CATALYTIC REARRANGEMENT AND KINETIC RESOLUTION OF N-ACYL

AZIRIDINES

Allen D. Martin

A Thesis Submitted to the

University of North Carolina Wilmington in Partial Fulfillment

of the Requirements for the Degree of

Masters of Science.

Department of Chemistry and Biochemistry

University of North Carolina Wilmington

2011

Approved by

Advisory Committee

John Tyrell Antje Almeida

Pamela Seaton Jeremy Morgan

Chair

Accepted by

Dean, Graduate School

ii

TABLE OF CONTENTS

ABSTRACT ................................................................................................................................... iv

ACKNOWLEDGMENTS………………………………………………………………………. ..v

DEDICATION…………………………………..………………………………………………..vi

LIST OF TABLES ........................................................................................................................ vii

LIST OF FIGURES ..................................................................................................................... viii

CHAPTER 1: PHOSPHINE-CATALZYED REARRANGMENT OF AZIRIDINES ..................1

INTRODUCTION ...........................................................................................................................2

RESULTS AND DISCUSSION ......................................................................................................8

Reaction Optimization .....................................................................................................................8

Substrate Scope ..............................................................................................................................13

Conclusions ....................................................................................................................................19

EXPERIMENTAL .........................................................................................................................20

Representative Procedure for the Synthesis of 2-Methyl Aziridines .............................................21

Representative Procedure for the Synthesis of Substituted 3,5-Dinitrobezoyl Aziridines ............25

Experimental Conditions for the Phosphine Catalyst Screen ........................................................30

Representative Procedure for the Phosphine-Catalyzed Rearrangement .......................................30

Procedure for the Rearrangement of an Enantioenriched Aziridine ..............................................37

CHAPTER 2: KINETIC RESOLUTION OF N-ACYL AZIRIDINES .......................................38

INTRODUCTION .........................................................................................................................39

RESULTS AND DISCUSSION ....................................................................................................43

Substrate Scope ..............................................................................................................................51

Conclusions ....................................................................................................................................53

iii

EXPERIMENTAL .........................................................................................................................53

HPLC Methodology .......................................................................................................................53

Reaction Optimization ...................................................................................................................54

Experimental Conditions of Isolated Yields ..................................................................................55 54

REFERENCES ..............................................................................................................................57

APPENDIX ....................................................................................................................................60

iv

ABSTRACT

Aziridines are three-membered nitrogen-containing heterocycles that exhibit extensive

reactivity because of the strain inherent in the ring. Aziridines have found uses as intermediates

in the synthesis of bioactive molecules. The aziridine moiety is also found in a number of

naturally occurring compounds. One common transformation of aziridines is to oxazolines via a

nucleophile-catalyzed pathway. Oxazolines, like aziridines, have found a great deal of use in

organic synthesis as well as appearing in natural molecules. The focus of our research is to

develop a novel nucleophile-catalyzed rearrangement of aziridines to oxazolines. Phosphines

were chosen as catalysts for this reaction as it is known that they can open aziridine rings. A

variety of phosphines were explored and standard reaction conditions were generated for this

new synthesis of oxazolines. There has been an increased interest in the synthesis of bio-active

organic compounds that are of a single enantiomer. Many of these compounds contain some

type of carbon–nitrogen bond. Aziridines possess two carbon–nitrogen bonds that are reactive as

well as a chiral carbon. The second focus of our research to explore the kinetic resolution of a

variety of substituted N-acyl aziridines to form useful enantioenriched aziridines.

v

ACKNOWLEDGMENTS

I would like to thank my parents for always encouraging me to chase my dreams and

fostering my love of chemistry with countless chemistry sets. Their relentless support, even

when I thought it was pointless means more to me than they will ever know. I am indebted to

my grandmother, Norma, without her years of love and support this would have never come to

fruition.

I am very appreciative to my advisor, Dr. Jeremy Morgan, for his support and guidance

through this entire process. He was my advisor, my mentor and now I’m proud to call him my

friend.

Finally I would like to thank my committee for their time and guidance through my time

at the university.

vi

DEDICATION

I would like to dedicate this thesis to my wife, Julie. Without her unconditional love and

support this work would have never been possible.

vii

LIST OF TABLES

Table Page Page

1. Phosphine selection .....................................................................................................................9

2. Data from 2-(Di-tert-butylphosphino) biphenyl and X-PHOS .................................................13

3. Exploration of various protecting groups .................................................................................15

4. Substrate scope for the phosphine-catalyzed rearrangement ....................................................17

5. Kinetic resolution initial experimental results ..........................................................................44

6. Experimental results long chain substituted aziridine ..............................................................46

7. Experimental results tert-butyl aziridine ...................................................................................47

8. Experimental results O-benzyl aziridine ...................................................................................48

9. Experimental results isopropyl substituted aziridine ................................................................49

10. Experimental results methyl aziridine ....................................................................................50

11. Experimental results long chain alkene substituted aziridine .................................................51

12. Experimental isolated results for isopropyl substituted aziridine ...........................................51

13. Experimental isolated results for long chain alkene substituted aziridine ..............................52

viii

\

LIST OF FIGURES

Figure Page

1. Various aziridine transformations ...............................................................................................3

2. Biologically active aziridine containing compounds ..................................................................3

3. Oxazolidine, oxazoline and oxazole ...........................................................................................4

4. Ascidiacyclamide structure .........................................................................................................4

5. Privileged ligands........................................................................................................................5

6. Aziridine rearrangement in the presence of iodide ion ...............................................................6

7. Aziridine rearrangement in presence of iodide or thiocyanate ion .............................................6

8. Aziridine opening via phosphine catalysis .................................................................................7

9. Phosphine-catalyzed rearrangement ...........................................................................................7

10. Phosphines resulting in little or no conversion to product ......................................................11

11. Phosphines resulting in highest conversion to product ...........................................................12

12. Rearrangement of enantiopure aziridine .................................................................................18

13. Proposed catalytic cycle for the rearrangement ......................................................................19

14. Kinetic resolution of two enantiomers ....................................................................................39

15. Jacobsen hydrolytic kinetic resolution ....................................................................................40

16. Palladium catalyst ...................................................................................................................41

17. Pd-catalyzed asymmetric alcoholysis .....................................................................................41

18. Aziridine opening by borates ..................................................................................................42

19. Borate synthesis ......................................................................................................................42

20. HPLC of racemic aziridine (left) and enantioenriched (right) ................................................55

21. HPLC of racemic aziridine (left) and enantioenriched (right) ................................................56

CHAPTER 1: PHOSPHINE-CATALZYED REARRANGMENT OF AZIRIDINES

2

INTRODUCTION

Aziridines (1, Figure 1) are three-membered nitrogen-containing heterocyclic rings.

They exhibit high reactivity which is partially due to a high ring strain energy (SE) of 26.7

kcal/mol for an unsubstituted aziridine.1 This large ring strain energy makes them very reactive

towards a host of different nucleophiles resulting in ring cleavage (Figure 1).2 Aziridines are

useful as intermediates for the synthesis of nitrogen-containing pharmaceuticals and bio-active

natural product intermediates. The aziridine group serves as a useful intermediate but it is also

found as a structural fragment in many molecules that are biologically active. The rigidity

aziridines possess as well as their ability to accept protons and undergo ring opening all

contribute to the observed biological activity. Several naturally occurring substances such as

mitomycin C (8), porfiromycin (9), and carzinophilin A (10) contain the aziridine moiety (Figure

2). Mitomycin C and porfiromyin have been used an chemotherapeutic agents while

carzinophilin has been used as an antitumor antibiotic.3

3

Figure 1: Various Aziridine Transformations

Figure 2: Biologically Active Aziridine-Containing Compounds

4

Oxazolines have a variety of uses in organic chemistry. They serve as useful precursors

to a range of other heterocycles. For example, oxazolidine (11) and oxazole (12) are components

of a number of natural products and are usually generated by oxazoline reduction or oxidation,

respectively (Figure 3).4

Oxazolines have been incorporated into peptide-mimics in order to

provide rigidity to compounds that were of pharmacological interest. The oxazoline moiety has

been utilized by nature in the form of many cyclic hepta- and octa-peptides. Many of these

peptides have been shown to be mildly cytotoxic and have exhibited antitumor properties. One

example of these naturally occurring peptides is ascidiacyclamide (14, Figure 4).4

Figure 3: Oxazolidine, Oxazoline and Oxazole

Figure 4: Ascidiacyclamide Structure

Over 20 years ago oxazolines were first being using as recoverable ligands. They were

able to facilitate both ketone reductions as well as nucleophilic additions both in asymmetric

fashion.5

Oxazolines appear in a group of compounds known as privileged catalysts which have

seen much use in asymmetric catalysis. Some examples of which include PHOX (15), BOX (16)

5

and PYBOX (17) (Figure 5). These ligands form superior catalysts with a host of metals

resulting in a variety of transformations. Some of these include aziridinations, copper-catalyzed

cyclopropanations, ruthenium-catalyzed oxidation, and palladium-catalyzed allylations.6

Figure 5: Privileged Ligands

Different aziridine derivatives can possess a variety of groups attached to either of the

carbons in the ring as well as varied protecting groups on the nitrogen. The presence of these

groups has been shown to affect reactivity such that stable compounds can be isolated and

transformed into other new aziridine derivatives.7

Specifically, it is known that aziridines can

undergo rearrangement to oxazolines via a nucleophile-catalyzed pathway first reported in 1959.

