiment in TFE

4

6

5

6

Figure 1.4 ESI-MS spectrum for aziridine aldehyde dimer crossover experiment in MeOH

Figure 1.5 ESI-MS spectrum for aziridine aldehyde dimer crossover experiment in THF

These findings were contrary to what R. Hili found, as he showed that the crossover product was

not observed in methanol.8 A good explanation for this is that the reactivity and stability of the

aziridine aldehyde dimer depends entirely on the substituents on the aziridine ring.

4

6

5

4

5

7

2.2 Synthesis of mixed aziridine aldehyde adducts and their applications

2.2.1 Development of mixed aziridine aldehyde adducts

In an unsuccessful attempt by R. Hili to carry out an aldol reaction on the aziridine aldehyde

dimers, he discovered a new compound, termed mixed aziridine aldehyde adducts. The general

reaction which was used for this synthesis involved stirring an aziridine aldehyde (7), an

aldehyde (8) and two catalysts, pyrrolidine and benzoic acid in MeCN (Scheme 1.3).9

Scheme 1.3 R. Hili’s general synthesis of mixed aziridine aldehyde adducts9

In an attempt to expand the scope of the reaction, a range of aldehydes were screened with two

different aziridine aldehyde dimers, phenyl aziridine aldehyde (1) (Table 1.2), and leucine

aziridine aldehyde (4) (Table 1.3) on a very small scale (0.05 mmol). The presence of the

desired products was confirmed with ESI-MS and crude 1H NMR.

As seen in Table 1.2, results were not very promising when using phenyl aziridine aldehyde (1).

A total of six aldehydes were screened – four had no reaction occur at all (Entries 3 – 6), and

only one gave the desired product (Entry 1).

Table 1.2 Results of the synthesis of mixed adducts with phenyl aziridine aldehyde in acetonitrilea

8

Entry Aldehyde Resultb

1

Desired product observed

2 Me H

O

13c

No desired product observed

3 H H

O

14c

No reaction

4 H

O

15

No reaction

5 H

O

16

No reaction

6

No reaction

a Unless specified otherwise, reactions were performed at room temperature using 3.0

equivalents of aldehyde, 1.0 equivalent of aziridine aldehyde dimer, and 0.2 equivalents each

of pyrrolidine and benzoic acid in acetonitrile (0.1 M). b As observed by ESI-MS and crude

1H NMR.

c An excess (> 10.0 equivalents) of aldehyde were added.

A total of four aldehydes were reacted with leucine aziridine aldehyde (4). Unfortunately only

two of the reactions gave the desired product (Entries 1 and 2), with the other two reactions

going to completion, but giving undesired products (Entries 3 and 4) (Table 1.3).

9

Table 1.3 Results of the synthesis of mixed adducts with leucine aziridine aldehyde in acetonitrilea

Entry Aldehyde Resultb

1

Desired product observed

2 H H

O

14c

Desired product observed

3 Me H

O

13c

No desired product observed

4 H

O

16

No desired product observed

a Unless specified otherwise, reactions were performed at room temperature using 3.0

equivalents of aldehyde, 1.0 equivalent of aziridine aldehyde dimer, and 0.2 equivalents each

of pyrrolidine and benzoic acid in acetonitrile (0.1 M). b As observed by ESI-MS and crude

1H NMR.

c An excess (> 10.0 equivalents) of aldehyde were added.

Due to the lack of desired results it was necessary to make some changes to the reaction

conditions. The first condition that was changed was the solvent. The crossover experiments

done by R. Hili showed that the aziridine aldehyde dimers dissociate either into monomers or

into half-open dimers (Figure 1.1) when they are in the solvent TFE,8 so this was the first

solvent which was tried. Two aldehydes (Figure 1.6) were screened with phenyl (1) and leucine

10

(4) aziridine aldehydes, and it was found that all of the starting material was consumed to give

the desired products.

Figure 1.6 The two aldehydes which were reacted with phenyl and leucine aziridine aldehydes

Once it was proven that the reaction could reach completion in TFE within a reasonable time

frame (16 hours), it was important to determine the necessity of the catalysts used in the

reaction. A reaction which was known to give the mixed aziridine aldehyde adduct (20) was

done under varying conditions (Table 1.4).

Table 1.4 Results of the catalytic experiment between phenyl aziridine aldehyde and hydrocinnamaldehydea

11

Entry Catalytic Condition Starting Material

Consumed?

Desired Product

Observed?

1 pyrrolidine (20 mol %) and

benzoic acid (20 mol %) Yes Yes

2 pyrrolidine (20 mol %) Yes Yes

3 benzoic acid (20 mol %) Yes Yes

4 none Yes Yes

a Unless specified otherwise, reactions were performed at room temperature using 3.0 equivalents of

hydrocinnamaldehyde, 1.0 equivalent of phenyl aziridine aldehyde, and 0.2 equivalents each of

pyrrolidine and benzoic acid in TFE (0.1 M).

As seen in Table 1.4 the reaction went to completion without the addition of any catalysts.

These results were then confirmed using leucine aziridine aldehyde (4), where the desired

product was also observed without the addition of pyrrolidine or benzoic acid.

With a new set of reaction conditions, it was necessary to screen aldehydes with the aziridine

aldehydes, and build a reaction scope. Phenyl (1) and 4-phenylbutene (5) aziridine aldehydes

were each reacted with seven aldehydes (Tables 1.5 and 1.6 respectively).

