NEW SYNTHETIC METHODOLOGIES FOR ACCESS TO 5-MEMBERED
HETEROCYCLES
By
Michael Robert Kuszpit

A DISSERTATION
Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of
Chemistry-Doctor of Philosophy
2013

ABSTRACT
NEW SYNTHETIC METHODOLOGIES FOR ACCESS TO 5-MEMBERED
HETEROCYCLES
By
Michael Robert Kuszpit
The majority of the work in this dissertation presents a new synthetic methodology to
synthesize an imidazoline from either a chiral or a racemic aziridine. The purpose of
synthesizing imidazolines is for their known biological activity. Previous research in the
Tepe group has developed a method to diastereoselectively synthesize racemic
imidazolines from the trimethyl silyl chloride mediated cycloaddition of imines with
azlactones. This methodology allowed access to a variety of imidazolines that have been
shown to inhibit NF-κB mediated gene transcription. NF-κB is a nuclear transcription
factor of activated B cells found in almost all animal cell types. It is a protein complex,
that binds to certain DNA sequences and controls the transcription of genes. An SAR
study has been conducted in our research group on this class of compounds. The ability of
the imidazolines to inhibit NF-κB mediated gene transcription was measured by an assay
on human cervical epithelial (HeLa) cells and human whole blood. The results of these
studies have determined which functional groups were essential for efficient inhibition of
NF-κB. These studies have also determined that one imidazoline enantiomer was a much
more potent inhibitor than the other. Although our research group had created a
diastereoselective method to synthesize imidazolines, there was still not a method to
synthesize chiral imidazolines. Due to the cost, time, and inefficiencies of separation of
racemic imidazolines by chiral HPLC or by other resolution methods an enantioselective
method was needed. This thesis represents the progress towards an enantioselective

synthesis of imidazolines. New synthetic methodologies to access an oxazolidin-2-one
and an amino alcohol have been developed. In addition progress toward new synthetic
methodologies to access guanidine heterocycles and diamines will also be discussed.

This dissertation is dedicated to my wife, Beth Kuszpit who has always stood by my side,
as well as my brother, Greg Kuszpit, and my parents Sandra Kuszpit and Kenneth
Kuszpit who have always supported me in everything I have pursued in my life.

iv

ACKNOWLEDGEMENTS

I would like to thank my wife, Beth Kuszpit, I would not have made it through
graduate school without her support and love. I would also like to thank my father, Ken
Kuszpit, my mother Sandy Kuszpit and my brother, Greg Kuszpit, for their support and
encouragement.
I would also like to thank my advisory committee Dr. Aaron Odom, Dr. James
Jackson, and Dr. William Wulff. They were always available for any questions I had
throughout my research here at MSU. Thank you, Dr. Wulff, for our conversations about
aziridine ring expansion chemistry it was very helpful and helped me with my chemistry.
In addition thank you for giving me VANOL and VAPOL catalysts necessary to conduct
my research.
I would also like to acknowledge Aman Kulshrestha, Munmun Mukherjee, Aman
Desai, and Anil Gupta, who were extremely helpful in conversations about my research.
I would like to express my gratitude to current and former members of the Tepe group for
their help and support. Dr. Jason Fisk, Dr. Adam Mosey, and Dr. Daljinder Kahlon were
particularly helpful when I first started research. I would like to thank Nicole Hewlett,
Brandon Dutcher, and Rahmen Saleem; I really enjoyed the time I spent with them and I
wish them the best. I would also like to thank Tom Jurek who has been a great new
friend that I have made here at MSU.
Lastly I would like to express my gratitude to my graduate advisor, Dr. Jetze J.
Tepe, for giving me the opportunity to conduct research in his group. He took time to
listen to my thoughts about my career and my research project. I liked Dr. Tepe’s

v

research style, he allowed me to pursue my own ideas and learn from my mistakes. I
believe this research style was the best way for me to grow as a scientist. He has a great
sense of humor and I always enjoyed cracking jokes with him. Sometimes they were
jokes at the expense of others, but it was all in good fun. He is also a person that I
respect and admire.

vi

TABLE OF CONTENTS

LIST OF TABLES……………...…………………………………..………………….….viii
LIST OF FIGURES ………….…………………………………………………...……..…iv
LIST OF SCHEMES …………….………………………………………….……….........xiv
KEY TO ABBREVIATIONS…..……….…………………...……………………..........xvi
CHAPTER 1
INHIBITION OF NF-κB GENE TRANSCRIPTION BY IMIDAZOLINES…….…….....1
REFERENCES…………….…….………………………..………..……..............12
CHAPTER 2
RING EXPANSION OF AN AZIRIDINE AND AN
AZETIDINE WITH VARIOUS ELECTROPHILES……………………….....……........15
APPENDIX..…………............…..…..………………………………..….............38
REFERENCES ……………………………….……………...…..……...…..........67
CHAPTER 3
REACTION OF BROMINE REAGENTS WITH
OLEFINS AND SYNTHESIS OF HETEROCYCLES……………...…………….……..71
APPENDIX..…………………………………………………………..................117
REFERENCES ……………………………….…………………...…...…...........160
CHAPTER 4…………………………………………………………………...…...........165
APPENDIX………………………………………………….……………….…..177
REFERENCES ………………………………………………………..…....…....244

vii

LIST OF TABLES

Table 2-1:

Lewis acid isomerization of an imidoyl aziridine to an imidazoline ..........17

Table 2-2:

Optimization of one pot aziridine ring expansion to an imidazoline….......19

Table 2-3.

Variation at R3, R4, and R5 of the aziridine ring…………………………..22

Table 2-4:

Attempted synthesis of (E)-N-methylformimidoyl chloride ……………...36

Table 3-1:

Reaction of pyrrole amides with cyclohexene…………………………......74

Table 3-2:

Reaction of NBS with benzamide and cyclohexene…………………….....78

Table 3-3:

Study on the reaction of NBS with styrene……………….…………….....82

Table 3-4:

Bromination of benzamide………………………………………..........….86

Table 3-5:

Bromination of amides and imides…………………………………….…..87

Table 3-6:

Reaction of N-bromo amides and N-bromo imides with styrene….............89

Table 3-7:

Br-N(CO2Me)2 addition to olefins…………………………….……..........90

Table 3-8:

Synthesis of methyl 2-oxooxazolidine-3-carboxylate……………..............93

Table 3-9:

Hydrolysis of methyl 2-oxooxazolidine-3-carboxylate…………………....96

Table 3-10: Attempted halogenation of oxooxazolidine-3-carboxamides…….…..........99
Table 3-11: Reaction optimization of addition of 3-83 to 3,4-dihydro-2H-pyran.........103
Table 3-12: Addition reaction of N-bromourea with enol ethers and enamines............104

viii

LIST OF FIGURES

Figure 1-1:

Compounds 1-1 and 1-1a ……………………………………………...…..4

Figure 1-2:

Compounds 1-2 and 1-2a………………………………………………..…6

Figure 1-3:

Nanomolar imidazoline proteasome inhibitors……………………….........7

Figure 1-4:

Proposed new proteasome scaffold…………………………………….….9

Figure 1-5:

Urea and guanidine ring containing natural products………………….…10

Figure 2-1:

Determination of ee of compound 2-6 by Mosher’s Acid………………..24

Figure 2-2:

X-ray crystallography of compound 2-18………………………...………25

Figure 2-3:

Nanomolar 20S Proteasome inhibitors 2-26, 2-27, 2-28 …………...…....30

Figure 2-4:

Manzacidin natural products……………………………………………...32

Figure 2-5:

X-ray crystallography of compound 2-47…………………………….......35

Figure 3-1:

Biologically significant natural products…………………………………72

Figure 3-2:

Urea and guanidine ring containing natural products………….………..101

Figure 3-3:

NMR data for compound 3-83………………………………………......113

Figure 3-4:

Experimental data for compounds 3-101 and 3-102 by Castro…………114

Figure 4-1:

Synthetic strategy to access important natural
products through the SN2’ reaction……………………………………..167

Figure 4-2: Proposed new bromine reagents for the synthesis of new heterocycles....169
1

Figure 4-3: H NMR spectrum for compound 2-16…………………………………...178
Figure 4-4:

13

C NMR spectrum for compound 2-16…………………………………..179

1

Figure 4-5: H NMR spectrum for compound 2-17…………………………………...180

ix

Figure 4-6:

13

C NMR spectrum for compound 2-17…………………………………...181

1

Figure 4-7: H NMR spectrum for compound 2-18………………………………..…...182
Figure 4-8:

13

C NMR spectrum for compound 2-18……………………………..….....183

1

Figure 4-9: H NMR spectrum for compound 2-19 regioisomer 1…………………….184
Figure 4-10:

13

C NMR spectrum for compound 2-19 regioisomer 1……………….….185

1

Figure 4-11: H NMR spectrum for compound 2-19 regioisomer 2…………………...186
Figure 4-12:

13

C NMR spectrum for compound 2-19 regioisomer 2…………………..187

1

Figure 4-13: H NMR spectrum for compound 2-20……………………………….......188
Figure 4-14:

13

C NMR spectrum for compound 2-20……………………………….....189

1

Figure 4-15: H NMR spectrum for compound 2-21…………………………………...190
Figure 4-16:

13

C NMR spectrum for compound 2-21……………………………..…...191

1

Figure 4-17: H NMR spectrum for compound 2-22…………………………………...192
Figure 4-18:

13

C NMR spectrum for compound 2-22……………………………..…...193

1

Figure 4-19: H NMR spectrum for compound 2-23……………………………..…....194
Figure 4-20:

13

C NMR spectrum for compound 2-23…………………………….…....195

1

Figure 4-21: H NMR spectrum for compound 2-16………………………………......196
Figure 4-22:

13

C NMR spectrum for compound 2-16……………………………..…...197

1

Figure 4-23: H NMR spectrum for compound 3-18………………………………......198
x

Figure 4-24:

13

C NMR spectrum for compound 3-18……………………………….....199

1

Figure 4-25: H NMR spectrum for compound 3-34………………………………......200
Figure 4-26:

13

C NMR spectrum for compound 3-34……………………………….....201

1

Figure 4-27: H NMR spectrum for compound 3-47………………………………......202
Figure 4-28:

13

C NMR spectrum for compound 3-47……………………………….....203

1

Figure 4-29: H NMR spectrum for compound 3-52………………………………......204
Figure 4-30:

13

C NMR spectrum for compound 3-52……………………………….....205

1

Figure 4-31: H NMR spectrum for compound 3-53………………………………......206
Figure 4-32:

13

C NMR spectrum for compound 3-53……………………………….....207

1

Figure 4-33: H NMR spectrum for compound 3-54………………………………......208
Figure 4-34:

13

C NMR spectrum for compound 3-54……………………………….....209

1

Figure 4-35: H NMR spectrum for compound 3-56………………………………......210
Figure 4-36:

13

C NMR spectrum for compound 3-56……………………………….....211

1

Figure 4-37: H NMR spectrum for compound 3-57………………………………......212
Figure 4-38:

13

C NMR spectrum for compound 3-57……………………………….....213

1

Figure 4-39: H NMR spectrum for compound 3-58…………………………………...214
Figure 4-40:

13

C NMR spectrum for compound 3-58……………………………….....215

1

Figure 4-41: H NMR spectrum for compound 3-63…………………………………..216
xi

Figure 4-42:

13

C NMR spectrum for compound 3-63…………………………….…...217

1

Figure 4-43: H NMR spectrum for compound 3-64……………………………..…...218
Figure 4-44:

13

C NMR spectrum for compound 3-64………………………………...219

1

Figure 4-45: H NMR spectrum for compound 3-65……………………………….....220
Figure 4-46:

13

C NMR spectrum for compound 3-65………………………………....221

1

Figure 4-47: H NMR spectrum for compound 3-66……………………………….....222
Figure 4-48:

13

C NMR spectrum for compound 3-66………………………………....223

1

Figure 4-49: H NMR spectrum for compound 3-67……………………………….....224
Figure 4-50:

13

C NMR spectrum for compound 3-67………………………………....225

1

Figure 4-51: H NMR spectrum for compound 3-68……………………………….....226
Figure 4-52:

13

C NMR spectrum for compound 3-68………………………………....227

1

Figure 4-53: H NMR spectrum for compound 3-70…………………………….…....228
Figure 4-54:

13

C NMR spectrum for compound 3-70………………………………...229

1

Figure 4-55: H NMR spectrum for compound 3-71……………………………..…...230
Figure 4-56:

13

C NMR spectrum for compound 3-71………………………………...231

1

Figure 4-57: H NMR spectrum for compound 3-72……………………………….....232
Figure 4-58:

13

C NMR spectrum for compound 3-72………………………………....233

1

Figure 4-59: H NMR spectrum for compound 3-77……………………………….....234
xii

Figure 4-60:

13

C NMR spectrum for compound 3-77………………………………....235

1

Figure 4-61: H NMR spectrum for compound 3-78………………………………...,,236
Figure 4-62:

13

C NMR spectrum for compound 3-78………………………………...237

1

Figure 4-63: H NMR spectrum for compound 3-79………………………………....238
Figure 4-64:

13

C NMR spectrum for compound 3-79………………………………...239

1

Figure 4-65: H NMR spectrum for compound 3-89………………………………....240
Figure 4-66:

13

C NMR spectrum for compound 3-89………………………………...241

1

Figure 4-67: H NMR spectrum for compound 3-90…………………………….…...242
Figure 4-68:

13

C NMR spectrum for compound 3-90………………………………...243

xiii

LIST OF SCHEMES

Scheme 1-1: Activation of NF-κB pathway……………………………………………....3
Scheme 1-2: Resolution of compounds 1-1 and 1-1a………………………………….....5
Scheme 1-3: Possible mechanism for non-competitive covalent 20S
proteasome inhibitition…………………………………………………..….8
Scheme 1-4: General synthesis of a guanidine, oxazolidin-2-one, an urea, a diamine
and an amino alcohol via addition to an olefin with bromine reagents…...11
Scheme 2-1: Synthesis of aziridine invertomers …………………………………..........16
Scheme 2-2: Synthesis of enantiopure 2-6 and racemic imidazoline 2-6………….…….23
Scheme 2-3: Proposed reaction mechanism for imidazoline synthesis……………….....26
Scheme 2-4: Proposed synthesis of TCH-013. ………………………………..……......28
Scheme 2-5: Proposed synthesis of 26S proteasome inhibitors ………………………..30
Scheme 2-6: Attempted ring expansion of 2-2 with ethyl benzimidate•HCl…………...31
Scheme 2-7: Synthesis of cis and trans diethyl azetidine-2,4-dicarboxylate……….…..33
Scheme 2-8: Attempted synthesis of tetrahydropyrimidine 2-46………………….…....34
Scheme 2-9: Attempted synthesis of tetrahydropyrimidine 2-50…………………….....37
Scheme 3-1: Proposed synthesis of biologically significant natural products……….....72
Scheme 3-2: Reaction of 3-5 with cyclohexene and NBS……………………………....75
Scheme 3-3: Synthesis of compound 3-9 by Zhoa and coworkers……………………...76
Scheme 3-4: Intramolecular oxygen cyclization…………………………………….......79
Scheme 3-5: Nitrogen cyclization versus oxygen cyclization via HSAB theory……......81
Scheme 3-6: Proposed mechanism for addition of NBS to styrene…………………......83
Scheme 3-7: Synthesis of important organic building blocks
from an 1-bromo, 2-N-amide……………………………………................84
xiv

Scheme 3-8: Proposed reaction mechanism for formation of methyl
2-oxooxazolidine-3-carboxylate via a bromonium ion...............................97
Scheme 3-9: Attempted diastereoselective synthesis with Evan’s auxillary………......100
Scheme 3-10: Addition of 1-bromo-1,3-dimethylurea to 3,4-dihydro-2H-pyran…........102
Scheme 3-11: Enol ether alpha bromination mechanism……………………..…….…..106
Scheme 3-12: SN2’ reaction mechanism for the addition of 3-81 with
an enol or enamine with 3,4-dihydro-2H-pyran as an example………....107
Scheme 3-13: Bromonium mechanism for the cycloaddition of 3-81 with an enol
ether or an enamine with 3,4-dihydro-2H-pyran as an example………...108
Scheme 3-14: Bromoniun mechanism and ring closure through AgOTf abstraction......110
Scheme 3-15: Rreaction mechanism for addition of an enol ether with a
N-bromourea and ring closure with AgOTf……………………………...111
Scheme 3-16: Formation of a methyl 2-oxooxazolidine-3-carboxylate
through a SN2’ mechanism……………………………….………….…..115
Scheme 4-1: Possible mechanism for the synthesis of compound 4-7………….……. 166
Scheme 4-2: Synthesis of compound 4-16………………………………………....…..170
Scheme 4-3: Proposed synthesis of isourea and urea heterocycles……………….…...171
Scheme 4-4: Proposed synthesis of guanidine heterocyle 4-23…………………….…172
Scheme 4-5: Proposed synthesis of urea heterocyle 4-26………………………….….173
Scheme 4-6: Addition of TsNH2 to an alpha beta unsaturated olefin……………....…174
Scheme 4-7: Proposed synthesis of oxazolidin-2-ones from Alpha,
beta unsaturated aldehydes……...............................................................175

xv

KEY TO ABBREVIATIONS

BF3•O(Et)2: Boron trifluoride diethyl etherate
Bh:

Benzhydryl

DABCO:

1,4-diazabicyclo[2.2.2]octane

DCE:

Dichloroethane

DCM:

Dichloromethane

DMAP:

4-dimethylamino pyridine

DME:

Dimethoxy ethane

DMF:

Dimethyl formamide

DMSO:

Dimethyl sulfoxide

DNA:

Deoxyribonucleic acid

EC50:

Half maximal effective concentration

EDCI:

Ethyldimethylaminopropyl carbodiimide

HeLa:

Human cervical epithelial

HRMS:

High resolution mass spectrometry

I-κB:

Inhibitory kappa B

LA:

Lewis Acid

MsOH:

Methanesulfonic acid

NBS:

N-Bromosuccinimide

NCS:

N-Chlorosuccinimide

NIS:

N-Iodosuccinimide

NF-κB:

Nuclear transcription factor kappa B
xvi

SAR:

Structure activity relationship

TfOH:

Triflic acid

THF:

Tetrahydrofuran

TNF-α:

Tumor necrosis factor alpha

Ts:

Tosyl

TMSCl:

Trimethylsilyl chloride

TEA:

Triethylamine

TCICA:

Trichloroisocyanuric acid

TBICA:

Tribromoisocyanuric acid

xvii

CHAPTER 1
INHIBITION OF NF-κB GENE TRANSCRIPTION BY IMIDAZOLINES AND
RELATED HETEROCYCLES
Apoptosis (programmed cell death) is a defense mechanism to remove infected,
1,2

mutated, or damaged cells from the body.

Traditional cancer treatment uses ionizing

radiation or chemotherapy to induce apoptosis in cancer cells.

1,2

One example of a

chemotherapy drug is camptothecin which is a DNA topoisomerase I inhibitor and induces
a stable ternary topoisomerase I-DNA cleavable complex.

1,2

This complex is recognized

as damaged DNA and initiates a programmed cell death signaling pathway.

1,2

Another

chemotherapy drug, cisplatin, covalently bonds to DNA base pairs, which induces a similar
signaling pathway to that of camptothecin.

1,2

Unfortunately, camptothecin and cisplatin

also initiate DNA repair signaling pathways. Cellular resistance is, in part, the result of
activation of anti-apoptotic (cell survival) signaling pathways. One of the cell survival
pathways activated by camptothecin and cisplatin is the NF-κB pathway and as a result the
efficacy of chemotherapy is reduced.

1,2

NF-κB is a mammalian transcription factor responsible for the regulation of many
genes,

3,4

5

6

7

such as those associated with stress, inflammatory stimuli, anti-apoptosis, and
8

apoptosis. Misregulation of NF-κB mediated gene transcription is associated with many

1

9

diseases, such as rheumatoid arthritis, inflammatory bowel disease,

10-12

and cancer.

13,14

In most mammalian cells, NF-κB exists as either a p50/p50 homodimer or a p50/p65
heterodimer both of which are anti-apoptotic gene regulators. In non-stimulated normal
cells, NF-κB is located in the cytoplasm and bound by I-κB.

15

The NF-κB pathway can be

activated by the correct extracellular signal, such as cytokines TNF-α and IL-1ß, as seen in
4,6,16-18

scheme 1-1.

IKK kinases phosphorylate I-κB on serine residues 32 and 36,

followed by ubiquitinylation and degradation of I-κB by the 26S proteasome.

20,21

15,19

The
22

26S proteasome degrades I-κB and releases NF-κB so NF-κB can go into the nucleus.
Inside the nucleus, NF-κB binds to various DNA control elements and initiates antiapoptotic gene transcription and thus cell survival (Scheme 1-1).

2

New chemotherapeutic methods have moved towards a combination of inducers of
apoptosis and inhibitors of cancer cell survival pathways. There has been a search for
small molecules that can either selectively induce apoptosis or inhibit cell survival
1

pathways in cancer cells to prevent cellular chemoresistance. One focus of the Tepe
group has been the development of inhibitors of cancer cell survival pathways to improve
traditional chemotherapy. The Tepe group has created small molecule imidazolines, which
have been shown to inhibit the cancer cell survival signaling pathway mediated by NF-κB.1
Therefore, imidazolines inhibit the NF-κB pathway, resulting in sensitization of cancer
cells to chemotherapeutic agents like camptothecin, and subsequent reduction of
chemoresistance.

1,2

2

Scheme 1-1: Activation of NF-κB Pathway
The Tepe lab has prepared an imidazoline scaffold as a potent inhibitor of NF-κB
mediated gene transcription. Inhibition of NF-κB has been shown to proceed by
modulation of I-κB-α degradation by inhibition of the 20S proteasome, although the precise
binding site within the 20S proteasome is still unknown at this time.

1,2

Racemic

imidazolines were first developed in our laboratory by a 1,3-dipolar cycloaddition reaction

3

between azlactones and imines.
NF-κB (Figure 1-1).

23

Compounds 1-1 and 1-1a were shown to be inhibitors of

1

Figure 1-1: Compounds 1-1 and 1-1a
Previously, the two enantiomers have been separated by reaction with R(+)-1phenylethanol to yield two diastereomeric esters. The esters were then separated by
column chromatography and the resolving agent was removed to yield each pure
1

enantiomer (Scheme 1-2).

4

1

Scheme 1-2: Resolution of Compounds 1-1 and 1-1a.

Resolution of the enantiomers of compound 1-1 was also accomplished by transformation
of the carboxylic acid of compound 1-1 to the ethyl ester and separation on chiral HPLC.
However, only small amounts of the compound could be separated at a time using this
method. Since compounds 1-1 and 1-1a are prone to spontaneous decarboxylation, they
1,2

were transformed into the ethyl esters.

The resulting compounds 1-2 and 1-2a were the
2

lead compounds developed in our lab (Figure 1-2).

5

Figure 1-2: Compounds 1-2 and 1-2a
Imidazolines 1-2 and 1-2a were measured for their ability to inhibit NF-κB mediated gene
transcription by using a luciferase based reporter assay in human cervical epithelial (HeLa)
cells. Cells were pretreated for 30 minutes with compound 1-2 or 1-2a (20 to 0.5 µM)
followed by treatment with the cytokine TNF-α, which initiated the activation of the NFκB pathway. This caused degradation of I-κB and translocation of NF-κB into the nucleus,
where it initiated transcription of genes, including those needed for the production of the
enzyme luciferase. Luciferase production was evaluated after 8 hours by a luminometer.
From this data the EC50 values for compounds 1-2 and 1-2a were determined to be 1.6 µM
and 2.9 µM, respectively.
Since the discovery of the lead compounds, an SAR study has shown which
functional groups on the imidazoline scaffold were essential for inhibition of NF-κB.

2,24

The Tepe group has also determined that the enantiomers of the lead compound were not
equally potent inhibitors of NF-κB. The (R,R) enantiomer was a more potent inhibitor of
NF-κB mediated gene transcription than the (S,S) enantiomer.

2,13

Separation of the

enantiomers 1-1 and 1-1a by resolution or chiral HPLC methods is very expensive and time
6

consuming. Clearly, an enantioselective synthesis of imidazolines would not require the
enantiomers to be separated, assuming the enantioselectivity of the reaction was greater
than 98% enantiomeric excess (ee). A new methodology may also be able to introduce
new functional groups onto the imidazoline scaffold, while still maintaining the proper
stereochemistry. The ultimate goal would be to not only synthesize chiral imidazolines,
but to synthesize chiral imidazolines that are more potent inhibitors of NF-κB mediated
gene transcription than the lead compound. This dissertation presents a new methodology
to synthesize imidazolines enantioselectively.
The most recent work in the Tepe lab has synthesized nanomolar 20S proteasome
inhibitors (Manuscript submitted to J. Med. Chem. 2013) (Figure 1-3).

Figure 1-3: Nano-molar imidazoline proteasome inhibitors
The mechanism for 20S proteasome inhibition by an imidazoline has been
25

determined to be non-competitive.

We have also hypothesized that an imidazoline is a

7

covalent inhibitor of the 20S proteasome. An imidazoline may function as a covalent
inhibitor through a covalent bond formed at the C-2 position of the imidazoline scaffold.
Covalent bond formation at the C-2 position of the imidazoline may occur through a serine
oxygen atom and this is aided by the fact that the N-1 nitrogen can be protonated in the 20S
proteasome (Scheme 1-3).

Scheme 1-3: Possible mechanism for non-competitive covalent 20S proteasome
inhibition

8

The substituent at the C-2 position of the imidazoline scaffold was almost always a
substituted phenyl group. Placing an even stronger electron donating group than a p-MeOPh at the C-2 position would increase the carbocation stability at the C-2 position and may
be the key to even more potent 20S proteasome inhibition (Figure 1-4).

Figure 1-4: Proposed new proteasome scaffold
The Tepe lab is also interested in natural products and their derivatives as potential new
20S proteasome inhibitors. We are particularly interested in the Phakellins, Phakellstatins,
Nagelamide M, and Palau’amine derivatives

26-28

9

(Figure 1-5).

Figure 1-5: Urea and guanidine ring-containing natural products
New synthetic methodologies to access these natural products are needed. New
synthetic methodologies to synthesize imidazolines with the general scaffold in Figure 1-5
are also needed. One way to create these scaffolds would be by guanidine addition, urea
addition and an iso-urea addition to electron poor, electron rich, and electron neutral
olefins. This dissertation represents the work towards the synthesis of new bromine
reagents and their addition to olefins to create new 5-membered ring heterocycles. Initially
studies have focused on racemic synthesis of these 5-membered heterocycles but future
endeavors will focus on diastereoselective and/or enantioselective syntheses (Scheme 1-4).
10

Scheme 1-4: General synthesis of a guanidine, oxazolidin-2-one, a urea, a diamine
and an amino alcohol via addition to an olefin with bromine reagents.
These synthetic methodologies will provide a method to make 1,2 amino alcohols and 1,2
diamines and hopefully lead to the next generation of proteasome inhibitors in our lab.

11

REFERENCES

12

REFERENCES
(1)

Hewlett, N. M.; Tepe, J. J. Org. Lett. 2011, 13, 4550.

(2)

Reid, R. M.; Vigneau, E. S.; Gratia, S. S.; Marzabadi, C. H.; Castro, M. D.
Eur. J. Org. Chem. 2012, 3295.

(3)

Sharma, V.; Peddibhotla, S.; Tepe, J. J. J. Am. Chem. Soc. 2006, 128,
9137.

(4)

Kahlon, D. K.; Lansdell, T. A.; Fisk, J. S.; Hupp, C. D.; Friebe, T. L.;
Hovde, S.; Jones, A. D.; Dyer, R. D.; W.;, H. R.; Tepe, J. J. J. Med. Chem.
2009, 52, 1302.

(5)

Perkins, N. D. Trends Biochem. Sci. 2000, 25, 434.

(6)

Baldwin, A. S. J. Annu. Rev. Immunol. 1996, 14, 649.

(7)

Piva, R.; Belardo, G.; Santoro, M. G. Antioxid. Redox Signal 2006, 8, 478.