This rearrangement is often referred to as the Heine reaction.8,9

Heine describes a reaction in

which 1-p-nitrobenzoylaziridine (18) is regioselectively isomerized in the presence of excess

sodium iodide in acetone (Figure 6). Heine later described a reaction in which 1-(N-

arylbenzimidoyl) aziridines (20) isomerize to 2-arylimidazoline (21) in the presence of iodide or

thiocynate ion (Figure 7).9 This reaction appears to be an efficient synthetic pathway to

nitrogen-containing heterocycles.

6

Figure 6: Aziridine Rearrangement in the Presence of Iodide Ion

Figure 7: Aziridine Rearrangement in Presence of Iodide or Thiocynate Ion

We considered that phosphines might replace iodide as an efficient catalyst for the

rearrangement of aziridines. Phosphines are stronger nucleophiles than amines but are much

weaker bases, and most of their chemistry is dependent on their nucleophilicity.

Organophosphines can act as nucleophiles at saturated or unsaturated carbon centers. It has been

demonstrated that phosphines have the ability to open aziridine rings (Figure 8) to give 2

regioisomers 23, 24. The first step of this reaction involves phosphine attacking the aziridine

and forming a phosphonium salt 26. This phosphonium salt has been isolated as validation for

this mechanism.10

The steric and electronic character of phosphines can be dictated by the

substituents that are added to the phosphorus. Of most importance is the fact that there are

numerous enantiopure phosphines commercially available. These enantiopure phosphines can be

used for the exploration of controlling enantiomer synthesis or separation by kinetic resolution.

7

Figure 8: Aziridine Opening via Phosphine Catalysis

We considered designing a phosphine-catalyzed rearrangement of aziridines into 5-

membered heterocycles (29, Figure 9). This reaction would constitute novel reactivity in

phosphine catalysis. It will allow for the synthesis of enantiopure heterocycles from enantiopure

aziridines. Eventually, new reaction pathways for the proposed phosphonium intermediate could

be developed.

Figure 9: Phosphine-Catalyzed Rearrangement

8

RESULTS AND DISCUSSION

Reaction Optimization

The research began with the optimization of conditions for the rearrangement of

aziridines to oxazolines. N-Acyl aziridine 30 was the first protected aziridine to be generated,

since it was readily available by protection of commercially available 2-methylaziridine. A

series of initial experiments were run under constant conditions using this aziridine with varying

phosphine catalysts. Reaction progress was followed by thin layer chromatography (TLC). The

TLC plates were visualized using a ultra-violet (UV) lamp and basic potassium permanganate

stain. During the optimization process, yields were determined by 1H-NMR through the use of

an internal standard. Specifically 1,3,5-trimethoxybenzene was chosen as an internal standard as

it is stable and provides 2 distinctive peaks that exhibit shifts different from any peaks of interest.

The actual formulas used for calculating the % yield from 1H NMR appear as equations 1 and 2.

We anticipated that the electronic nature of the acyl group bound to the aziridine nitrogen

may play a role in reactivity. The p-nitrobenzoyl group, the same group utilized in aziridine 30,

was originally used by Heine. Depending on where aziridine 30 is opened, two possible

oxazoline regioisomers are formed (31 and 32). Several commercially available phosphine

compounds were used under reflux in tetrahydrofuran (THF) (Table 1). It’s worth noting that the

reaction using the original catalyst published by Heine was reproduced under our conditions with

9

successful results (entry 11, Table 1).8 Attempts were made to repeat the original published

procedure and were not successful.

Table 1: Phosphine Selection

Phosphines catalyze the aziridine rearrangement but reactivity varied greatly between the

different phosphines. This experimental data suggests that both sterics and electronics control

the reactivity of the phosphines. Structures of selected phosphine catalysts that resulted in no or

very little conversion have been provided (Figure 10). Additional structures of phosphines that

resulted in the highest percent yields have been provided as well (Figure 11). Interesting trends

10

begin to emerge when one considers the structures of these phosphines. Several of the

phosphines share similar structural properties, but provide very different results. Phosphine 42

resulted in very high yields while phosphine 33 resulted in 0 % yield (entry 1 and 10). The main

difference between the two is the replacement of a benzene ring with a cyclohexyl ring makes 33

less basic than 42. This suggests that electronics are responsible for the high reactivity seen with

42. Compounds 37 and 39 are both similar in structure yet they both exhibit vastly different

yields (entries 5 and 7). Compound 37 has bulky groups attached to the ring ortho to phosphorus

in comparison with compound 39 suggesting steric influence on reactivity. An interesting

comparison can be made between compounds 36 and 40 as well (entry 4 and 8). Both

compounds have similar structure at phosphorus with 40 possessing the more bulky t-butyl

substituents. It appears a balance between sterics and electronics of the phosphine catalyst is

important for optimal reactivity.

11

Figure 10: Phosphines resulting in little or no conversion to product.

12

Figure 11: Phosphines resulting in highest conversion to product.

Efforts were next placed on forcing the reactions to go to 100 % completion. The

strategy to accomplish complete conversion was raising the temperature to 80°C which

necessitated a change of solvent. Toluene, acetonitrile, and dimethoxyethane (DME) were

chosen due to their higher boiling points. The concentration was increased from .2 M to .3 M

and all reactions were allowed to go for 24 hours. The two most productive previously used

catalysts, 2-(Di-tert-butylphosphino)biphenyl and X-PHOS were used under these new

conditions (Table 2). It can be seen from this data that X-PHOS (40) resulted in higher yields

than phosphine 39 in all cases. For this reason X-PHOS was chosen as the primary catalyst for

future experimentation. X-PHOS was also optimal since it is an air stable solid that can be

weighed on the bench top. A thermal rearrangement of N-acylaziridines to allylamides has been

reported.11

We made the observation that 30 undergoes this same rearrangement at 90ºC in

13

DME and 1,4-dioxane. Based on this development, THF was explored as a possible solvent

choice and provided similar values. From this data, THF was chosen as the standard solvent.

Table 2: Data from 2-(Di-tert-butylphosphino) biphenyl and X-PHOS

Substrate Scope

Using the results from this first round of experimentation, the most active catalyst was

used with a variety of protected 2-methyl aziridine compounds. These various aziridine

compounds were synthesized by William Morris, an undergraduate research, according to a

general procedure. A range of aziridines with varying protecting groups were generated for

rearrangement reactions. Once synthesized and checked for purity, each aziridine was reacted

with phosphine 40, one of the most active catalyst (Table 2). Phosphine 42 exhibited the highest

yields of any of the phosphines but results were inconsistent on a larger scale. This necessitated

the use of the second most productive phosphine.

14

With optimized conditions in hand, efforts were then focused on determining actual

isolated yields (Table 3). All aziridines examined showed some rearrangement with the most

productive being the benzoyl groups with electron withdrawing substituents. Compounds 43–45

exhibit low yields due to low conversion of starting material. Heating these aziridines for longer

periods of time did not appreciably increase yields. Starting material was totally consumed for

compounds 46–50. The variation in protecting groups resulted in a noticeable trend. Compound

43 has no additional substituents and resulted in a yield of 21%, one of the lowest yields of all

the protecting groups. Adding an inductive electron withdrawing group to the para position, as

with compound 44, the yield exhibits no change at 21%. Compound 45 suggests that electron

donating groups do not aid the rearrangement. The addition of the electron withdrawing dinitro

group in 46 increased the yield to 77%. Compound 49 suggests that the location of the electron

withdrawing group is important as well. It was decided that the 3,5-dinitrobenzoyl (DNB)

protecting group would be utilized in further substrate exploration since it displayed the best mix

of yield and regioselectivity. The DNB protecting group is crystalline in nature, and there is

precedence for its removal.

15

Table 3: Exploration of various protecting groups.

Since methyl aziridine was the only commercially available aziridine, various other

DNB-protected aziridines were synthesized (see experimental section) and subjected to the

standard X-PHOS-catalyzed rearrangement (Table 4). Two long chain substituted aziridines

were reacted and provided very differing results (entries 1 and 2). The long chained alkane

provided a promising yield of 94% while the corresponding alkene version was more

disappointing at 64%. The only structural difference between the two is the presence of a double

bond. This reduction in yield suggests either an electronic influence on reactivity or a competing

side reaction involving the double bond. The two more sterically hindered aziridines (entry 3

and 4) exhibited high yields. This suggests that the increase in steric bulk did not affect the

16

reactivity negatively. The two oxygen substituted aziridines displayed similar reactivity (entry 5

and 6). Their yields are lower and similar to that of the alkene substituted aziridine (entry 2).

The lower reactivity would again suggest either that electronics are at play. Either electronic

effects are affecting the reactivity of the analyte or resulting in a side reaction which is lowering

the yield. The only disubstituted aziridine (entry 7) showed no reactivity.

17

Table 4: Substrate scope for the phosphine-catalyzed rearrangement.

18

Terminal aziridines possess a chiral center that is maintained in the resulting oxazoline

product. In order to verify this was true for this rearrangement, aziridine 65 was synthesized

with >99% ee and was subjected to the optimized rearrangement conditions. The resulting

oxazoline product (66) was isolated with a 94% yield without any loss of the original

enantiopurity. The fact that the stereocenter is maintained is important for applications in

asymmetric synthesis. It also provides some insight into the mechanistic pathway of the

reaction.

Figure 12: Rearrangement of enantiopure aziridine.