The scope of mixed aziridine aldehyde adducts synthesized from phenyl aziridine aldehyde (1)

can be seen in Table 1.5. Unfortunately for the reactions with the phenyl aziridine aldehyde the

desired product was only observed in one of the reactions (Entry 1).

Table 1.5 Scope of mixed aziridine aldehyde adduct synthesized from phenyl aziridine aldehydea

12

Entry Aldehyde Mixed Aziridine

Aldehyde Adduct d.r.

b

Isolated

Yieldc

1

NO

OH

20

3:1 45 %

2 H H

O

14d

- 0 %

3 Me H

O

13d

- 0 %

4 H

O

15

NO

OH27

- 0 %

5 H

O

H

O23

- 0 %

13

6 H

O

O

HO

24

- 0 %

7

NO

OH30

- 0 %

a Unless specified otherwise, reactions were performed at room temperature using 3.0

equivalents of aldehyde, and 1.0 equivalent of aziridine aldehyde in TFE (0.1 M). b Determined

from crude 1H NMR.

c Isolated yield of the major diastereomer.

d 10.0 equivalents of aldehyde

were added.

The reaction scope was expanded with 4-phenylbutene aziridine aldehyde (5) to give three

mixed aziridine aldehyde adducts. Entries 1 – 3 show three new mixed aziridine aldehyde

adducts while Entries 4 – 7 show the reactions which failed to give the desired product (Table

1.6).

Table 1.6 Scope of mixed aziridine aldehyde adduct synthesized from 4-phenylbutene aziridine aldehydea

14

Entry Aldehyde Mixed Aziridine

Aldehyde Adduct d.r.

b

Isolated

Yieldc

1

NO

OH32

2.5:1 39 %

2 H H

O

14d

- 80 %

3 Me H

O

13d

5:1 23 %

4 H

O

15

- 0 %

5 H

O

H

O23

- 0 %

15

6 H

O

O

HO

24

- 0 %

7

NO

OH

38

- 0 %

a Unless specified otherwise, reactions were performed at room temperature using 3.0

equivalents of aldehyde, and 1.0 equivalent of aziridine aldehyde in TFE (0.1 M). b Determined

from crude 1H NMR.

c Isolated yield of the major diastereomer.

d 10.0 equivalents of aldehyde

were added.

Entry 1 from Table 1.6 was also done using 2.2 equivalents of hydrocinnamaldehyde (12)

instead of 3.0 equivalents. It was found that the reaction went to 100 % conversion after stirring

at room temperature overnight. This indicates that there is a driving force pushing the 4-

phenylbutene aziridine aldehyde (5) to be converted into the mixed aziridine aldehyde adduct

(32). It is believed that the driving force of the reaction is the solvent, TFE. This is because it is

thought that TFE breaks the hydrogen bond in the aziridine aldehyde dimer (see Figure 1.2) in

solution,6b

thus forming an intermediate. If the energy barrier going to the product is lower than

the energy barrier going back to the starting material then the mixed aziridine aldehyde adduct

product will be formed. Since there is an excess of TFE in the reaction it causes the equilibrium

between the dimeric species and the intermediate to be pushed heavily to the intermediate. A

proposed energy diagram showing this conversion can be seen in Figure 1.7.

16

Figure 1.7 Proposed energy diagram for the synthesis of mixed aziridine aldehyde adducts

A fifth mixed aziridine aldehyde adduct was synthesized using leucine aziridine aldehyde (4)

and hydrocinnamaldehyde (12) (Scheme 1.4). The resulting product (39) was obtained in a

respectable 67 % yield as can be seen below.

Scheme 1.4 Synthesis of compound 39 from leucine aziridine aldehyde (4) and hydrocinnamaldehyde (12)

The stereochemistry of the major isolated diastereomer of the mixed aziridine aldehyde adducts

was determined using the nuclear Overhauser effect (NOE). The interactions between protons

can be seen in below in Figure 1.8.

17

Figure 1.8 NOE between protons in the mixed aziridine aldehyde adducts

As shown above, you can see there is a 1.4 % NOE interaction between HA and HB, and a 1.5 %

NOE interaction between HC and HD. These interactions were determined by selectively

irradiating HA and HC and seeing the through space, or NOE, interactions with HB and HD

respectively.

2.2.2 Attempt at the applications of mixed aziridine aldehyde adducts

2.2.2.1 Nucelophilic ring opening of the aziridine

With a scope of five mixed aziridine aldehydes adducts in hand, their reactivity and applications

were explored. The first application which was explored was the nucelophilic ring opening of

the aziridine. Typical nucleophiles used include thiols,10

azides,11

alcohols, amines and

halogens.10a

However, results published from the Yudin group have shown that an ideal

nucleophile to use is thiobenzoic acid.12

The following reaction was screened in three different solvents: dichloromethane, methanol, and

acetonitrile (Scheme 1.5). The reaction was set up by mixing equal equivalents of a mixed

aziridine aldehyde adduct (33) with thiobenzoic acid (40), which was allowed to stir at room

temperature. After four days no reaction had occurred.