(8)

D’Acquisto, F.; May, M. J.; Ghosh, S. Mol. Interventions 2002, 2, 22.

(9)

Baeuerle, P. A.; T.;, H. Rev. Immunol. 1994, 12, 141.

(10)

Wang, C. Y.; Mayo, M. W.; Baldwin, A. S. J. Science 1996, 274, 784.

(11)

Makarov, S. S. Arthritis Res. 2001, 3, 200.

(12)

Ardizzone, S.; Bianchi, P. G. Drugs 2005, 65, 2253.

(13)

Boone, D. L.; Lee, E. G.; Libby, S.; Gibson, P. J.; Chien, M.; Chan. F.;
Madonia, M.; Burkett, P. R.; Ma, A. Inflamm. Bowel Dis. 2002, 8, 201.

(14)

Schreiber, S.; Nikolaus, S.; Hampe, J. Gut. 1998, 42, 477.

(15)

Sharma, V.; Hupp, C. D.; Tepe, J. J. Curr. Med. Chem. 2007, 14, 1061.

(16)

Haefner, B. Cancer Treat. Res. 1998, 130, 219.

(17)

Karin, M.; Ben-Neriah, Y. Ann. Rev. Immunol. 2000, 18, 621.

(18)

Siebenlist, U.; Franzoso, G.; Brown, K. Ann. Rev. Cell Biol. 1994, 10, 405.

(19)

Ghosh, S.; May, M. J.; Kopp, E. B. Annu. Rev. Immunol. 1998, 16, 225.

13

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Morello, S.; Ito, K.; Yamamura, S.; Lee, K. Y.; Jazrawi, E.; Desouza, P.;
Barnes, P.; Cicala, C.; Adcock, I. M. J. Immunol. 2006, 177, 7173.

(21)

Pickart, C. M.; Eddins, M. J. Biochim. Biophys. Acta. 2004, 169, 55.

(22)

Baeuerle, P. A.; Henkel, T. Annu. Rev. Immunol. 1994, 12, 141.

(23)

Chen, F. M.; Kuroda, K.; Benoition, N. L. Synthesis 1979, 230.

(24)

Lin, Y. C.; Brown, K.; Siebenlist, U. Proc. Natl. Acad. Sci. U.S.A. 1995,
92, 552.

(25)

Satymaheshwar, P.; Jayakumar, S.; Tepe, J. J. Org. Lett. 2002, 4, 3533.

(26)

Kahlon, D. K.; Lansdell, T. A.; Fisk, J. S.; Tepe, J. J. Bioorganic &
Medicinal Chemistry 2009, 17 3093.

(27)

Lansdell, T. A.; Hurchla, M. A.; Xiang, J.; Hovde, S.; Weilbaecher, K. N.;
Henry, R. W.; Tepe, J. J. ACS Chem. Biol. 2012, 10.1021/cb300568r.

(28)

Kubota, T.; Araki, A.; Ito, J.; Mikami, Y.; Fromont, J.; Kobayashi, J.
Tetrahedron 2008, 64, 10810.

(29)

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62, 7155.

14

CHAPTER 2
RING EXPANSION OF AN AZIRIDINE AND AN AZETIDINE WITH VARIOUS
ELECTROPHILES
In the Tepe lab we are interested in new synthetic methodologies to synthesize
heterocycles. Among these heterocycles imidazolines have been shown to be 20S
proteasome inhibitors.

1-6

The Tepe lab is interested in proteasome inhibition for the

treatment of cancer. We desire to create new synthetic routes to synthesize new
imidazolines as well as enantiopure imidazolines. I pursued a new methodology to
synthesize an imidazoline enantioselectively. We hypothesized that we could synthesize an
enantiopure imidazoline by developing a stereospecific reaction. We envisioned we could
develop a ring expansion reaction of an enantiopure aziridine with an imidoyl electrophile
to synthesize an enantiopure imidazoline. An imidoyl chloride proved to be the best
imidoyl electrophile for a (3+2) aziridine ring expansion reaction. The details of this
reaction have been described in detail in the master’s thesis but will be summarized along
with further progress made on this methodology.

7

Methods to synthesize an imidoyl chloride have typically employed thionyl
8-10

chloride, phosphorous pentachloride, or oxalyl chloride.

Oxalyl chloride was superior

to both thionyl chloride and phosphorous pentachloride to synthesize (Z)-Nbenzylbenzimidoyl chloride 2-2 with the greatest yield and shortest reaction time. Initial
attempts to make the imidoyl aziridine 2-4 were by reaction of ethyl-3-phenylaziridine-21

carboxylate 2-3 with 2-2 in DCM with TEA present in excess. The H NMR spectrum of
15

compound 2-4 was complicated because compound 2-4 existed as mixture of rotational
isomers about the amidine bond. The phenyl and benzyl group can be cis (Z) or trans (E)
to one another, but after purification of 2-4 by column chromatography caused hydrolysis
of the imidoyl group to benzyl amine and aziridine 2-5. Obviously, after hydrolysis of
compound 2-4, compound 2-5 did not contain any rotational isomers, but both 2-4 and 2-5
exist as the major invertomer with the nitrogen protecting group on the opposite side of the
two cis aziridine substituents at the C-2 and C-3 positions (Scheme 2-1).

Scheme 2-1: Synthesis of aziridine invertomers
Since column chromatography was not sufficient to purify compound 2-4, the solvent was
removed and the triethyl ammonium hydrochloride salt (Et3NHCl) was precipitated with
ethyl acetate and removed by filtration. The product was concentrated in vacuo and then
placed under high vacuum to remove the excess TEA. The product 2-4 was carried on to

16

the next reaction without further purification. The ring expansion reaction of the imidoyl
aziridine to an imidazoline was attempted with various Lewis acids (Table 2-1). The
proposed mechanism is discussed in my Master’s Thesis.

Table 2-1: Lewis acid isomerization of an imidoyl Aziridine to an imidazoline
Entry
1

Solvent
DCM

2

DCM

3

CHCl3

BF3•OEt2

5

CHCl3
THF

BF3•OEt2

6

THF

7

THF

AlCl3

8

THF

9

THF

10

THF

11

THF

12

CHCl3

4

a

LA
BF3•OEt2
BF3•OEt2

AlCl3
MgBr2
Zn(OTf)2
Sc(OTf)3
Yb(OTf)3
CuBr2
BF3•OEt2,
NaI

LA equiv.
0.5

Temp. °C
RT

Time h
24

% Yield 2-6
No Rxn

3.0

RT

36

No Rxn

5.0

Reflux

46

37a

2.0

Reflux

19

24a

0.5

RT

24

No Rxn

1.5

Reflux

48

No Rxn

0.5

Reflux

48

No Rxn

0.5

RT

24

Dec.

0.5

RT

24

Dec.

0.5

RT

24

Dec.

0.5

RT

24

Dec.

5.0, 1.0

Reflux

64

32

These results were not reproducible which lead us to believe HCl was the true catalyst
generated by residual water with chloroform or BF3O•Et2
17

The ring expansion of compound 2-4 was not observed in DCM or THF at room
temperature. The only Lewis acid that successfully synthesized the imidazoline 2-6 in low
yield was BF3O•Et2. The other imidazolines 2-7, 2-8, and 2-9 were not produced in this
reaction. The ring expansion reaction was attempted with the metal triflates and CuBr2 but
did not yield imidazoline 2-6. Instead workup with sat. aq. NaHCO3 caused hydrolysis of
compound 2-4 to compounds 2-5 and benzyl amine (Table 2-1, entries 8-11).
The imidoyl aziridine 2-4 was refluxed in chloroform with BF3O•Et2 with and without NaI
to yield the cis imidazoline 2-6 (Table 2-1, entries 3, 4, and 12). Compound 2-8 was not
formed in any of these reactions which could only occur by breaking the aziridine C-3
nitrogen bond. However, there was not any evidence for the formation of either transimidazoline stereoisomers compounds 2-7 or 2-9.
Synthesis of an imidazoline in one step from an aziridine would be a more efficient
procedure than trying to manipulate the water sensitive and acid sensitive intermediate
imidoyl aziridine through a two step procedure. A methodology to synthesize an
imidazoline in one step from an aziridine has been successful (Table 2-2). We discovered
that the ring expansion of the imidoyl aziridine occurred by use of a Brønsted acid instead
of a Lewis acid. The Brønstead acid was 2,6-lutidine•HCl which was generated in situ by
reaction of an amide, (COCl)2, and 2,6-lutidine to yield the imidoyl chloride.

18

Table 2-2: Optimization of one pot aziridine ring expansion to an imidazoline
Entry
1
2
3
4
5
6
7
8
9
10
10
11
11
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25

Temp
°C
55
80
80
80
80
80
80
80
55
RT
RT
RT
RT
RT
RT
RT
55
40
55
80
80
80
55
80
55
130
55
55

Solvent
DCM
Toluene
Toluene
Toluene
Acetone
MeCN
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DCM
DMF
DMF
DCM
DCE
DMF
DMF
DMF
DMF
DMF
DMF

Time h
12
12
9
21
21
21
21
9
9
23
117
23
44
117
65
65
21
21
21
21
21
21
21
21
21
3
6
6

Base
Hunig'sBase
TEA
DABCO
2,6-lutidine
2,6-lutidine
2,6-lutidine
2,6-lutidine
2,6-lutidine
2,6-lutidine
2,6-lutidine
2,6-lutidine
2,6-lutidine
2,6-lutidine
2,6-lutidine
Pyridine
DMAP
2,6-lutidine
2,6-lutidine
2,6-lutidine
2,6-lutidine
2,6-lutidine
2,6-lutidine
2,6-lutidine
NaOAc
2,6-lutidine
2,6-lutidine
2,6-lutidine
none

19

2-2
equiv.
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.3
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.2
1.2

Base
equiv.
6
2.4
1.2
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
7.5
7.5
7.5
7.5
7.5
6.5
5.5
5.5
5.5
5.5
5.5
5.5
1.1
5.5
5.5
6
6

% Yield
2-6
a

0
a
0
a
0
20
37
b
20
b
5
46
32
b
10
b
33
b
38
b
60
b
67
b
62
b
0
35
46
50
47
39
37
bc
50
0
bd
50
b
20
52
0

a

The reaction stopped at the intermediate compound 2-4.
c

b

1

Yield based on the crude H

NMR. The imidoyl chloride was added over 4 hours with a syringe pump to compound 2d

3, DMF, and 2,6-lutidine. Compound 2-3 was added over 4 hours with a syringe pump to
the DMF, compound 2-2, and 2,6-lutidine
A bulky base like 2,6-lutidine was the key in synthesizing the imidazoline 2-6.
Other bases stopped the reaction at the intermediate compound 2-4 (Table 2-2, entries 13). Excess of other bases like TEA would actually inhibit the formation of compound 2-6
and would stop the reaction at the intermediate compound 2-4. This ring expansion
reaction was optimized with respect to the solvent and DMF was found to be the best
(Table 2-2, entries 4-8, 17-19). To minimize the formation of impurities the optimal
temperature was determined to be 55°C (Table 2-2, entry 16). If the reaction was carried
out at 80°C in DMF a new impurity, which was not present at 55°C formed and the new
impurity was hard to remove by column chromatography (Table 2-2, entry 8). This ring
expansion reaction of aziridine 2-3 with imidoyl chloride 2-2 to imidazoline 2-6 did occur
very slowly at room temperature in CDCl3 with 2,6-lutidine as the base. Two reactions
1

were carried out in CDCl3 and were monitored by H NMR at room temperature. In one
reaction 7.5 equivalents of 2,6-lutidine was used and in another reaction 1.5 equivalents of
1

2,6-lutidine was used (Table 2-2, entries 10, 11). It was observed by H NMR that
compound 2-6 was formed at a faster rate with 7.5 equivalents of 2,6 lutidine than with 1.5
equivalents of 2,6 lutidine. An excess amount of 2,6-lutidine did not stall the reaction at
the intermediate imidoyl aziridine like other bases such as TEA, DABCO and Hünig’s
base. The reaction went to completion very fast at elevated temperatures in DMF, but a
significant amount of decomposition occurred as well (Table 2-2, entry 23). The
20

formation of impurities formed when an excess of compound 2-2 was used. If less than
one equivalent of compound 2-2 was used then residual aziridine 2-3 would be present at
the end of the reaction. This was due to the fact that residual water in the reaction would
hydrolyze some of the imidoyl chloride 2-2 to form benzyl benzamide. Changing the order
of addition of either the imidoyl chloride to the aziridine in DMF with 2,6-lutidine or the
addition of the aziridine to the imidoyl chloride in DMF with 2,6-lutidine had very little
effect on the yield (Table 2-2, entries 20, 22). The best yield obtained was 52% of
imidazoline 2-6 (Table 2-2, entry 24). These optimal reaction conditions were used to
screen the scope of this methodology by the reaction of various imidoyl chlorides with
trans-2,3 diphenyl aziridine. These results are summarized in the master’s thesis.

7

Upon completion of the master’s thesis this methodology was further studied by the
reaction of (Z)-benzylbenzimidoyl chloride with different aziridines substituted at the C-2
and C-3 positions. These aziridines were synthesized from the expoxide precusor. The
epoxides were synthesized by the Darzen epoxidation reaction of an aldehyde with ethyl 2chloroacetate. The expoxide was then opened at the C-3 position with NaN3 and closed to
the aziridine by the Staudinger reaction with PPh3. The majority of the aziridines were
synthesized from an epoxide and a few aziridines were synthesized by reaction of a nitrene
with an alkene.

21

Table 2-3. Variation at R3, R4, and R5 of the Aziridine Ring
Entry

Aziridine
#

R3

R4

R5

T
(h)

Imidazoline
#

yield
(%)

1

2-7

H

2-16

45

2-8

CO2Et

10

2

p-MeO-C6H4
Ph

12

2-17

42

3

2-9

Ph

Me

12

2-18

59

4

2-10

H

6

2-19

5

2-11

p-NO2-C6H4
PhCH=CH

20

2-20

6

2-12

2-21

40

2-13
2-14

H
Bn

CO2Et
COPh
H

12

7
8

n-C6H13
Ph
Ph

H

CO2Et

40
41

12
12

2-22
2-23

9

2-15

Ph

H

H

12

NA

41
a
40
0

a

H

CO2Et
CO2Et
CO2Et

H

a

The compound was synthesized as a 2:1 mixture of regioisomers with a major
regioisomer from breaking the aziridine C-3 nitrogen bond

The scope of the reaction was subsequently investigated with respect to the R3, R4,
and R5 positions of the aziridine. Electron withdrawing and donating aryl groups, along
with vinyl, ketone, ester, and alkyl functionalities were readily tolerated at these positions
(Table 2-3).
It was important to note that it was not possible to have just a hydrogen atom for the
R4 and R5 substituents at the C-2 position of the aziridine (Table 2-3, entry 9). With
respect to the regiochemistry only one regioisomer was produced in all cases except when
R3 was a p-NO2-C6H4- substituent or when R4 was a benzyl substituent (Table 2-3,
22

entries 4, 8). A side product that formed in these reactions was a 2-imidazole due to
oxidation of the imidazoline ring by loss of H2. This oxidation may have occurred by
residual oxygen in the reaction solution through a radical mechanism remove the two
imidazoline methane CH protan atoms to form hydroxide radicals and the imidazole.
Of particular note is that this one pot reaction showed an overall retention of
stereochemistry. In comparing the cis and trans stereoisomers of ethyl 3-phenylaziridine2-carboxylate the stereochemistry was preserved to yield the cis and trans 2-imidazolines
respectively (Compounds 2-6 and 2-17). The coupling constants of the two methine
imidazoline CH protons at the C-4 and C-5 positions of the imidazoline ring, were larger
12.0 Hz for the cis imidazoline 2-6, and smaller 7.5 Hz for the trans imidazoline 2-17.
The 2-imidazoline, compound 2-6, was synthesized from both a racemic aziridine
2-3 and enantiopure aziridine 2-3 (98% ee). This would presumably yield the 2imidazoline (2-6) as a racemate or enantiopure (98% ee) depending on the enantiopurity of
the starting aziridine 2-3 (Scheme 2-2).

Scheme 2-2: Synthesis of enantiopure 2-6 and racemic imidazoline 2-6
23

The racemate, compound 2-6, was treated with (S)-Mosher’s acid and analysis by
1

H NMR showed a 1:1 ratio of diasteromeric salts. However, the enantiopure compound

2-6 was also treated with (S)-Mosher’s acid but only one diasteromeric salt was observed
1

in the H NMR spectrum. Thus the enantiopurity of compound 2-6 was preserved in the
ring expansion reaction. A stereospecific ring expansion reaction of an enantiopure
aziridine with an imidoyl chloride to yield an enantiopure imidazoline has been developed.
Therefore, this methodology has provided a new way to synthesize enantiopure
imidazolines of interest to our lab (Figure 2-1).

Figure 2-1: Determination of ee of compound 2-6 by Mosher’s Acid
The synthesis of a 2-imidazoline with a quaternary carbon at the C-5 position (2-18)
proceeded with complete retention of stereochemistry (Table 2-1, entry 3). The identity of
compound 2-18 was supported by x-ray crystallography. The x-ray structure revealed that
the phenyl at C-2 can be oriented above or below the plane of the imidazoline ring (Figure
2-2).

24

For interpretation of the references to color in this and all other figures, the reader is
referred to the electronic version of this dissertation

Figure 2-2: X-ray crystallography of compound 2-18

This retention of stereochemistry could be accomplished by SN2 attack of the
chloride anion at the 2-position of the imidoyl aziridine ring carbon and then ring closure
11-13

through a second SN2 (Mechanism 2).

However, another possible mechanism could

involve attack of the imidoyl carbon atom by the chloride anion followed by ring closure
(Mechanism 1). This mechanism would be analogous to the earlier proposed mechanism
of attack of the imidoyl carbon by the iodine anion from NaI and subsequent ring closure
11,14

(Scheme 2-3).

25

Scheme 2-3: Proposed reaction mechanism for imidazoline synthesis
The latter mechanism would suggest that an imidoyl aziridine would undergo ring
expansion by a 4-endo-tet ring closure which is not favorable by Baldwin’s rules for ring
closure. Both a SNi or a stepwise process are possible mechanisms; evidence for these
mechanisms has been supported by Tomasini and coworkers

15

via the ring expansion of an

N-tert-butoxycarbonyl aziridine to an oxazolidinone. These mechanisms for imidoyl
aziridine isomerization to a 2-imidazoline would likely involve activation of the imidoyl
26

aziridine intermediate by the Brønsted acid, 2,6-lutidine•HCl. Nitrogen-carbon bond
formation occurred at the most electropositive carbon atom in the imidoyl aziridine
intermediate. The most electropositive carbon was the C-2 position of the aziridines in all
of these reactions except when a p-NO2-C6H4 substituent (aziridine 2-10) was introduced
at the C-3 position or a benzyl group (aziridine 2-14) at the C-2 position. In this case the
C-3 and C-2 positions of the aziridine ring carbons had similar electronics. Therefore, in
both of these reactions of aziridine 2-10 or 2-14 with imidoyl chloride 2-2 yielded a
mixture of 2-imidazoline regioisomers (Table 2-3, entries 4, 8).
We have developed a simple one pot stereospecific synthesis of 2-imidazolines
from the ring expansion of an aziridine with an imidoyl chloride consistent with a Heine
reaction. The scope of the reaction indicated that the reaction tolerated many diverse
functional groups. The purification of imidoyl chlorides and imidoyl aziridines
intermediates were not needed, therefore creating a simple one pot method to synthesize
these biologically significant highly-substituted 2-imidazolines.
One limitation of the reaction scope was that it did not allow access to enantiopure
trans-4,5-diphenyl imidazolines di-substituted at the C-5 position. Specifically the
enantiomers of the lead compound TCH-013 could not be synthesized through this
methodology. This was due to the fact that there was not a known synthesis for either
aziridine enantiomer 2-24 or 2-25 (Scheme 2-4).

27

Scheme 2-4: Proposed synthesis of TCH-013.
However, these imidazolines were tested for their ability to inhibit the 20S
proteosome and were typically found to be EC50 1-2 µM for the trans-4,5-diphenyl
imidazolines (see master’s thesis). The imidazolines 2-16 through 2-23 unfortunately were
found to be poor inhibitors of the 20S proteosome. They were poor inhibitors because the
imidazolines 2-16 through 2-23 contained the opposite regiochemistry than that of TCH013. The regiochemistry and position of the benzyl substituent proved to be very important
for 20S proteosome inhibition.

7

Recently Teri Landsdell, Dillion Cogan, and Jake Ludwig have discovered that
imidazolines 2-26, 2-27, and 2-28 all inhibit the 20S proteosome in the nanomolar range
(Manuscript submitted to J. Med. Chem. 2013) (Figure 2-3).

28

Figure 2-3: Nanomolar 20S Proteasome Inhibitors 2-26, 2-27, 2-28
These nanomolar 20S proteasome inhibitors 2-26, 2-27, and 2-28 all contained substituted
aniline substituent at the C-4 carbon of the imidazoline ring. As mentioned earlier the ring
expansion of aziridine 2-10 with a p-NO2 substituent gave imidazoline 2-19 in a 2:1
mixture of regioisomers because it this case the electronics of the aziridine C-3 and C-2
were similar. By making the C-3 carbon of the aziridine ring the most electropositive the
desired imidazoline regioisomer would be synthesized by opening the aziridine at the C-3
position instead of the C-2 position. The imidazoline could be synthesized enantiopure by
the reaction of an enantiopure aziridine 2-29 provided by the methodology by Wulff and
16,17

coworkers.

Alkylation of aziridine 2-29 with methyl iodide followed by removal of

the MDAM group would yield aziridine 2-31. The ring expansion of 2-31 to 2-32 would
be expected to yield the desired regiochemistry due to the increased sterics at C-2 position
of aziridine 2-31. The most electropositive carbon of aziridine 2-31 would be C-3 position
29

due to the donating methyl group at C-2 position and the electron withdrawing p-NO2-Ph
group at C-3 position. Reductive amination of 2-32 or reduction of 2-32 to an aniline
followed by alkylation would yield the enantiopure imidazolines 2-33, 2-34, and 2-35
(Scheme 2-5).

Scheme 2-5: Proposed Synthesis of 26S Proteosome Inhibitors

30

The only difference between compounds 2-33, 2-34, and 2-35 versus 2-26, 2-27, and 2-28
would be that a methyl group instead of a phenyl group would be at the imidazoline C-5
position. However, imidazolines substituted with a methyl group at the C-5 position have
been shown to be potent 20S proteosome inhibitors based on SAR studies.

18,19

This

would hopefully lead to a library of enantiopure 20S proteosome inhibitors.
We next turned our attention to other applications of this ring expansion reaction.
We first attempted the ring expansion reaction of an aziridine with ethyl benzimidate
hydrogen chloride 2-36. The best way to generate ethyl benzimidate hydrogen chloride was
by reaction of benzonitrile with HCl (g) followed by addition of ethanol. Compound 2-36
was unstable and had to be used in situ with aziridine 2-8 under the usual reaction
conditions. Unfortunately this reaction was not successful because the exocyclic nitrogen
was less nucleophilic with a hydrogen atom substituent instead of an N-alkyl group
substituent. The imidazoline 2-37 was also very prone to oxidation by residual oxygen in
the reaction solution driven by “its strong desire” to become aromatic. The ring CH
hydrogen atoms of 2-37 were oxidized to an imidazole 2-38 (Scheme 2-6).

Scheme 2-6: Attempted ring expansion of 2-8 with ethyl benzimidate•HCl
31

The ring expansion of aziridine 2-8 was also attempted with ethyl chloroformate and
benzyl isocyanate under the standard reaction conditions. In both of these cases alkylation
of aziridine 2-8 occurred but the ring expansion reaction to a heterocycle did not occur.
Instead of changing the nature of the electrophile we decided to keep the
electrophile the same and change the nucleophile from an aziridine to an azetidine.
Azetidines are four membered nitrogen heterocycles that have similar strain energy to that
of an aziridine.
aziridine.

21

20

However, the bond angles of an azetidine are different than that of an

Based on previous reports

20,22

we envisioned that an azetidine would undergo

a (4+2) ring expansion with an imidoyl chloride to a six membered ring called a
tetrahydropyrimidine. Tetrahydropyrimidines substituted at the C-4 and C-6 positions
make up an important class of natural products known as the Manzacidins

23,24

(Figure 2-

4).

Figure 2-4: Manzacidin natural products
Analogous to a C-2 substituted ester aziridine which underwent a ring expansion to
an imidazoline an azetidine substituted at the C-2 and C-4 positions with an ethyl ester
group may also undergo a ring expansion to a tetrahydropyrimidine. The azetidines 2-42
32

and 2-43 were thought of to be good substrates to try a ring expansion with an imidoyl
chloride because they are activated by the ethyl ester groups at the azetidine C-2 and C-4
positions. Azetidines 2-42 and 2-43 were synthesized from commercially available
glutaroyl dichloride. Glutaroyl dichloride was heated to 85°C with molecular bromine
while being irradiated with a sunlamp followed by reaction with anhydrous ethanol to yield
25,26

compound 2-39.

Reaction of 2-39 with benzyl amine yielded 2-40 and 2-41, which

were separated by column chromatography. The benzyl protecting group was removed by
25,26

hydrogenolysis with Pearlman’s catalyst to yield 2-42 and 2-43

(Scheme 2-7).

Scheme 2-7: Synthesis of cis and trans-diethyl azetidine-2,4-dicarboxylate

33

The Manzacidin natural products all contained a hydrogen atom substituent at the
C-2 carbon and hydrogen or methyl substituent at the N-1 nitrogen. The synthon required
would be an (E)-N-methylformimidoyl chloride 2-44. Ring expansion of a formimidoyl
chloride with an azetidine would yield a tetrahydropyrimidine with a methyl or benzyl
substituent at the N-1 position. The benzyl protecting group could be removed to yield a
hydrogen atom at the N-1 position. This would form the tetrahydropyrimidine ring in the
Manzacidin natural products. However, transformation of a formamide into an imidoyl
chloride is not well known. Very few examples exist in the literature and a formimidoyl
chloride is considered an unstable molecule that will undergo decomposition.

27

The

reaction of N-methyl formamide with oxalyl chloride with 2,6-lutidine did not yield an
imidoyl chloride. When azetidine 2-43 was added to 2-44 the compound 2-47 was isolated
and verified by x-ray crystallography. Unfortunately, the desired tetrahydropyrimidine 246 was not formed nor were the intermediates 2-44 and 2-45 (Scheme 2-8).

Scheme 2-8: Attempted Synthesis of tetrahydropyrimidine 2-46
34

Figure 2-5: X-ray crystallography of compound 2-47

N-methyl formamide underwent N-acylation with (COCl)2 followed by nitrogen
substitution of the azetidine 2-43 to yield compound 2-47. A variety of reaction conditions
were employed to synthesize (E)-N-methylformimidoyl chloride, but these reactions failed
to yield any of the desired product. Instead reaction exclusively occurred at the nitrogen
atom

28

of N-methyl formamide instead of the oxygen atom, a reaction did not occur, or a

complicated mixture of products was obtained (Table 2-2).

35

Table 2-4: Attempted Synthesis of (E)-N-methylformimidoyl chloride

entry

reagent

base

base equiv

yield (%) 2-44

1

SOCl2

2, 6-lutidine

2

2

SOCl2

None

0

0
a
0

3

PCl5

None

0

0

4

PCl5

2, 6-lutidine

6

0

5

COCl2

2, 6-lutidine

6

0

COCl2

None

0

0

CCl4/PPh3

None

0

0

6
7

a

rxn was carried out at 75°C

Many of the reactions in Table 2-4 gave evidence for decomposition products which could
not be elucidated by NMR analysis. Frustrated by these results I went back to my standard
reaction conditions with the N-benzyl benzamide with (COCl)2 to yield the imidoyl
chloride 2-48. The reaction of imidoyl chloride 2-48 with azetidine 2-43 was attempted in
DMF at 55°C with 6 equivalents of 2,6-lutidine. The tetrahydropyrimidine 2-50 was not
synthesized but instead only the intermediate imidoyl azetidine 2-49. Even upon heating to
140°C 2-49 did not undergo ring expansion to 2-50 (Scheme 2-9).