We suggest the rearrangement takes place through a catalytic cycle that is similar to what

was originally suggested by Heine8 (Figure 13). The least hindered carbon of aziridine 67 is

open to attack by a nucleophilic phosphine (70). The catalyst must be small enough that it can

get in and open the aziridine. Any added steric bulk that is present around the phosphine may

stop any decomposition of 68 which would be hindering to the catalytic cycle. Once 68

collapses onto the oxygen the correct oxazoline product (69) is formed.

19

Figure 13: Proposed catalytic cycle for the rearrangement.

Conclusions

Herein we describe a new variation on the Heine reaction using phosphine catalysts.

Based on experimentation, X-PHOS was found to be the most suitable catalyst and general

reaction conditions were developed around this catalyst. These new conditions were used on a

variety of substituted N-acyl aziridines resulting in the synthesis of a variety of oxazoline

counterparts. The aziridines synthesized as well as the oxazolines may find use as starting

materials for a variety of further synthesis.

20

EXPERIMENTAL

General. 1H NMR spectra were recorded on Bruker DRX (400 MHz). Chemical shifts are

reported in ppm from tetramethylsilane with the solvent resonance as the internal standard

(CDCl3: 7.27 ppm). Data are reported as follows: chemical shift, integration, multiplicity (s =

singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constants (Hz),

and assignment. 13

C NMR spectra were recorded on a Bruker DRX 400 (100 MHz)

spectrometer with complete proton decoupling. Chemical shifts are reported in ppm from

tetramethylsilane with the solvent as the internal standard (CDCl3: 77.0 ppm). High resolution

mass spectrometry was acquired with an Agilent DART-TOF at Duke University. Infrared (IR)

spectra were obtained using a Nicolet 6700 FT-IR.

Liquid chromatography was performed using forced flow (flash chromatography) on

EMD Chemicals Geduran® 60 silica gel (SiO2, 40 to 63m) purchased from VWR International.

Thin layer chromatography (TLC) was performed on EMD Chemicals 0.25 mm silica gel 60

plates. Visualization was achieved with UV light or basic potassium permanganate in water

followed by heating.

All reactions were conducted in oven and flame dried glassware under an inert

atmosphere of argon. All solvents were EMD Chemicals anhydrous solvents sold by VWR

International. Each solvent was purged with Argon for a minimum of 15 minutes and stored

over activated 3Å molecular sieves in sure-seal bottles. All phosphine catalysts were purchased

from the Strem Chemical Company, except cyclohexyldiphenylphosphine which was purchased

from Alfa Aesar. All remaining chemicals were purchased from Alfa Aesar, TCI International,

or Aldrich Chemical Company and were used as received.

21

Representative Procedure for the Synthesis of 2-Methylaziridines

A flame-dried round bottom flask was charged with a Teflon-covered stir bar and the

corresponding acyl chloride (1.05 equiv.) under argon. Dry toluene (0.25 M) was added to the

flask via syringe. Triethylamine (2 equiv.) was added to the solution via syringe. Solution was

then cooled with stirring in an ice bath and 2-methylaziridine (1 equiv.) was added to the

solution dropwise. The resulting solution was stirred for 30 minutes in the ice bath and then

allowed to reach room temperature and stirred for another 30 minutes. The resulting suspension

was vacuum filtered to remove solids, and the volatiles were then removed by rotary evaporator.

The resulting product was purified via silica flash column chromatograph with hexanes and ethyl

acetate.

(2-methylaziridin-1-yl)(4-nitrophenyl)methanone (30). Reaction performed by

representative procedure beginning with 4-nitrobenzoyl chloride (20 mmol, 3.9

g). Purification was performed by silica gel flash column chromatography (80%

hexanes, 20% ethyl acetate) yielding 3.65 g (88%) of aziridine as a pale yellow

solid. HRMS: Calculated for C10H10N2O3: 207.0770 (M+H+), found 207.0769 (M+H

+);

1H

NMR (CDCl3, 400 MHz): δ 8.31 (m, 2H), 8.18 (m, 2H), 2.66 (m, 1H), 2.60 (d, J = 5.6 Hz, 1H),

2.23 (d, J = 3.6 Hz), 1.42 (d, J = 5.2 Hz); 13

C NMR (CDCl3, 100 MHz): δ 177.01, 150.28,

138.84, 130.01, 123.63, 35.07, 32.52, 17.61; IR (NaCl Plate): 2971, 1647, 1601, 1345 cm-1

.

22

(2-methylaziridin-1-yl)(phenyl)methanone (entry 1, table 2). Reaction

performed by representative procedure beginning with benzoyl chloride (21

mmol, 3.90 g). Purification was performed by silica gel flash column

chromatography (89% Hexanes, 11% Ethyl Acetate) yielding 2.6 g (76%) of aziridine as a clear

oil. HRMS: Calculated for C10H11NO: 162.0919 (M+H+), found 162.0916 (M+H

+);

1H NMR

(CDCl3, 400 MHz): δ 8.03 (m, 2H), 7.55 (m, 1H), 7.46 (m, 2H), 2.58 (m, 1H), 2.55 (d, J = 5.6

Hz, 1H), 2.15 (d, J = 3.6 Hz, 1H), 1.40 (d, J = 5.6 Hz, 3H); 13

C NMR (CDCl3, 100 MHz): δ

179.32, 133.52, 132.65, 129.04, 128.42, 34.62, 32.14, 17.79; IR (NaCl Plate): 3061, 1658, 1535,

1317 cm-1

.

(4-chlorophenyl)(2-methylaziridin-1-yl)methanone (entry 5, table 2).

Reaction performed by representative procedure beginning with 4-chlorobenzoyl

chloride (10.5 mmol, 1.34 mL). Purification was performed by silica flash column

chromatography (83%: Hexanes, 17% ethyl acetate) yielding 1.59g (81%) of

aziridine as a clear oil. HRMS: Calculated for C10H10ClNO: 196.0529 (M+H+), found 196.0528

(M+H+);

1H NMR (CDCl3, 400 MHz): δ 7.95 (m, 2H), 7.42 (m, 2H), 2.57 (m, 1H), 2.53 (d, J =

5.6 Hz, 1H), 2.14 (d, J = 3.6 Hz, 1H), 1.37 (d, J = 5.2 Hz, 3H); 13

C NMR (CDCl3, 100 MHz): δ

178.21, 138.97, 131.95, 130.40, 128.73, 34.77, 32.23, 17.71; IR (NaCl Plate): 2969, 1672, 1406,

1091 cm-1

.

(4-methoxyphenyl)(2-methylaziridin-1-yl)methanone (entry 3, table 2).

Reaction performed by representative procedure beginning with 4-

methoxybenzoyl chloride (10.5 mmol, 1.79 g). Purification was performed by

23

silica flash column chromatograph (83% hexanes, 17% ethyl acetate) yielding 1.14 g (60%) of

aziridine as a clear oil. HRMS: Calculated for C11H13NO2: 192.1025 (M+H+), found 192.1022

(M+H+);

1H NMR (CDCl3, 400 MHz): δ 8.00 (m, 2H), 6.94 (m, 2H), 3.87 (s, 1H), 2.56(m, 1H),

2.52 (d, J = 5.6 Hz, 1H), 2.11 (d, J = 3.6 Hz, 1H), 1.39 (d, J = 5.2 Hz, 3H); 13

C NMR (CDCl3,

100 MHz): δ 178.87, 163.14, 131.10, 126.11, 113.61, 55.45, 34.60, 32.06, 17.81; IR (NaCl

Plate): 2966, 2258, 1651, 1091 cm-1

.

(3,5-dinitrophenyl)(2-methylaziridin-1-yl)methanone (entry 1, table 4).

Reaction performed by representative procedure beginning with 3,5-

dinitrobenzoyl chloride (21 mmol, 4.84g). Purification was performed by silica

flash column chromatography (75% hexanes, 25% ethyl acetate) yielding 3.97

g (79%) of aziridine as a white solid. HRMS: Calculated for C10H9N3O5: 252.0620 (M+H+),

found 252.0616 (M+H+);

1H NMR (CDCl3, 400 MHz): δ 9.22 (t, J = 4 Hz, 1H), 9.16 (d, J = 2

Hz, 2H), 2.77 (m, 1H), 2.68 (d, J = 4 Hz, 1H), 2.69 (d, J = 6, 1H), 2.34 (d, J = 3.6 Hz, 1H), 1.51

(d, J = 5.2 Hz); 13

C NMR (CDCl3, 100 MHz): δ 174.32, 148.73, 137.00, 128.69, 121.92, 35.77,

32.93, 17.56; IR (NaCl Plate): 3095, 1648, 1541, 1344 cm-1

.

(3,5-bis(trifluoromethyl)phenyl)(2-methylaziridin-1-yl)methanone (entry

6, table 4). Reaction performed by representative procedure beginning with

3,5-bis(trifluoromethyl)benzoyl chloride (10.5 mmol, 1.9 mL). Purification

was performed by silica flash column chromatography (83% hexanes, 17%

ethyl acetate) yielding 2.09 g (70%) of aziridine as a clear oil. HRMS: Calculated for

C12H9F6NO: 298.0667 (M+H+), found 298.0661 (M+H

+);

1H NMR (CDCl3, 400 MHz): δ 8.47

(m, 2H), 8.06 (m, 1H), 2.67 (m, 1H), 2.63 (d, J = 6 Hz, 1H), 2.25 (d, J = 3.6 Hz), 1.44 (d, J = 5.2

24

Hz); 13

C NMR (CDCl3, 100 MHz): 176.18, 135.31, 132.64, 132.30, 131.97, 131.63, 129.09,

129.06, 127.00, 125.96, 125.92, 125.89, 125.85, 124.28, 121.57, 118.86, 35.31, 32.55, 17.54; IR

(NaCl Plate): 3000, 1688, 1280, 1136 cm-1

.