18

Scheme 1.5 Nucleophilic ring opening of compound 33

Research done in the Yudin group has shown that when the aziridine ring was opened with

thiobenzoic acid, the optimal amount of thiobenzoic acid to be added was 1.0 equivalent. The

formation of the desired product was inhibited with the addition of more than 1.0 equivalent of

thiobenzoic acid.13

Despite this, it was hopeful that the addition of 1.5 equivalents of

thiobenzoic acid would cause a reaction to occur. Unfortunately neither of the desired products

were observed in any of the three solvents (methanol, dichloromethane and acetonitrile).

Another mixed aziridine aldehyde adduct (20) was subjected to the same reaction conditions as

was shown in Scheme 1.5. Compound 20 was chosen because it was derived from phenyl

aziridine aldehyde which is known to undergo nucelophilic ring opening of the aziridine with

1.0 equivalent of thiobenzoic acid.13

Scheme 1.6 Nucleophilic ring opening of compound 20

Unfortunately after stirring for 19 hours in methanol, dichloromethane or acetonitrile neither of

the desired products were observed in Scheme 1.6.

19

It is still uncertain as to why the aziridine ring would not open upon the addition of thiobenzoic

acid, however a possibility is that the aziridine is not as active when it is in the mixed aziridine

aldehyde adduct.

2.2.2.2 Crossover experiments of mixed aziridine aldehyde adducts

The second experiment done with the mixed aziridine aldehyde adducts was a crossover

experiment. The same procedure that was used in Scheme 1.2 with the aziridine aldehydes was

used here with the mixed aziridine aldehyde adducts (Scheme 1.7).

Scheme 1.7 Crossover reaction of two mixed aziridine aldehyde adducts and the five possible crossover products

The reaction was carried out with equal equivalents of each mixed aziridine aldehyde adduct in

seven different solvents (acetonitrile (Figure 1.9), dichloromethane, 2,2,2-trifluoroethanol,

methanol, toluene, tetrahydrofuran, and ethyl acetate (Figure 1.10)). Unlike the crossover

experiment of the two aziridine aldehydes (Scheme 1.2), where the crossover products were

only observed in two solvents, the crossover products were observed in six out of the seven

solvents screened. Ethyl acetate was the only solvent where none of the crossover products were

detected by ESI-MS. It should be noted, that compound 32 was not detected in the crossover

reaction (Scheme 1.7) in acetonitrile.

20

Figure 1.9 ESI-MS spectrum for mixed aziridine aldehyde adduct crossover experiment in acetonitrile

Figure 1.10 ESI-MS spectrum for mixed aziridine aldehyde adduct crossover experiment in ethyl acetate

From this crossover experiment it appears that the mixed aziridine aldehyde was able to

dissociate easier than the aziridine aldehyde dimers in solution. This is likely due to the lack of

the hydrogen bonding (Figure 1.2) which was observed in the aziridine aldehyde dimers.6a

The

ability of the mixed aziridine aldehyde adducts to dissociate in a range of solvents is promising.

Some reactions involving the aziridine aldehydes wouldn’t proceed to completion,9 however

42 33

4

39 41

5

39

21

they might if a mixed aziridine aldehyde adduct was used instead. These reactions will need to

be explored further by another student in the Yudin group.

2.2 Synthesis of N-H aziridines containing a 1,3-dicarbonyl functionality

2.2.1 Development of N-H aziridines containing a 1,3-dicarbonyl functionality

The discovery of N-H aziridines containing a 1,3-dicarbonyl functionality came about from

reacting phenyl aziridine aldehyde (1) with ethyl diazoacetate (43) to give compound 44

(Scheme 1.8).

Scheme 1.8 Addition of ethyl diazoacetate (43) to phenyl aziridine aldehyde (1)

After allowing the reaction to stir at room temperature for a week, and using stronger bases than

1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), such as n-butyllithium (n-BuLi) and lithium

diisopropyl amide (LDA), the starting material was never completely consumed. Stopping the

reaction after 2.5 days gave the best yield, however the diastereomeric ratio (d.r.) was poor at

1:1. Despite this low d.r. further transformations were explored. As diazo groups are commonly

used to make carbenoid reagents,14

this is what was attempted. In this case, a carbenoid

intermediate was formed which then underwent an intramolecular reaction to give a N-H

aziridine containing a 1,3-ketoester functionality (45) (Scheme 1.9).

Scheme 1.9 Synthesis of an N-H aziridine containing a 1,3-ketoester functionality

22

With compound 45 showing potential to be a synthetically rich compound, a shorter synthesis

was sought after. The literature revealed a shorter synthesis15

which involved using a precursor

to the phenyl aziridine aldehyde (1), phenyl aziridine ester (46)6a

in a Claisen type reaction with

ethyl acetate (47) to give compound 45 (Scheme 1.10).

Scheme 1.10 Alternate synthesis of compound 45

This synthesis of compound 45 was a vast improvement over the previous synthesis from phenyl

aziridine aldehyde (1). It required two fewer overall steps and resulted in a 30 % overall yield,

which was much better than the 14 % overall yield which was achieved in the synthesis shown

in Scheme 1.9.

Aside from the typical methods used to confirm the structure of a compound: 1H NMR,

13C

NMR, and ESI-MS, a deuterium exchange experiment was also done. The signal on the 1H

NMR spectra which was believed to belong to the two protons alpha to the carbonyl groups

should disappear upon addition of deuterium oxide and deuterated pyridine. This in fact was

observed, thus confirming the structure of compound 45.