36

Scheme 2-9: Attempted synthesis of tetrahydropyrimidine 2-50
The only compound that was isolated was 2-51 upon purification on silica gel due to
hydrolysis of compound 2-49. Similarly the reaction of the cis-azetidine also did not
undergo ring expansion into a tetrahydropyrimidine. The reactions of an azetidine with an
acid chloride, a chloroformate, or an isocyanate also did not lead to a ring expansion
reaction to 6-membered heterocycle, but instead just alkylated the azetidine nitrogen atom.
The bond angles of an azetidine were different than an aziridine bond angles and must have
been the determining factor for prevention of the ring expansion to occur. Perhaps stronger
reaction conditions are needed such as a stronger Brønstead acid or a different nucleophile
besides chloride to cause the ring expansion to occur. This ring expansion of an azetidine
with an imidoyl chloride should be possible analogous to an aziridine and should occur
through one of the two possible proposed mechanisms for the aziridine ring expansion.

37

APPENDIX

38

EXPERIMENTAL

Acetonitrile, TEA, and DMF were distilled from calcium hydride under nitrogen. Toluene,
and DCM were purified through a column packed with dry alumina and were dispensed by
a nitrogen pressure delivery system. THF and ether were distilled from sodium under
nitrogen. Acetone, DCE, and chloroform were distilled from calcium sulfate under
nitrogen. Anisole was distilled from calcium hydride under nitrogen. All other reagents
and solvents were purchased from Aldrich, Alfa Aesar, or TCI and used without further
purification. All flasks were oven dried overnight and cooled under argon or nitrogen. All
reactions were monitored by TLC with 0.25 μM precoated silica gel plates and UV light
was used to visualize the compounds. It some cases phosphomolybdic acid (PMA) stain or
I2 was used to visualize the compounds. Column chromatography silica gel was provided
by EM Science (230-400 mesh). All NMR spectra were recorded on a Varian Unity Plus500 or 300 spectrometer. Chemical shifts are reported relative to the solvent peak of
1

chloroform (δ 7.24 for H and δ 77.0 for

13

C). Infrared spectra were recorded on a Nicolet

IR/42 spectrometer. Melting points were determined on a Mel-Temp apparatus with a
microscope attachment. HRMS were obtained at the Mass Spectrometry Facility of
Michigan State University with a JEOL JMS HX-110 mass spectrometer.
General procedure to neutralize silica gel
Silica gel was saturated with TEA, the slurry was mixed for 5 minutes and then
concentrated in vacuo to remove the excess TEA to give a free flowing powder once again.

39

General Procedure for Darzen Epoxidation
The typical reaction scale was based on 3 g of the epoxide for a 100% yield reaction.

32

To

a 250 mL round bottom flask under nitrogen was added THF (75 mL) and NaOEt (1
equiv.). This solution was cooled to 0°C in an ice water bath. The desired aldehyde (1
equiv.) was added to the reaction flask followed by addition of ethyl chloroacetate (1
equiv.). The solution was left in the ice water bath and was allowed to react and slowly
warm to room temperature for approximately 18 hours. After 18 hours the solution was
poured into a separatory funnel. Water (100 mL) was added to the separatory funnel and
the solution was extracted with EtOAc (50 mL x 3). The combined organic extracts were
washed with brine (50 mL), dried with MgSO4, filtered, and concentrated in vacuo. The
resulting epoxide was purified by silica gel chromatography.
Trans-ethyl 3-(4-methoxyphenyl)oxirane-2-carboxylate

The compound was synthesized by the general procedure. The silica gel was neutralized
with TEA by the general procedure. The compound was purified by silica gel plug. 1: 2
DCM: hexane, Rf = 0.7 to give a mixture of the epoxide and residual p-methoxy
benzaldehyde. The residual p-methoxy benzaldehyde was removed by vacuum distillation
with heating to approximately 150°C in vacuo (approx. 10 mm Hg), the pure epoxide did
not distill over at this temperature but removed the residual aldehyde to give the epoxide
1

sufficiently pure for characterization. Oil; 48% yield; H NMR (300 MHz) CDCl3: 1.37
(3H, t, J = 7.2 Hz), 3.54 (1H, d, J = 1.8 Hz), 3.85 (3H, s), 4.08 (1H, d, J = 1.5 Hz), 4.2340

4.41 (2H, m), 6.92 (2H, d, J = 8.7 Hz), 7.25 (2H, d, J = 9 Hz);

13

C NMR (75 MHz) CDCl3:

14.18, 55.38, 56.73, 57.93, 61.76, 114.15, 126.87, 127.27, 160.28, 168.43; IR (NaCl):
+

3154, 2984, 1740, 1516, 1466, 1251, 1205; HRMS: Calculated for C12H14O4 (M ):
223.0970; Found 223.0975.
Ethyl 2-methyl-3-phenyloxirane-2-carboxylate

The product was synthesized according to the general procedure except ethyl 2bromopropanoate was used instead of ethyl chloroacetate. Residual benzaldehyde and
ethyl 2-bromopropanote were removed in vacuo (approx. 10 mm Hg) at room temperature.
Further purification was not needed; oil; 52% yield. The compound matched the reported
29 1

literature data.

H NMR (300 MHz) CDCl3: 1.33 (1H, s), 1.35 (3H, t, J = 7.8 Hz), 4.29

(2H, m), 4.33 (1H, s), 7.29-7.40 (5H, m);

13

C NMR (75 MHz) CDCl3: 13.00, 14.51,

60.20, 62.10, 62.60, 126.80, 128.40, 134.00, 170.00.
Trans-ethyl 3-(4-nitrophenyl)oxirane-2-carboxylate

The compound was synthesized according to the general procedure. Residual p-nitro
benzaldehyde was removed by sublimation at 150°C in vacuo (approx. 10 mm Hg). This
left the residual epoxide which was purified by silica gel chromatography. The silica gel
was neutralized with TEA by the general procedure. Silica gel chromatography, 1: 1
1

DCM: hexane, Rf = 0.1, 41% yield; solid; mp = 62-63°C; H NMR (500 MHz) CDCl3:
41

1.35 (3H, t, J = 7.0 Hz), 3.50 (1H, d, J = 2.0 Hz), 4.21 (1H, d, J = 2.0 Hz), 4.29-4.36 (2H,
m), 7.49 (2H, d, J = 8.5 Hz), 8.25 (2H, d, J = 9.0 Hz);

13

C NMR (125 MHz) CDCl3: 14.31,

56.89, 57.20, 57.23, 124.13, 126.93, 142.56, 148.49, 167.52; IR (NaCl): 3154, 2922, 1742,
1526, 1348, 1208. The compound has been previously reported.

30

Trans-(E)-ethyl 3-styryloxirane-2-carboxylate

The product was synthesized according to the standard procedure. The silica gel was
neutralized according to the general procedure. Silica gel chromatography 25: 75 DCM:
1

hexane Rf = 0.33; 46% yield; H NMR (500 MHz) CDCl3: 1.34 (3H, t, J = 7.0 Hz), 3.52
(1H, d, J = 2.0 Hz), 3.77 (1H, d, J = 7.5 Hz), 5.88 (1H, dd, J1 = 16.0 Hz, J2 = 8.5 Hz), 6.88
(1H, d, J = 16.5 Hz), 7.21-7.46 (5H, m);

13

C NMR (125 MHz) CDCl3: 14.39, 55.34, 58.60,

62.02, 124.18, 126.87, 128.81, 128.97, 136.71, 165.82, 168.79; IR (NaCl): 2918, 1734,
1456, 1381, 1203; HRMS: Calculated for C13H14O3 (M+): 219.1021; Found 219.1024.
31

The compound has been previously reported.
Trans-ethyl 3-hexyloxirane-2-carboxylate

The compound was synthesized according to the general procedure. Silica gel
chromatography 25: 75 DCM: hexane Rf = 0.35 (visualize the product by using a I2 stain),
1

38% yield; H NMR (500 MHz) CDCl3: 0.89 (3H, t, J = 6.5 Hz), 1.31 (3H, t, J = 7.0 Hz),

42

1.28-1.37 (6H, m), 1.42-1.51 (2H, m), 1.54-1.69 (2H, m), 3.15 (1H, dt, J1 = 4.5 Hz, J2 =
2.0 Hz), 3.21 (1H, d, J = 2.0 Hz), 4.18-4.29 (2H, m);

13

C NMR (125 MHz) CDCl3: 14.17,

14.28, 22.68, 25.86, 29.07, 31.62, 31.82, 53.22, 58.62, 61.61, 169.51; IR (NaCl): 2928,
+

1740, 1464, 1375, 1280, 1247, 1201; HRMS: Calculated for C11H21O3 (M ): 201.1491;
Found 201.1497.

General Procedure for the Staudinger Reaction: Synthesis of
ethyl aziridine-2-carboxylates
The typical reaction scale was based on 2 g of the aziridine for a 100% yield reaction.

32

To a 100 mL round bottom flask under nitrogen was added the epoxide (1 equiv.), NaN3 (3
equiv.), NH4Cl (3 equiv.), and 95% ethanol (50 mL). The reaction solution was brought to
reflux for 12 hours. The reaction was then cooled to room temperature and poured into a
separatory funnel along with water (100 mL). The solution was extracted with EtOAc (50
mL x 3), the combined organic extracts were washed with brine (50 mL), dried with
MgSO4, filtered, and concentrated in vacuo. The crude azide alcohol was used without
further purification. The azide alcohol was added to a 100 mL round bottom flask along
with MeCN (50 mL) and PPh3 (0.9 equiv.). This solution was brought to reflux for 15
hours, cooled to room temperature, and the solvent was removed in vacuo. To the crude
product was added ether (75 mL) followed by hexane (75 mL). This solution was put in
the fridge for 30 minutes. The majority of the PPh3O had precipitated out of the solution.

43

The PPh3O was removed by vacuum filtration and the mother liquor was concentrated to
dryness in vacuo. The resulting aziridine was purified by silica gel chromatography.
2-7: Trans-ethyl 3-(4-methoxyphenyl)aziridine-2-carboxylate

The product was synthesized according to the standard procedure. The crude product was
purified by silica gel chromatography. The silica gel was neutralized with TEA by the
general method and was purified by column chromatography. 1:3 DCM: hexane; Rf = 0.55;
1

solid; mp = 46-48; 58% yield (2 steps); H NMR (300 MHz) CDCl3: 1.35 (3H, t, J = 6.9
Hz), 1.89 (1H, s, br), 2.56 (1H, d, J = 7.5 Hz), 3.24 (1H, d, J = 7.5 Hz), 3.84 (3H, s), 4.214.38 (2H, m), 6.89 (2H, d, J = 8.7 Hz), 7.27 (2H, d, J = 8.7 Hz);

13

C NMR (75 MHz)

CDCl3: 14.21, 39.38, 40.08, 53.32, 61.75, 113.92, 114.09, 127.27, 129.92, 159.32; IR
+

(NaCl): 3155, 2984, 1721, 1515, 1250, 1219; HRMS Calculated for C12H16NO3 (M ):
222.1130; Found 222.1137.
2-8: Trans-ethyl 3-phenylaziridine-2-carboxylate

The product was synthesized according to the standard procedure. The crude product was
purified by silica gel chromatography; 20: 80 EtOAc: Hexane; Rf = 0.25; oil; 59% yield (2
steps). The compound matched the reported literature data.
44

32 1

H NMR (300 mHz),

CDCl3: 1.31 (3H, t, J = 7.0 Hz), 1.90 (1H, s, br), 2.58 (1H, s), 3.25 (1H, s), 4.25 (2H, m),
7.36-7.25 (5H, m);

13

C NMR (75 mHz), CDCl3: 14.00, 39.30, 40.20, 61.60, 126.10,

127.60, 128.30, 137.80, 171.60.
2-9: Trans-ethyl 2-methyl-3-phenylaziridine-2-carboxylate

The product was synthesized according to the standard procedure. The crude product was
purified by silica gel chromatography; 20: 80 EtOAc: hexane; Rf = 0.30; oil; 43% yield (2
1

steps). H NMR (500 MHz) CDCl3: 1.13 (3H, s), 2.14 (1H, s, br), 3.49 (1H, s), 4.24-4.29
(2H, m), 7.27-7.36 (5H, m);

13

C NMR (125 MHz) CDCl3: 14.54, 14.43, 41.03, 45.70,

62.23, 127.70, 128.23, 128.35, 136.04, 174.57; IR (NaCl): 2920, 1717, 1456, 1387, 1284,
+

1196; HRMS Calculated for C12H15N1O2 (M ): 206.1181; Found 206.1189.
2-10: Trans-ethyl 3-(4-nitrophenyl)aziridine-2-carboxylate

The product was synthesized according to the standard procedure. Silica gel
chromatography; the silica gel was neutralized with TEA by the general method; 1:3 DCM:
1

hexane; Rf = 0.3; solid; mp 79-80°C; 56 % yield (2 steps), H NMR (300 MHz) CDCl3:
1.36 (3H, t, J = 7.2 Hz), 2.09 (1H, s, br), 2.61 (1H, s), 3.37 (1H, s), 4.26-4.37 (2H, m), 7.49
(2H, d, J = 9 Hz), 8.22 (2H, d, J = 9 Hz);

13

C NMR (75 MHz) CDCl3: 14.10, 39.30, 40.02,
45

62.12, 123.60, 127.06, 145.57, 147.39, 170.88; IR (NaCl): 2927, 2856, 1724, 1464, 1376,
+

1213; HRMS Calculated for C11H12N2O4 (M ): 237.0875; Found 237.0883.
2-11: Trans-(E)-ethyl 3-styrylaziridine-2-carboxylate

The product was synthesized according to the standard procedure. Silica gel
chromatography; the silica gel was neutralized with TEA by the general method; 1:2 DCM:
1

Hexane; Rf = 0.31; Oil; 27% yield (2 steps); H NMR (300 MHz) CDCl3: 1.36 (3H, t, J =
7.2 Hz), 1.74 (1H, s, br), 2.61 (1H, s, br), 2.95 (1H, d, J = 6.9 Hz), 4.21-4.37 (2H, m), 5.91
(1H, dd, J1 = 15.9 Hz, J2 = 7.8 Hz), 6.75 (1H, d, J = 15.9 Hz), 7.25-7.41 (5H, m);

13

C

NMR (75 MHz) CDCl3: 14.23, 37.37, 40.31, 61.79, 126.31, 127.42, 127.88, 128.66,
133.21, 136.29, 171.87; IR (NaCl): 2984, 1722, 1452, 1373, 1213; HRMS: Calculated for
+

C13H15NO2 (M ): 218.1174; Found 218.1181.
2-12: Trans-ethyl 3-hexylaziridine-2-carboxylate

The product was synthesized according to the standard procedure with the exception that
the reaction time for the Darzen reaction and Staudinger reaction was 24 hours. The crude
product was purified by silica gel chromatography. 1: 2 DCM: Hexane, Rf = 0.36
1

(visualized spot by PMA stain); oil, 33% yield (two steps); H NMR (500 MHz) CDCl3:
0.89 (3H, t, J = 7.0 Hz), 1.2-1.35 (8H, m), 1.31 (3H, t, J = 7.0 Hz), 1.40-1.78 (3H, m), 2.22
46

(1H, dt, J1 = 3.5 Hz, J2 = 2.5 Hz), 2.28 (1H, d, J = 2.5 Hz), 4.16-4.27 (2H, m);

13

C NMR

(125 MHz) CDCl3: 14.29, 14.43, 22.80, 27.30, 29.19, 31.98, 32.97, 35.55, 39.86, 61.69,
165.82. IR (NaCl): 2925, 1725, 1524, 1346, 1219; HRMS: Calculated for C11H22N1O2
+

(M ): 200.1651; Found 200.1657.

Synthesis of Aziridines by other Methods
2-phenyl-1-tosylaziridine

Caution: Chloramine T can explode if heated; check MSDS. Chloramine T was sold as
a hydrate but had to be dried in order for the reaction to work. Chloramine T was dried by
placing it in a round bottom flask under vacuo at room temperature for 72 hours. The
33

compound was prepared according to a literature method.

To a 100 mL round bottom

flask under nitrogen was added chloramine T (2.97 g, 10.50 mmol), anhydrous acetonitrile
(50 mL), and styrene (1.1 mL, 9.55 mmol). Pyridinium hydrogen tribromide (0.34 g, 0.95
mmol) was added to the round flask at room temperature. After 6 hours the reaction
solution was poured into water (50 mL) and extracted with EtOAc (50 mL x 3), the
combined organic extracts were washed with brine (30 mL), dried over MgSO4, filtered,
and concentrated in vacuo. Silica gel chromatography 20: 80 EtOAc: hexane; Rf = 0.5;
white solid; mp 94-96°C, 54% yield. The compound matched the reported literature
33 1

data.

H NMR (300 MHz), CDCl3: 2.40 (1H, d, J = 4.6 Hz), 2.45 (3H, s), 3.0 (1H, d, J

47

= 7.3 Hz), 3.80 (1H, dd, J1 = 7.3 Hz, J2 = 4.6 Hz), 7.15-7.45 (7H, m), 7.90 (2H, d, J = 8.2
13

Hz);

C NMR (75 MHz), CDCl3: 23.5, 37.0, 42.5, 127.0, 128.0, 128.5, 129.0, 130.0,

135.5.
2-15: 2-phenylaziridine

34

The compound was prepared according to the literature method.

2-phenyl-1-

0

tosylaziridine (0.30 g, 1.10 mmol), Mg (0.13 g, 5.0 mmol), and anhydrous methanol (10
mL), was added to a 25 mL round bottom flask. The solution was sonicated at room
temperature for 1 hour. NH4Cl sat. aq was added to reaction flask until the excess Mg

0

was consumed and the solution was extracted with EtOAc (25 mL x 3). The combined
organic extracts were washed with brine (25 mL), dried with MgSO4, filtered, and
concentrated in vacuo. The crude product was purified by silica gel chromatography; 30:
70 EtOAc: hexane; Rf = 0.2; oil; 59% yield. The compound matched the reported literature
34 1

data.

H NMR (300 MHz), CDCl3: 1.50 (1H, s, br), 1.81 (1H, d, J = 3.2 Hz), 2.21 (1H,

d, J = 6.0 Hz), 3.02 (1H, m), 7.15-7.40 (5H, m);

13

C NMR (75 MHz), CDCl3: 29.20,

32.10, 125.60, 126.70, 128.20, 140.70.
2-13: Trans-phenyl(3-phenylaziridin-2-yl)methanone

48

35

The compound was prepared according to the literature method.

To a 25 mL round

bottom flask was added S,S-diphenylsulfilimine (0.58 g, 2.89 mmol), chalcone (0.30 g,
1.45 mmol), and benzene (4.5 mL). The solution was refluxed for 16 h and then
concentrated in vacuo. The crude product was purified by silica gel chromatography;
100% DCM; Rf = 0.2; solid; mp 124-125°C; 63% yield. The compound matched the
reported literature data.

36 1

H NMR (300 MHz), CDCl3: 2.67 (1H, s, br), 3.18 (1H, d, J =

7.1 Hz), 3.51 (1H, d, J = 5.6 Hz), 7.29-7.39 (5H, m), 7.47-7.51 (2H, m), 7.60 (1H, m), 8.0
(2H, m);

13

C NMR (75 MHz), CDCl3: 43.51, 44.07, 126.18, 127.86, 128.30, 128.53,

128.79, 133.79, 135.89, 138.30, 195.68.
2-14: Cis-2-benzyl-3-phenylaziridine

The compound was prepared by a literature method.

37

To a 250 mL round bottom flask

cooled under nitrogen was added LiAlH4 (0.34 g, 8.88 mmol) and THF (30 mL). To
another 100 mL round bottom flask was added 1,3-diphenylpropan-2-one oxime (1g, 4.44
mmol), and THF (30 mL). The oxime/THF solution was added to the LiAlH4 solution
dropwise over 10 minutes with a syringe at room temperature. The solution was brought to
reflux for 3 hours. The solution was then cooled to 0°C and water was slowly added
followed by 2M NaOH until a white precipitate formed. The precipitated was removed by
vacuum filtration and was washed with ether. The ether was dried with MgSO4, filtered,
and concentrated in vacuo. The crude compound was purified by silica gel
49

chromatography; 1: 1; ether: hexane; Rf = 0.3; 81% yield; solid mp 44-45°C. The
compound matched the reported literature data.

37 1

H NMR (500 MHz) CDCl3  1.21 (1H,

s., br) 2.39 - 2.51 (1H, dd, J1= 8.35 Hz, J2 = 5.85 Hz), 2.52 - 2.71 (2H, m), 3.38 (1H, d, J
=5.85 Hz), 7.09 (2H,d, J=7.34 Hz), 7.16 - 7.23 (1H, m) 7.23 - 7.29 (2H, m), 7.31 (1H, m),
7.37 (2H, t, J = 7.34 Hz) 7.44 (2H, d, J = 7.34 Hz);

13

C NMR (75 MHz), CDCl3 34.33,

37.19, 38.61, 126.07, 126.85, 127.84, 127.99, 128.29, 128.76, 137.52, 139.79
2-3: Synthesis of Racemic ethyl 3-phenylaziridine-2-carboxylate

(Z)-N-benzylidene-4-methoxyaniline

The compound was synthesized by a literature method.

38

To a 250 mL round bottom flask

was added 4-methoxyaniline (4.67 g, 38.00 mmol), MgSO4 (7.64 g, 63.46 mmol), and
50

DCM (125 mL). The solution was mixed for 5 minutes under nitrogen at room
temperature. Benzaldehyde (3.82 mL, 39.00 mmol) was added with a syringe. The
solution was mixed for 24 hours and the MgSO4 was removed by vacuum filtration. The
mother liquor was concentrated to give a light brown solid. The compound was
recrystallized from hexane, off-white solid, 91% yield, mp 72-73°C. The compound
matched the reported literature data.

39 1

H NMR (300 MHz), CDCl3: 3.72 (3H, s), 6.43-

7.49 (5H, m), 6.83 (2H, d, J = 9.0 Hz), 7.16 (2H, d, J = 9.0 Hz), 8.20 (1H, s);

13

C NMR (75

MHz), CDCl3: 55.30, 158.40, 152.20, 145.60, 145.20, 144.20, 122.20, 115.50, 114.30,
112.00, 55.30.
Racemic ethyl 1-(4-methoxyphenyl)-3-phenylaziridine-2-carboxylate

The compound was synthesized by a literature method.

40

To a 250 mL round bottom flask

under nitrogen was added (Z)-N-benzylidene-4-methoxyaniline (2.5 g, 12.00 mmol), DCM
(100 mL), and BF3•O(Et)2 (0.30 mL, 2.36 mmol). Ethyl diazoacetate (1.35 mL, 13.00
mmol) was added to the reaction solution with a syringe. The reaction starting releasing
nitrogen gas and was mixed a room temperature for 24 hours. The reaction solution was
washed with sat. aq. NaHCO3 (50 mL), dried with MgSO4, filtered, and concentrated in
vacuo. The compound was purified by silica gel chromatography 20: 80 EtOAc: hexane;
51

Rf = 0.4; oil; 51% yield. The compound matched the reported literature data.

40 1

H NMR

(300 MHz), CDCl3: 0.87 (3H, t, J = 7.3 Hz), 3.03 (1H, d, J = 7.0 Hz), 3.40 (1H, d, J = 7.0
Hz), 3.62 (3H, s), 3.80-3.99 (2H, m), 6.69 (2H, d, J = 9.3 Hz), 6.87 (2H, d, J = 9.3 Hz),
7.36-7.44 (5H, m);

13

C NMR (75 MHz), CDCl3: 13.70, 45.60, 47.20, 55.30, 60.71,

114.20, 120.60, 127.50, 127.60, 127.80, 128.30, 128.60, 134.60, 145.60, 155., 167.50.
2-3: Racemic ethyl 3-phenylaziridine-2-carboxylate

The compound was prepared by the literature method.

41

To a 250 mL round bottom flask

was added 1-(4-methoxyphenyl)-3-phenylaziridine-2-carboxylate (1.80 g, 6.06 mmol),
acetonitrile (120 mL) and water (80 mL). The round bottom flask was cooled in an ice
bath and cerric ammonium nitrate (8.30 g, 15.15 mmol) was added. The reaction was
maintained at 0°C for 2 hours and then sat. aq. NaHCO3 was added until the pH was 7.
Sodium bisulfate was added to consume the residual cerric ammonium nitrate. The pH was
adjusted to 9 with sat. aq. NaHCO3 and then the solution was extracted with EtOAc (50
mL x 3), the combined extracts were washed with brine (30 mL), dried with MgSO4,
filtered, and concentrated in vacuo. The crude product was purified by silica gel
chromatography; 1: 1 hexane: ether; Rf = 0.13; white solid; mp 66-68°C. The compound
7,16

matched the reported literature data and can be found in the my master’s thesis.

52

General procedure for synthesis of imidazolines
7

The reaction scale was based on 100 mg of the starting aziridine. To a 10 mL round
bottom flask under argon was added the desired amide (1.2 equiv.), 2,6-lutidine (6 equiv.),
and DCM (4 mL). The solution was either cooled to 0°C or left at room temperature
depending on the amide (located below). Oxalyl chloride (1.2 equiv.) was added to the
round bottom flask over 3 minutes with a syringe. The reaction was mixed for the desired
time (located below) and then the DCM was removed in vacuo at room temperature. This
gave the crude product as a mixture of the desired imidoyl chloride, excess 2-6-lutidine (bp
144°C, 760 mm Hg), and 2,6-lutidine hydrogen chloride. This round bottom flask was
then placed under argon again and the desired aziridine (100 mg, 1 equiv.) and DMF (4
mL) were added. The solution was heated to 55°C for the desired time (see Table 2 or 3).
An aliquot of the reaction solution was taken, placed under vacuum (approx. 10 mm Hg) at
1

room temperature and a H NMR was taken to determine the imidazoline reaction times.
The reactions could also be monitored by TLC 30:70 EtOAc: hexane and was the most
polar spot on the bottom of the TLC as the imidazoline salt. The reaction solution was then
cooled to room temperature and poured into a separatory funnel followed by an addition of
sat. aq. NaHCO3 (15 mL) and water (15 mL). The product was extracted with EtOAC (20
mL x 3), the combined organic extracts were washed with brine (20 mL), dried over
MgSO4, filtered, and concentrated in vacuo. The imidazolines were purified by column
chromatography on silica gel. In some cases the silica gel had to be neutralized with TEA
to avoid product decomposition.

53

2-6: Racemic or enantiopure ethyl 1-benzyl-2,4-diphenyl-4,5-dihydro-1H-imidazole5- carboxylate

The compound was synthesized according to the general procedure. Either racemic or
enantiopure ethyl 3-phenylaziridine-2-carboxylate was used. The imidoyl chloride reaction
time was 1.25 hours at 0°C. The imidazoline reaction time was 6 hours. Silica gel
1

chromatography; 50: 50 EtOAc: hexane; Rf = 0.35; oil; 52% yield; H NMR (500 MHz)
CDCl3: 0.76 (3H, t, J = 7.0 Hz), 3.34-3.36 (2H, m), 4.15 (1H, d, J = 15.5 Hz), 4.42 (1H, d,
J = 12.0 Hz), 4.68 (1H, d, J = 15.5 Hz), 5.55 (1H, d, J = 12.0 Hz), 7.08-7.27 (10H, m),
7.43-7.44 (3H, m), 7.71-7.72 (2H, m);

13

C NMR and DEPT (125 MHz) CDCl3: 13.36

(CH3), 49.94 (CH2), 60.39 (CH2), 67.03 (CH) 71.32 (CH), 127.33 (CH), 127.51 (CH),
127.58 (CH), 127.65 (CH), 127.96 (CH), 128.42 (CH), 128.57 (CH), 129.99 (CH), 130.52
(CH), 130.70 (C), 136.25 (C), 139.00 (C), 146.33 (C), 169.79 (C); IR (NaCl) 3075, 2980,
1738, 1597, 1496, 1452, 1406, 1194, 1132, 1018; HRMS: Calculated for C25H25N2O2
+

(M ): 385.1916; Found 385.1922.

