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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.
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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
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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)
47
-1012345678910111213f1 (ppm)
-100102030405060708090100110120130140150160170180190200210220f1 (ppm)