An attempt to expand the scope of this reaction (Scheme 1.10) was unsuccessful. A total of two

aldehydes and numerous conditions were tried, however, no desired product was observed in

any of the reactions. The first aldehyde used to expand the scope was acetone (48). Initially the

base LDA was used, however, this resulted in the starting material decomposing, and no desired

product being detected. Hoping for better results, the base lithium bis(trimethylsilyl)amide

(LiHMDS) was used. Unfortunately all of the starting material decomposed and none of the

desired product was observed with this base either (Scheme 1.11).

23

Scheme 1.11 Initial attempts to expand the scope of 1,3-dicarbonyl compounds

An assumption was made that reactivity issues might be occurring because acetone has two sets

of alpha protons which could be de-protonated. In an attempt to address this issue, acetophenone

(50) was used in place of acetone (48) (Scheme 1.12).

Scheme 1.12 Attempts to expand the scope of the 1,3-dicarbonyl compounds with acetophenone (50)

In total eight conditions were tried, and in all of them the starting material decomposed with

none of the desired product being observed. A summary of the conditions can be found in Table

1.7.

Table 1.7 Summary of conditions tried to make compound 51a

Entry Base Temperature Solventb

1 LDA -78 °C THF

2 t-BuOK -78 °C THF

3 KHMDS -78 °C THF

4 LiHMDS -78 °C THF

5 NaH -78 °C THF

24

6 n-BuLi,

HMPAc

0 °C THF

7 NaOMe rt THF

8 NaH rt toluene

a In all cases 3.0 equivalents of base was used unless otherwise

specified, b

Concentration of solvent was 0.2 M and all reactions

were stopped after 2 hours, c 6.0 equivalents of base was used

It is still unknown as to why the desired products were not formed in Schemes 1.11 and 1.12

despite all of the conditions which were tried. This will need to be investigated further by

another student in the Yudin group.

An analogue to compound 45 which was successfully synthesized was an N-H aziridine

containing a 1,3-ketoester with a diazo functionality (52) as shown in Scheme 1.13.

Scheme 1.13 Synthesis of an analogue of compound 45

The yield of the above reaction was quite low at 23 %, and although there was not enough time

to make a carbenoid reagent out of this compound, it is an idea that should be tried by future

students in the Yudin group.

2.2.2 Attempt at the applications of N-H aziridine compounds containing a 1,3-

dicarbonyl

2.2.2.1 Michael Reaction

In an attempt to incorporate the nitrogen into the 1,3-dicarbonyl functionality in the form of a

bicyclic compound, compound 45 was reacted with acrolein (53) (Scheme 1.14). Upon

searching the literature the six most promising conditions were tried16

as shown in Table 1.8.

25

Scheme 1.14 Michael reaction between compound 45 and acrolein (53)

Table 1.8 Conditions tried to make compounds 54 and 55a

Entry Reagent(s) Temperature Solventb

1 Aluminum Oxide 0 °C to rt CHCl3

2 Pyrrolidine, benzoic acid rt MeCN

3 Cerium (III) chloride,

sodium iodide rt CHCl

3

4 Cesium carbonate rt CHCl3

5 Potassium t-butoxide rt THF

6 Potassium carbonate,

pyrrolidine rt CHCl

3

a Reactions were performed using 1.0 equivalent of reagent(s) and 1.5 equivalents of

acrolein at the temperature indicated. b The concentration of the solvent was 0.02 M.

Unfortunately with all of the conditions tried all that was observed was decomposed starting

material, and neither of the desired products. Background reactions showed no reactions or

decomposition after stirring for 24 hours, so a reactive species was being formed upon addition

of all reactants and reagents.

Presuming that acrolein was too reactive of a compound, other enones were tried in the Michael

reaction in place of acrolein (Figure 1.11).

26

Figure 1.11 Three enones tried in the Michael reaction with compound 45

The conditions used in these reactions were the same as those in Entry 2 of Table 1.8. However,

after allowing the reaction to stir at room temperature for 24 hours no reaction had occurred, so

the reaction was heated to 50 °C where it stirred for 18 hours. Unfortunately these enones were

not as reactive as acrolein and no reaction was observed after heating.

2.2.2.2 Synthesis of N-vinyl aziridines

Another method which was hypothesized to incorporate the aziridine nitrogen with the 1,3-

dicarbonyl was to add a vinyl group to the nitrogen,17

and subsequently cyclize to give a seven

membered ring. The proposed synthesis can be seen below in Scheme 1.15.

Scheme 1.15 Proposed synthesis of a seven membered ring via an N-vinyl aziridine18

Unfortunately it was not possible to get the first step, the vinylation of the nitrogen, to produce

the desired product (60). A new compound was made in this step which co-eluted with pyridine

no matter what method of separation was tried. Crude 1H NMR showed no hints as to what the

new compound was, however it did confirm that it was not the desired N-vinyl product.

Referring to N. Afagh’s thesis,17

and considering the Claisen type reaction which was used to

synthesize 45 a new method was considered in the synthesis of 60 (Scheme 1.16). This first

reaction was very clean and resulted in the desired product (62) in a moderate 63 % yield.

27

Scheme 1.16 The first step towards the synthesis of an N-vinyl aziridine containing a 1,3-ketoester functionality

(60)

The second step of the synthesis was the hard one (Scheme 1.17).