54

Determination of enantiomeric excess of compound 2-19 by (S)-Mosher’s Acid

Racemic compound 2-6 and (S)-Mosher’s acid were combined in equal molar quantities in
1

an NMR tube along with CDCl3. Analysis by H NMR revealed that the (S, R, R) and the
(S, S, S) diastereomeric salts were formed in a 50:50 mixture. Enantiopure compound 2-6
and (S)-Mosher’s acid were combined in equal molar quantities in an NMR tube along with
1

CDCl3. Analysis by HNMR revealed that only one the (S, S, S) diastereomeric salt was
1

detected. (S, R, R) diastereomeric salt: H NMR (500 MHz) CDCl3: 0.78 (3H, t, J = 7.5
Hz), 3.34 (3H, s), 3.49-3.76 (2H, m), 4.33 (1H, d, J = 15.0 Hz), 4.62 (1H, d, J = 12.5 Hz),
4.94 (1H, d, J = 15.0 Hz), 5.86 (1H, d, J = 12.5 Hz), 7.15-7.90 (20H, m), 9.20 (1H, s, br).
1

(S, S, S) diastereomeric salt: H NMR (500 MHz) CDCl3: 0.79 (3H, t, J = 7.5 Hz), 3.35
(3H, s), 3.49-3.76 (2H, m), 4.34 (1H, d, J = 15.0 Hz), 4.64 (1H, d, J = 12.5 Hz), 4.95 (1H,
d, J = 15.0 Hz), 5.90 (1H, d, J = 12.5 Hz), 7.15-7.89 (20H, m), 9.51 (1H, s, br).
2-16: ethyl 1-benzyl-4-(4-methoxyphenyl)-2-phenyl-4,5-dihydro-1H-imidazole-5carboxylate

55

The compound was synthesized according to the general procedure. The imidoyl chloride
reaction time was 1.25 hours at 0°C. The imidazoline reaction time was 10 hours. Silica
1

gel chromatography; 50: 50 EtoAc: hexane; Rf = 0.45; oil; 45 % yield; H NMR (500
MHz) CDCl3: 1.29 (3H, t, J = 7 Hz), 3.85 (3H, s), 3.97 (1H, d, J = 16.0 Hz), 4.20-4.26
(2H, m), 4.63 (1H, d, J = 8.0 Hz), 4.64 (1H, d, J = 16.0 Hz), 4.85 (1H, d, J = 8.0 Hz), 6.916.93 (2H, m), 7.05 (2H, d J = 7 Hz), 7.23-7.32 (5H, m), 7.43-7.49 (3H, m), 7.68-7.72 (2H,
m);

13

C NMR (125 MHz) CDCl3: (One CH carbon not found) 14.39 (CH3), 40.01 (CH2),

55.56 (CH3), 61.53 (CH2), 66.11 (CH), 76.00 (CH), 114.61 (CH), 127.67 (CH), 127.74
(CH), 128.68 (CH), 128.85 (CH), 128.86 (CH), 130.59 (CH), 130.71 (C), 132.83 (C),
136.64 (C), 159.79 (C), 167.22 (C), 172.19 (C); IR (NaCl): 3031, 2934, 1734, 1613, 1512,
+

1451, 1361, 1249, 1178; HRMS: Calculated for C26H27N2O3 (M ): 415.1977; Found
415.2022.
2-17: ethyl 1-benzyl-2,4-diphenyl-4,5-dihydro-1H-imidazole-5-carboxylate

56

The compound was synthesized according to the general procedure. The imidoyl chloride
reaction time was 1.25 hours at 0°C. The imidazoline reaction time was 12 hours. Silica
gel column chromatography; 50: 50 EtOAc: hexane; Rf = 0.4; solid; 78-80°C; 42% yield;
1

H NMR (500 MHz) CDCl3: 1.27 (3H, t, J = 7.0 Hz), 3.97 (1H, d, J = 7.5 Hz), 4.12-4.28

(2H, m), 4.42 (1H, d, J = 15.5 Hz), 4.61 (1H, d, J = 15.5 Hz), 5.28 (1H, d, J = 7.5 Hz), 7.09
(2H, dd, J1 = 6.0 Hz, J2 = 1.5 Hz), 7.22-7.31 (10H, m), 7.46-7.49 (3H, m), 7.79-7.81 (2H,
m);

13

C NMR and DEPT (125 MHz) CDCl3: 14.12 (CH3), 51.32 (CH2), 61.26 (CH2),

69.92 (CH), 72.30 (CH), 126.58 (CH), 127.28 (CH), 127.67 (CH), 127.91 (CH), 128.43
(CH), 128.57 (CH), 128.58 (CH), 128.75 (CH), 130.29 (CH), 130.61 (C), 136.32 (C),
143.23 (C), 165.81 (C), 172.10 (C); IR (NaCl): 3030, 2980, 1734, 1593, 1496, 1448, 1221,
+

1184; HRMS: Calculated for C25H25N2O2 (M ): 389.2023; Found 389.2027.
2-18: ethyl 1-benzyl-5-methyl-2,4-diphenyl-4,5-dihydro-1H-imidazole-5-carboxylate

The compound was synthesized according to the general procedure. The imidoyl chloride
reaction time was 1.25 hours at 0°C. The imidazoline reaction time was 12 hours. Silica
gel column chromatography; 50: 50 EtOAc: hexane; Rf = 0.3; solid; mp 100-102°C; 59%
1

yield; H NMR (500 MHz) CDCl3: 0.97 (3H, s), 1.31 (3H, t, J = 7.0 Hz), 4.17 (2H, q, J =
7.0 Hz), 4.32 (1H, d, J = 17.5 Hz), 4.58 (1H, d, J = 17.5 Hz), 5.45 (1H, s), 7.18-7.42 (13H,
57

m), 7.62-7.64 (2H, m);

13

C NMR (125 MHz) CDCl3: (One CH carbon not found); 14.42

(CH3), 18.44 (CH3), 48.36 (CH2), 61.90 (CH2), 73.67 (CH), 75.83 (C), 127.02 (CH),
127.27 (CH), 127.85 (CH), 128.29 (CH), 128.45 (CH), 128.63 (CH), 128.68 (CH), 130.14
(CH), 131.64 (C), 138.37 (C), 139.33 (C), 167.02 (C), 175.22 (C); IR (NaCl): 3029, 2988,
+

1732, 1616, 1595, 1497, 1454, 1421; HRMS: Calculated for C29H27N2 (M ): 403.2174;
Found 403.2185.
2-19: ethyl 1-benzyl-4-(4-nitrophenyl)-2-phenyl-4,5-dihydro-1H-imidazole-5carboxylate

The compound was synthesized according to the general procedure. The imidoyl chloride
reaction time was 1.25 hours at 0°C. The imidazoline reaction time was 13 hours. Silica
gel column chromatography; 40: 60 EtOAc: hexane; Rf = 0.29; oil; 13% yield; the
1

regiochemistry was confirmed by NOESY. H NMR (500 MHz) CDCl3: 1.33 (3H, t, J =
7.5 Hz), 3.92 (1H, d, J = 7.5 Hz), 4.19-4.38 (2H, m), 4.35 (1H, d, J = 15.0 Hz), 4.71 (1H, d,
J = 15.5 Hz), 5.38 (1H, d, J = 7.5 Hz), 7.02-7.04 (2H, m), 7.23-7.26 (3H, m), 7.38 (2H, d, J
= 8.5 Hz), 7.50-7.54 (3H, m), 7.79-7.82 (2H, m), 8.15 (2H, d, J = 9.0 Hz);

13

C NMR and

DEPT (125 MHz) CDCl3: 14.46 (CH3), 51.48 (CH2), 62.02 (CH2), 69.30 (CH), 71.50
(CH), 124.03 (CH), 127.75 (CH), 128.23 (CH), 128.25 (CH), 128.99 (CH), 129.02 (CH),
129.09 (CH), 130.37 (C), 131.01 (CH), 136.09 (C), 147.46 (C), 150.76 (C), 167.10 (C),
58

171.81 (C); IR (NaCl, CDCl3): 3028, 2918, 1734, 1524, 1456, 1350; HRMS Calculated for
+

C25H24N3O4 (M ): 430.1767; Found 430.1780.
2-19: ethyl 1-benzyl-5-(4-nitrophenyl)-2-phenyl-4,5-dihydro-1H-imidazole-4carboxylate

Silica gel column chromatography; 40: 60 EtOAc: hexane; Rf = 0.2; oil; 27% yield; the
1

regiochemistry was confirmed by NOESY; H NMR (500 MHz) CDCl3: 1.30 (3H, t, 7.0
Hz), 4.04 (1H, d, J = 15.5 Hz), 4.18-4.31 (2H, m), 4.55 (1H, d, J = 8.0 Hz), 4.64 (1H, d, J =
15.5 Hz), 4.95 (1H, d, J = 15.5 Hz), 7.01 (2H, dd, J1 = 5.5 Hz, J2 = 2.0 Hz), 7.23-7.28 (4H,
m), 7.47-7.28 (4H, m), 7.74-7.77 (2H, m), 8.23 (2H, d, J = 9.0 Hz);

13

C NMR (125 MHz)

CDCl3: 14.22 (CH3), 51.25 (CH2), 61.77 (CH2), 66.35 (CH), 76.53 (CH), 124.46 (CH),
127.99 (CH), 128.14 (CH), 128.17 (CH), 128.94 (CH), 128.98 (CH), 129.03 (CH), 130.29
(C), 130.96 (CH), 135.84 (C), 147.89 (C), 148.74 (C), 167.82 (C), 171.56 (C); IR (NaCl):
+

3029, 2984, 1742, 1595, 1523, 1350; HRMS Calculated for C25H24N3O4 (M ): 430.1767;
Found 430.1780.
2-20: ethyl 1-benzyl-2-phenyl-4-styryl-4,5-dihydro-1H-imidazole-5-carboxylate

59

The compound was synthesized according to the general procedure. The imidoyl chloride
reaction time was 1.25 hours at 0°C. The imidazoline reaction time was 20 hours. The
silica gel was neutralized by the general method. Silica gel column chromatography; 40:
1

60 EtOAc: hexane; Rf = 0.48; oil; 41% yield; H NMR (500 MHz) CDCl3: 1.22 (3H, t, J =
7.0 Hz), 4.10-4.21 (2H, m), 4.20 (1H, d, J = 17 Hz), 4.46 (1H, d, J = 0.5 Hz), 4.47 (1H, d, J
= 0.5 Hz), 4.49 (1H, d, J = 16.0 Hz), 6.08-6.14 (1H, m), 6.39 (1H, d, J = 16.0 Hz), 7.07
(2H, d, J = 5.0 Hz), 7.15-7.38 (11H, m), 7.55-7.59 (2H, m);

13

C NMR and DEPT (125

MHz) CDCl3: (One CH carbon not found) 14.43 (CH3), 49.50 (CH2), 61.57 (CH2), 66.39
(CH), 77.10 (CH), 126.86 (CH), 127.68 (CH), 127.72 (CH), 127.83 (CH), 128.33 (CH),
128.80 (CH), 128.86 (CH), 128.90 (CH), 130.54 (CH), 130.84 (C), 134.06 (CH), 136.40
(C), 137.10 (C), 167.39 (C), 172.09 (C); IR (NaCl): 3154, 2984, 1733, 1594, 1469, 1381,
+

1216, 1098; HRMS Calculated for C27H27N2O2 (M ): 411.2073; Found 411.2086.
2-21: ethyl 1-benzyl-4-hexyl-2-phenyl-4,5-dihydro-1H-imidazole-5-carboxylate

60

The compound was synthesized according to the general procedure. The imidoyl chloride
reaction time was 1.25 hours at 0°C. The imidazoline reaction time was 12 hours. Silica
1

gel chromatography; 50: 50 EtOAc: hexane; Rf = 0.4; oil; 40% yield; H NMR (500 MHz)
CDCl3: 0.86 (3H, t, J = 6.5 Hz), 1.26 (3H, t, J = 7.0 Hz), 1.27-1.39 (8H, m), 1.48-1.55
(1H, m), 1.62-1.71 (1H, m), 3.72 (1H, d, J = 7.0 Hz), 4.11-4.13 (1H, m), 4.11-4.33 (2H, m),
4.34 (1H, d, J = 15.5 Hz), 4.56 (1H, d, J = 15.5 Hz), 7.12 (2H, d, J = 7.0 Hz), 7.25-7.33
(3H, m), 7.42-7.44 (3H, m), 7.67-7.69 (2H, m);

13

C NMR (125 MHz) CDCl3: 14.09

(CH3), 14.15 (CH3), 22.57 (CH2), 25.04 (CH2), 29.14 (CH2), 31.72 (CH2), 36.77 (CH2),
50.98 (CH2), 61.07 (CH2), 66.82 (CH), 69.82 (CH), 127.69 (CH), 127.94 (CH), 128.55
(CH), 128.62 (CH), 128.67 (CH), 130.11 (CH), 130.74 (C), 136.70 (C), 164.67 (C), 172.58
(C); IR (NaCl): 3029, 2928, 1734, 1595, 1452, 1409, 1244, 1199; HRMS Calculated for
+

C25H33N2O2 (M ): 393.2542; Found 393.2548.
2-22: 1-benzyl-2,4-diphenyl-4,5-dihydro-1H-imidazol-5-yl)(phenyl)methanone

The compound was synthesized according to the general procedure. The imidoyl chloride
reaction time was 1.25 hours at 0°C. The imidazoline reaction time was 12 hours. Silica
1

gel chromatorgraphy; 50: 50 EtOAc: hexane; Rf = 0.45; oil; 41% yield; H NMR (500
MHz) CDCl3: 4.31 (1H, d, J = 15.5 Hz), 4.72 (1H, d, J = 15.5 Hz), 4.89 (1H, d, J = 6.5
61

Hz), 5.08 (1H, d, J = 6.5 Hz), 7.08-7.11 (2H, m), 7.14-7.17 (2H, m), 7.24-7.37 (6H, m),
7.37-7.41 (2H, m), 7.51-7.56 (3H, m), 7.57-7.61 (1H, m), 7.71 (2H, d, J = 8.0 Hz), 7.847.86 (2H, m);

13

C NMR (125 MHz) CDCl3: 51.10 (CH2), 73.17 (CH), 73.25 (CH), 127.25

(CH) , 127.92 (CH), 128.04 (CH), 128.36 (CH), 128.89 (CH), 128.93 (CH), 128.94 (CH),
128.96 (CH), 129.03 (CH), 129.09 (CH), 130.60 (CH), 133.81 (CH), 134.96 (C), 136.70
(C), 142.96 (C), 165.82 (C), 166.27 (C), 197.66 (C); IR (NaCl): 3065, 2925, 1688, 1595,
+

1451, 1233; HRMS: Calculated for C29H25N2O (M ): 417.1967; Found 417.1960.
2-23: 1,5-dibenzyl-2,4-diphenyl-4,5-dihydro-1H-imidazole and 1,4-dibenzyl-2,5diphenyl-4,5-dihydro-1H-imidazole

The compound was synthesized according to the general procedure. The imidoyl chloride
reaction time was 1.25 hours at 0°C. The imidazoline reaction time was 12 hours. Silica
gel chromatorgraphy; 50: 50 EtOAc: hexane; Rf = 0.45; oil; 41% yield; the compounds
1

were isolated as an inseparable mixture of regioisomers (2:1 ratio). Regioisomer 1: H
NMR (500 MHz) CDCl3: 2.53 (1H, dd, J1 = 8.5 Hz, J2 = 5.5 Hz), 3.01 (1H, dd, J1 = 8.0
Hz, J2 = 6.0 Hz), 3.81 (1H, d, J = 16.0 Hz), 4.63 (1H, d, J = 11.0 Hz), 4.67 (1H, d, J = 16.0
1

Hz), 4.77-4.83 (1H, m), 6.80-7.90 (20H, m); Regioisomer 2: H NMR (500 MHz) CDCl3:
2.33 (1H, dd, J1 = 7.5 Hz, J2 = 6 Hz), 2.65 (1H, dd, J1 = 8.5 Hz, J2 = 5.5 Hz), 3.61 (1H, d, J
62

= 16.0 Hz), 4.07-4.12 (1H, m), 4.49 (1H, d, J = 16.0 Hz), 5.30 (1H, d, J = 10.5 Hz), 6.807.90 (20H, m). Both Regioisomers

13

C NMR (125 MHz) CDCl3: (3 carbon signals not

found); 37.66, 38.96, 48.93, 51.30, 64.60, 66.88, 70.55, 72.75, 125.87, 126.37, 127.30,
127.67, 127.69, 127.75, 127.82, 128.10, 128.15, 128.20, 128.50, 128.58, 128.77, 128.79,
128.85, 128.92, 129.11, 129.20, 129.41, 130.25, 130.55, 131.60, 131.64, 137.40, 137.80,
138.42, 139.33, 139.80, 139.96, 165.75, 167.68; IR (NaCl, CDCl3): 3028, 2918, 1616,
+

1595, 1452, 1412; HRMS Calculated for C26H27N2O2 (M ): 399.2073; Found 399.2086.
2-39: Cis and trans-diethyl 2,4-dibromopentanedioate

Cis and trans-diethyl 2,4-dibromopentanedioate was synthesized according to a known
procedure.

25

To a 25 mL round bottom flask was added glutaryl dichloride (10 mL, 0.078

mol) and the flask was attached to a reflux condenser. The flask was placed in an oil bath
preheated to 85°C. A sunlamp 300W was positioned as close as possible to the round
bottom flask. Neat bromine (4.85 mL, 0.094 mol) was then added dropwise in small
increments over a period of 1.25 h, while maintaining the temperature at 85°C. Attached to
the reflux condenser was a tube connected to a beaker containing a solution of 1M NaOH
(500 mL) and 10% aq. Na2S2O3 (50 mL) to quench the HBr and excess Br2. After the
addition of Br2 the reaction was maintained at 85°C for an additional 4 h. The reaction was
then cooled to room temperature. To another 250 mL round bottom flask was added
anhydrous ethanol (50 mL) under argon and the solution was cooled with an ice water bath.
The reflux condenser was removed and replaced will a septum and put under argon. The
63

reaction solution was transferred to the ethanol solution over ¼ h with a canulla. The
solution was stirred at room temperature overnight and then was poured into a sep. funnel
containing NaHCO3. The solution was slowly mixed until CO2 stopped evolving and then
was extracted 3x with ether. The ether extracts were combined, dried with MgSO4, filtered
and concentrated in vacuo. The crude product was pure enough to be used in the following
reaction without further purification.
2-40 and 2-41: Cis and trans-diethyl 1-benzylazetidine-2,4-dicarboxylate

The compounds were synthesized by a modified procedure from the literature.

25,26

To a

500-mL round bottom flask was added cis and trans-diethyl 2,4-dibromopentanedioate (8
g, 24.48 mmol), DMF (200 mL), and benzyl amine (8.82 mL, 80.78 mmol). The reaction
solution was heated to 85°C with an oil bath for 4 hours. The reaction solution was cooled
to room temperature and poured into a sep. funnel containing 500 mL of 5% aq. LiBr
solution. Water (1000 mL) was added to the sep. funnel and the product was extracted
with EtOAc, died with MgSO4, vacuum filtered, and concentrated in vacuo. The product
was purified by silica gel chromatography, 1:9 ether: hexane until the trans-diethyl 1benzylazetidine-2,4-dicarboxylate was isolated and then 1:2 ether: hexane to isolate the cisdiethyl 1-benzylazetidine-2,4-dicarboxylate. 2-40: Cis isomer: Rf = 0.30; 1: 2 ether:
1

hexane; yellow oil; 2.38 g, 35% yield; H NMR (300 MHz), CDCl3: 1.18 (6 H, t, J = 7.1
Hz), 2.41 (2H, m), 3.59 (2H, t, J = 8.3 Hz), 3.88 (2H, s), 4.08 (4 H, m), 7.29-7.33 (5H, m);
13

C NMR (75 MHz), CDCl3: 14.00, 14.05, 24.69, 59.39, 59.44, 60.19, 60.71, 60.74,
64

127.42, 128.16, 129.88, 135.59, 171.58, 171.63; 2-41: Trans-isomer: Rf = 0.35; 1: 2
1

ether: hexane; yellow oil; 2.45 g, 36% yield; H NMR (300 MHz), CDCl3: 1.20 (6H, t, J =
7.1 Hz), 2.50 (2H, t, J = 6.8 Hz); 3.88 (2H, s), 4.12 (4 H, q, J = 7.1 Hz); 4.20 (2H, t, J = 6.7
Hz); 7.21-7.30 (5H, m);

13

C NMR (75 MHz), CDCl3: 14.16, 14.19, 25.46, 55.74, 60.61,

60.64, 61.77, 61.80, 127.14, 128.15, 128.91, 137.12, 172.45, 172.48.
2-42: Cis-diethyl azetidine-2,4-dicarboxylate

To a 100-mL round bottom flask under nitrogen was added cis-diethyl 1-benzylazetidine2,4-dicarboxylate (1.20 g, 4.11 mmol), anhydrous ethanol (40 mL), and Pd(OH)2 on carbon
(600 mg). A balloon filled with hydrogen was attached to the round bottom flask a needle
was used to vent the nitrogen out of the flask and replace it with a hydrogen atmosphere.
The reaction was mixed overnight at room temperature. The reaction solution was filtered
through a glass frit containing celite and the celite was washed with DCM. The solvents
were removed in vacuo. The product was consistent with the literature data.25,26 Yellow
1

oil; 0.79 g; 95% yield; H NMR (500 MHz) (CDCl3) δ 1.26 (6H, t, J = 7.0 Hz), 2.27 (1H,
m), 2.95 (1H, m), 3.0 (1H, s, br), 4.18 (4H, q, J = 6.85 Hz), 4.85 (2H, dd, J1 = 10.30, J2 =
5.90 Hz;

13

C NMR (75 MHz), CDCl3 δ 14.05, 25.74, 58.65, 61.37, 171.02.

2-43: Trans-diethyl azetidine-2,4-dicarboxylate

65

To a 100-mL round bottom flask was added trans-diethyl 1-benzylazetidine-2,4dicarboxylate (1.20 g, 4.11 mmol), anhydrous ethanol (40 mL), and Pd(OH)2 on carbon
(600 mg). A balloon filled with hydrogen was attached to the round bottom flask a needle
was used to vent the nitrogen out of the flask and replace it with a hydrogen atmosphere.
The reaction solution was filtered through a glass frit containing celite and the celite was
washed with DCM. The solvents were removed in vacuo. The product was consistent with
the literature data.25,26 Silica gel chromatography; 50: 50 EtOAc: hexane; Rf = 0.25;
1

yellow oil; 0.69 g; 84% yield; H NMR (500 MHz) (CDCl3) δ 1.18 - 1.31 (6, t, J = 6.85
Hz), 2.65 (2H, t, J = 7.80 Hz), 2.89 (1H, s, br), 4.18 (2H, m); 4.22 (2H, t, J = 7.80 Hz);
NMR (75 MHz), CDCl3 δ 14.12, 28.66, 55.74, 61.15, 76.83, 77.08, 77.33, 174.00.

66

13

C

REFERENCES

67

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Sharma, V.; Hupp, C. D.; Tepe, J. J. Curr. Med. Chem. 2007, 14, 1061.

(4)

Sharma, V.; Lansdell, T. A.; Peddibhotla, S.; Tepe, J. J. Chem. Biol. 2004,
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Kuszpit, M., Michigan State University, 2010.

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Fergus, S.; Eustace, S. J.; Hegarty, A. F. J. Org. Chem. 2004, 69, 4663.

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Cunico, R. F.; Pandey, R. K. J. Org. Chem. 2005, 70, 5344.

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Mukund, S. P.; Takahiro, S.; Craig, J. P. Org. Lett. 2009, 11, 5366.

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Bender, H. S.; Heine, H. W. J. Org. Chem. 1960, 25, 461.

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Zhang, Y.; Lu, Z.; Desai, A.; Wulff, W. D. Org. Lett. 2008, 10, 5429.

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Patwardhan, A. P.; Pulgam, V. R.; Zhang, Y.; Wulff, W. D. Angew. Chem.
Int. Ed. 2005, 44, 6169.

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Kahlon, D. K.; Lansdell, T. A.; Fisk, J. S.; Tepe, J. J. Bioorganic &
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Francois, C.; Gwilherm, E. Synlett 2009, 3053.

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Bartnik, R.; Marchand, A. P. Synlett 1997, 1029.

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Brandi, A.; Cicchi, S.; Cordero, F. M. Chem. Rev. 2008, 108, 3988.

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Wehn, P. M.; Du Bois, J. J. Am. Chem. Soc. 2002, 124, 12950.

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Wang, B.; Wu, X.; Wong, O. A.; Nettles, B.; Zhao, M.; Chen, D.; Shi, Y.
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70

CHAPTER 3
REACTION OF BROMINE REAGENTS WITH OLEFINS AND SYNTHESIS OF
HETEROCYCLES

Several syntheses of agesamide A and B, longamide, cyclooroidin, hanishin, and
agelastatin A have already been developed.

1-3

Our lab is interested in the biological

activity of these natural products and their analogs. Therefore, we would like to develop a
new synthetic methodology to access these compounds. We envisioned one possible
method may be by activation of an olefin with an electrophilic halogen source and
subsequent nucleophilic attack by either the pyrrole nitrogen or the amide nitrogen of a 2substituted indole or pyrrole. The indole / pyrrole nitrogen’s lone pair of electrons is
locked into the aromaticity of the indole / pyrrole ring and as a result the nitrogen atom is a
poor nucleophile. The amide nitrogen would be predicted to be a better nucleophile than
the indole / pyrrole nitrogen unless the amide was substituted with a strong electron
withdrawing group. Reaction of the following compound with base would close the ring in
a 6-exo-tet Baldwin favorable ring closure (Scheme 3-1).

71

Scheme 3-1: Proposed synthesis of biologically significant natural products

Figure 3-1: Biologically significant natural products

72

As expected initial trials of the reaction of cyclohexene with a pyrrole amide all
resulted in halogenation of the C-2 position, C-3 position and very slowly the C-4 position
of the pyrrole ring (Table 3-1). Reactions with benzyl (3-1), tosyl (3-2), and benzoyl (3-3)
substituted pyrrole amides did not form any of the desired product 3-4 even with 3 or 4
equivalents of NBS for 24 hours. Theoretically it was also possible to halogenate the amide
1

N-H of 3-1, 3-2 or 3-3 with NBS but this was not observed by H NMR. Analysis of these
1

compounds by H NMR showed that the amide and pyrrole NH peaks were exchangeable
with D2O (Table 3-1).

73

Table 3-1: Reaction of pyrrole amides with cyclohexene

entry R1 SM# halogen Source halogen source equiv. Yield (%) 3-4
1
2
3
4
5
6

Bn
Bn
Bn
Bn
Ts
Bz

3-1
3-1
3-1
3-1
3-2
3-3

NCS
NBS
NIS
NBS
NBS
NBS

3
3
3
4
4
4

0
0
0
0
0
0

One explanation for these results was that the pyrrole amide nitrogen was too poor
of a nucleophile. The halonium ion intermediate formed with cyclohexene and an Nhalosuccinimide was not attacked by the pyrrole amide nitrogen. Therefore 4,5-dibromoN-methoxy-1H-pyrrole-2-carboxamide 3-5 was synthesized. This solved two problems
now the pyrrole C-2 and C-3 positions of 3-5 were already brominated so only one

74

equivalent of NBS should be needed to synthesize compound 3-6. Secondly, the pyrrole
amide now had an electron donating N-OMe group and should increase the nitrogen amide
nucleophilicity to attack the halonium ion formed with NBS and cyclohexene.
Unfortunately, the reaction of compound 3-5 with cyclohexene and NBS only resulted in
bromination of the amide N-H and some bromination at the C3-position of the pyrrole ring
and compound 3-6 was not synthesized. As a result the reaction was repeated with 2
equivalents of NBS, but this only resulted in the formation of N,3,4,5-tetrabromo-Nmethoxy-1H-pyrrole-2-carboxamide as the major product 3-7. Once the bromo-amide was
formed the bromine atom did not transfer to the cyclohexene to form a bromonium ion. As
a result compound 3-8 was not formed and only the N-bromo pyrrole amide compound 3-7
was synthesized (Scheme 3-2).