(2-methylaziridin-1-yl)(2-nitrophenyl)methanone (entry 7, table 4). Reaction

performed by representative procedure beginning with 2-nitrobenzoyl chloride

(10.5 mmol, 1.39 mL). Purification was performed by silica flash column

chromatography (75% hexanes, 25% ethyl acetate) yielding 1.57 g (75%) of aziridine as a clear

oil. HRMS: Calculated for C10H10N2O3: 207.0770 (M+H+), found 207.0768 (M+H

+);

1H NMR

(CDCl3, 400 MHz): δ 7.94 (dd, J = 8, .8 Hz), 7.71 (m, 2H), 7.59 (m, 1H), 2.80 (m, 1H), 2.63 (d,

J = 6Hz, 1H), 1.32 (d, J = 5.6 Hz, 3H); 13

C NMR (CDCl3, 100 MHz): 177.41, 147.33, 133.41,

132.59, 130.88, 129.33, 124.12, 34.33, 32.83, 17.41; IR (NaCl Plate): 2972, 1733, 1645, 1348

cm-1

.

(2-methylaziridin-1-yl)(perfluorophenyl)methanone (entry 8, table 4).

Reaction performed by representative procedure beginning with

pentafluorobenzoyl chloride (10.5 mmol, 1.5 mL). Purification was performed by

silica gel flash column chromatography (89% hexanes, 11% ethyl acetate)

yielding 2.04 g (81%) of aziridine as a clear oil. HRMS: Calculated for C10H6F5NO: 252.0448

(M+H+), found 252.0446 (M+H

+);

1H NMR (CDCl3, 400 MHz): δ 2.78 (m, 1H), 2.61 (d, J = 6

Hz, 1H), 2.20 (d, J = 3.6 Hz, 1H), 1.35 (d, J = 5.6 Hz, 3H); 13

C NMR (CDCl3, 100 MHz):

168.48, 145.67, 145.62, 143.84, 143.13, 143.09, 143.02, 141.27, 138.94, 136.52, 136.39, 111.65,

35.18, 32.79, 29.72, 17.38; IR (NaCl Plate): 2978, 1689, 1652, 1495 cm-1

.

25

Representative Procedure12

for the Synthesis of Substituted 3,5-Dinitrobezoylaziridines.

A round bottom flask was charged with a Teflon-covered stir bar, the corresponding

epoxide (20 mmol), 30 mL of MeOH, and 10 mL of H2O under argon. Sodium azide (40 mmol)

and ammonium chloride (30 mmol) were added to this solution. The reaction was stirred for 4

hours under argon at 60 °C. Methanol was removed by rotary evaporator and the remaining

solution was extracted 3 x 60 mL with dichloromethane. The organic layers were combined,

washed with 20 mL of brine solution, and dried over anhydrous MgSO4. The mixture was

filtered, and volatiles were then removed by rotary evaporator. The total crude azido alcohol

was dissolved in 50 mL of acetonitrile under argon. Triphenylphosphine (20 mmol) was added,

and the solution was heated for 20 hours at 80 °C. The reaction mixture was cooled to –30 °C

with stirring, and triethylamine (24 mmol) was added via syringe (in some cases a solvent swap

to tetrahydrofuran was beneficial at this point). In a flame dried flask, 3,5-dinitrobenzoyl

chloride (21 mmol) was dissolved in a minimal amount of acetonitrile and then transferred to the

reaction flask dropwise via syringe. The reaction mixture was allowed to stir at –30°C for 50

minutes, 0 °C for 30 minutes, and room temperature for 30 minutes. De-ionized water (20 mL)

was added and the solution was extracted 3 x 60 mL with ethyl acetate. The organic layers were

combined, washed with 20 mL of brine solution, and dried over anhydrous MgSO4. The mixture

was filtered, and volatiles were then removed by rotary evaporator. The crude product was

purified immediately via flash column silica gel chromatography using hexanes and ethyl

acetate.

26

(3,5-dinitrophenyl)(2-hexylaziridin-1-yl)methanone (51). Reaction

performed by representative procedure beginning with 1,2-

epoxyoctane (20 mmol, 3.09 mL). Purification was performed by

flash column chromatography (89% hexanes, 11% ethyl acetate)

yielding 2.8 g (43%) of aziridine as a white solid. HRMS: Calculated for C15H19N3O5: 322.1403

(M+H+), found 322.1405 (M+H

+);

1H NMR (CDCl3, 400 MHz): δ 9.21 (t, J = 2.4 Hz, 1H), 9.15

(d, J = 2.4 Hz, 2H), 2.72 (m, 1H), 2.63 (d, J = 6 Hz, 1H), 2.38 (d, J = 3.6 Hz, 1H), 1.90 (m, 1H),

1.60-1.26 (m, 9H), 0.90 (t, J = 7.2 Hz, 3H); 13

C NMR (CDCl3, 100 MHz): 174.45, 148.65,

136.96, 128.76, 121.91, 39.87, 32.33, 31.93, 31.65, 28.89, 26.41, 22.53, 14.03; IR (NaCl Plate):

3104, 1646, 1542, 1343 cm-1

.

(3,5-dinitrophenyl)(2-(hex-5-en-1-yl)aziridine-1-yl)methanone (53).

Reaction performed by representative procedure beginning with 1,2-

epoxy-7-octene (20 mmol, 2.96 mL). Purification was performed by

flash column chromatography (83% hexanes, 17% ethyl acetate)

yielding 2.4 g (41%) of aziridine as a pale yellow solid. HRMS: Calculated for C15H17N3O5:

320.1246 (M+H+), found 320.1240 (M+H

+);

1H NMR (CDCl3, 400 MHz): δ 9.20 (t, J = 2 Hz,

1H), 9.14 (d, J = 9.14 Hz), 5.78 (m, 1H), 4.97 (m, 1H), 2.73 (m, 1H), 2.63 (d, J = 6 Hz, 1H), 2.38

(d, J = 2 Hz, 1H), 2.09 (m, 2 H), 1.54 (m, 1H), 1.50 (m, 5H); 13

C NMR (CDCl3, 100 MHz):

174.42, 148.68, 138.36, 136.93, 128.73, 121.90, 114.78, 39.69, 33.50, 32.35, 31.78, 28.40,

25.89; IR (NaCl Plate): 3094, 1645, 1462, 1343 cm-1

.

27

(2-(tert-butyl)aziridine-1-yl)(3,5-dinitrophenyl)methanone (57). Reaction

performed by representative procedure beginning with 3,3-dimethyl-1,2-

epoxybutane (20 mmol, 2.44 mL). Purification was performed by flash

column silica gel chromatography (86% hexanes, 14% ethyl acetate) yielding

2.19 g (48%) of aziridine as a white solid. HRMS: Calculated for C13H15N3O5: 294.1090

(M+H+), found 294.1088 (M+H

+);

1H NMR (CDCl3, 400 MHz): δ 9.21 (t, J = 2 Hz, 1H), 9.16

(d, J = 2 Hz, 2H), 2.63 (dd, J = 6.4, 4 Hz, 1H), 2.55 (d, J = 4 Hz, 1H), 2.43 (d, J = 6.4 Hz, 1H),

1.05 (s, 9H); 13

C NMR (CDCl3, 100 MHz): 175, 148.58, 136.89, 128.84, 121.91, 47.77, 30.86,

30.15, 26.47; IR (NaCl Plate): 3097, 1678, 1543, 1344 cm-1

.

(3,5-dinitrophenyl)(2-(phenoxymethyl)aziridine-1-yl)methanone

(61). Reaction performed by representative procedure beginning with

glycidyl phenyl ether (20 mmol, 2.73 mL). Purification was performed

by flash column silica gel chromatography (50% hexanes, 50% ethyl

acetate) yielding 2.1 g (31%) of aziridine as a pale yellow solid. HRMS: Calculated for

C16H13N3O6: 344.0883 (M+H+), found 344.0881 (M+H

+);

1H NMR (CDCl3, 400 MHz): 9.30 (d,

J = 2 Hz, 2 H) 9.21 (t, J = 2 Hz, 1 H), 7.29 (m, 2H), 6.99 (m, 1H), 6.85 (m, 2 H), 4.38 (dd, J =

10.4, 2.8 Hz, 1 H), 4.06 (dd, J = 10.8, 6.8 Hz, 1 H), 3.22 (m, 1 H), 2.83 (d, J = 6.4 Hz, 1 H) 2.61

(d, J = 3.6 Hz, 1H); 13

C NMR (CDCl3, 100 MHz) 173.95, 157.73, 148.62, 136.37, 129.69,

129.13, 122.14, 121.84, 114.42, 68.00, 38.32, 28.70; IR (NaCl Plate): 3094, 1678, 1543, 1344

cm-1

.

28

(2-((benzyloxy)methyl)aziridine-1-yl)(3,5 dinitrophenyl)methanone

(59).