Scheme 1.17 Attempted synthesis of compound 60

Despite N-vinyl aziridine compounds being stable under basic conditions,17

it was found that the

starting material decomposed under the reaction conditions within the first 30 minutes of the

reaction. Due to this result it was evident that the desired seven membered ring (61) would not

be synthesized during my time in the Yudin group.

3 Conclusion

In conclusion it has been shown that unprotected N-H aziridine aldehydes can undergo

transformations without the need of protecting groups. Mass spectrometry experiments have

shown that in methanol and 2,2,2-trifluoroethanol two aziridine aldehyde dimers can dissociate

and re-dimerize with a different aziridine aldehyde monomer. Mixed aziridine aldehyde adducts

can be synthesized in moderate to high yields. Despite their promise, it appears that they will not

undergo nucelophilic ring opening of the aziridine ring. They do however; produce crossover

products in solvents of ranging polarity. Although there was trouble expanding the scope of N-H

aziridine compounds containing a 1,3-dicarbonyl functionality, a new class of compounds, N-H

aziridine compounds with a 1,3-ketoester functionality has been developed. As with the mixed

28

aziridine aldehyde adducts the applications of these 1,3-dicarbonyl compounds was proven to be

dismal.

4 Experimental Procedures

General Information: Anhydrous toluene and dichloromethane were purchased and used as

received. Tetrahydrofuran (THF) was distilled from sodium benzophenone ketyl under nitrogen.

All other solvents including 2,2,2,-trifluoroethanol (TFE) were of reagent grade quality.

Chromatography: Flash column chromatography was carried out using Silicycle 230-400 mesh

silica gel and thin-layer chromatography (TLC) was performed on EMD pre-coated glass

backed TLC plates (TLC Silica Gel 60 F254, 0.25 mm) and visualized using a UV lamp (254 nm)

and potassium permanganate stain (KMnO4).

Nuclear magnetic resonance spectra: 1H NMR and

13C NMR spectra were recorded on Varian

Mercury 400 MHz spectrometers. 1H NMR spectra were referenced to TMS (0 ppm) and

13C

NMR spectra were referenced to CDCl3 (77.23 ppm). Peak multiplicities are designated by the

following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, doublet of

doublets; td, triplet of doublets; tdt, doublet of triplet of doublets.

Mass Spectroscopy: Low resolution mass spectra (ESI) were obtained on a Hewlett Packard

Series 1100MSD mass spectrometer at 60 eV, 70 eV and 100 eV.

4.1 Protocols for unprotected aziridine aldehydes

(2R,4R,5S,6R)-6-phenyl-2-((2S,3R)-3-phenylaziridin-2-yl)-3-oxa-1-azabicyclo[3.1.0]hexan-

4-ol (1):

Prepared according to the literature procedure.6a

29

(2S,4S,5R,6S)-6-isobutyl-2-((2R,3S)-3-isobutylaziridin-2-yl)-3-oxa-1-

azabicyclo[3.1.0]hexan-4-ol (4):

Prepared according to the literature procedure.6b

(2R,4R,5S,6R)-6-phenethyl-2-((2S,3R)-3-phenethylaziridin-2-yl)-3-oxa-1-

azabicyclo[3.1.0]hexan-4-ol (5):

Prepared according to the literature procedure.6d

4.2 Protocols for mixed aziridine aldehyde adducts

NO

OH

(5S,6R)-2-phenethyl-6-phenyl-3-oxa-1-azabicyclo[3.1.0]hexan-4-ol (20):

To a solution of phenyl dimer (200 mg, 0.68 mmol) in 2,2,2-trifluoroethanol (TFE) (6.8 mL)

was added hydrocinnamaldehyde (0.27 mL, 2.04 mmol) under N2 at room temperature. The

reaction was left to stir at room temperature for 19 hours at which point it was concentrated to

30

give a brown oil. The crude oil was purified by flash chromatography eluting from a gradient of

hexanes:EtOAc (0 – 15 % EtOAc) to give the title compound as a orange solid (172 mg, 45 %).

Rf = 0.64 (silica; hexanes:EtOAc, 1:1); 1H NMR (400 MHz, CDCl3) δ 7.33 – 7.15 (m, 5H), 5.59

(s, 1H), 5.04 (t, J = 6.2 Hz, 1H), 2.84 – 2.80 (m, 2H), 2.77 (d, J = 2.4 Hz, 1H), 2.63 (d, J = 2.1

Hz, 1H), 2.09 – 1.96 (m, 2H) ppm; 13

C NMR (100 MHz, CDCl3) δ 141.2, 137.4, 127.4, 126.5,

126.0, 96.0, 93.6, 51.4, 36.9, 33.0, 32.1 ppm.