Scheme 3-2: Reaction of 3-5 with cyclohexene and NBS

75

It seemed that the electronics of the amide nitrogen were very important. If the amide
contained a nitrogen-electron withdrawing group (N-EWG) then bromination of the amide
with NBS did not occur. If an amide contained an N-EWG then it was not nucleophilic
enough to attack the bromonium ion intermediate formed with cyclohexene. If the amide
contained a nitrogen-electron donating group (N-EDG) then the amide was more
nucleophilic and may undergo substitution with the cyclohexene bromonium ion. However,
the NBS just brominated the N-EDG instead of forming a bromonium ion with
cyclohexene. Once compound 3-7 was formed it was too stable to react with cyclohexene
through a bromonium ion intermediate to form the desired compound 3-8.
These results led us to investigate the reaction of benzamide with cylohexene with
various halogenating agents in the presence of different Lewis acids (Table 3-2). This
model reaction was done to try to reproduce the results by Zhoa and coworkers (Scheme 34

3).

Scheme 3-3: Synthesis of compound 3-9 by Zhoa and coworkers

4

Initial results only gave low yields of a single product with NBS working the best. The
presumed product was the result of attack of the amide nitrogen of benzamide on the
cyclohexene-NBS halonium intermediate to yield trans-N-2-bromocyclohexyl benzamide
3-9. However, purification of the crude product by silica gel chromatography revealed
76

compound 3-12 as the main product. Trans-2-bromocyclohexyl benzimidate 3-10 was
evidently formed under these reaction conditions and then hydrolyzed into trans-2bromocyclohexyl benzoate 3-12 during silica gel chromatography (Table 3-2). The
1

product was isolated as a mixture of 3-10 and 3-12 as observed by H NMR,

13

C NMR and

LRMS. A review of the literature revealed another synthesis of 3-9 by Corey and
5

coworkers. The reaction of benzonitrile, water, NBS, BF3•O(Et)2 , and cyclohexene
yielded compound 3-9. Undoubtedly, Corey and coworkers have made the right compound
based on their mechanism and experimental data. The experimental data for 3-9 had the
NH proton clearly identified by Corey and coworkers as well as the cyclized compound 4,5
dihydrooxazole 3-11. In my hands compound 3-9 and 3-11 were not synthesized by the
reaction of cyclohexene, NBS, benzamide and a Lewis acid but instead compound 3-10
was formed. Therefore, I could not reproduce the results by Zhoa and coworkers.
These reactions were very slow and gave low yields of 3-10. The cyclohexene and
halogenating reagent were consumed but approximately 70% of benzamide was recovered.
There was also the formation of other impurities perhaps by elimination of the halonium/
cyclohexene ion intermediate. The last entry in the table resulted in decomposition and
compound 3-9 was formed with TCICA. The results are summarized in the table below
(Table 3-2).

77

Table 3-2: Reaction of NBS with benzamide and cyclohexene

Halogen
Agent

Lewis
Acid

Lewis Acid
equiv

Time
(h)

X

yield
(%)
3-12

None
None
FeCl2
CuI
CuBr2
None

0
0
0.15

48
48
16

Cl
Br
Br

0
27

0.15
0.15

16
16

Br
Br

0

1

Cl

Entry

solvent

1
2

DCM
DCM
EtOAc

NCS
NBS
NBS

EtOAc
EtOAc

NBS
NBS

DCM

TCICA

3
4
5
6

26
16
23
dec

The benzamide oxygen atom was more nucleophilic than the nitrogen atom due to
resonance of the amide electrons into the more electronegative carbonyl oxygen atom. The
ability for oxygen versus nitrogen attack is illustrated by examples of intramolecular
cyclization reactions shown below in the following schemes. An excellent paper by
6

Zhenfeng Xi and coworkers synthesized a variety of dioxolan-2-imines where the nitrogen

78

atom was substituted with an alkyl or aryl group. Another report by Uei and coworkers

7

studied the intramolecular cyclization to yield a 5 membered ring dioxolan-2-imine
compound 3-13 which hydrolyzed to a dioxanone compound 3-14. Uei and coworkers
also reported this cyclization to 6 membered dioxanones 3-15. The intramolecular amide
cyclization to an dioxolan-2-imine and hydrolysis to an dioxolan-2-one has been reported
8

9

by Corey, Minobe, and also currently being explored by the Borhan laboratory (scheme
3-4).

Scheme 3-4: Intramolecular oxygen cyclization

79

These reports were intramolecular examples instead of intermolecular examples. However,
they help explain the synthesis of the imido ester compound 3-10 and hydrolysis to the
ester compound 3-12. The selectivity of oxygen versus nitrogen intramolecular selectivity
was explained very well in a great paper by Taguchi.

10

Taguchi explained oxygen versus

nitrogen attack by Hard Soft Acid Base (HSAB) theory. They reported that the amide or
cabamate oxygen is a hard nucleophile and the halonium intermediate formed with a
carbon-carbon pi bond is a hard electrophile. The amide or carbamate nitrogen atom is a
soft nucleophile. Based on HSAB theory the hard electrophile should react with the hard
nucleophile preferably over the soft nucleophile to give oxygen cyclization. However,
Taguchi reported that if the amide nitrogen is substituted with an EWG then the pKa of the
NH proton is significantly lowered. The reaction of compound 3-16 with BuLi to remove
the NH proton converted the nitrogen into a strong hard nucleophile. Iodine was then
added to this reaction to make the iodonium ion followed by N-cyclization to yield
compound 3-17. Taguchi and coworkers reported many examples to make 5 and 6
membered rings through this methodology (Scheme 3-5).

80

Scheme 3-5: Nitrogen cyclization versus oxygen cyclization via HSAB theory
Carbon amide nitrogen bond formation seemed more complicated than initially
thought. One way to simplify the reaction would be to put the halogen atom on the amide
or an imide nitrogen. This would make the nitrogen atom the nucleophile instead of the
oxygen atom. So as a model reaction we decided to study the addition of NBS to styrene
with various Lewis acid catalysts. BF3•OEt2 worked the best and yielded compound 3-18
in 81% yield and TMSOTf yielded compound 3-18 in 54% yield (Table 2-3,entries 5 and

81

11). All the other Lewis acids formed precipitates and the desired product was not formed
(Table 3-3).
Table 3-3: Study on the Reaction of NBS with Styrene

Entry

solvent

Lewis acid

Time (h)

temp (°C)

3-18 yield (%)

1

DCM

18

rt

78

2

DCM

BF3•OEt2

18

rt

0

3

DCM

rt

0

4
5

DCM

SnCl4

18

ZnCl2
TMSOTf
TiCl4

18

rt

18
18

rt
rt

0
54

18

rt

0

18

rt

18
1

rt
rt

0
0

18

rt

6

DCM
THF

8

THF

9
10

THF

11
12

THF
DCM
DCM

TiCl4

ZnCl2
Zn(OTf)2
CuI
BF3•OEt2
none

0

81
0

NBS was added to styrene to form 1-(2-bromo-1-phenylethyl)pyrrolidine-2,5-dione 3-18
in 81% yield. Presumably, BF3•O(Et)2 coordinated to the imide group and created an
electrophilic bromine to initiate the addition to styrene (Scheme 3-6).

82

Scheme 3-6: Proposed mechanism for addition of NBS to styrene

Unfortunately, the reaction of cyclohexene, NBS, benzamide, and BF3•O(Et)2 did not yield
the trans bromo amide adduct compound 3-9 but instead yielded compound 3-18. This
reaction was repeated with excess benzamide but still only compound 3-18 was formed and
not compound 3-9. The benzamide was a neutral and therefore a much poorer nucleophile
than the negatively charged succinimide ion. By replacing the hydrogen atom on a
nitrogen nucleophile with a bromine atom would increase its nucleophilicity based on the
mechanism in Scheme 3-6. It was therefore determined that having the bromine atom on
the intended nucleophile was the key for this reaction to work successfully. We were
hoping to explore this reaction as a new amino-halogenation methodology of olefins.
Olefins are commercially available and easily synthetically accessible from
commercially available aldehydes via the Wittig reaction. Aminohalogenation of an olefin
creates both a nitrogen-carbon bond and carbon-halogen bond adjacent to one another.
Thus it is a valuable tool to create a variety of different important organic building blocks.

83

11,12

Aminohalogenation of an olefin with Chloramine-T

, TsNH2

13,14

, TsNCl2

15-17

has

already been extensively studied and is a great method to functionalize an olefin to a cis-N18,19

Ts aziridine

via nitrogen substitution of the halogen atom. An N-Ts aziridine can

undergo ring opening to yield important organic molecules such as a trans-1,2
diamine.

20,21

To this date addition of an amide to an olefin has been much less studied

than TsNH2, but has high synthetic utility. A 1-halo, 2-N-amide can undergo
intramolecular nitrogen substitution to a cis-N-acyl aziridine
23,24

an azide and reduced to a trans-1,2-diamine.

26

which can be opened with

A 1-halo, 2-N-amide can also undergo

intramolecular oxygen attack to a 4,5-dihydrooxazole
alcohol

22

22,25

and hydrolysis to a cis amino

(Scheme 3-7).

Scheme 3-7: Synthesis of important organic building blocks from an 1-bromo, 2-Namide

84

27,28

Addition of an N-halo-amide / carbamate

29-32

, or a N,N-dihaloamide / carbamate
33

olefin has been much less studied, but has been reported by Swern.

to an

Swern reported the

reaction occurred through a radical mechanism by initiation through heat or light to give
anti-Markovnikov addition of the N-halo-amide / carbamate to an olefin. In addition, of
the addition of N-halo-amide / carbamate, other reports have included radical antiMarkovnikov addition of a N-halo-imide to an olefin.

28,34

Markovnikov addition of a N-

halo-imide has been reported to occur with activated olefins like an enol ether
36

enamine

35

or an
37

without the use of radical initiator or a catalyst. A report by Heasley

and

coworkers described the synthesis of a 1-bromo, 2-fluoride adduct by addition of an Nbromo-amine to an olefin in the presence of BF3•OEt2. In a side note they noticed that
NBS underwent addition to cyclohexene to yield the trans-1-bromo, 2-N-imide
stereoisomer adduct.

37

This report by Heasley and coworkers motivated us to explore this

reaction. NBS has very little synthetic utility, but addition of other imides with easily
removable nitrogen protecting groups would be much more synthetically useful. We
wanted to synthesize an N-bromo imide that was not a sterically hindered nucleophile but
also contained N-protecting groups that could be easily deprotected. Nitrogen methyl ester
protecting groups accomplished both of these goals and improved the synthetic utility
beyond simple NBS.
We needed a general procedure to synthesize N-bromo amides and N-Bromo
imides. We first used benzamide as a model substrate to brominate the nitrogen amide. Of
all the methods employed most of them resulted in no reaction and recovery of benzamide.
85

However, N-bromo-benzamide was synthesized by reaction with bromoacetate in CCl4
(Table 3-4, Entry 5).
Table 3-4: Bromination of benzamide

Entry

Reagents

Solvent

Temp

Time (h)

Yield (%) 3-19

1

water

0

0.5

0

2

NaOH, Br2
NBS

DCM

reflux

18

0

3

Br-hydantoin

DCM

refux

18

0

4

BuLi, Br2

THF

-78-rt

5

5

MeCO2Br

CCl4

rt

1.5

0
100%

a

a
a
a
a

No rxn occurred

Bromo-acetate was a general great method to brominate the N-H of an amide or the N-H of
38

an imide.

In general the reaction worked well but did not successfully brominate the N-

H of (Boc)2NH due to the sterically hindered boc groups which blocked the nitrogen
proton from reacting. These reactions were carried out while taking care to protect the
reaction solutions from light. An N-bromo amide or an N-bromo imide was isolated from
the reaction solution by removal of the acetic acid by-product and CCl4 by evaporation in
vacuo at room temperature in the dark. Alternatively, the N-bromo products were also
isolated by precipitation from the CCl4 solution by adding hexene. If, the product was

86

heated in vacuo for too long a debromination reaction occurred to yield the N-H amide or
N-H imide (Table 3-5).
Table 3-5: Bromination of amides and imides

Entry

SM #

R1

R2

X

P#

Yield (%)

1
2

NA

PhCO
PhCO

H
Br

Br
Br

3-27
3-28

100
a
100

3

3-20
NA

PhCO

Bn

Br

3-29

PhCO
PhCO

Me
Ph

Br
Br

3-30
3-31

Br
Br
Br
Br

3-32
3-33
3-34
3-35

Br

3-36

91:9
100
c
0
100
100
75
d
50
0

NA

4
5

3-21
3-22
3-23
3-24

6
7
8

3-25
3-26

9
a

PhCO
Cy
PhCO
Boc
CO2Me CO2Me
PhCO
Ts
Boc

Boc

b

b

c

PhCON(Br)2 was synthesized, ratio of N-bromo amide to N-H amide, a mixture of
d

products were formed, the product was made by another method see experimental section
The N-bromo amides and N-bromo imides were reacted with styrene in the presence
of BF3•OEt2 (Table 3-6). The reaction of NIS, styrene, and BF3•OEt2 was too vigorous
and did not form the desired product 3-39. NCS was not reactive enough under these
conditions and did not form compound 3-37. NBS was superior to the other N-halosuccinimides to form the desired product 3-38 in 81% yield (Table 3-6). Unfortunately, Nbromobenzamide debrominated back to benzamide in the presence of BF3•OEt2 and
87

styrene and did not form the desired product 3-40. Similarly, debromination also occurred
for N-benzyl, N-bromo benzamide, N-Methyl, N-bromo benzamide, N-cyclohexyl, Nbromo benzamide, N-cylohexyl, N-bromo benzamide and N-bromo-N-tosyl benzamide
(Table 3-6, entries 4, 6-9). N,N-dibromobenzamide was reacted with styrene without
catalyst to yield a mixture of regioisomers in 40% yield. N, N-dibromobenzamide was too
reactive and did not seem to give a very useful reaction since it yielded a mixture of
regioisomers. Compound 3-46 and 3-47 did undergo reaction with styrene in 41 and 81%
yield (Table 3-6, entries 10, 11). As a result, as was seen with NBS, and with the earlier
reported studies, two electron-withdrawing acyl groups on the nitrogen atom were needed
to prevent the debromination reaction from occurring and formation of the desired addition
product.

88

Table 3-6: Reaction of N-bromo amides and N-bromo imides with styrene

Entry

R1

1

NA

2
3
4
5
6
7
8
9
10
11

a

R2

X

#

Yield (%)

NA

c

Cl

3-37

NA

NA

c

Br

3-38

Trace
81

NA
PhCO
PhCO

NA
H
Br

c

I

3-39

0

Br
Br

3-40
3-41

PhCO
PhCO
PhCO
PhCO
PhCO
CO2Me

Bn
Me
Cy
Ts
Boc
CO2Me

Br
Br
Br
Br
Br
Br

3-42
3-43
3-44
3-45
3-46
3-47

0
b
40
0
0
0
0
41
81

c
c
c

b

a

1

The rxn time was 24 h, No cat was added, the yield was based on H NMR and resulted
c

in a mixture of regioisomers, The N-halosuccinimides were used; entry 1 NCS, entry 2
NBS, entry 3 NIS
Other reagents such as Ti(OiPr)4, CuI, TiCl4, ZnCl2, Zn(OTf)2 and B(OPh)3 were
screened as a potential catalyst for the reaction of compound 3-34 (Br-N-(CO2Me)2) with
styrene and did not give any desired product 3-47 but instead yielded H-N-(CO2Me)2.
However, stoichiometric TMSOTf, styrene, and Br-N(CO2Me)2 did yield compound 3-47
although the reaction was much slower than with BF3•OEt2. The reaction of 3-34 and
styrene with a Brønsted acid such as TFA, CSA, or diphenyl phosphate all resulted in
89

debromination of compound 3-34 to yield H-N-(CO2Me)2. Only a trace amount of the
1

desired product 3-47 was observed by H NMR in these reactions with a Brønsted acid.
The bromine added to styrene to yield (Z) and (E)-(2-bromovinyl)benzene as the only
product that was able to be identified in these reactions.

Table 3-7: Br-N-(CO2Me)2 addition to olefins

P#

Yield

3-47

81

3-51

0

NA

3-52

88

3-48

3-53

38

3-54

52

SM #

Substrate

Product

NA

NA

NA

90

Table7: Cont’d
SM #

Substrate

Product

#

Yield
trace

3-55
NA

a

NA

3-56

NA

3-57

3-49

3-58

50

3-59

0

3-60

0

3-61

0

34

a, b

37

c

3-50

NA

NA

a

b

d

c

2.0 equiv. of 3-34 was used, Rxn yielded a 52:48 mixture of regioismers, 2:1 ratio of
d
1, 4 addition to 1, 2 addition to the terminal alkene, The compound was synthesized but
was thermally unstable and turned into a mess of anonymous products

91

Compound 3-34 underwent Markovnikov addition to an olefin in the presence of
catalytic BF3•OEt2. The reaction worked the best in DCM or chloroform and occurred
very quickly at room temperature (Table 3-7). The scope of the reaction was investigated
and it was found to work well with styrene and indene, but lower yields were obtained with
the aliphatic olefins. In contrast to indene an aromatic olefin, benzofuran, gave the desired
product in very low yield (Table 3-7, 3-55). Once the bromonium ion was formed with
benzofuran the driving force for the reaction was to regain aromaticity with the loss of a
proton and formation of brominated benzofuran. Compound 3-34 did not undergo
nucleophilic addition to benzofuran but instead resulted in formation of NH(CO2Me)2.
Compound Br-N(CO2Me)2 did react with an enol ether but the resulting product 3-61 was
1

thermally unstable. The identity of compound 3-61 was seen in the crude H NMR
spectrum.
After the synthesis of the 1-bromo, 2-N-imide we focused on deprotection of one of
the two methyl carbamate groups of compound 3-47. This would yield a trans-1-bromo, 2N-methyl carbamate adduct which could be transformed into an aziridine or a 4,5dihydrooxazole through intramolecular substitution of the bromine atom. However, it was
1

observed via H NMR that after 3-47 was purified by column chromatography that
cyclization into a methyl-2-oxooxazolidine-3-carboxylate slowly occurred at room
temperature to yield compound 3-63, through loss of CH3Br which was observed as a
1

singlet in the H NMR. Compounds 3-56 and 3-57 had to be purified on neutralized silica
gel and were not very stable compounds. A two step reaction sequence seemed much more
92

efficient to yield a methyl 2-oxooxazolidine-3-carboxylate without purification of the 1bromo, 2-N-imide adducts compounds 3-47-3-61. A trans-1-bromo, 2-N-imide adduct was
synthesized in only ¾ hours, was quenched with sat. aq. NaHCO3, and then extracted with
DCM. The trans-1-bromo, 2-N-imide adduct was concentrated in vacuo and underwent
smooth transformation into a methyl 2-oxooxazolidine-3-carboxylate by heating neat at
75°C (Table 3-8).
Table 3-8: Synthesis of methyl 2-oxooxazolidine-3-carboxylate

P#

Yield
(2 Steps)

NA

3-63

78

NA

3-64

83

NA

3-65

43

SM #

Substrate

Product

93

a

a

Table 3-8: Cont’d
P#

Yield
(2 Steps)

NA

3-66

52

NA

3-67

48

NA

3-68

36

NA

3-69

NA

3-62

3-70

50

SM #

a

Substrate

Product

b

c

b

The intermediate was purified before cyclization to 3-65 and 3-66, The compound was
c

synthesized in a 2:1 mixture of regioisomers, Compound 3-69 was synthesized with 2.0
equiv of 3-34 and could not be purified sufficiently without decomposition and was
hydrolyzed to oxazolidin-2-one 3-72
This two step reaction was investigated and worked better for electron donating
styrenes than electron withdrawing styrenes to give the methyl-2-oxooxazolidine-3carboxylates in good yields. The addition of 3-34 also worked well with an alpha beta
unsaturated ketone to yield 3-70 in satisfactory yield. The reaction also occurred with
94

trans-4-octene but the methyl-2-oxooxazolidine-3-carboxylate 3-69 could not be isolated in
high purity and was hydrolyzed in the following reaction to an oxazolidin-2-one 3-72
(Table 3-9). The methyl-2-oxooxazolidine-3-carboxylate could be easily deprotected to an
39

NH-oxazolidin-2-one by reaction with LiOH and THF at room temperature to yield 3-71
40

and 3-72

and their spectral data were consistent with the reported literature data (Table

3-9). The second step in the reaction sequence occurred very efficiently through a 5-exotet ring closure via a SN2 mechanism for the primary alkyl bromide substrates 3-63, 3-64,
and 3-65. The trans methyl-2-oxooxazolidine-3-carboxylates were formed in all other
1

cases as supported by H NMR and NOE. Carbon-carbon bond rotation occurred to give
the thermodynamically more favorable trans methyl 2-oxooxazolidine-3-carboxylate
stereoisomer presumably through a SN1 mechanism. However, 3-67 was the cis
stereoisomer due to the geometry of the indene starting material. The reason for mediocre
yields in some cases was the result of the low yields obtained in the first step as the second
step occurs in near quantitative yield.

95

Table 3-9: Hydrolysis of methyl 2-oxooxazolidine-3-carboxylate

Entry

#

Yield

1

3-71

81

2

a

Substrate

Product

3-72

37

a

The compound was synthesized in three steps from trans-4-octene

The role of the BF3•OEt2 was to coordinate to the oxygen atom of compound 3-34
and release a positive bromonium cation (Scheme 3-8). This then formed a bromonium
ion intermediate with the olefin followed by attack of the bromonium ion with the imide
nitrogen atom. Evidence for a bromonium ion mediated mechanism over a radical
mechanism was supported by several factors. First, the more stable the resulting
bromonium ion intermediate the higher the yield for the 1-bromo, 2-N-imide adduct. This
was seen by the yield from reaction of 3-34 with styrene, p-MeO styrene and p-NO2
styrene (Table 3-7).

Secondly, the reaction occurred through Markovnikov addition to

the most stable carbon in the bromonium ion intermediate. In addition, the reaction of (E)buta-1,3-dien-1-ylbenzene with 3-34 gave a 2:1 mixture of 1,4 addition and 1,2 addition to
the terminal olefin (Table 3-7, 3-58). Thus the bromonium ion intermediate formed at the
96

terminal olefin and underwent rearrangement to the most stable benzylic/allylic carbocation
before nucleophilic attack of the imide occurred. Lastly, the reaction gave only the trans 1bromo, 2-N-imide stereoisomer in all cases and not a mixture of anti and syn stereoisomers.

Scheme 3-8: Proposed reaction mechanism for formation of methyl 2-oxooxazolidine-3carboxylate via a bromonium ion
The new aminobromination reagent 3-34 underwent Markovnikov addition
regioselectivly and stereoselectivly to an olefin under catalytic Lewis acid conditions. This
methodology provides a new synthetic route to an N-carbamate amino bromide with an
easily removable carbamate protecting group. It also represents a new efficient synthesis
of a methyl-2-oxooxazolidine-3-carboxylates in a two step sequence from an olefin. The
97

N-CO2Me group can be easily removed by hydrolysis into an oxazolidin-2-one. The
greatest attribute of this methodology is it may have the potential to provide a synthesis of
an enantiomerically pure methyl-2-oxooxazolidine-3-carboxylate if a chiral Lewis acid is
employed.
A chiral boron Lewis acid would be ideal to synthesize enantiopure methyl-2oxooxazolidine-3-carboxylates. An enantiomerically pure methyl-2-oxooxazolidine-3carboxylate could be hydrolyzed into an enantiomerically pure aminol alcohol. However,
we first thought that an easier goal may be to synthesize an N-bromo imide with a chiral
auxiliary and attempted a diastereoselective synthesis of a methyl-2-oxooxazolidine-3carboxylate. We hoped to induce diastereoselectivity with an Evan’s auxiliary. A couple
of oxooxazolidine-3-carboxamides were synthesized by the reactions of (S)-4benzyloxazolidin-2-one with an isocyanate. Halogenation of these substrates proved to be
very difficult. Bromoacetate was not an effective method to brominate these substrates and
resulted in no reaction and recovery of the starting materials. The only exception was that
3-77 was successfully brominated with bromo-acetate. Halogenation with
dibromoisocyanuric acid (DBICA) or trichloroisocyanuric acid (TCICA) resulted in no
reaction and recovery of the starting matericals. Bromination under basic conditions also
failed (Table 3-10).

98

Table 3-10: Attempted halogenation of oxooxazolidine-3-carboxamides

SM #

R

1

X

Solvent

Method

Temp

P#

Yield (%)

3-74

Bz

Br

water

rt

NA

0

3-74

Bz

Br

THF

Br2, NaHCO3

0°C-rt

NA

0

3-74
3-74

Bz
Bz

Br
Br

rt
rt

NA
NA

0
0

3-74

Bz

Br

DCM
CHCl3
TFA

NaH, Br2
DBICA
Br-acetate

rt

NA

0

3-74
3-75

Bz
Ph

Cl
Br

rt
rt

NA
NA

0
0

3-75

Ph

Cl

DCM
CHCl3

Br2, Ag2O
TCICA
Br-Acetate
TCICA

reflux

NA

0

3-76

Ethyl

Br

Br-Acetate

rt

NA

0

3-76

Ethyl

Br

Br-Acetate

reflux

NA

0

3-77

H

Br

Br-Acetate

rt

3-78

74

CHCl3
CHCl3
CHCl3
CCl4

Compound 3-78 was reacted with styrene by the standard reaction conditions, but
unfortunately an equal mixture of diastereomers was synthesized. This supported the
mechanism above shown in Scheme 3-8 that the reaction mechanism preceded through a
bromonium ion. This 3-membered bromonium ion released its ring strain by opening to
2

form a stable carbocation 3-73, The sp planar geometry of the carbocation would cause
C-N bond formation to occur with approach of the chiral nucleophile to the Re or Si face
with equal probability. Cooling the reaction may prevent the bromonium ion from opening
up to a carbocation. A small amount of diasteroselectivity occurred by conducting the
reaction at -78°C but unfortunately the yield dropped significantly. (Scheme 3-9).
99

Scheme 3-9: Attempted diastereoselective synthesis with Evan’s auxillary

We decided to focus our attention on the synthesis of new bromine reagents for the
construction of other interesting heterocycles. We decided to explore the reactions of an
electron rich enol ether or an enamine with different bromine reagents. The reaction of BrN(CO2Me)2 with an enol ether occurred without the need of a Lewis acid. In fact
BF3•OEt2 was incompatible with an enol ether or an enamine and reacted with them to
cause decomposition. The addition of urea and N-boc-guanidine to an electron rich olefin
has been previously reported by Nicole Hewlett in our lab in the total synthesis of
Dibromophakellin and some analogues

41

42,43

as well as by Al-Mourabit.

The addition of

N-boc-guanidine and urea was accomplished in one pot with NBS as the bromine source.
The synthesis of Dibromophakellin by Nicole Hewlett from the Tepe lab

41

led us

to hypothesize that the addition of a urea or guanidine to an olefin and cyclization would be
a great methodology to access important natural products (Figure 3-2).
100

Figure 3-2: Urea and guanidine ring containing natural products

41

In addition we wanted to better understand the reaction mechanism for the
addition of an urea or guanidine to an electron rich olefin in the presence of NBS. We
were interested in determining if the N-boc, N-bromoguanidine or N-bromourea were
possible reaction intermediates before addition to an electron rich olefin or if the reaction
occurred through a bromonium ion with the halogen source. The reaction was first
investigated with 3,4-dihydro-2H-pyran, NBS, and 1,3-dimethyl urea. The major product
isolated was the addition of NBS to 3,4-dihydro-2H-pyran to yield compound 3-80. It was
necessary to put the halogen atom on the nitrogen atom of the desired nucleophile to
101

prevent the halogen source (NBS in this case) from undergoing reaction with the enol
ether. 1-chloro-1,3-dimethylurea did not undergo reaction with 3,4-dihydro-2H-pyran even
with reflux in CHCl3. 1-bromo-1,3-dimethylurea did react with 3,4-dihydro-2H-pyran by
refluxing in CHCl3 to give 3-methylhexahydro-2H-pyrano[2,3-d]oxazol-2ylidene)methanamine 3-83 and did not yield the urea 3-82. Compound 3-83 was isolated
as the HBr salt (Scheme 3-10).