Reaction performed by representative procedure beginning with

benzyl glycidyl ether (24.1 mmol, 3.96 g). Purification was performed

by flash column silica (50% hexanes, 50% ethyl acetate) yielding 1.82 g (67%) of aziridine as a

pale yellow solid. HRMS: Calculated for C17H15N3O6: 358.1039 (M+H+), found 358.1043

(M+H+);

1H NMR (CDCl3, 400 MHz): δ 9.37 (d, J = 2 Hz, 2 H), 7.39 (m, 3H), 7.26 (m, 2H),

4.60 (m, 2H), 3.88 (dd, J = 10.4, 2.8 Hz, 1 H), 3.40 (dd, J = 10.4, 7.2 Hz, 1 H), 3.00 (m, 1 H),

2.71 (d, J = 6 Hz, 1 H), 2.43 (d, J = 3.6 Hz, 1H); 13

C NMR (CDCl3, 100 MHz) 173.88, 148.50,

137.01, 136.47, 129.31, 128.53, 128.11, 127.94, 121.94, 73.56, 69.81, 39.19, 28.46; IR (NaCl

Plate): 3094, 1652, 1454, 1343 cm-1

.

7-azabicyclo[4.1.0]heptan-7-yl(3,5-dinitrophenyl)methanone12

(63).

Reaction performed by representative procedure beginning with

cyclohexene oxide (20.4 mmol, 2.00 g). Purification was performed

by flash column silica (86% hexanes, 14% ethyl acetate to 77% hexanes, 33% ethyl acetate)

yielding 3.2 g (54%) of aziridine as a white solid. HRMS: Calculated for C13H13N3O5: 292.0933

(M+H+), found 292.0938 (M+H

+);

1H NMR (CDCl3, 400 MHz): 9.20 (t, J = 2 Hz, 1H), 9.11 (d,

J = 2.4 Hz, 2H), 2.92 (m, 2H), 2.13 (m, 2 H), 2.02 (m , 2H), 1.61 (m, 2 H), 1.46 (m, 2 H); 13

C

NMR (CDCl3, 100 MHz): 175.10, 148.65, 137.05, 128.74, 121.78, 38.47, 23.69, 19.79; IR

(NaCl Plate): 3095, 1640, 1540, 1343 cm-1

.

29

(3,5-dinitrophenyl)(2-isopropylaziridin-1-yl)methanone13

(55). DL-

Valinol14

(13.9 mmol, 1.4 g) was dissolved in dry toluene (21 mL), and then

added to a solution of triphenylphosphine (14.57 mmol, 3.82 g) and

diisopropyl azodicarboxylate (14.57 mmol, 2.87 mL) in toluene (32 mL).

This mixture was heated to 100 °C and stirred overnight. After cooling to –30 °C, triethyl amine

(16.66 mmol, 2.32 mL) was added to this solution. 3,5-Dinitrobenzoyl chloride (14.57 mmol,

3.36 g) in THF (4 mL) was added to solution dropwise. Solution was allowed to stir at –30 °C

for 20 minutes and 40 minutes at 0 °C. Water (20 mL) was added dropwise, the mixture was

extracted 3 x 60 mL with ethyl acetate. The combined organics were washed with brine (20 mL),

dried over MgSO4, and filtered. Volatiles were removed by rotary evaporator. The crude

material was purified by flash column silica gel chromatography (86% hexanes, 14% ethyl

acetate) yielding 1.25 g (32%) of aziridine as a white solid. HRMS: Calculated for C12H13N3O5:

280.0933 (M+H+), found 280.0928 (M+H

+);

1H NMR (CDCl3, 400 MHz): δ 9.20 (t, J = 2.4 Hz,

1H) 9.15 (d, J = 2 Hz, 2H), 2.61 (m, 1H), 2.53 (d, J = 6.4 Hz, 1H), 2.50 (d, J = 4 Hz, 1H), 1.87

(m, 1H), 1.12 (d, J = 6.8 Hz, 3H), 1.05 (d, J = 6.8 Hz, 3H); 13

C NMR (CDCl3, 100 MHz):

174.72, 148.61, 136.89, 128.81, 121.91, 44.97, 31.06, 29.98, 19.85, 18.36; IR (NaCl Plate):

3101, 1647, 1542, 1343 cm-1

.

30

Experimental conditions for the phosphine catalyst screen.

Aziridine 30 (20.6 mg, 0.1 mmol) and 0.01 mmol of a phosphine catalyst were weighed

into an oven-dried reaction vial. Dry tetrahydrofuran (500 L) was added under argon. The

solution was heated at 70 °C under argon for 24 hours. Volatiles were removed by rotary

evaporator. All yields and ratios of regioisomers were determined using 1H NMR following the

addition of 1,3,5-trimethoxybenzene as an internal standard. Since the NMR spectra of 31 have

not been reported, identification of the major regioisomer was possible by extrapolation of know

oxazolines.15,16

Representative procedure for the phosphine-catalyzed rearrangements.

Aziridine (0.3 mmol) and 14.3 mg (0.03 mmol) of X-Phos were weighed into an oven-

dried reaction vial. Dry tetrahydrofuran (1.5 mL) was added under argon. The solution was

heated at 70 °C under argon for 24 hours. Volatiles were removed by rotary evaporator. The

crude reaction mixture was purified via flash column silica gel chromatography using various

hexanes/ethyl acetate solvent systems.

31

4-methyl-2-(4-nitrophenyl)-4,5-dihydrooxazole (31,32). Reaction performed

by representative procedure beginning with 62 mg of the corresponding

aziridine. Purification was performed by flash column chromatography (83%

hexanes, 17% ethyl acetate) yielding 42 mg (71%) of oxazoline. HRMS:

Calculated for C10H10N2O3: 207.0770 (M+H+), found 207.0770 (M+H

+);

1H NMR (CDCl3, 400

MHz): δ 8.27 (d, J = 9.2 Hz, 2H), 8.12 (d, J = 8.8 Hz, 2H), 4.59 (5, J = 9.2 Hz, 1H), 4.43 (m,

1H), 4.02 (t, J = 8 Hz, 1H), 1.40 (d, J = 6.8 Hz, 3H); 13

C NMR (CDCl3, 100 MHz): 161.69,

149.49, 133.71, 129.25, 123.52, 74.57, 62.46, 21.30; IR (NaCl Plate): 3109, 1737, 1524, 1349

cm-1

.

4-methyl-2-phenyl-4,5-dihydrooxazole15

(entry 1, table 2). Reaction performed

by representative procedure beginning with 48 mg of the corresponding aziridine.

Purification was performed by flash column chromatography (89% hexanes, 11%

ethyl acetate) yielding 11 mg (21%) of oxazoline. 1H NMR (CDCl3, 400 MHz): δ 7.93 (t, J = 7.2

Hz, 2 H), 7.43 (m, 3H), 4.50 (dd, J = 8 Hz, 9.2, 1H), 4.35 (m, 1H), 3.93 (t, J = 7.6 Hz, 1H), 1.35

(d, J = 6.8 Hz, 3H); 13

C NMR (CDCl3, 100 MHz): 163.42, 131.25, 128.30, 128.19, 127.85,

74.04, 61.99, 21.47; IR (NaCl Plate): 2966, 1449, 1302, 1055 cm-1

.

2-(4-chlorophenyl)-4-methyl-4,5-dihydrooxazole (entry 5, table 2). Reaction

performed by representative procedure beginning with 59 mg of the

corresponding aziridine. Purification was performed by flash column

chromatography (83% hexanes, 17% ethyl acetate) yielding 13 mg (21%) of

oxazoline. HRMS: Calculated for C10H10ClNO: 196.0529 (M+H+), found 196.0530 (M+H

+);

32

1H NMR (CDCl3, 400 MHz): δ 7.88 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 4.54 (t, J = 9.2

Hz, 1H), 4.39 (m, 1H), 3.97 (t, J = 7.6 Hz, 1H), 1.37 (d, J = 6.8 Hz); 13

C NMR (CDCl3, 100

MHz): 162.62, 137.44, 129.58, 128.63, 126.36, 74.24, 62.11, 21.41; IR (NaCl Plate): 2966,

2258, 1651, 1091 cm-1

.

2-(4-methoxyphenyl)-4-methyl-4,5-dihydrooxazole (entry 3, table 2).

Reaction performed by representative procedure beginning with 57 mg of the

corresponding aziridine. Purification was performed by flash column

chromatography (83% hexanes, 17% ethyl acetate) yielding 3 mg (5%) of

oxazoline. HRMS: 1H NMR (CDCl3, 400 MHz): δ 7.89 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.8 Hz,

2H), 4.49 (dd, J = 8, 9.2 Hz, 1H), 4.35 (m, 1H ), 3.92 (t, 7.6 Hz, 1H), 3.82 (s, 3H), 1.35 (d, J =

6.4 Hz); 13

C NMR (CDCl3, 100 MHz): 163.37, 162.06, 129.98, 120.15, 113.66, 74.03, 61.74,

55.34, 21.49; IR (NaCl Plate): 1648, 1609, 1512, 1254 cm-1

.

2-(3,5-dinitrophenyl)-4-methyl-4,5-dihydrooxazole (entry 5, table 5).

Reaction performed by representative procedure beginning with 75 mg of

the corresponding aziridine. Purification was performed by flash column

chromatography (75% hexanes, 25% ethyl acetate) yielding 58 mg (77%) of

oxazoline. HRMS: Calculated for C10H9N3O5: 252.0620 (M+H+), found 252.0615 (M+H

+);

1H

NMR (CDCl3, 400 MHz): δ 9.12 (t, J = 2 Hz, 1H), 9.07 (d, J = 2 Hz, 2H), 4.66 (dd, J = 9.2, 8

Hz, 1H), 4.49 (m, 1H), 4.10 (t, J = 8 Hz, 1H), 1.41 (d, J = 6.8 Hz, 3H); 13

C NMR (CDCl3, 100

MHz): 159.73, 148.49, 131.66, 128.17, 120.69, 75.14, 62.69, 21.23; IR (NaCl Plate): 3097,

2970, 1543, 1344 cm-1

.