NO

OH

(5S,6R)-2,6-diphenethyl-3-oxa-1-azabicyclo[3.1.0]hexan-4-ol (32):

To a solution of 4-phenylbutene dimer (600 mg, 1.71 mmol) in 2,2,2-trifluoroethanol (TFE) (8.6

mL) was added hydrocinnamaldehyde (0.68 mL, 5.14 mmol) under N2 at room temperature. The

reaction was left to stir at room temperature for 16 hours at which point it was concentrated to

give an orange oil. The crude oil was purified by flash chromatography eluting from a gradient

of hexanes:EtOAc (0 – 80 % EtOAc) to give the title compound as a white solid (414 mg, 39

%). Rf = 0.64 (silica; hexanes:EtOAc, 2:8); 1H NMR (400 MHz, CDCl3) δ 7.31 – 7.16 (m, 10H),

5.37 (s, 1H), 4.86 (t, J = 6.2 Hz, 1H), 3.61 (s, 1H), 2.84 – 2.76 (m, 3H), 2.42 (d, J = 2.2 Hz, 1H),

1.89 – 1.78 (m, 3H), 1.69 – 1.61 (m, 2H) ppm; 13

C NMR (100 MHz, CDCl3) δ 141.3, 141.2,

128.4, 128.4, 128.3, 128.3, 126.3, 126.0, 95.6, 92.9, 48.6, 35.0, 33.6, 33.1, 32.4, 32.1 ppm.

(5S,6R)-6-phenethyl-3-oxa-1-azabicyclo[3.1.0]hexan-4-ol (33):

To a solution of 4-phenylbutene dimer (1.0 g, 1.86 mmol) in 2,2,2-trifluoroethanol (TFE) (16

mL) was added paraformaldehyde (856 mg, 28.6 mmol) under N2 at room temperature. The

31

reaction was left to stir at room temperature for 16 hours at which point it was concentrated to

give an orange/yellow oil. The crude oil was purified by flash chromatography eluting from a

gradient of hexanes:EtOAc (0 – 80 % EtOAc) to give the title compound as a white solid (940

mg, 80 %). Rf = 0.50 (silica; hexanes:EtOAc, 2:8); 1H NMR (400 MHz, CDCl3) δ 7.30 – 7.16

(m, 5H), 5.39 (d, J = 4.5 Hz, 1H), 4.61 (d, J = 5.5 Hz, 1H), 4.45 (d, J = 5.5 Hz, 1H), 3.60 (d, J =

4.5 Hz, 1H), 2.74 (dtd, J = 21.5, 13.8, 7.5 Hz, 2H), 2.43 (d, J = 2.7 Hz, 1H), 1.78 – 1.72 (m, 2H),

1.49 (dt, J = 6.3, 2.7 Hz, 1H) ppm; 13

C NMR (100 MHz, CDCl3) δ 141.5, 128.7, 126.3, 95.4,

84.9, 49.1, 38.7, 33.6, 32.7 ppm.

(5S,6R)-2-methyl-6-phenethyl-3-oxa-1-azabicyclo[3.1.0]hexan-4-ol (34):

To a solution of 4-phenylbutene dimer (600 mg, 1.71 mmol) in 2,2,2-trifluoroethanol (TFE) (8.6

mL) was added acetaldehyde (0.58 mL, 10.3 mmol) under N2 at room temperature. The reaction

was left to stir at room temperature for 16 hours at which point it was concentrated to give an

orange oil. The crude oil was purified by flash chromatography eluting from a gradient of

hexanes:EtOAc (0 – 80 % EtOAc) to give the title compound as a light yellow oil (175 mg, 23

%). Rf = 0.56 (silica; hexanes:EtOAc, 2:8); 1H NMR (400 MHz, CDCl3) δ 7.29 – 7.15 (m, 5H),

5.34 (s, 1H), 5.00 (q, J = 5.6 Hz, 1H), 2.81 – 2.75 (m, 1H), 2.70 – 2.62 (m, 1H), 2.40 (d, J = 2.4

Hz, 1H), 1.84 – 1.79 (m, 1H), 1.67 – 1.58 (m, 2H), 1.29 (d, J = 5.6 Hz, 3H) ppm; 13

C NMR (100

MHz, CDCl3) δ 141.4, 128.7, 128.6, 126.2, 96.0, 89.7, 49.1, 34.9, 33.8, 32.6, 16.8 ppm.

32

NO

OH

(5R,6S)-6-isobutyl-2-phenethyl-3-oxa-1-azabicyclo[3.1.0]hexan-4-ol (39)

To a solution of leucine dimer (100 mg, 0.39 mmol) in 2,2,2-trifluoroethanol (TFE) (4.0 mL)

was added hydrocinnamaldehyde (0.16 mL, 1.18 mmol) under N2 at room temperature. The

reaction was left to stir at room temperature for 19 hours at which point it was concentrated to

give a yellow oil. The crude oil was purified by flash chromatography eluting from a gradient of

hexanes:EtOAc (0 – 80 % EtOAc) to give the title compound as a colourless oil (136 mg, 67 %).

Rf = 0.68 (silica; hexanes:EtOAc, 2:8); 1H NMR (400 MHz, CDCl3) δ 7.31 – 7.28 (m, 2H), 7.23

– 7.18 (m, 3H), 5.44 (s, 1H), 4.89 (t, J = 6.4 Hz, 1H), 2.83 – 2.77 (m, 2H), 2.44 (d, J = 2.6 Hz,

1H), 1.96 – 1.87 (m, 2H), 1.74 (dq, J = 13.6, 6.9 Hz, 1H), 1.64 (dt, J = 6.4, 2.6 Hz, 1H), 1.36 –

1.24 (m, 2H), 0.95 (dd, J = 13.6, 6.9 Hz, 6H) ppm

4.3 Protocols for 1,3-dicarbonyl compounds

ethyl 2-diazo-3-hydroxy-3-((2S,3R)-3-phenylaziridin-2-yl)propanoate (44):