Scheme 3-10: Addition of 1-bromo-1,3-dimethylurea to 3,4-dihydro-2H-pyran
This reaction was optimized with respect to the solvent and it was found that relatively non
polar solvents were the key to obtain the desired product in high yield. CHCl3 and DCM
gave very similar yields (Table 3-11).
Table 3-11: Reaction optimization of addition of 3-83 to 3,4-dihydro-2H-pyran

102

Entry

solvent

Time (h)

Temp °C

Yield 3-83

1

CDCl3

120

20

NA

2
3
4
5

CHCl3
THF
MeCN
DCM
CCl4
Hexane
DCE
Toluene

4
4
4
4

61
66
55
40

78
Trace
0
76

4
4
4
4

77
69
84
75

33
31
55
50

6
7
8
9
a

a

1

Monitored by H NMR the reaction was very slow

The addition reaction was screened with a variety of alkenes, enol ethers and
enamines. A reaction did not occur with simple alkenes like cyclohexene, styrene and
trans stillbene. When BF3•O(Et)2 was added as a catalyst the 1-bromo-1,3-dimethylurea
was transformed into 1,3-dimethylurea and the desired product was not formed. The scope
of the reaction was unfortunately very limiting. The enol ether had to be disubstituted
alpha to the oxygen atom if the enol ether was linear in order to yield the desired product.
Compounds 3-87 and 3-88 were not synthesized under these reaction conditions (Table 312, entries 1-2).

103

Table 3-12: Cycloaddition reaction of N-bromourea with enol ethers and enamines

Entry T (h) Temp °C SM #

Substrate

Product

P#

Yield
(%)

1

24

rt

NA

3-87

0

2

2

reflux

NA

3-88

0

3

24

rt

NA

3-89

75

4

24

rt

3-84

3-90

80

5

24

rt

NA

3-91

0

104

a

Table 3-12: Cont’d
Entry

T (h)

Temp
°C

SM
#

6

2

reflux

7

24

8

P#

Yield
(%)

NA

3-83

78

rt

NA

3-92

0

1

reflux

3-85

3-93

12

9

24

rt

3-86

3-94

23

10

24

rt

NA

3-95

0

a

Substrate

Product

a

a

1

Two regioisomers were observed by H NMR but was not stable to purification

However, the enol ether did not have to be disubstituted alpha to the enol ether oxygen
atom if the enol ether was a five or six membered ring (Table 3-11, entries 5-6). The
1

product 3-91 was detected by H NMR but was not stable enough to be isolated. The
reactions of 3-81 with an enol acetate were successful. However, these products did not

105

seem stable and unfortunately seemed to decompose even at room temperature after only a
few hours. The reaction of an N-bromourea was much more exothermic with an enamine
than an enol ether. In general the more electron rich the olefin was the faster the reaction
occurred. The reactions of 3-81 with any of the linear enol ethers were not successful.
Compound 3-81 did not act as a nucleophile but instead it simply acted as a base by
abstracting a proton after the halonium ion was formed with any of the linear enol ethers
(Scheme 3-11). As a result the alpha bromo ketones 3-93 and 3-94 were isolated after
hydrolysis of the alpha bromo enol ethers during silica gel chromatography (Table 3-11,
entries 9, 10).

Scheme 3-11: Enol ether alpha bromination mechanism
Reaction of 2,3-dihydrofuran or 1-(cyclohex-1-en-1-yl)pyrrolidine with 3-81 gave a
mixture of two regioisomers 3-92. Perhaps the reaction could go through multiple reaction
mechanisms. One possible mechanism for the reaction of an enol ether with 3-81 was
through a SN2’ mechanism. First attack of the enol ether pi bond on the oxygen atom of the
bromourea 3-81 and loss of the bromine atom as a leaving group would yield the

106

intermediates 3-96 and 3-97. Secondly, ring closure to compound 3-83 would occur
through an SN1 mechanism through an oxonium carbocation. Typically a SN2’ mechanism
was observed by addition of a nucleophile to an alkyl halide. There was not any literature
precedent for a SN2’ mechanism between an enol ether and an N-bromourea. Nonetheless,
this was one possible mechanism to explain the regiochemistry of the products (Scheme 312).

Scheme 3-12: SN2’ reaction mechanism for the addition of 3-81 with an enol or
enamine with 3,4-dihydro-2H-pyran as an example
Yet another possible mechanism was formation of the bromonium ion intermediate
followed by either attack of the oxygen atom or the nitrogen atom of the urea. The
nucleophilicity of the nitrogen atom and oxygen atom are similar and as a result two
different products may be formed. The attack of either the nitrogen atom or the oxygen
atom would be expected to occur alpha to the enol ether oxygen atom or the enamine
nitrogen atom due to the greater stability of a positive charge at the alpha position relative
107

to the beta position. Nitrogen attack on the oxonium 3-98 would yield the intermediate 399 which could react further to make compound 3-83 through oxygen substitution or
nitrogen substitution to yield 3-85 (Scheme 3-13).

Scheme 3-13: Bromonium mechanism for the cycloaddition of 3-81 with an enol ether
or an enamine with 3,4-dihydro-2H-pyran as an example

The compounds 3-83, 3-84, and 3-85 can be can be distinguished from one another
by NMR and other experimental observations. The reaction of N-bromourea 3-81 with 3,4dihydro-2H-pyran at room temperature slowly formed the desired product over several
days. This reaction seemed to show the accumulation of 3-97 or 3-99 as an intermediate.
1

The N-H proton of compound 3-97 or 3-99 was a broad singlet around 5.0 ppm in the H

108

NMR. After the intermediate 3-97 or 3-99 was formed AgOTf was added and a yellow
solid AgBr(S) precipitated out of the solution. If compounds 3-99 and 3-100 were formed
as intermediates the silver would have to abstract the bromine to make a secondary
carbocation in the case of the bromonium mechanism (Scheme 3-14).

109

Scheme 3-14: Bromonium mechanism and ring closure through AgOTf abstraction
110

In the SN2’ mechanism AgOTf would abstract the bromine atom of intermediate 3-97 and
1

would result in an oxonium carbocation. Analysis of H NMR showed formation of the
product 3-83 as a TfOH salt and the formation of this product occurred without refluxing in
chloroform as shown in above in Table 3-11 (Scheme 3-15).

Scheme 3-15: SN2’ mechanism for addition of an enol ether with a Nbromourea and ring closure with AgOTf

If the reaction mechanism of the reaction of an N-bromourea with an enol ether is an SN2’
mechanism in the first step of the reaction then how is an alpha bromo ketone formed in
111

some cases (Table 3-12, entries 8, 9)? An enol ether that contained a conjugated Π system
of electrons like enol ether 3-85 or 3-86 did not form the desired heterocycle with the Nbromo urea, but instead an α-bromoketone which can only be explained by a bromonium
mechanism. However, the isolated yield of the alpha bromoketones were low so perhaps
the reaction occurred through a combination of a bromonium mechanism and a SN2’
mechanism. The reaction also gave a mixture of regioisomers (Table 3-12, Entries 5, 7)
which supports the idea that the reaction of an enol ether with a N-bromourea must then go
through both mechanisms.
Compounds 3-83, 3-84, and 3-85 have would have different chemical shifts in their
1
C NMR and H NMR. The reaction to yield compound 3-83 by refluxing in chloroform

13

Table 3-12 or by forming compound 3-83 by bromine abstraction with AgOTf showed an
1

acid proton at around 10 ppm in the H NMR. Compound 3-85 was not supported by the
1

NMR data because an acid proton was not observed in the H NMR. There was also a
1

doublet in the H NMR with an integration of 3 consistent with the methyl group on the
imide nitrogen coupling with the acid N-H proton. After washing the unknown product
1

with aqeous NaHCO3; analysis by H NMR showed that the acid proton at 10 ppm was
absent. The methyl doublet transformed from a doublet into a singlet when the unknown
product was washed with NaHCO3. This acid proton at 10 ppm was consistent with a
protonated imine of structures 3-83 or 3-84. The

13

C NMR spectra of structure 3-83 or 3-

84 showed carbon peaks at C1 = 85.27 ppm and C2 = 72.92 ppm. The

112

13

C NMR shifts of

the carbon peak at C2 of compound 3-85 should be less than 72.92 ppm because the carbon
peak of a C-N bond would be more up field than a C-O bond (Figure 3-3).

Figure 3-3: NMR data for compound 3-83

Compound 3-83 and 3-84 were distinquished from one another by comparing the
NMR shifts of the peaks at the C1 and C2 positions. A report by Castro

44

13

C

and coworkers

provided experimental data for the chemical shifts of the peaks at the C1 and C2 position of
some similar compounds. As shown below in Figure 3-3 compound 3-101 had

13

C NMR

chemical shifts of 79.05 ppm for the C-O bond and 93.35 ppm for the C-N bond at the C2
and C1 positions. Compound 3-102 had

13

C NMR chemical shifts of 74.30 ppm for the C-

N bond and 100.60 ppm for the C-O bond at the C2 and C1 positions (Figure 3-4).
113

Figure 3-4: Experimental data for compounds 3-101 and 3-102 by Castro

The

44

13

C NMR chemical shifts of the unknown product at the C2 and C1 positions were

closer to the data of compound 3-101 than 3-102. Two oxygen atoms attached to the same
carbon would have a chemical shift of around 100 ppm in the

13

C NMR and the data for

the unknown compound showed a carbon peak at 85.27 ppm for a carbon attached to a
nitrogen atom and oxygen atom. Therefore, the regiochemistry was decided to be 3-83 and
not 3-84 which could have formed through either a bromonium or SN2’ mechanism.
An SN2’ mechanism was the only rationale to explain the regiochemistry of the boc
group after the addition of N-bocguanidine to an enamine reported by Nicole Hewlett in
41

our lab.

This reaction was presumed to occur by first forming N-boc, N-bromoguanidine

with N-bocguanidine and NBS. In contrast to the reactions of an enol ether with Nbromourea the reactions of Br-N(CO2Me)2 3-34 with an olefin was proposed to occurr
only through a bromonium ion mechanism and not a SN2’ mechanism (scheme 3-8).
Reaction of compound 3-34 with cyclohexene yielded the trans 1-bromo, 2-N-imide adduct
114

and not the cis 1-bromo, 2-N-imide adduct. The coupling constants between the two
methine protons were around 5 Hz. The coupling constants were consistent with the data
by Corey for a trans 1-bromo, 2-N-amide adduct.

22

If the reaction of 3-34 did occur

through an SN2’ reaction (scheme 3-16) then compound 3-103 would be the isolated
intermediate and not the trans 1-bromo, 2-N-imide adducts in Table 3-7.

Scheme 3-16: Formation of a methyl 2-oxooxazolidine-3-carboxylate through a SN2’
mechanism
1

Compound 3-103 was not supported by H NMR data because a singlet with an integration
of 6 was observed instead of two singlets both of which would have an integration of 3.
Compound 3-103 was also not supported by the

13

C NMR data because two different

peaks downfield would be observed one for the C=O group and one for the C=N group.
However only one peak downfield was present in the

13

C NMR due to two symmetrical

C=O groups in the intermediate trans 1-bromo, 2-N-imide adduct (Table 3-7). Compound
115

3-103 was not supported by the IR data because a C=N stretch was not present but just one
C=O stretch. The identity of the trans 1-bromo, 2-N-imide adducts in Table 3-7 are
1

supported by H NMR,

13

C NMR, and IR.

A bromonium ion mechanism versus an SN2’ mechanism must depend on the
substrate, N-bromo compound, and the reaction conditions. The Lewis acid BF3•OEt2
coordinated to one of the oxygen atoms of Br-N(CO2Me)2. This would prevent the olefin
from nucleophilically attacking the C=O oxygen atom via a SN2’ mechanism. A Lewis
acid also made the bromine atom “fall off” the N-bromo compound to make a bromine
cation and therefore favored a bromonium ion mechanism. An electron neutral olefin does
not have a very nucleophilic carbon-carbon pi bond. However an enol ether or an enamine
has a much more nucleophilic carbon-carbon pi bond. Therefore, a neutral olefin occurred
through a bromonium ion mechanism and an electron rich olefin occurred through a SN2’
mechanism. The reaction of Br-N(CO2Me)2 with an electron rich 3,4-dihydro-2H-pyran
occurred through a bromonium ion mechanism and not a SN2’ mechanism without
BF3•OEt2 (Table 3-7, 3-61).

This result meant that the structure of the N-bromo

compound must also be important for a SN2’ over a bromonium ion mechanism. The
electronics of a N-bromoguanidine or a N-bromourea favored an SN2’ mechanism whereas
the electronics of a N-bromo imide 3-34 favored a bromonium ion mechanism.

116

APPENDIX

117

EXPERIMENTAL

3-1: N-benzyl-1H-pyrrole-2-carboxamide

To a 25-mL round bottom flask under nitrogen was added 1,4-dioxane (5 mL) and pyrrole
(0.52 mL, 7.46 mmol). Benzyl isocyanate ( 0.92 mL, 7.46 mmol) was added followed by
BF3•(OEt)2 (0.94 mL, 7.46 mmol). The reaction was mixed for 24 hours and then the
reaction was partitioned between EtOAc and NaHCO3 aq., the EtOAC was dried with
MgSO4, filtered and concentrated in vacuo. The compound was purified by column
chromatography. The compound matched the reported literature data.

45

Solid; mp = 118-

1

120°C; 52% Yield; H NMR (500 MHz) (CDCl3) δ 4.65 (2H, d, J = 8.9 Hz (m, 1H), 6.23
(1H, m), 6.35 (1H, br), 6.60 (1H, m), 6.91 (1H, m). 7.25-7.40 (5H, m), 10.06 (1H, s, br).
13

C NMR (300 MHz) (CDCl3) δ 43.5, 109.8, 109.8, 122.4, 125.9, 127.7, 127.9, 129.0,

138.8, 161.8.
3-2: N-(1H-Pyrrol-2-ylcarbonyl)-4-methylbenzenesulfonamide

To a 50-mL round bottom flask under nitrogen was added 1,4-dioxane (10 mL) and pyrrole
(1.03 mL, 14.93 mmol). The round bottom flask was cooled to 0°C with an ice bath and
tosyl isocyanate ( 2.28 mL, 14.93 mmol) was added dropwise with a syringe over 3
minutes. The reaction was mixed for 1 hour during that time the product began to
118

precipitate out of the reaction solution. The solvent was removed in vacuo. The compound
46

matched the reported literature data.

1

White solid; mp 224-225°C; quantitative yield; H

NMR (300 MHz) (DMSO-d6) δ 2.37 (3H, s), 6.12 (1H, m), 7.00 (1H, m), 7.11 (1H, m),
7.39 (2H, d, J = 8.4 Hz), 7.84 (2H, d, J = 8.4 Hz).

13

C NMR (300 MHz) (DMSO-d6) δ

21.1, 109.6, 114.9, 123.3, 125.1, 127.7, 129.4, 137.1, 144.0, 157.9.
3-3: N-benzoyl-1H-pyrrole-2-carboxamide

Benzoyl isocyante (water sensitive) was made and used immediately for reaction with
pyrrole. To a 250-mL round bottom flask was added benzamide (5.42 g, 44.80 mmol) and
DCE (100 mL). (COCl)2 (4.60 mL, 53.75 mmol) was added with a syringe over 5 minutes.
The solution was mixed at room temperature for 10 minutes and then was heated to reflux
for 4 hours. The reaction solution was cooled to room temperature and the solvent was
removed in vacuo at room temperature (dimerization of the benzoyl isocyante can occur at
elevated temperatures while concentrating). To the crude benzoyl isocyante under an
argon atmosphere was added 1,4-dioxane (60 mL), and pyrrole (3.09 mL, 44.80 mmol).
The reaction was mixed overnight and then the solvent was removed in vacuo to give a
solid. The solid was triturated with EtOAc, the solvent was removed and the compound
was dried in vacuo. The compound matched the reported literature data.
1

46

Solid, mp =

180-181°C; 80% Yield; H NMR (500 MHz) (DMSO-d6) δ 3.44 (3H, s), 6.21 (1H, m),

119

13

7.10 (1H, m), 7.24 (1H, m), 7.51-7.86 (5H, m).

C NMR (75 MHz) (DMSO-d6) δ 110.2,

115.8, 125.6, 125.8, 126.0, 129.2, 132.9, 135.2, 159.8, 168.3.

2,2,2-trichloro-1-(1H-pyrrol-2-yl)ethanone
To a 100-mL round bottom flask was added pyyrole (3.09 mL, 44.78 mmol) and anhydrous
ether (50 mL). The solution was mixed at room temperature under nitrogen and 2,2,2trichloroacetyl chloride (6.50 mL, 58.21 mmol) was added all at once with a syringe. The
solution was mixed for 24 hours and turned a purple color. The reaction was washed with
NaHCO3 aq., the ether was dried with MgSO4, filtered and concentrated in vacuo. The
2

1

compound matched the reported literature data. Solid 72-74°C, 88% Yield; H NMR
(500 MHz) (CDCl3) δ 6.76 (1H, m), 7.10 (1H, m), 7.33 (1H, m), 9.46 (1H, s, br).

13

C

NMR (75 MHz) (CDCl3) δ 111.9, 121.2, 123.01, 127.10, 173.2.

2,2,2-trichloro-1-(4,5-dibromo-1H-pyrrol-2-yl)ethanone
To a 250-mL round bottom flask was added 2,2,2-trichloro-1-(1H-pyrrol-2-yl)ethanone
(8.36 g, 39.34 mmol) and reagent grade chloroform (100 mL). The solution was mixed
under nitrogen with an adaptor and vent line to an Erlenmeyer flask containing 1M NaOH
aq. to trap HBr. The solution was cooled to -10°C with a ice/ NaCl bath and Br2 (4.06 mL,
78.67 mmol) slowly added with a syringe over 5 minutes. The solution was allowed to
120

slowly warm to room temperature over the course of 2.5 hours. The reaction solution was
washed with NaHCO3 aq., dried with MgSO4, filtered, and concentrated in vacuo. The
compound matched the reported literature data.
(DMSO-d6) δ 7.36 (1H, s), 9.52 (1H, s, br).

13

47

1

Oil; 92% Yield; H NMR (500 MHz)

C NMR (75 MHz) (DMSO-d6) δ 94.1,

100.9, 114.6, 122.5, 123.3, 170.9.
3-5: 4,5-dibromo-N-methoxy-1H-pyrrole-2-carboxamide

To a sealed tube was added 2,2,2-trichloro-1-(4,5-dibromo-1H-pyrrol-2-yl)ethanone (4.4 g,
11.88 mmol), methoxyamine hydrogen chloride (1.5 g, 17.83 mmol), TEA (8 mL), and
DCM (2 mL). The tube was sealed and heated to 80°C for 12 hours. The solution was
cooled to room temperature and poured into EtOAc (50 mL). The solution was extracted
with 1M HCl aq., then with NaHCO3 aq., washed with brine, dried with MgSO4, filtered
and concentrated in vacuo. The resulting solid was triturated with ether (40 mL) and
hexane (20 mL). The liquid was decanted off and the solid was dried in vacuo. Compound
48

was consistent with the literature data.

1

Solid; mp = 199-200°C; H NMR (500 MHz)

(CDCl3) δ 3.94 (3H, s), 7.26 (1H, s, br), 9.39 (1H, s), 10.18 (1H, s, br);
MHz) (CDCl3) δ 65.22, 100.41, 104.01, 106.43, 122.81, 157.35.
3-7: N,3,4,5-tetrabromo-N-methoxy-1H-pyrrole-2-carboxamide

121

13

CNMR (125

To a 10-mL round bottom flask was added 4,5-dibromo-N-methoxy-1H-pyrrole-2carboxamide ( 0.1 g, 0.34 mmol), CHCl3 (4 mL), cyclohexene (34.25 uL, 0.34 mmol), and
NBS (0.12 g, 0.68 mmol). The solution was mixed for 24 h at room temperature. The
solvent was removed in vacuo. The crude product was added ether and was washed with
water to remove the succinimide, dried with MgSO4, filtered, and concentrated in vacuo.
1

Solid; mp 178-180°C ; H NMR (500 MHz) (CDCl3) δ 3.78 (3H, s), 9.21 (1H, s, br,
exchanges with D2O).

13

CNMR (125 MHz) (CDCl3) δ 65.23, 100.47, 104.02, 106.52,

122.74, 157.4; IR (NaCl) 2910, 2849, 1653, 1558; HRMS: Compound was not stable
HRMS could not be obtained.
3-10: Trans-2-bromocyclohexyl benzimidate and 3-12: Trans-2-bromocyclohexyl
benzoate

To a round bottom flask was added benzamide (100 mg, 0.83 mmol), CHCl3 (3 mL),
cyclohexene (83.56 uL, 0.83 mmol), and NBS (162 mg, 0.91 mmol). The reaction was
mixed for 48 h and then the solvent was removed in vacuo. The reaction was purified by
silica gel chromatography and some of the product hydrolyzed upon purification into
1

Trans-2-bromocyclohexyl benzoate. Oil; 27 % overall Yield; H NMR (500 MHz)

122

(CDCl3) δ 1.40–2.50 (6 H, m), 4.21-4.26 (2H, m), 4.47 (1H, s, br), 7.40-7.64 (5H, m);
13

CNMR (125 MHz) (CDCl3) δ 169.6, 131.2, 130.1, 128.0, 127.9, 82.4, 53.1, 35.2, 30.7,
+

24.9, 23.0; IR (NaCl): 2939, 1533, 1074; LRMS for C13H16BrNO (M ) 282.1 (52%) 284.1
(48%).
1

3-12: Trans-2-bromocyclohexyl benzoate; HNMR (500 MHz) (CDCl3) δ 1.40–2.50 (6
H, m), 4.12 (1H, m), 5.18 (1H, m), 7.46-7.64 (5H, m);

13

CNMR (125 MHz) (CDCl3) δ

23.3, 25.6, 31.5, 35.8, 55.1, 79.0, 128.5, 128.9, 130.5, 133.5, 170.7; IR (NaCl): 2939, 1637,
+

1074; LRMS for C13H15BrO2 (M ): 283.1 (52 %), 285.1 (48%).
3-13: 1-(2-bromo-1-phenylethyl)pyrrolidine-2,5-dione

To a 10-mL round bottom flask under nitrogen was added NBS (0.1 g, 0.56 mmol), DCM
(4 mL), styrene (0.07 mL, 0.56 mmol), and BF3•OEt2 (20 uL, 0.17 mmol). The solution
was mixed for 1h at room temperature and then was quenched with NaHCO3 sat. aq.
solution. The product was extracted with DCM, dried over MgSO4, filtered, and
concentration in vacuo. The product was purified by silica gel chromatography; 50:50
1

DCM: hexane; Rf = 0.5; solid; mp = 90-92°C ; H NMR (500 MHz) δ 2.71 (4H, s), 3.83
(1H, dd, J1 = 10.5 Hz, J2 = 5.5 Hz), 4.66 (1H, t, J = 10.5 Hz), 5.44 (1H, dd, J1 = 10.5 Hz,
J2 = 5.5 Hz), 7.33 (3H, m), 7.48 (2H, d, J = 6.5 Hz); (CDCl3)
123

13

CNMR (125 MHz)

(CDCl3) δ 28.2, 30.6, 57.7, 128.4, 129.2, 129.2, 136.9, 177.2. IR (NaCl): 1705, 1390,
1363, 1140.

General procedure for bromination of amides and imides
through bromo-acetate with bromo-benzamide as a
representative example
3-14: N-bromo benzamide

38

Bromoacetate was made in situ for the bromination of benzamide.

The hood lights were

turned off. To a 250-mL round bottom flask under nitrogen was added silver acetate (2g,
11.98 mmol) and CCl4 (60mL). The flask was cooled in an ice bath for 15 minutes and
then Br2 (0.62 mL, 11.98 mmol) was added neat with a syringe over 1 minute (addition
time seemed to be very important slow addition times gave much lower yield). AgBr(S)
formed instantly and the ice bath and round bottom flask were wrapped with aluminium
foil. The reaction was mixed for 20 minutes at 0°C, vacuum filtered and washed once with
CCl4 (10mL) into an oven dried round bottom flask. The concentration of bromoacetate
was determined by titration. PPh3 (10 mg, 0.04 mmol) and CHCl3 (1 mL) were added to a
20-mL vial. The bromoacetate solution was added dropwise until the PPh3 CHCl3 solution
changed from colorless to yellow. From this volume the molarity of the bromoacetate
solution was then determined. Typically, the concentration was ½ of the theoretical
concentration. To a 25-mL round bottom flask under nitrogen was added benzamide (0.1g,
124

0.83 mmol), and bromoacetate solution in CCl4 (1.2 equiv., 1.00 mmol). The round
bottom flask was wrapped with aluminium foil and mixed at room temperature for 1.5 h.
The solvent was removed in vacuo at room temperature while keeping the flask wrapped in
aluminium foil (Prolonged exposure to high vacuum or heating on the rotovap caused
debromination to occur). The orange solid was briefly dried under high vacuum for ten
minutes. The compound was stored in the freezer (seemed stable for a few days in the
freezer). The compound was consistent with the literature data.

49

Solid; mp=127-129°C;

1

quantitative Yield; HNMR (500 MHz) (CDCl3) δ 6.79 (s, 1H), 7.39-7.56 (3H, m), 7.777.81 (2H, m);

13

CNMR (125 MHz) (CDCl3) δ 127.89, 128.66, 132.06, 133.17, 169.74.

Compounds 3-20, 3-21, and 3-22 have been reported in the master’s thesis50
3-23: N-Boc benzamide

To a round bottom flask under nitrogen was added freshly prepared benzoyl isocyanate (2
g, 13.51 mmol), toluene (100 mL) and tert-butanol (2 g, 27.02 mmol). The solution was
mixed at room temperature overnight and then filtered. The solid was dried in vacuo. The
compound matched the reported literature data.

51

MHz, CDCl3) δ 1.52 (9H, s), 7.41–7.83 (5H, m), 8.10 (1H, s, br);
CDCl3) δ 28.2, 82.9, 127.7, 128.9, 132.9, 133.5, 149.9, 165.5.
3-24: N-methyl ester methyl carbamate

125

1

Solid; mp = 149-151°C; H NMR (500
13

CNMR (125 MHz,

To a dry 500 mL round bottom flask under nitrogen was added methyl carbamate (10 g,
0.133 mol), DCE (200 mL), and (COCl)2 (11.43 mL, 0.133 mol) was added all at once.
The solution was heated to reflux for 19 h and then was cooled to room temperature under
nitrogen. MeOH (26.80 mL, 0.66 mol) was added all at once and the solution was mixed
for 5 h and concentrated in vacuo to give a white solid. The solid was triturated with ether
(100 mL), filtered and dried in vacuo. The product was isolated in 90% yield. The product
contained a small amount of impurity (<10%) and could be removed by a tedious column
chromatography Rf = 0.2 PMA stain, 100% CHCl3 but found it much more efficient to just
to use the reagent with the small impurity in the following step. Compound has been
previously synthesized.

52

(6H, s), 7.20 (1H, s, br);

1

Solid; mp = 128-130°C; H NMR (500 MHz) (CDCl3) δ 3.78

13

C NMR and DEPT (125 MHz) (CDCl3) δ 53.0 (CH3). 151.9

(C).
3-25: N-Tosyl benzamide

To a 25 mL round bottom flask was added tosylamide (3 g, 17.54 mmol) and benzoyl
chloride (3.06 mL, 26.32 mmol). The solution was heated to 140°C with an oil bath for 1h
and then was cooled to room temperature to form a solid. The solid was triturated with
ethanol (10 mL) and was filtered. The product was dried in vacuo and matched the
reported literature data.