33

2-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-4,5-dihydrooxazole (entry 6,

table 5). Reaction performed by representative procedure beginning with 90

mg of the corresponding aziridine. Purification was performed by flash

column chromatography (83% hexanes, 17% ethyl acetate) yielding 52 mg (60%) of oxazoline.

HRMS: Calculated for C12H9F6NO: 298.0667 (M+H+), found 298.0668 (M+H

+);

1H NMR

(CDCl3, 400 MHz): δ 8.41 (s, 2 H), 7.97 (s, 1 H), 4.60 (dd, J = 9.2, 8 Hz, 1 H), 4.45 (m, 1 H),

4.03 (t, J = 8.4 Hz, 1 H), 1.40 (d, J = 6.4 Hz, 3 H); 13

C NMR (CDCl3, 100 MHz): 160.98,

132.44, 132.11, 131.77, 131.43, 130.09, 128.40, 128.36, 127.05, 124.65, 124.62, 124.58, 124.54,

124.51, 124.34, 121.62, 118.91, 74.67, 62.41, 21.21; IR (NaCl Plate): 2975, 2931, 1280, 1136

cm-1

.

4-methyl-2-(2-nitrophenyl)-4,5-dihydrooxaole16

(entry 7, table 5). Reaction

performed by representative procedure beginning with 62 mg of the

corresponding aziridine. Purification was performed by flash column

chromatography (83% hexanes, 17% ethyl acetate) yielding 64 mg (92%) of oxazoline. HRMS:

Calculated for C10H10N2O3: 207.0770 (M+H+), found 207.0769 (M+H

+);

1H NMR (CDCl3, 400

MHz): δ 7.85 (m, 2H), 7.63 (m, 2H), 4.53 (t, 9.2 Hz, 1H), 4.40 (m, 1H), 3.99 (t, J = 7.6 Hz, 1H),

1.39 (d, J = 6.4 Hz, 3H); 13

C NMR (CDCl3, 100 MHz): 161.00, 149.14, 132.46, 131.36, 131.04,

123.90, 123.54, 75.11, 62.48, 20.99; IR (NaCl Plate): 2917, 1660, 1534, 1356 cm-1

.

4-methyl-2-(perfluorophenyl)-4,5-dihydrooxazole (entry 8, table 5).

Reaction performed by representative procedure beginning with 75 mg of the

34

corresponding aziridine. Purification was performed by flash column chromatography (83%

hexanes, 17% ethyl acetate) yielding 24 mg (34%) of oxazoline. HRMS: Calculated for

C10H6F5NO: 252.0448 (M+H+), found 252.0449 (M+H

+);

1H NMR (CDCl3, 400 MHz): 4.56 (t,

J = 8 Hz, 1H), 4.46 (m, 1H), 4.02 (t, J = 8 Hz, 1 H), 1.40 (d, J = 6.8 Hz, 3H); 13

C NMR (CDCl3,

100 MHz): 153.97, 146.86, 146.81, 146.74, 144.37, 144.30, 144.25, 144.19, 144.14, 144.02,

143.94, 143.89, 143.84, 143.76, 141.45, 141.37, 141.32, 141.27, 141.19, 139.15, 139.11, 139.00,

138.95, 138.88, 138.81, 136.66, 136.59, 136.52, 136.47, 136.39, 136.32, 105.13, 105.08, 104.97,

104.93, 104.81, 104.78, 74.32, 62.54. 21.23; IR (NaCl Plate): 2975, 1625, 1502, 994 cm-1

.

2-(3,5-dinitrophenyl)-4-hexyl-4,5-dihydrooxazole (52).

Reaction performed by representative procedure beginning

with 88 mg of the corresponding aziridine. Purification was

performed by flash column silica gel chromatography (83%

hexanes, 17% ethyl acetate) yielding 85 mg (94%) of oxazoline. HRMS: Calculated for

C15H19N3O5: 322.1403 (M+H+), found 322.1398 (M+H

+);

1H NMR (CDCl3, 400 MHz): 9.13 (t,

J = 2 Hz, 1 H), 9.09 (d, J = 2 Hz, 2 H), 4.62 (dd, J = 9.2, 8.8 Hz, 1 H), 4.39 (m, 1 H), 4.16 (t, J =

8 Hz, 1 H), 1.77 (m, 1 H), 1.53 (m, 9 H), 0.903 (t, J = 6.8 Hz, 3 H); 13

C NMR (CDCl3, 100

MHz): 159.64, 148.52, 131.76, 128.18, 120.64, 73.72, 67.43, 35.78, 31.73, 29.22, 25.86, 22.61,

14.08; IR (NaCl Plate): 3101, 1544, 1466, 1344 cm-1

.

2-(3,5-dinitrophenyl)-4-(hex-5-en-1-yl)-4,5-dihydrooxazole

(54). Reaction performed by representative procedure

beginning with 87 mg of the corresponding aziridine.

35

Purification was performed by flash column silica gel chromatography (83% hexanes, 17% ethyl

acetate) yielding 64 mg (73%) of oxazoline. HRMS: Calculated for C15H17N3O5: 320.1246

(M+H+), found 320.1252 (M+H

+);

1H NMR (CDCl3, 400 MHz): 9.14 (t, J = 2 Hz, 1 H), 9.10 (

d, J = 2 Hz, 2 H), 5.83 (m, 1 H), 5.00 (m, 2 H), 4.63 (dd, J = 9.6, 8.4 Hz, 1H), 4.39 (m, 1 H), 4.16

(t, J = 8 Hz, 1 H), 2.1 (m, 2 H), 1.78 (m, 1 H), 1.54 (m, 5 H); 13

C NMR (CDCl3, 100 MHz):

159.72, 148.52, 138.62, 131.70, 128.21, 120.69, 114.69, 73.71, 67.35, 35.62, 33.60, 28.76,

25.36; IR (NaCl Plate): 3099, 1653, 1544, 1344 cm-1

.

4-(tert-butyl)-2-(3,5-dinitrophenyl)-4,5-dihydrooxazole17

(58).

Reaction performed by representative procedure beginning with 88 mg of

the corresponding aziridine. Purification was performed by flash column

silica gel chromatography (83% hexanes, 17% ethyl acetate) yielding 86

mg (98%) of oxazoline. HRMS: Calculated for C13H15N3O5: 294.1090 (M+H+), found 294.1089

(M+H+);

1H NMR (CDCl3, 400 MHz): 9.14 (t, J = 2 Hz, 1H), 9.10 (d, J = 2 Hz, 2 H), 4.49 (dd,

J = 10.4, 8.8 Hz, 1 H), 4.35 (t, J = 8.4 Hz, 1 H), 4.16 (dd, J = 10, 8.4 Hz, 1 H), .988 (s, 9 H); 13

C

NMR (CDCl3, 100 MHz): 159.00, 148.52, 131.75, 128.19, 120.61, 69.91, 34.10, 25.86; IR

(NaCl Plate): 2956, 1657, 1545, 1343 cm-1

.

2-(3,5-dinitrophenyl)-4-(phenoxymethyl)-4,5-dihydrooxazole

(62). Reaction performed by representative procedure beginning

with 50 mg of the corresponding aziridine. Purification was

performed by flash column silica gel chromatography (75%

hexanes, 25% ethyl acetate) yielding 33 mg (66%) of oxazoline. HRMS: Calculated for

36

C16H13N3O6: 344.0883 (M+H+), found 344.0887 (M+H

+);

1H NMR (CDCl3, 400 MHz): 9.16 (t,

J = 2 Hz, 1 H), 9.12 (d, J = 2 Hz, 2 H), 7.29 (m, 2 H) 6.95 (m, 3 H), 4.83 (m, 1 H), 4.72 (dd, J =

9.6, 8.4 Hz, 1 H), 4.62 (dd, J = 8.4, 7.2 Hz, 1 H) 4.28 (dd, J = 9, 4 Hz, 1 H), 4.13 (dd, J = 9, 6 Hz,

1H); 13

C NMR (CDCl3, 100 MHz): 161.55, 158.39, 148.55, 131.25, 129.58, 128.37, 121.42,

120.99, 114.59, 71.43, 68.93, 66.56; IR (NaCl Plate): 3099, 2925, 1543, 1344 cm-1

.

4-((benzyloxy)methyl)-2-(3,5-dinitrophenyl)-4,5-

dihydrooxazole (60). Reaction performed by representative

procedure beginning with 107 mg of the corresponding

aziridine. Purification was performed by flash column silica

gel chromatography (75% hexanes, 25% ethyl acetate) yielding 68 mg (67%) of oxazoline.

HRMS: Calculated for C17H15N3O6: 358.1039 (M+H+), found 358.1043 (M+H

+);

1H NMR

(CDCl3, 400 MHz): 9.13 (t, J = 2.4 Hz, 1 H), 9.09 (d, J = 2 Hz, 2H), 7.31 (m, 5 H), 4.61 (m, 4

H), 4.47 (m, 1 H), 3.76 (dd, J = 4.4, 2.4 Hz), 3.64 (dd, J = 10, 5.2 Hz); 13

C NMR (CDCl3, 100

MHz): 161.08, 148.49, 137.76, 131.44, 128.48, 128.30, 127.87, 127.75, 120.82, 77.39, 77.07,

76.76, 73.53, 71.46, 71.26, 67.08; IR (NaCl Plate): 3099, 2919, 1543, 1344 cm-1

.