To a solution of phenyl dimer (100 mg, 0.34 mmol) in MeCN (2 mL) was added

ethyldiazoacetate (0.14 mL, 1.36 mmol) and DBU (0.05 mL, 0.34 mmol). The reaction was

allowed to stir at room temperature for 2.5 days at which point the reaction was quenched with a

saturated aqueous solution of NaHCO3 (4 mL) and extracted into Et2O (3 x 5 mL). The organic

layer was dried over MgSO4, filtered and concentrated to give a dark orange oil. The crude oil

was purified by flash chromatography eluting from a gradient of hexanes:EtOAc (0 – 60 %

EtOAc) to give the title compound as a yellow oil (105 mg, 59 %). Rf = 0.20 (silica;

33

hexanes:EtOAc, 1:1); 1H NMR (300 MHz, CDCl3) δ 7.35 – 7.18 (m, 5H), 4.95 (d, J = 2.7 Hz,

1H), 4.25 (q, J = 7.1 Hz, 2H), 3.10 (d, J = 2.7 Hz, 1H), 2.50 (s, 1H), 1.28 (t, J = 7.1 Hz, 3H)

ppm; 13

C NMR (100 MHz, CDCl3) δ 166.4, 138.9, 128.9, 127.7, 125.9, 65.2, 64.1, 61.4, 43.0,

42.3, 14.8 ppm.

(2S,3R)-ethyl 3-phenylaziridine-2-carboxylate (46):

Prepared according to the literature procedure.6a

ethyl 3-oxo-3-((2S,3R)-3-phenylaziridin-2-yl)propanoate (45):

To a solution of LDA (2.0 M, 23.5 mL, 47.06 mmol) in anhydrous THF (50 mL) under N2 at -

78 °C was added ethyl diazoacetate (2.3 mL, 23.53 mmol). The reaction was left to stir at -78 °C

for 45 minutes, at which point a solution of phenyl aziridine ester (3.0 g, 15.69 mmol) in

anhydrous THF (28.5 mL) was added slowly over 30 minutes. The reaction was then allowed to

warm up to 0 °C where it stirred for 3.5 hours. The reaction was quenched with a saturated

aqueous solution of NH4Cl (50 mL). The two layers were separated and the aqueous layer was

washed with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (75

mL), dried over MgSO4, filtered and concentrated to give an orange/brown oil. The crude oil

was purified by flash chromatography eluting from a gradient of hexanes:EtOAc (0 – 20 %

EtOAc) to give the title compound as an orange oil (1.30 g, 49 %). Rf = 0.69 (silica;

hexanes:EtOAc, 1:1); 1H NMR (400 MHz, CDCl3) δ 7.35 – 7.27 (m, 5H), 4.19 (q, J = 7.1 Hz,

2H), 3.66 (d, J = 1.4 Hz, 2H), 3.14 (dd, J = 9.5, 2.2 Hz, 1H), 2.94 (dd, J = 8.0, 2.2 Hz, 1H), 2.39

34

(t, J = 8.0 Hz, 1H), 1.23 (t, J = 7.1 Hz, 3H) ppm; 13

C NMR (100 MHz, CDCl3) δ 199.2, 166.3,

137.8, 128.5, 128.0, 126.1, 61.7, 48.8, 46.6, 44.0, 14.0 ppm.

ethyl 2-diazo-3-oxo-3-((2S,3R)-3-phenylaziridin-2-yl)propanoate (52):

To a solution of LDA (2.0 M, 0.78 mL, 1.56 mmol) in anhydrous THF (1.6 mL) under N2 at -78

°C was added ethyl diazoacetate (82 µL, 0.78 mmol). The reaction was left to stir at -78 °C for

30 minutes, at which point a solution of phenyl aziridine ester (100 mg, 0.52 mmol) in

anhydrous THF (1.0 mL) was added slowly over 15 minutes. The reaction was left to stir at -78

°C where is stirred for 5 hours. The reaction was quenched with a saturated aqueous solution of

NH4Cl (2 mL). The two layers were separated and the aqueous layer was washed with EtOAc (3

x 1 mL). The combined organic layers were washed with brine (1 mL), dried over MgSO4,

filtered and concentrated to give a brown oil. The crude oil was purified by flash

chromatography eluting from a gradient of hexanes:EtOAc (0 – 40 % EtOAc) to give the title

compound as a yellow oil (31 mg, 23 %). Rf = 0.26 (silica; hexanes:EtOAc, 8:2); 1H NMR (400

MHz, CDCl3) δ 7.32 – 7.23 (m, 5H), 4.25 (q, J = 7.1 Hz, 2H), 3.87 (d, J = 7.2 Hz, 1H), 3.16(d, J

= 7.2 Hz, 1H), 2.55 (t, J = 7.2 Hz, 1H), 1.21 (t, J = 7.1 Hz, 3H) ppm; 13

C NMR (100 MHz,

CDCl3) δ 188.6, 161.2, 138.3, 128.63, 128.0, 126.6, 62.1, 43.6, 14.4 ppm.

(2S,3R)-ethyl 3-phenyl-1-vinylaziridine-2-carboxylate (62):

Prepared according to the literature procedure.17

35

5 References

(1) Izawa, K.; Onishi, T. Chem. Rev. 2006, 106, 2811.

(2) (a) Wipf, P.; Fritch, P. C.; J. Org. Chem. 1994, 59, 4875. (b) Righi, G.; Ciambrone, S.