53

1

Solid; mp = 147-149; 39% Yield; HNMR (500 MHz)
126

(Acetone-D6) δ 2.46 (3H, s), 7.46 (2H, d, J = 8.0 Hz), 7.52 (2H, t, J = 8.0 Hz), 7.64 (1H, t,
J = 7.0 Hz), 7.95 (2H, d, J = 8.5 Hz), 8.02 (2H, d, J =8.5 Hz), 10.90 (1H, s, br);

13

C NMR

(Acetone-D6) δ 21.88, 129.22, 129.50, 129.79, 130.54, 133.02, 134.31, 137.94, 145.84,
166.14.
3-26: N-Boc tert-butyl carbamate

The compound was made by the following literature procedure.

54

A solution of DMAP

(0.61g, 5.0mmol) in MeCN (15ml) was slowly added to a solution of formamide (2.5g,
56mmol) and Boc2O (24 g, 110 mol) in MeCN (15ml). After stirring for 4h at room
temperature the yellow solution was cooled down to 0 °C and N,N-diethylethylenediamine
(6.97g, 60mmol) was slowly added. The resulting mixture was stirred while cooled in the
ice bath and allowed to slowly warm to room temperature for 12h. The crude reaction was
then filtered through a thin pad of silica and the solvent was removed in vacuo. Silica gel
chromatography; EtOAc: hexane 1:5; Rf = 0.3; 92 % yield; white solid; mp = 118-119 °C;
1

H NMR (500 MHz) (CDCl3) δ 6.79 (1H, br), 1.46 (18H, s).

δ 28.0, 81.9, 149.7.
3-28: N, N-dibromobenzamide

127

13

C NMR (125 MHz, CDCl3)

Bromoacetate was made by the general procedure above. To a round bottom flask was
added benzamide (0.1 g, 0.83 mmol) and bromo-acetate in CCl4 (2.5 equiv., 2.06 mmol).
The reaction solution was mixed for 2h at room temperature and the compound was
isolated as described above. The compound was unstable and was used immediately in the
next reaction with styrene.
3-29: N-bromo, N-benzyl benzamide

Bromoacetate was made by the general procedure above. To a round bottom flask was
added N-benzylbenzamide (0.1 g, 0.47 mmol) and bromoacetate in CCl4 (1.5 equiv., 0.71
mmol). The reaction solution was mixed for 7h at room temperature and the compound
was isolated by removing the solvent in vacuo as described in the general procedure above.
The compound seemed to be unstable and contained some impurities, but was used
immediately in the next reaction with styrene and BF3•O(Et)2.
3-30: N-bromo, N-methyl benzamide

Bromo-acetate was made by the general procedure above. To a round bottom flask was
added N-methylbenzamide (0.3 g, 1.41 mmol) and bromoacetate in CCl4 (1.5 equiv., 2.11
mmol). The reaction solution was mixed for 2h at room temperature and the compound
was isolated by removing the solvent in vacuo as described in the general procedure above.
128

The compound seemed to be unstable and contained some impurities, but was used
immediately in the next reaction with styrene and BF3•O(Et)2 .
3-32: N-bromo, N-cyclohexyl benzamide

Bromo-acetate was made by the general procedure above. To a round bottom flask was
added N-cyclohexylbenzamide (0.3 g, 1.07 mmol) and bromoacetate in CCl4 (1.5 equiv.,
1.60 mmol). The reaction solution was mixed for 2h at room temperature and the
compound was isolated by removing the solvent in vacuo as described in the general
procedure above. The compound seemed to be unstable and contained some impurities,
but was used immediately in the next reaction with styrene and BF3•O(Et)2 .
3-33: N-bromo, N-boc benzamide

Bromoacetate was made by the general procedure. To a 250 mL round bottom flask under
nitrogen was added tert-butyl benzoylcarbamate (1.9 g, 8.59 mmol) and bromoacetate in
CCl4 (12.89 mmol). The reaction flask was wrapped in aluminium foil and the solution
was mixed at room temperature for 3h. The compound was isolated by adding excess
hexanes to precipitate out the product by the general procedure described above. The
product was not very stable and was storred in the freezer. Yellow solid, mp = 100-102°C;
1

HNMR (500 MHz) (CDCl3) 1.25 (9H, s), 7.42-7.63 (5H, m);
129

13

CNMR (125 MHz)

(CDCl3) δ 21.96, 80.61, 122.90, 123.00, 126.64, 129.62, 146.32, 164.97; IR (NaCl) 1741,
1653, 1228, 1143; HRMS: Not stable molecule could not obtain HRMS.
3-34: N-methyl ester methyl, N-bromocarbamate:

Bromo-acetate was made in situ and was used immediately. To a 250 mL round bottom
flask under argon was added AgOAc (4g, 0.024 mol) and CCl4 (120 mL). The reaction
flask was cooled in an ice bath for ¼ h and then Br2 (1.23 mL, 0.024 mol) was added neat
dropwise over 2 minutes. After the addition of Br2 the flask was stirred for another 1/3 h at
0°C and the formation of a yellow solid formed (AgBr). The reaction solution was vacuum
filtered to remove the AgBr and the mother liquor (Bromoacetate solution) was poured into
a dry 500 mL round bottom flask under argon at room temperature. Compound 3-24 (1.6
g, 0.012 mol) was added neat all at once to the bromo-acetate in CCl4 at room temperature.
The reaction exothermed and was stirred for 2.5 h and then the reaction solution was
poured into a 1L Erlenmeyer and hexanes (500 mL) was added and the flask was
parafilmed and placed in the freezer for 3h. A precipitate formed and was isolated by
vacuum filtration and was washed with hexanes. The white solid was briefly dried at room
temperature in vacuo for 5 minutes to remove residual solvent and acetic acid. The
compound was placed in an amber bottle and was stored in the freezer and was found to be
stable for several weeks. (Compound 3-34 would undergo debromination when isolated by
removing the CCl4 in vacuo with heating and was found that crystallization worked better.
Also compound 3-28 would undergo debromination under prolonged time in vacuo or with
130

1

heating in vacuo. White solid; mp = 76-78°C; 75% Yield; H NMR (500 MHz) (CDCl3) δ
3.89 (6H, s);

13

C NMR and DEPT (125 MHz) (CDCl3) δ 55.57 (CH3), 152.03 (C); IR

(NaCl): 1782, 1190.
HRMS: Compound is not very stable, HRMS could not be obtained.
3-35: N-bromo, N-tosyl benzamide

To a beaker was added N-tosylbenzamide (1.8 g, 6.55 mmol), and NaOH (2M, 40 mL) at
room temperature. To a 20 mL vial was added CCl4 (1 mL) and Br2 (0.36 mL, 7.20
mmol). The Br2/CCl4 solution was added to the N-tosylbenzamide/ NaOH solution
dropewise. The reaction was mixed for 2h add then was poured into a sep. funnel. The
solution was extracted with CHCl3 (1x), EtOAc (2x), dried with MgSO4, filtered, and
concentrated in vacuo. Compound matched the reported literature data.
1

53

White solid; mp

= 204-206°C; 52% Yield; H NMR (Acetone-D6) δ 2.28 (3H, s), 7.13–8.00 (9H, m);

13

NMR (Acetone-D6) δ 21.81, 127.44, 128.45, 129.09, 130.00, 130.64, 132.49, 138.22,
143.21, 165.28.
3-46: tert-butyl benzoyl(2-bromo-1-phenylethyl)carbamate

131

C

Compound 3-46 was synthesized by the general procedure below (Table 3-7), N-boc, N1

Bromo benzamide and styrene were used. HNMR (500 MHz) (CDCl3) δ 1.05 (9H, s),
4.06 (1H, dd, J1 = 5.5 Hz, J2 = 3.5 Hz), 4.58 (1H, dd, J1 = 10 Hz, J2 = 2 Hz), 5.92 (1H, dd,
J1 = 5.5 Hz, J2 = 1.5 Hz), 7.37-7.68 (10H, m);

13

CNMR (125 MHz) (CDCl3) δ 27.43,

33.25, 60.85, 83.72, 128.01, 128.20, 128.38, 128.40, 128.77, 131.65, 137.88, 133.05,
153.33, 173.45.

General synthesis of styrenes compounds 3-48, 3-49, 3-50
To 100 mL round bottom flask was added PPh3MeI, THF (100 mg of PPh3MeI per mL of
THF) and the solution was cooled to 0°C for 20 minutes. BuLi (2.5 M in hexanes, 1.05
equiv.) was added dropwise the solution turned a dark red color. The solution was mixed
for 20 minutes and the appropriate aldehyde was added (1 equiv) dropwise and the solution
was mixed for 3 hours. The solution turned from red to yellow and the reaction solution
was quenched with water and extracted with EtOAc (3x), dried with MgSO4, filtered, and
concentrated in vacuo. The crude styrene was purified by silica gel chromatography 50:50
DCM: hexane. The styrenes were commercially available and matched the literature data.

General Procedure for Addition of Compound 3-34 to an Olefin
(Table 3-7)
To a 10 mL round bottom flask under argon were added DCM (4 mL) and the olefin (50
mg if a solid or 50 µL in a liquid). BF3•O(Et)2 ( 0.3 equiv.) was measured with a 50 µL
syringe and set aside. The N-bromo imide 3-34 (1.1 equiv.) was added all at once neat
followed by immediate addition of the BF3•O(Et)2 . The reaction was exothermic and
132

would often form a color for about a minute from dark yellow, orange and purple. The
solution was mixed at room temperature for 3/4 hour and was then poured into a sep.
funnel containing sat. aq. NaHCO3. The solution was extracted with DCM (3x), dried with
MgSO4, vacuum filtered, and concentration in vacuo at room temperature. Prolonged
heating of the crude product at a higher temperature when concentrating in vacuo caused a
reaction to occur to yield a methyl-2-oxooxazolidine-3-carboxylate. The crude product
was purified by silica gel chromatography.
3-47: Table 3-7

The compound was synthesized according to the general procedure. Column
chromatography 97:3 DCM : TEA; Rf = 0.3; oil; 111 mg; 81% yield; 1H NMR (500 MHz)
(CDCl3) δ 3.78 (6H, s), 4.01 (1H, dd, J1 = 10.5 Hz, J2 = 6.1 Hz) 4.31 (1H, t, J = 10.3 Hz)
5.78 (1H, dd, J1 = 9.8, J2 = 5.9 Hz), 7.25-7.40 (5H, m);

13

C NMR and DEPT (125 MHz)

(CDCl3) δ 32.2 (CH2), 54.0 (CH3), 60.9 (CH), 127.4 (CH), 128.1 (CH), 128.4 (CH), 137.1
(CH), 154.2 (C); IR (NaCl): 2957, 1753, 1709, 1344, 1296, 1253; LRMS Calculated for
C12H14BrNO4 (M +Na): 339.9978; Found 340.1334
3-52: Table 3-7

133

The compound was synthesized according to the general procedure. Column
1

chromatography 97 : 3 DCM : TEA; Rf = 0.5; oil; 113 mg; 88% yield; H NMR (500
MHz) (CDCl3) δ 3.75 (3H, s) 3.77 (6H, s) 3.94 (1H, dd, J1 = 10.3 Hz, J2 = 5.9 Hz) 4.28
(1H, t, J = 10.3 Hz) 5.69 (1H, dd, J1 = 10.3, J2 = 5.4 Hz), 6.85 (2H, d, J = 8.1 Hz), 7.29
(1H, d, J = 8.1 Hz);

13

C NMR and DEPT (125 MHz) (CDCl3) δ 32.4 (CH2), 54.0 (CH3),

55.2 (CH3), 60.7 (CH), 113.8 (CH), 129.0 (CH), 129.1 (C), 154.3 (C), 159.4 (C); IR
(NaCl): 2975, 1751, 1707, 1253; HRMS Calculated for C13H16BrNO5 (M +Na):
368.0106; Found 368.0110.
3-53: Table 3-7

The compound was synthesized according to the general procedure. Column
1

chromatography 100 % DCM, Rf = 0.45; oil; 45 mg; 38% yield; H NMR (500 MHz)
(CDCl3) δ 3.79 (6 H, s), 4.05 (1H, dd, J1 = 10.5, J2 = 6.6 Hz), 4.23 (1H, t, J = 10.5 Hz),
5.83 (1H, dd, J1 = 8.8, J2 = 6.9 Hz), 7.57 (2H, d, J = 8.3 Hz) 8.20 (2H, d, J =8.8 Hz);

13

C

NMR and DEPT (125 MHz) (CDCl3) δ 30.8 (CH2), 54.4 (CH3), 60.3 (CH), 123.7 (CH),
128.6 (CH), 144.2 (C), 147.6 (C), 153.9 (C).
3-54: Table 3-7

134

The compound was synthesized according to the general procedure. Column
1

chromatography 97 : 3 DCM : TEA; Rf = 0.5; oil; 78 mg; 52% yield; H NMR (500 MHz)
(CDCl3) δ 3.32 (1H, dd, J1 = 8.4 Hz, J2 = 7.8 Hz), 3.71 (1H, dd, J1 = 8.4 Hz, J2 = 7.8 Hz),
3.76 (6H, s), 4.95 (1H, q, J = 7.8 Hz) 6.16 (1H, d, J =7.3 Hz) 7.08 (1H, d, J = 7.3 Hz), 7.177.27 (3H, m);

13

C NMR and DEPT (125 MHz) (CDCl3) δ 41.9 (CH2), 49.7 (CH), 54.0

(CH3), 70.9 (CH), 121.8 (CH), 124.4 (CH), 127.3 (CH), 128.3 (CH), 138.9 (C), 139.4 (C),
154.1 (C); IR (NaCl): 2955, 1757, 1713, 1342; HRMS Calculated for C13H14BrNO4 (M
+Na): 349.9996; Found 350.0004.
3-56: Table 3-7

The compound was synthesized according to the general procedure but 2.0 equivalents of
3-34 was used instead of 1.1 equivalents. The crude product was dissolved in ether and
was washed once with sat. aq. NaHCO3, dried with MgSO4, filtered and concentrated in
vacuo. Column chromatography on TEA neutralized silica gel; the crude product was
loaded on the column with CHCl3 and eluted with 100 % hexane, Rf = 0.8 visualized with
1

PMA stain; oil; 49 mg; 34% yield; H NMR (500 MHz) (CDCl3) δ 1.30–1.46 (2H, m),
1.68-1.75 (1H, m), 1.79-1.86 (2H, m), 1.87-1.94 (1H, m), 1.96-2.05 (1H, m), 2.42-2.48
135

(1H, m), 3.84 (6H, s), 4.30 (1H, m), 4.72 (1H, m);

13

C NMR and DEPT (125 MHz)

(CDCl3) δ 25.4 (CH2), 26.7 (CH2), 30.4 (CH2), 38.3 (CH2), 53.2 (CH), 53.9 (CH3), 63.8
(CH), 154.5 (C); IR (NaCl): 2955, 1753, 1437, 1228; HRMS Calculated for
C10H17BrNO4 (M +H): 294.0339; Found 294.00341.
3-57: Table 3-7

The compound was synthesized according to the general procedure but 2.0 equivalents of
3-34 were used instead of 1.1 equivalents. The crude product was dissolved in ether and
was washed once with sat. aq. NaHCO3, dried with MgSO4, filtered and concentrated in
vacuo. Column chromatography on TEA neutralized silica gel; the crude product was
loaded on the column with CHCl3 and was eluted with 100 % hexane, Rf = 0.8 visualized
1

with PMA stain; oil; 44 mg; 37% yield; 52: 48 ratio Regioisomer 1: H NMR (500 MHz)
(CDCl3) δ 0.80-0.91 (3H, m), 1.24-1.35 (4H, m), 1.65 - 1.92 (2H, m), 3.51 (1H, dd, J1 =
10.3, J2 = 5.9 Hz, 1 H), 3.83 (6H, s), 3.86 (1H, dd, J1 = 10.3, J2 = 4.9 Hz), 4.56 (1H, m).
1

Regioisomer 2: H NMR (500 MHz) δ 0.80 - 0.91 (3H, m), 1.24-1.35 (4H, m), 1.65-1.92
(2H, m), 3.84 (6H, s), 3.95 (1H, dd, J1 = 14.2, J2 = 5.9 Hz), 4.13 (1H, dd, J1 = 14.2, J2 =
8.3), 4.25 (1H, m); Both Regioisomers

13

C NMR and DEPT (125 MHz) (CDCl3) δ 13.81

(CH3), 13.83 (CH3), 22.0 (CH2), 22.3 (CH2), 28.7 (CH2), 29.5 (CH2), 30.8 (CH2), 33.9
136

(CH2), 35.5 (CH2), 52.5 (CH2), 53.7 (CH), 53.9 (CH3), 54.0 (CH3), 59.5 (CH), 154.0 (C),
154.5 (C); IR (NaCl): 2959, 1755, 1705, 1437, 1346; HRMS Calculated for
C10H18BrNO4 (M +Na): 318.0315; Found 318.0317.
3-58: Table 3-7

The compound was synthesized according to the general procedure. Column
1

chromatography 100 % DCM, Rf = 0.45; oil; 63 mg; 50% yield; H NMR (500 MHz)
(CDCl3) δ Regioisomer 1 (1,4 addition product) 1H NMR (500 MHz) (CDCl3) δ 3.75 (6H,
s), 4.04 (2H, d, J = 7.34 Hz), 5.98-6.08 (1H, m), 6.11 (1H, d, J = 8.30 Hz), 6.36 (1H, dd, J1
1

= 16.0 Hz, J2 = 8.30 Hz), 7.29-7.40 (5H, m); Regioisomer 2 (1,2 addition product) H
NMR (500 MHz) (CDCl3) δ 3.67 (1H, dd, J1 = 10.3 Hz, J2 = 6.4 Hz), 3.87 (6H, s), 3.99
(1H, t, J = 9.8 Hz), 5.30 (1H, m), 6.40 (1H, m), 6.67 (1H, d, J = 16 Hz), 7.25-7.40 (5H, m);
13

C NMR and DEPT (Both Regioisomers) (125 MHz) (CDCl3) δ 31.42 (CH2), 32.82

(CH2), 53.88 (CH3), 54.12 (CH3), 60.74 (CH), 60.8 (CH), 124.34 (CH), 126.41(CH), 126.7
(CH), 127.42 (CH), 128.32 (CH), 128.41 (CH), 128.62 (CH), 131.36 (CH), 131.8 (CH),
135.15 (CH), 135.91 (C), 139.05 (C), 154.02 (C), 154.06 (C); IR (NaCl): 2953, 1753,
1707, 1282, 1259; HRMS Calculated for C14H16BrNO4 (M +Na): 364.0161; Found
364.0160.
137

3-55: (E)-3-(4-methoxyphenyl)-1-phenylprop-2-en-1-one

To a 100 ml round bottom flask was added NaOH (2.5 M, 5 mL, 12.5 mmol) and ethanol
(3 mL). The solution was cooled with an ice water bath. Acetophenone (10 mmol) and pmethoxy benzaldehyde (10 mmol) were added neat all at once to the solution. The solution
was allowed to slowly warm to room temperature over 3h. Solids formed and the product
was extracted with EtoAc (3x), dried with MgSO4, filtered, and concentrated in vacuo.
The solid was triturated with ether to give a yellow solid, 80% yield. The product is
commercially available and the product matched the literature data.

General Procedure for Synthesis of methyl-2-oxooxazolidine-3carbylates (Table 3-8)
To a 10 mL round bottom flask under argon were added DCM (4 mL) and the olefin (50
mg if a solid or 50 µL in a liquid). BF3•O(Et)2 ( 0.3 equiv.) was measured with a 50 µL
syringe and set aside. The N-bromo imide 3-34 was added all at once neat followed by
immediate addition of the BF3•O(Et)2 . The solution exothermed and would often form a
color for about a minute from dark yellow, orange and purple. The solution was mixed at
room temperature for 3/4 hour and was then poured into a sep. funnel containing sat. aq.
NaHCO3. The solution was extracted with DCM (3x), dried with MgSO4, vacuum filtered,
and concentration in vacuo. The crude compound was transferred into a 20 mL glass vial
and the solvent was removed in vacuo to yield a residue. The crude product was heated in
the glass vial neat under nitrogen atmosphere with an oil bath to 75°C for 3 h unless
138

otherwise indicated. The crude product could be dissolved in ether and washed with water
to remove residual H-N(CO2Me)2 if needed. The crude methyl-2-oxooxazolidine-3carboxylate was purified by silica gel chromatography.
3-63: methyl 2-oxo-4-phenyloxazolidine-3-carboxylate

The compound was made by the general procedure above. The crude product was purified
by column chromatography; 98:2 DCM: TEA; Rf = 0.32; solid mp = 79-82°C; 75 mg; 78%
1

yield; H NMR (500 MHz) (CDCl3) δ 3.76 (3H, s), 4.23 (1H, dd, J1 = J2 8.80 Hz), 4.68
(1H, t, J = 8.80 Hz), 5.29 (1H, dd, J1 = 8.80, J2 = 4.40 Hz), 7.31 (2H, d, J = 6.85), 7.337.40 (3H, m);

13

C NMR and DEPT (125 MHz) (CDCl3) δ 53.9 (CH3), 58.4 (CH), 69.5

(CH2), 125.8 (CH), 128.8 (CH), 129.1 (CH), 138.8 (C), 151.1 (C), 151.9 (C); IR (NaCl):
2959, 1882, 1734, 1342, 1080; HRMS Calculated for C11H11NO4 (M +Na): 244.0586;
Found 244.0586.
3-64: methyl 4-(4-methoxyphenyl)-2-oxooxazolidine-3-carboxylate

3-52 was synthesized and purified by the general procedure above. 3-52 was heated neat at
75°C for 3h and was transformed into 3-64 and did not require further purification. Oil,
1

77mg; 83% yield; H NMR (500 MHz) (CDCl3) δ 3.80 (3H, s), 3.81 (3H, s), 4.24 (1H, dd,
139

J1 = 8.80 Hz, J2 = 3.91 Hz) 4.67 (1H, t, J = 8.56 Hz), 5.26 (1H, dd, J1 = 8.56 Hz, J2 = 4.16
Hz), 6.92 (2H, d, J = 8.80 Hz) 7.27 (2H, d, J = 8.80 Hz);

13

C NMR and DEPT (125 MHz)

(CDCl3) δ 53.97 (CH3), 55.29 (CH3), 58.09 (CH), 69.72 (CH2), 114.51(CH), 127.41 (CH),
130.73 (C), 151.28 (C), 151.93 (C), 159.94 (C); IR NaCl: 1819, 1720, 1253, 1080; HRMS
Calculated for C12H13NO5 (M +Na): 274.0696; Found 244.06091.
3-65: methyl 4-(4-fluorophenyl)-2-oxooxazolidine-3-carboxylate

The compound was made by the general procedure for the intermediate 1-bromo, 2-N
imide and was purified by column chromatography. Oil; Rf = 0.5; 100% DCM; the
intermediate was heated neat at 75°C for 3h to yield compound 3-65 and did not require
1

any further purification. Solid mp = 67-68°C; 42 mg; 43% yield; H NMR (500 MHz)
(CDCl3) δ 3.79 (3H, s), 4.23 (1H, dd, J1 = 9.05 Hz, J2 = 4.16 Hz), 4.69 (1H, t, J = 8.80
Hz), 5.30 (1H, dd, J = 8.56, J2 = 4.16 Hz), 7.09 (2H, t, J = 8.56 Hz,), 7.30-7.45 (2H, m);
13

C NMR and DEPT (125 MHz) (CDCl3) δ54.08 (CH3), 57.87 (CH), 69.48 (CH2), 116.13
3

4

(d, 2Jc/f = 22.50 Hz), (CH), 127.86 (d, Jc/f = 8.75 Hz), (CH), 134.60 (d, Jc/f = 3.80 Hz),
1

(C), 151.17 (C), 151.69 (C), 161.84 (d, Jc/f = 246.30 Hz), (C); IR NaCl: 1819, 1734,
1336, 1080;

140

HRMS Calculated for C11H10NO4F (M +Na): 262.0497; Found 262.0492.
3-66: trans-methyl 5-methyl-2-oxo-4-phenyloxazolidine-3-carboxylate and transmethyl 4-methyl-2-oxo-5-phenyloxazolidine-3-carboxylate

The compound was made by the general procedure above. The crude product was
dissolved in ether and was washed with sat. aq. NaHCO3, the ether layer was dried with
MgSO4, filtered and concentrated in vacuo. The crude product was purified by column
chromatography 98:2 DCM: TEA; Rf = 0.35; Oil ; 48 mg; 52% yield; Regioisomer 1:

1

H

NMR (500 MHz) (CDCl3) δ 0.98 (3H, d, J = 6.35 Hz), 3.77 (3H, s), 4.94 (1H, m), 5.24
(1H, d, J = 7.8 Hz), 7.15-7.40 (5H, m) Regioisomer 2: 1.51 (3H, d, J = 6.35 Hz), 3.76 (3H,
s), 4.45 (1H, m), 4.80 (1H, d, J = 4.4 Hz), 7.15-7.40 (5H, m); Both Regioisomers:

13

C

NMR and DEPT (125 MHz) (CDCl3) δ 15.9 (CH3), 20.2 (CH3), 54.0 (CH3), 54.0 (CH3),
62.7 (CH), 65.6 (CH), 74.8 (CH), 78.4 (CH), 125.9 (CH), 126.7 (CH), 128.9 (CH), 128.9
(CH), 129.2 (CH), 129.2 (CH), 134.9 (C), 138.3 (C), 151.2 (C), 151.5 (C), 151.6
(C),152.02 (C); IR NaCl: 1819, 1734, 1327, 1074; HRMS Calculated for C12H13NO4 (M
+Na): 258.0744; Found 258.0742.
3-67: cis-methyl 2-oxo-8,8a-dihydro-2H-indeno[1,2-d]oxazole-3(3aH)-carboxylate

141

The compound was made by the general procedure above. The crude product was
dissolved in ether and was washed with sat. aq. NaHCO3, the ether layer was dried with
MgSO4, filtered and concentrated in vacuo. The crude product was purified by column
chromatography 1: 1 ether: hexane; Rf = 0.5; solid mp = 98-100°C; 48 mg; 48% yield; 1H
NMR (500 MHz) (CDCl3) δ 3.38 (2H, m), 4.00 (3H, s), 5.31 (1H, m), 5.79 (1H, d, J = 6.85
Hz), 7.29 (2H, d, J = 5.4 Hz), 7.37 (1H, t, J = 7.3 Hz), 7.66 (2H, d, J = 7.83 Hz); 13C NMR
and DEPT (125 MHz) (CDCl3) δ 38.0 (CH2), 54.2 (CH3), 63.7 (CH), 77.7 (CH), 125.3
(CH), 126.7 (CH), 128.1 (CH), 130.1 (CH), 138.4 (C), 139.6 (C), 151.2 (C), 152.2 (C); IR
(NaCl): 1824, 1734, 1334, 1253, 1068; HRMS Calculated for C12H11NO4 (M +Na):
256.0586; Found 256.0586.
3-68: trans-methyl 2-oxo-4,5-diphenyloxazolidine-3-carboxylate

The compound was made by the general procedure above except that the residue only had
to be heated at 75°C for 1 h to yield 3-68. The crude product was purified by column
chromatography 1: 1 ether:hexane; Rf = 0.28; solid; mp = 120-122°C ; 30 mg; 36% yield;
1

H NMR (500 MHz) (CDCl3) δ 3.78 (3H, s), 5.13 (1H, d, J = 4.89 Hz), 5.34 (1H, d, J =

4.89 Hz), 7.33 (4H, m), 7.43 (6H, m);

13

C NMR and DEPT (125 MHz) (CDCl3) δ 54.1

142

(CH3), 66.6 (CH), 82.4 (CH), 125.2 (CH), 126.0 (CH), 129.1 (CH), 129.2 (CH), 129.4
(CH), 129.4 (CH), 137.2 (C), 138.4 (C), 151.2 (C), 151.6 (C); IR (NaCl): 1824, 1797,
1327, 1074; HRMS Calculated for C17H15NO4 (M +Na): 320.0901; Found 320.0899.
3-70: trans-methyl 5-benzoyl-4-(4-methoxyphenyl)-2-oxooxazolidine-3-carboxylate

The compound was made by the general procedure above except that the residue only had
to be heated at 75°C for 1 h to yield 3-70. The crude product was dissolved in ether and
was washed with sat. aq. NaHCO3, the ether layer was dried with MgSO4, filtered and
concentrated in vacuo. The crude product was purified by column chromatography 40:57:3
EtOAc: hexane: TEA; Rf = 0.45; oil; 34 mg; 50% yield; 1H NMR (500 MHz) (CDCl3) δ
3.77 (3H, s), 3.83 (3H, s) 5.48 (1H, d, J = 2.93), 5.55 (1H, d, J = 2.93 Hz) 6.96 (2H, d, J =
8.80 Hz), 7.32 (2H, d, J = 8.31 Hz), 7.51 (1H, t, J = 7.58 Hz), 7.66 (1H, t, J = 7.34 Hz),
7.91 (2H, d, J = 7.85 Hz); 13C NMR and DEPT (125 MHz) (CDCl3) δ 54.1 (CH3), 55.4
(CH3), 59.5 (CH), 79.9 (CH), 114.8 (CH), 127.7 (CH), 129.1 (CH), 129.1 (CH), 129.8 (C),
132.8 (CH), 134.8(C), 150.5 (C), 150.8 (C), 160.3 (C), 191.3 (C); IR (NaCl): 1821, 1792,
1728, 1369, 1082; HRMS Calculated for C19H17NO6 (M +Na): 378.0959; Found
378.0954.
3-71: 4-phenyloxazolidin-2-one

143

Compound 3-56 (50 mg) was dissolved in THF (2 mL) and 2M LiOH (1 mL) was added.
The solution was mixed fast to cause and emulsion for 2h at room temperature. The crude
reaction was poured into a sep. funnel containing water. The product was extracted EtOAc
(3x), dried with MgSO4, filtered and concentrated in vacuo to give a solid. The solid was
triturated with 50: 50 ether: hexane (3 mL) was placed in the fridge for 1h. The solvent
was removed from the crystals with a pipette and the crystals were dried in vacuo. solid
1

mp = 132-133; 30 mg; 81% yield; H NMR (500 MHz) (CDCl3) δ 4.19 (1H, dd, J1 = 8.56,
J2 = 7.09 Hz), 4.74 (1H, t, J = 8.80 Hz), 4.96 (1H, t, J = 7.83 Hz), 5.76 (1H, s, br), 7.317.43 (5H, m);

13

C NMR and DEPT (125 MHz) (CDCl3) δ 56.36 (CH), 72.52 (CH2),

126.03 (CH), 128.87 (CH), 129.21 (CH), 139.40 (C), 159.49 (C).
3-72: trans-4,5-dipropyloxazolidin-2-one

The compound was made by the general procedure above. The crude product was
hydrolyzed to 3-72 by dissolving in THF (2 mL) and cooling the crude reaction to 0°C.
2M LiOH (1 mL) was added and the solution was mixed fast to cause an emulsion for 2h
while warming slowly to room temperature. The crude product was extracted with EtOAc,
dried with MgSO4, filtered and concentrated in vacuo. The crude product was purified by

144

column chromatography; 100% DCM; Rf = 0.2 (PMA stain); oil; 20 mg; 37% yield (over 3
steps). The compound matched the reported literature data.