2-(3,5-dinitrophenyl)-4-isopropyl-4,5-dihydrooxazole17

(56). Reaction

performed by representative procedure beginning with 84 mg of the

corresponding aziridine. Purification was performed by flash column silica

gel chromatography (83% hexanes, 17% ethyl acetate) yielding 67 mg

(80%) of oxazoline. Calculated for C12H13N3O5: 280.0933 (M+H+), found 280.0933 (M+H

+);

1H

NMR (CDCl3, 400 MHz): 9.14 (t, J = 2.4 Hz, 1 H), 9.10 (d, J = 2.4 Hz, 2 H), 4.56 (dd, J = 9.2, 8

37

Hz, 1 H), 4.22 (m, 2 H), 1.90 (m, 1 H), 1.07 (d, J = 6.8 Hz, 3 H), .98 (d, J = 6.8 Hz); 13

C NMR

(CDCl3, 100 MHz): 159.61, 148.51, 131.74, 128.19, 120.63, 73.23, 71.46, 32.86, 18.81, 18.31;

IR (NaCl Plate): 2961, 1656, 1544, 1344 cm-1

.

Procedure for the rearrangement of an enantioenriched aziridine

The enantiopure aziridine 65 (0.2 mmol, 56 mg) and 9.5 mg (0.02 mmol) of X-Phos (40)

were weighed into an oven-dried reaction vial. Dry tetrahydrofuran (1 mL) was added under

argon. The solution was heated at 70 °C under argon for 24 hours. Volatiles were removed by

rotary evaporator. The crude reaction mixture was purified via flash column silica gel

chromatography (83% hexanes, 17% ethyl acetate) to form 53 mg (94%) of the enantiopure

oxazoline 66 as a white solid. The NMR data for enantiopure oxazoline was identical to (56).

Enantiomers of the starting aziridine and oxazoline were separated using a Chiralpak I-B column

(Daicel Chemical Ind.) on HPLC with 85% hexanes, 15% isoproanol as the mobile phase.

2

Chapter 2: KINETIC RESOLUTION OF N-ACYL AZIRIDINES

39

INTRODUCTION

Over the past few decades there has been an increased interest in the generation of bio-

active organic compounds that are single enantiomers. A vast majority of these compounds

contain a carbon–nitrogen bond. Since aziridines possess a chiral carbon and two reactive

carbon–nitrogen bonds, they are key intermediates for the synthesis of chiral bio-active

molecules. Despite their importance in synthesis, methods to produce aziridines as single

enantiomers remains underdeveloped. Progress has been made with aziridine synthesis but

generation in enantiopure form is still a formidable challenge.18-23

There are known synthetic

routes from alkenes to aziridines,24-32

some of which are catalytic enantioselective routes. These

utilize a small range of substrates which thereby decreases the usefulness of the resulting

aziridine. Kinetic resolution of racemic aziridines to form enantiopure aziridines is a viable

solution to the problem.

A kinetic resolution is a process in which one of the two enantiomers of a racemic

mixture is more readily converted to product than the other (Figure 14). In order for a kinetic

resolution to occur kR ≠ kS and the reaction is halted between 0 and 100% conversion. The

desired reaction is one in which only one enantiomer reacts (kS>>kR), in such that 50%

conversion of a mixture yields 50% R enantiomer and 50% product Q. Either a chiral catalyst or

chiral reagent is utilized to effect the difference in rate constants.33

Figure 14: Kinetic resolution of two enantiomers.

40

Efficiency of a kinetic resolution is given by the rate constant ratio krel= k1/k2 = s (s is the

stereoselectivity value). This stereoselectivity value (s) can be calculated by using equation 5 or

6, where c is equivalent to conversion (0≤c≤1), eesm and eeprod (0≤eesm, eeprod ≤ 1) are

enantiomeric excesses of the product and starting material.34

Kinetic resolution has revolutionized asymmetric synthesis for epoxides, the oxygen

containing heterocycle equivalent of aziridines, despite a maximum yield of only 50%. The

Jacobsen hydrolytic kinetic resolution (HKR)35

is an efficient route to enantiopure terminal

epoxides which are useful intermediates for further synthesis (Figure 15). The HKR produces

epoxides with very high krel values (as high as 1000). The racemic epoxides are readily produced

from alkenes in a single step synthetic step.

Figure 15: Jacobsen Hydrolytic Kinetic Resolution

Leung and coworkers have reported a kinetic resolution of racemic N-tosyl aziridines

using a chiral dicationic Pd(II) complexes (74, Figure 16). By treating a racemic N-tosyl

41

aziridine (75) with 0.5 equivalents of alcohol while in the presence of 10 mol % of 74, they were

able to isolate 2-alkoxy tosylamide 76 with a minor product of 2-hydroxy tosylamide 77 (Figure

17).36

The highest observed selectivity value was 8, with a majority of substrates leading to

lower values.

Figure 16: Palladium Catalyst

Figure 17: Pd-Catalyzed Asymmetric Alcoholysis

Even though aziridines and epoxides are analogues of one another their reactivity is

quite different.37

One of the complexities with developing asymmetric reactions of aziridines is

linked to the nitrogen-bound protecting group that is required to facilitate opening of the

aziridine ring. Binding of a Lewis acid to the aziridine is preferred but sites on the protecting

group that are Lewis basic often interfere with this binding. For this reason, the previously

mentioned Jabcobsen’s kinetic resolution has not been successful with aziridines.

Aziridines can be opened in the presence of aryl borates. Aziridine 78 will undergo a

ring opening when in the presence of aryl borates to yield 79 and 80 as a mixture of phenol

42

adducts (Figure 18).38

Using similar reaction conditions39

, aziridines will undergo a reaction to

selectively form a new carbon–carbon bond thereby generating only the ortho-phenol derivative.

Knowing that borates would open aziridines we thought if we could introduce chirality into the

reaction we would be able to effect a resolution.

Figure 18: Aziridine opening by borates.

Chiral borates have been used to aid both Diels–Alder40-45

and Mukiayama aza-aldol

reactions.46-47

Most of these reactions are aryl borates with the source of chirality from BINOL.

Yamamoto and coworkers early work was with borate 82. This was generated by mixing 1

equivalent of BINOL with 1 equivalent of triphenyl borate (B(OPh)3). Further research by

Yamamoto discovered that 1 equivalent of BINOL and 0.5 equivalents of B(OPh)3 generated

borate 83. The structure of 83 has been verified by X-ray crystallography.

43

Figure 19: Borate synthesis.

RESULTS AND DISCUSSION

Research on the resolution of aziridines began with the exploration of reaction conditions

and varying substrates. The resolution chemistry involves the addition of triphenyl borate

(B(OPh)3) to a solution (R)-BINOL and aziridine. Triphenyl borate is extremely air/moisture

sensitive, so a solution is prepared in a glove box. This solution is then added to the

aziridine/BINOL solution slowly as to maintain the reaction temperature. The reaction is

allowed to run at the determined temperature and time and is then quenched with methanol.

Passing the reaction mix through a silica plug is used to remove any residual borate, and the

yield is determined by 1H-NMR and the use of 1,3,5-trimethoxybenzene as an internal standard.

Conversion, which is necessary for the selectivity (s) value calculation, is reported as % yield.

Concentration of the reaction mixture without removal of boron using silica gel lead to higher

conversions. Calculations are exactly the same as shown previously. Enantiomeric excess was

determined by HPLC with the use of a chiral column. HPLC conditions were determined by

44

running a racemic mix of the aziridine and adjusting solvent polarity until the desired resolution

was achieved.

All of the initial work on resolution project was performed by another graduate student

(Mr. Jared Arnette) as seen in Table 6. Research on the resolution of aziridines started with the

addition of a solution of triphenylborate (B(OPh)3) to (R)-BINOL 81 and aziridine 84 in

dichloromethane at -78 °C (Table 5). Early data suggested that the use of polar, aprotic solvents

resulted in very poor reactivity. N-acyl aziridines and N-acyloxy aziridines exhibited a fast ring

opening reaction when reacted with BINOL at -78°C (entries 1–3). Replacing B(OPh)3 with

trimethyl borate (B(OCH)3) generated no consumption of aziridine. The nitrogen protecting

group greatly affects the selectivity. N-Acylaziridines exhibit the best of both conversion and

selectivity (entries 1 and 2). A carbamate exhibited no enantiomer selectivity but had excellent

reactivity (entry 3). Currently it is not apparent if electronics or sterics are responsible for

optimal selectivity.

The substituent that is attached to the carbon backbone may affect the selectivity (s)-

value. Two substrates were synthesized to consider aziridine substitution. It was a delighting

discovery to find that increases the size of R also resulted in an increase in the s-value for N-

acylaziridines (entries 5 and 6). The 3,5-dinitrobenzoyl protecting group was superior to the 3,5-

bis(trifluoromethyl)benzoyl group (entry 7). With this preliminary data in hand, further

experiments were designed for reaction optimization.

45

Table 5: Kinetic resolution initial experimental results.

Further experimental exploration involved the kinetic resolution of different aziridines

with varying substitutions under a set of standard conditions. Since the dinitro-protected

aziridines provided the most promising results, this group was used with varying substituted

aziridines that were synthesized. Experimental exploration began with a long chain hexyl

substituted aziridine (Table 6).