Tetrahedron Lett. 2004, 45, 2103. (c) Arai, H.; Sugaya, N.; Sasaki, N; Makino, K.; Lectard, S.;

Hamada, Y. Tetrahedron Lett. 2009, 50, 3329. (d) Wu, Y-C.; Zhu, J. Org. Lett. 2009, 11, 5558.

(3) Righi, G.; Ciambrone, S. Tetrahedron Lett. 2004, 45, 2103.

(4) (a) Arai, H.; Sugaya, N.; Sasaki, N; Makino, K.; Lectard, S.; Hamada, Y. Tetrahedron Lett.

2009, 50, 3329. (b) Wipf, P.; Fritch, P. C.; J. Org. Chem. 1994, 59, 4875.

(5) Wu, Y-C.; Zhu, J. Org. Lett. 2009, 11, 5558.

(6) (a) Hili, R; Yudin, A. K. J. Am. Chem. Soc. 2006, 128, 14772. (b) Hili, R.; Yudin, A. K. J.

Am. Chem. Soc. 2009, 131, 16404. (c) Hili, R.; Rai, V.; Yudin, A. K. J. Am. Chem. Soc. 2010,

132, 2889. (d) He, Z.; Yudin, A. K. Angew. Chem. Int. Ed. 2010, 49, 1607.

(7) (a) Hoffmann, R. W. Synthesis 2006, 21, 3531. (b) Thayer, A. M., Chemical & Engineering

News 2009, 87, 13-22.

(8) Hili, R. M. Unprotected Amino Aldehydes in Organic Synthesis. Ph.D. Thesis, University of

Toronto, Toronto, Ontario, December 2009.

(9) Hili, R. Unpublished results.

(10) (a) Zygmunt, J. Tetrahedron 1985, 41, 4979. (b) Hsu, J.-L.; Fang, J.-M. J. Org. Chem.

2001, 66, 8573. (c) Assem, N.; Natarajan, A.; Yudin, A. K. J. Am. Chem. Soc. 2010, 132, 10986.

(11) Cimarelli, C.; Fratoni, D.; Palmieri, G. Tetrahedron: Asymmetry 2009, 20, 2234.

(12) Li, X.; Yudin, A. K. J. Am. Chem. Soc. 2007, 129, 14152.

36

(13) Assem, N. Unpublished results.

(14) (a) Brookhart, M.; Studabaker, W. B. Chem. Rev. 1987, 87, 411. (b) Davies, J. R.; Kane, P.

D.; Moody, C. J. Tetrahedron 2004, 60, 3967.

(15) Park, C. S.; Choi, H. G.; Lee, W. K.; Ha, H.-J. Tetrahedron: Asymmetry 2000, 11, 3283.

(16) (a) Ranu, B. C.; Bhar, S. Tetrahedron 1992, 48, 1327. (b) Bartoli, G.; Bosco, M.; Bellucci,

M. C.; Marcantoni, E.; Sambri, L.; Torregiani, E. Eur. J. Org. Chem. 1999, 1999, 617. (c) Rios,

R.; Vesely, J.; Sundén, H.; Ibrahem, I.; Zhao, G.-L.; Córdova, A. Tetrahedron Lett. 2007, 48,

5835. (d) Hili, R.; Yudin, A. K. J. Am. Chem. Soc. 2009, 131, 16404.

(17) Afagh, N. A. The Synthesis and Applications of N-Alkenyl Aziridines. M.Sc. Thesis,

University of Toronto, Toronto, Ontario, January 2010.

(18) 2,4,6-trivinylcyclotriboroxane (59) was generously given to me by Mr. Nick Afagh, a

previous M.Sc. student in the Yudin group.

37

Appendix I: 1H,

13C, and NOE NMR Spectra

-2-1012345678910111213f1 (ppm)

-100102030405060708090100110120130140150160170180190200210220f1 (ppm)

38

-101234567891011121314f1 (ppm)

-100102030405060708090100110120130140150160170180190200210220f1 (ppm)

39

-2-101234567891011121314f1 (ppm)

-100102030405060708090100110120130140150160170180190200210220f1 (ppm)

40

-2-1012345678910111213f1 (ppm)

-100102030405060708090100110120130140150160170180190200210220f1 (ppm)

41

-2-1012345678910111213f1 (ppm)

-100102030405060708090100110120130140150160170180190200210220f1 (ppm)

42

-2-101234567891011121314f1 (ppm)

-2-101234567891011121314f1 (ppm)

ON

HB

HA

HC

OH

HD

NO

OH

NOE 1.5 %

43

-1012345678910111213f1 (ppm)

-100102030405060708090100110120130140150160170180190200210220f1 (ppm)

44

-1012345678910111213f1 (ppm)

-100102030405060708090100110120130140150160170180190200210220f1 (ppm)

45

-100102030405060708090100110120130140150160170180190200210220f1 (ppm)

46

-100102030405060708090100110120130140150160170180190200210220f1 (ppm)

47

-1012345678910111213f1 (ppm)

-100102030405060708090100110120130140150160170180190200210220f1 (ppm)

48

-100102030405060708090100110120130140150160170180190200210220f1 (ppm)

HN

OEt

O O

N2

49

-2-101234567891011121314f1 (ppm)

-100102030405060708090100110120130140150160170180190200210220f1 (ppm)