The initial run with a 2-hexyl aziridine was performed under standard conditions for 3

hours and was quite promising with an enantiomeric excess of 83% (entry 1). The s-value was

encouraging at 28. Considering that solubility may be an issue, several experiments were run

with dichloromethane (DCM) instead of toluene (entries 2–4). All other experimental conditions

were held constant. Employing DCM resulted in a higher conversion, a higher enantiomeric

46

excess, but unfortunately a significantly lower s-value. In light of these results we returned to

toluene as the reaction solvent (entries 5 and 6). In an attempt to increase the enantiomeric

excess, the catalyst amount was increased from 0.1 equivalents to 0.2 equivalents (entries 7–9).

The initial run was promising with an enantiomer excess of 89.9% and a surprising s-value of

47.0. We were skeptical of this result with the large increase in s-value compared to previous

data. The following experiments demonstrated that the enantiomeric excess could be increased

and the s-value maintained.

47

Table 6: Experimental results long chain substituted aziridine.

The next substrate to be explored was a tert-butyl substituted aziridine with the di-nitro

protecting group (Table 7). The initial run was performed at room temperature, instead of the

normal lowered temperature because the substrate had low solubility in toluene. The results of

the first run were disappointing (entry 1). Due to the low conversion, the enantiomeric excess

and s-value were not determined. We considered the low solubility may be hindering reactivity,

so the solvent was switched to DCM in an attempt to get the aziridine to fully dissolve (entry 2).

After 30 minutes at -20 °C only 13.4% conversion was observed. Due to these initial findings

and the availability of other substrates no further effort was spent on this compound.

48

Table 7: Experimental results tert-butyl aziridine.

Further exploration was attempted with a benzyl substituted aziridine containing the di-

nitro protecting group (Table 8). The initial run was performed at room temperature for only 30

minutes resulting in a very high conversion of the aziridine, but with a low selectivity (entry 1).

The temperature was then lowered in an attempt to decrease the amount of conversion (entry 2).

The lower temperature definitely slowed the conversion, but it also negatively impacted the

enantiomeric excess. There was also minimal improvement of the selectivity given by the small

increase in the s-value. We then dropped the temperature to -40 °C and increased the reaction

time to 1 hour (entries 3 and 4). The results of these two runs were not positive. Further

reactions were run at -40 °C under the standard 3 hour reaction time (entries 5–8). The results of

these runs were somewhat inconsistent but none of the resulting were outstanding. One run

looked promising with an enantiomeric excess of 93% and an s-value of 13.3 (entry 5).

However, repeated attempts could not reproduce this result.

49

Table 8: Experimental results O-benzyl aziridine.

The next substrate explored was an isopropyl substituted di-nitro protected aziridine,

(Table 9). The researchers were very excited with the high enantiomeric excess (ee) and s-value

of the first run (entry 1). Based on these high values, the reaction time was reduced to 1 hour

(entry 2). This resulted in a large s-value with a reduced ee. This particular run was repeated in

an attempt to duplicate the results; however, experimental error resulted in a negative s-value

(entry 3).

50

Table 9: Experimental results isopropyl substituted aziridine.

Efforts were then placed on the resolution of a methyl substituted aziridine with the di-

nitro protecting group. The results of these experiments appear in Table 10. This substrate was

challenging in that it was difficult to get reproducible results. Four runs were performed at the

standard 3 hour reaction time (entries 1–4). The values for conversion and ee were inconsistent

and the selectivity is very poor as well. For two of the runs the ee and s-value were not

determined because of the high conversion numbers (entries 3 and 4). In an attempt to lower the

conversion and hopefully increase the selectivity, the reaction time was lowered to one hour

(entry 5 and 6). This effectively lowered the conversion and generated results that seem to be

reproducible. The selectivity was so low that no further experiments were run with this

substrate.

51

Table 10: Experimental results methyl aziridine.

The final substrate for which reaction optimization experiments were performed was a

long chained alkene substituted aziridine with the di-nitro protecting group Table 11. Initial

reactions were run under the normal 3 hour reaction time (entries 1 and 2). Unfortunately, this

resulted in high conversion, with high ee and a very poor selectivity. The reaction time was

lowered to 2 hours to bring the conversion down (entries 3 and 4). This worked in lowering the

conversion. For both runs the ee was high but the s-value could not be determined for entry 3.

52

Table 11: Experimental results long chain terminal alkene substituted aziridine.

Substrate Scope

Once optimized conditions were realized, efforts were placed on determining values

based on isolated yields of compounds. Unfortunately due to time constraints values for only 2

substrates were realized.

Table 12: Experimental isolated results for isopropyl substituted aziridine.

53

Table 13: Experimental isolated results for long chain alkene substituted aziridine.

Conclusions

Here we have demonstrated a new pathway for the resolution of racemic acyl aziridines

to their enantioenriched counterpart, using a borate and (R)-BINOL. A variety of N-acyl

aziridines were explored under these conditions with varying success. The enantioenriched

aziridines may prove to be useful in further asymmetric synthesis of new compounds.

54

EXPERIMENTAL

General. 1H NMR spectra were recorded on Bruker DRX (400 MHz). Chemical shifts are

reported in ppm from tetramethylsilane with the solvent resonance as the internal standard

(CDCl3: 7.27 ppm). Data are reported as follows: chemical shift, integration, multiplicity (s =

singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constants (Hz),

and assignment. 13

C NMR spectra were recorded on a Bruker DRX 400 (100 MHz) and a

Bruker DRX 600 (NSF #0821552) spectrometer with complete proton decoupling. Chemical

shifts are reported in ppm from tetramethylsilane with the solvent as the internal standard

(CDCl3: 77.0 ppm). High resolution mass spectrometry was acquired with an Agilent DART-

TOF at Duke University. Infrared (IR) spectra were obtained using a Nicolet 6700 FT-IR.

Liquid chromatography was performed using forced flow (flash chromatography) on

EMD Chemicals Geduran® 60 silica gel (SiO2, 40 to 63m) purchased from VWR International.

Thin layer chromatography (TLC) was performed on EMD Chemicals 0.25 mm silica gel 60

plates. Visualization was achieved with UV light or basic potassium permanganate in water

followed by heating.

All reactions were conducted in oven and flame dried glassware under an inert

atmosphere of nitrogen. All solvents were EMD Chemicals anhydrous solvents sold by VWR

International. Each solvent was purged with Argon for a minimum of 15 minutes and stored

over activated 3Å molecular sieves in sure-seal bottles. All remaining chemicals were purchased

from Alfa Aesar, TCI International, or Aldrich Chemical Company and were used as received.

HPLC Methodology

55

Enantiomers of the starting aziridine and enantioenriched aziridine product were separated using

a Chiralpak I-B column (Daicel Chemical Ind.) on HPLC with varying mobile phases of

hexanes, isopropanol.

Reaction Optimization

An oven dried vial with stir bar was charged with the corresponding aziridine (1 equiv.)

and (R)-BINOL (0.55 equiv.). Dry toluene (0.2 M) was then added via syringe. The solution

was then allowed to cool down to the reaction temperature. A stock solution of B(OPh)3 (0.1

equiv.) in toluene (26 µL) was added to the aziridine solution dropwise over several minutes.

Once all of the borate was added the solution was allowed to stir at temperature for 3 hours. The

reaction was then quenched with methanol (5 equiv.) and diluted with hexanes. The solution

was passed through a small silica plug and eluted with a solution 9:1 hexanes/ethyl acetate.

Percent yields were then determined by 1H-NMR and the use of an internal standard (1,3,5-

trimethoxybenzene). Enantiomeric excess was determined by HPLC and the use of a chiral

column.

Experimental conditions of isolated yields

(3,5-dinitrophenyl)(2-isopropylaziridin-1-yl)methanone (Table 12) The

representative procedure was followed using 111.7 mg of the corresponding

aziridine and 62.9 mg of (R)-BINOL. A solution of B(OPh)3 (93 mg) in toluene

(250 µL, 0.2 M) was prepared in an oven dried vial within a glove box.

Approximately 27 µL of this solution was added to the aziridine solution dropwise over several

minutes. Purification was performed by flash column silica gel chromatography (84% hexanes,

16% ethyl acetate) yielding 58.5 mg (52.3%) of enantiopure aziridine. 1H-NMR data as

56

described in Chapter 1. Enantiomers were separated by HPLC using a IB Chiral column with

85% hexanes and 15% Isopropanol with a flow rate of 1 mL/min.

Figure 20: HPLC of racemic aziridine (left) and enantioenriched (right).

(3,5-dinitrophenyl)(2-(hex-5-en-1-yl)aziridine-1-yl)methanone (Table 13)

The representative procedure was followed using 127.6 mg of the

corresponding aziridine and 62.9 mg of (R)-BINOL. A solution of B(OPh)3

(93 mg) in toluene (250 µL, 0.2 M) was prepared in an oven dried vial within

a glove box. Approximately 27 µL of this solution was added to the aziridine solution dropwise

over several minutes. Purification was performed by flash column silica gel chromatography

(80% hexanes, 20% ethyl acetate) yielding 21.1 mg (16.5%) of enantiopure aziridine. 1H-NMR

data as described in Chapter 1. Enantiomers were separated by HPLC using a IB Chiral column

with 85% hexanes and 15% Isopropanol with a flow rate of 1 mL/min.

57

Figure 21: HPLC of racemic aziridine (left) and enantioenriched (right).

58

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APPENDIX

Appendix 1.

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Appendix 2.

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Appendix 3.

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Appendix 4.

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Appendix 5.

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Appendix 6.

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Appendix 58.