40 1

H NMR (500 MHz)

(CDCl3) δ0.94 (6H, m), 1.28-1.73 (8H, m), 3.42 (1H, q, J = 6.03 Hz), 4.15 (1H, dt, J =
7.95, 5.07 Hz) 6.21 (1H, s, br.);

13

C NMR and DEPT (125 MHz) (CDCl3) δ 13.75 (CH3),

13.83 (CH3), 18.15 (CH2), 18.74 (CH2), 36.88 (CH2), 37.51 (CH2), 57.85 (CH), 82.50
(CH), 159.56 (C).
3-74: (R)-N-benzoyl-4-benzyl-2-oxooxazolidine-3-carboxamide

To a 100 mL round bottom flask was added (S)-4-benzyloxazolidin-2-one (0.5 g, 3.38
mmol), toluene (50 mL), benzyl isocyanate (0.67 g, 5.41 mmol), and TEA (0.04 mL, 0.34
mmol). The solution was heated to 80°C with an oil bath for 3 h. The reaction solution
was cooled to room temperature and concentrated in vacuo. The solid was triturated with
1

EtOAc, the EtOAc was decanted, and the solid was dried in vacuo. HNMR (500 MHz)
(CDCl3) δ 2.94(1H, dd, J1 = 9.0 Hz, J2 = 4.5 Hz), 3.48 (1H, dd, J1 = 10.5 Hz, J2 = 2.5 Hz),
4.32-4.40 (2H, m), 4.83 (1H, m), 7.29 (2H, d, J = 7.0 Hz), 7.31 (1H, t, J = 7.5 Hz), 7.35
(2H, t, J = 7.5 Hz), 7.51 (2H, t, J = 8.0 Hz), 7.62 (1H, t, J = 7.5 Hz), 7.97 (2H, d, J = 8.5
Hz), 11.64 (1H, s, br);

13

CNMR (125 MHz) (CDCl3) δ 28.00, 55.05, 67.12, 127.55,

127.78, 129.05, 129.10, 129.45, 132.53, 133.36, 134.62, 146.64, 155.65, 164.07.
3-75: (R)-4-benzyl-2-oxo-N-phenyloxazolidine-3-carboxamide
145

To a sealed tube was added (S)-4-benzyloxazolidin-2-one (0.5 g, 3.38 mmol), toluene (20
mL), phenyl isocyanate (0.37 mL, 3.38 mmol), and TEA (0.09 mL, 0.04 mmol). The
solution was heated to 100°C with an oil bath for 24 h. The reaction solution was cooled to
room temperature and concentrated in vacuo. The solid was triturated with EtOAc, the
1

EtOAc was decanted, the solid was dried in vacuo. mp = 97-98°C; HNMR (500 MHz)
(CDCl3) δ 1.29 (3H, t, J = 7.5 Hz), 2.90 (1H, dd, J1 = 9 Hz, J2 = 4.5 Hz), 3.44 (1H, dd, J1 =
10.5 Hz, J2 = 3 Hz), 4.30 (2H, m), 4.79 (1H, m), 7.16 (1H, t, J = 7.5 Hz), 7.25-7.40 (8H,
m), 7.56 (2H, d, J = 7.5 Hz), 9.93 (1H, s, br);

13

C NMR (125 MHz) (CDCl3) δ 38.43,

55.14, 66.59, 120.08, 124.43, 127.38, 128.99, 129.11, 129.5, 135.09, 137.04, 148.78,
155.61; IR (NaCl): 3275, 1755, 1601, 1554, 1400, 1223; HRMS Calculated for
C17H16N2O3 (M +Na): 319.1060; Found 319.1059.
3-76: (R)-4-benzyl-N-ethyl-2-oxooxazolidine-3-carboxamide

To a sealed tube was added (S)-4-benzyloxazolidin-2-one (0.3 g, 2.02 mmol), toluene (20
mL), ethyl isocyanate (0.16 mL, 5.41 mmol), and TEA (0.23 mL, 0.04 mmol). The
solution was heated to 60°C with an oil bath for 16 h. The reaction solution was cooled to

146

room temperature and concentrated in vacuo. The product was purified by silica gel
1

chromatography. Oil, 95% Yield 70%; Rf = 0.5; 10:90 EtOAc: DCM; HNMR (500 MHz)
(CDCl3) δ 1.31(3H, t, J =5 Hz), 2.87 (1,H, dd, J1 = 10.0 Hz, J2 = 5.0 Hz), 3.37(1H, dd, J1
=10.0 Hz, J2 =5.0 Hz ), 4.27 (4H, m), 4.71 (1H, m), 7.20-7.35 (5H, m), 10.19 (1H, s, br);
13

CNMR (125 MHz) (CDCl3) δ 14.19, 37.97, 54.98, 62.50, 66.83, 127.50, 129.06, 129.47,

146.82, 150.32, 154.96; IR (NaCl): 3254, 1794, 1759, 1529, 1400, 1186.
3-77: (R)-4-benzyl-2-oxooxazolidine-3-carboxamide

To a 100 ml round bottom flask under argon was added (S)-4-benzyloxazolidin-2-one (1.0
g, 5.64 mmol) and THF (30 mL). The solution was cooled with a dry ice/acetone bath for
20 minutes. BuLi (2.48 mL, 6.21 mmol, 2.5 M in hexanes) was added dropwise the
solution was mixed for 5 minutes and then taken out of the dry ice bath and placed in an ice
bath. After 20 minutes the flask was placed in the dry ice / acetone bath once again for 20
minutes. To another dry round bottom flask was added p-NO2-phenyl chloroformate (1.14
g, 5.64 mmol) and THF (10 mL). This solution was added to the reaction solution with a
canulla over 2 minutes. The reaction was left in the dry ice bath to slowly warm up to
room temperature overnight. Dioxane (20 mL) was added to the reaction solution and
excess ammonia was bubbled into the reaction solution for about 20 minutes. The
ammonia gas was generated by adding concentrated NH4OH in an addition funnel to solid

147

NaOH in a round bottom flask attached to an outlet valve with a rubber tube and a pipette
to bubble the ammonia gas. The reaction instantly turned bright yellow and exothermed.
The rxn was mixed for another 3h. The crude reaction was portioned between EtOAc and
water, dried with MgSO4, filtered and concentrated in vacuo. The crude product was
purified by column chromatography; 20: 80 EtoAc: DCM, Rf = 0.3; 50% yield;
1

HNMR (500 MHz) (CDCl3) δ 2.89 (1H, dd, J1 = 13.69, J2 = 9.29 Hz), 3.36 (1H, dd, J1

=13.69, J2=2.93 Hz), 4.09 - 4.29 (2H, m), 4.68 (1H, m) 5.17 (1H, s, br), 7.19 - 7.36 (5H),
7.77 (1H, s, br);

13

C NMR and DEPT (125 MHz) (CDCl3) δ 38.33 (CH2), 54.81 (CH),

66.4 (CH2), 127.33 (CH), 128.93 (CH), 129.49 (CH), 135.05 (C), 151.85 (C), 155.34 (C);
IR (NaCl): 3427, 3262, 1747, 1718, 1680, 1595, 1375.
3-78: (R)-4-benzyl-N-bromo-2-oxooxazolidine-3-carboxamide

Bromoacetate was made by the general procedure in CCl4. To a dry round bottom flask
under argon was added (R)-4-benzyl-2-oxooxazolidine-3-carboxamide (0.6 g, 2.73 mmol)
and bromoacete in CCl4 (0.2 M, 15 mL). The solution turned from dark orange to yellow
1

over 2.5 h. An aliquot was taken in CDCl3 (CCl4 not present in H NMR) to determine
acetic acid by-product had formed and the desired product. Hexane (100 mL) was added to
the reaction solution and a precipitate formed placed in the freezer for 1h. The solids were
filtered and washed them with hexane. The solids were briefly dried under high vacuum
148

for about 10 minutes and stored the solid in the freezer. The compound looked like a
mixture of product and some starting material could be seen the

13

C NMR. Due to the

instability of the product purification was not attempted. The major

13

C NMR product

1

peaks could be elucidated. mp = 82-84°C; 74% yield; HNMR (500 MHz) (CDCl3) δ 2.78
- 2.92 (1H, m), 3.27 - 3.40 (1H, m), 4.08 - 4.21 (1H, m), 4.21 - 4.38 (2H, m), 4.60 - 4.76
13

(1H, m), 7.05 - 7.24 (2H, m,), 7.25 - 7.39 (3H, m), 8.05 (1H, s); CNMR and DEPT (125
MHz) (CDCl3) δ 38.22, 55.96, 67.27, 127.48, 127.93, 129.03, 129.43, 151.0, 155.68; IR
(NaCl): 3267, 1753, 1701, 1400, 1226
HRMS: Molecule was not stable
3-79: (R)-4-benzyl-N-((R)-2-bromo-1-phenylethyl)-2-oxooxazolidine-3-carboxamide
and (R)-4-benzyl-N-((S)-2-bromo-1-phenylethyl)-2-oxooxazolidine-3-carboxamide

To a 10 mL round bottom flask under argon were added DCM (4 mL) and styrene (0.05
mL, 0.44 mmol). BF3•O(Et)2 (16 uL, 0.13 mmol) was measured with a 50 µL syringe and
set aside. (R)-4-benzyl-N-bromo-2-oxooxazolidine-3-carboxamide (130 mg, 0.44 mmol)
was added all at once neat followed by immediate addition of the BF3•O(Et)2 . The
reaction was exothermic and mixed at room temperature for 3/4 hour and was then poured
into a sep. funnel containing sat. aq. NaHCO3. The solution was extracted with DCM (3x),
dried with MgSO4, vacuum filtered, and concentration in vacuo at room temperature.

149

Column Chromatography 100 % DCM, Rf = 0.5; The product were a 1:1 mixture of
1

diastereomers. Three H NMR peaks were clearly resolved from one another and are
assigned different chemical shifts but the rest of the peaks overlap one another so they were
1

assigned identical chemical shifts. Diastereomer 1: H NMR (500 MHz) (CDCl3) δ 2.87
(1H, dd, J1 = 13.45, J2 = 9.05 Hz), 3.25 (1H, dd, J1 = 13.69, J2 = 2.93 Hz), 3.62 - 3.73 (1H¸
m) 3.73 - 3.84 (1H, m), 4.17 - 4.34 (2H, m), 4.61 - 4.74 (1H, m), 5.29 - 5.37 (1H, m), 7.09 1

7.56 (10H, m), 8.62 (1H, s, br). Diastereomer 2: H NMR (500 MHz) (CDCl3) δ 2.91 3.00 (1H, dd, J1 = 13.45, J2 = 9.05 Hz), 3.29 - 3.36 (1H, dd, J1 = 13.69, J2 = 2.93 Hz), 4.17
- 4.34 (2H, m), 4.61 - 4.74 (1H, m), 5.29 - 5.37 (1H, m), 7.09 - 7.56 (10H, m), 8.63 (1H, s,
br);

13

CNMR (125 MHz) (CDCl3) δ 36.34, 36.41, 38.35, 38.39, 54.92, 54.95, 55.04,

55.04 66.63, 66.67, 125.97, 126.48, 126.51, 127.32, 127.35, 128.32, 128.68, 128.90,
128.90, 128.96, 129.48, 129.54, 134.97, 134.99, 138.84, 138.86, 150.87, 150.87, 155.60,
155.60; IR (NaCl): 1753, 1701, 1539, 1230.
3-81: 1-bromo-1,3-dimethylurea

To a 25 mL round bottom flask under nitrogen was added 1,3-dimethyl urea (1 g, 11.36
mmol), CDCl3 (10 mL), and TBICA (1.67 g, 4.54 mmol). The solution was mixed at room
temperature wrapped in aluminium foil. The hood lights were turned off and the solution
was mixed for 15h and the solution was filtered via a glass frit. The solution was diluted to

150

a volume of 18.9 mL with CDCl3 to give a concentration of 100 mg / mL of 1-bromo-1,3dimethylurea. The solution was storred in the freezer wrapped in aluminum foil
(concentrating the solution under vacuum caused irreproducible results with debromination
1

sometimes occurred). H NMR (500 MHz) (CDCl3) δ 2.78 (3H, d, J = 7.50 Hz), 3.35 (3H,
s), 5.35 (1H, s, br);

13

C NMR (125 MHz) (CDCl3) δ 28.51, 44.84, 160.40, 162.30; LRMS

C3H7BrN2O (M+H) 167.
3-83: 3-methylhexahydro-2H-pyrano[2,3-d]oxazol-2-ylidene)methanamine

To a 10 mL round bottom flask under nitrogen was added 1-bromo-1,3-dimethylurea (1.0
mL, 0.60 mmol, 100 mg / mL soln in CHCl3), CHCl3 (2 mL) and 3,4-Dihydropyran (66.60
uL, 0.72 mmol). The solution was heated to reflux for 2h and then was cooled to room
temperature. To the residue was added NaHCO3 sat. aq. and was extracted with DCM,
dried with MgSO4, filtered and concentrated in vacuo. The product was purified by silica
gel chromatography on TEA neutralized silica gel. Flash chromatography 100% DCM via
1

a short silica plug. Oil, 78 % Yield; H NMR (500 MHz) (CDCl3) δ 1.58 (1H, m), 1.70
(1H, m), 1.79 (1H, m), 2.12 (1H, m), 2.79 (3H, s), 2.89 (3H, s), 3.46 (1H, m), 3.66 (1H, m),
4.31 (1H, m), 4.83 (1H, d, J = 4.5 Hz);

13

C NMR (125 MHz) (CDCl3) δ 10.30 (CH2),

22.99 , 29.29, 33.08, 60.30, 72.92, 85.27, 154.92; HRMS calculated for C8H15N2O2 (M +
H) 171.1134; found 171.1127.

151

Synthesis of enol ethers
Some precursor reagents had to be synthesized to synthesize some of the enol ethers.
1,1-dimethoxyethyl)benzene

To a 25 mL round bottom flask was added benzaldehyde (3 mL, 27.21 mmol),
trimethoxymethane (3.4 mL, 32.66 mmol), and PTSA (0.22 g, 1.36 mmol). The solution
was mixed overnight and poured into ether and was extracted with NaHCO3 sat. aq., dried
with MgSO4, filtered, and concentrated in vacuo. The product matched the commercially
available starting material.
3-84: (1-methoxyvinyl)benzene

To a round bottom flask under argon was added (1,1-dimethoxyethyl)benzene (1 g, 6.58
mmol), DCM (50 mL), and Hünig’s base (1.49 mL, 8.55 mmol). The solution was cooled
to -20°C with a NaCl / ice bath and TMSOTf (1.25 mL, 7.23 mmol) was added over 2
minutes with a syringe. The solution turned bright red and was left in the ice bath to
slowly warm to room temperature for 4h. The solution was concentrated in vacuo and
triturated with ether (50 mL), and filtered via a plug of MgSO4. The mother liquor was
concentrated in vacuo and was synthesized in high yield. Unfortunately, polymerization
occurred during vacuum distillation but some product was isolated (bp = 50°C) to give a
colorless oil. The compound matched the reported literature data.
152

55

1

10% Yield; Oil; H

NMR (500 MHz) (CDCl3) δ 3.72 (3H, s), 4.20 (1H, d, J = 2.2 Hz), 4.68 (1H, d, J = 2.6 Hz),
7.31 (5H, m);

13

C NMR (125 MHz) (CDCl3) δ 55.2, 81.7, 82.1, 125.3, 125.4, 128.1, 128.4.

dimethyl (methoxy(phenyl)methyl)phosphonate

To a 25 mL round bottom flask under nitrogen was added P(OMe)3 (3.25 mL, 27.57
mmol), (dimethoxymethyl)benzene (4.0 g, 27.57 mmol), and TMSCl (5.58 mL, 46.32
mmol). The reaction was mixed for 48 h at room temperature. The reaction solution was
slowly poured into a solution of NaHCO3 sat. aq. and was extracted with DCM, dried with
MgSO4, filtered and concentrated in vacuo. The product was purified by vacuum
distillation. The starting materials distilled over first at 30°C and then the product at 118°C
1 mmHg (oil bath was 142°C; compound decomposed at >150°C). Compound matched
the reported literature data.

56

1

Colorless Oil; 40% Yield; H NMR (500 MHz) (CDCl3) δ

3.37 (3H, s), 3.63 (3H, d, J = 10.5 Hz), 3.67 (3H, d, J = 10.5 Hz, 4.51 (1H, d, J = 15.7 Hz),
7.32-7.43 (5H, m);

13

C NMR (125 MHz) (CDCl3) δ 58.48 (d, J = 1.9 Hz), 58.59 (d, J =

2.85), 80.82 (d, J = 168.75), 127.83, 127.87 (d, J = 5.0 Hz), 128.41, 128.43 (d, J = 2.5 Hz),
128.47, 128.49 (d, J = 2.5 Hz), 134.03, 134.05 (d, J = 2.5 Hz).
1,1-dimethoxyethane

153

To a 25 mL sealed tube was added acetaldehyde (6.35 mL, 0.11 mol), trimethoxymethane
(12.4 mL, 0.11 mol). The solution was cooled to -20°C with a dry ice / NaCl bath and one
crystal of PTSA was added and the tube was not sealed (Caution: the reaction is
exothermic and acetaldehyde has a bp = 20°C and can boil away and build up
pressure in sealed tube). After reaction for 0.33 h the reaction stopped exotherming so
much and the rest of the PTSA (1 g, 5.68 mmol) was added. The cap was sealed and the
tube was left in the ice bath overnight. The product was purified by atmospheric
distillation (bp = 61°C); colorless liquid; 62% Yield; the data was consistent with the
commercially available starting material.
3-85: (1-methoxyethene-1,2-diyl)dibenzene

To a 10 mL round bottom flask was added dimethyl (methoxy(phenyl)methyl)phosphonate
(0.2 g, 0.88 mmol) and THF (5 mL). The solution was cooled to -78°C and n-BuLi (0.35
mL, 2.5 M solution in hexanes, 0.88 mmol) was added dropwise. The solution turned from
colorless to a bright yellow colored solution. Benzaldehyde (88.0 uL, 0.88 mmol) was
added to THF (2 mL) and the solution was cooled to -78°C. The aldehyde solution was
added to the enolate over 2 minutes. The reaction was left in the dry ice bath and allowed
to slowly warm to room temperature and react overnight. The reaction solution had formed
a semisolid solution due to inorganic salts and was dissolved in water and extracted with
ether, dried with MgSO4, filtered and concentrated in vacuo. The product was purified by
silica gel chromatography; 9 : 1 hexane : DCM; Rf = 0.28; Oil; 67% Yield. The compound
matched the reported lit data.

57

1

3: 2 ratio; H NMR (500 MHz) (CDCl3) δ 3.65 (3H, s),
154

3.82 (3H, s), 5.84 (1H, s), 6.12 (1H, s), 6.97 (2H, d, J = 8.0 Hz), 7.05 (1H, t, J = 8.0 Hz),
7.11 (2H, t, J = 8.0 Hz), 7.22 (1H, t, J = 7.5 Hz), 7.29 (3H, m), 7.36 (5H, m), 7.41 (2H, t, J
= 7.5 Hz), 7.57 (2H, d, J =8.0 Hz), 7.73 (2H, d, J = 8.0 Hz);

13

C NMR (125 MHz) (CDCl3)

δ 55.51, 57.91, 101.50, 112.76, 125.21, 126.55, 126.6, 127.94, 128.18, 128.32, 128.37,
128.46, 128.54, 128.59, 128.85, 129.29, 135.91, 136.23, 136.38, 136.88, 156.25, 157.25
(1-methoxyethyl)triphenylphosphonium tetrafluoroboride

The compound was made to the literature procedure.

58

To a 250 mL round bottom flask

was added 1,1-dimethoxyethane (3.26 g, 36.22 mmol), toluene (100 mL) and Ph3P (9.5 g,
36.22 mmol). The solution was cooled to 0°C and BF3•OEt2 (6.8 mL, 54.33 mmol) was
added slowly over 5 minutes. After 0.5 h at 0°C the reaction formed an oil layer so the
flask was removed from the ice bath and formed solids after 0.25 h. The reaction solution
was mixed for 24 h. The crystals were isolated by vacuum filtration. The crystals were
washed with ether and dried in vacuo. The compound matched the reported literature data.
1

White solid; mp = ; 80% Yield; H NMR (300 MHz, CHCl3 = 7.26)δ 1.65 (3H, dd, J1 =
6.4 Hz, J2 = 17.8 Hz), 3.55 (3H, s,), 5.69 (1H, dq, J1 = 4.4, J2 = 6.4 Hz), 7.64−7.84 (15H,
m);

13

C NMR (75 MHz) δ 14.92, 59.47 (d, J = 10.5 Hz), 72.88 (d, J = 66.0 Hz), 116.60

(d, J = 82.5 Hz), 130.37 (d, J = 12.8 Hz), 134.23 (d, J = 9.8 Hz), 135.17 (d, J = 2.3 Hz).
3-86: (E)-(2-methoxyprop-1-en-1-yl)benzene

155

To a 25 mL round bottom flask was added (1-methoxyethyl)triphenylphosphonium
tetrafluoroborate (0.8 g, 1.96 mmol) and THF (8 mL). The solution was cooled to -40°C
with a dry ice / acetonitrile bath and NaHMDS (2.54 mL, 2.54 mmol, 1.0 M in THF) was
added dropwise. The solution turned a blood red color. To a 10 mL round bottom flask
was added benzaldehyde (0.20 mL, 1.96 mmol) and THF (2 mL). This solution was
cooled to -40°C and was added to the red solution over 2 minutes with a canulla. The
solution turned yellow and was mixed at -40 for ten minutes. It was then taken out of the
dry ice/ acetonitrile bath to warm to room temperature and react for 2.5 h. Water was
added to the reaction solution and it was extracted with ether, dried with MgSO4, filtered,
and concentrated in vacuo. The crude product was purified by silica gel chromatography;
97: 3 DCM: TEA; Rf = 0.95; the product still contained some impurities but was pure
enough for the next reaction. Product was consistent with the reported literature data.

59

The compound could not be isolated in high purity due to hydrolysis on silica gel.
Approximately 33% yield, 96 mgs but contained a little bit of impurities and was used in
1

the next reaction immediately. Mixture of E and Z isomers; Oil; HNMR (500 MHz)
(CDCl3) δ 3 2.02 (3H, s), 2.07 (3H, s), 3.68 (3H, s), 3.75 (3H, s), 5.33 (1H, s), 5.61 (1H,
s), 7.10-7.60 (10H, m);

13

CNMR (125 MHz) (CDCl3) δ 18.1, 18.9, 25.5, 34.9, 54.7, 55.3,

99.6, 100.1, 106.6, 125.2, 125.3, 127.9, 128.2, 128.8, 136.8, 153.5.
3-89: N-(4-methoxy-3,4-dimethyloxazolidin-2-ylidene)methanaminium bromide

156

To a 10 mL round bottom flask under nitrogen was added 1-bromo-1,3-dimethylurea (1.0
mL, 0.60 mmol, 100 mg / mL soln in CDCl3), CHCl3 (2 mL) and 2-methoxyprop-1-ene
(69 uL, 0.72 mmol). The solution was mixed for 24 h and the solution was concentrated in
vacuo at room temperature (heating caused decomposition). The residue was triturated
with EtOAc / hexane to give crystals and the solvent was removed with a pipette. The
crystals were dried in vacuo at room temperature. Solid; mp = 118-120°C; 75% Yield;
1

HNMR (500 MHz) (CDCl3) δ 1.62 (3H, s), 2.99 (3H, d, J = 4.5 Hz), 3.13 (3H, s), 4.57

(1H, d, J = 6.60 Hz), 4.78 (1H, d, J = 6.60 Hz), 10.42 (1H, s, br);

13

CNMR (125 MHz)

(CDCl3) δ 22.72, 27.83, 28.63, 50.54, 75.33, 94.28, 160.14; IR NaCl: 1705, 1543, 1248,
1006; HRMS calculated for C7H15N2O2 (M+H) 159.1134; found 159.1127
3-90: N-(4-methoxy-3-methyl-4-phenyloxazolidin-2-ylidene)methanaminium bromide

To a 10 mL round bottom flask under nitrogen was added 1-bromo-1,3-dimethylurea (1.0
mL, 0.60 mmol, 100 mg / mL soln in CDCl3), CHCl3 (2 mL) and (1methoxyvinyl)benzene (96.50 mg, 0.72 mmol). The solution was mixed for 24 h and the

157

solution was concentrated in vacuo at room temperature. The residue was triturated with
EtOAc / hexane to give crystals and the solvent was removed with a pipette. The crystals
1

were dried in vacuo at room temperature. Solid; mp = 258-260°C; 80% Yield; H NMR
(500 MHz) (CDCl3) δ 3.14 (3H, s), 3.14 (3H, s), 3.40 (3H, s), 4.67 (1H, d, J = 11.0 Hz),
4.98 (1H, d, J = 11.0 Hz), 7.44 (5H, m), 10.90 (1H, s, br);

13

CNMR (125 MHz) (CDCl3) δ

28.63, 28.74, 50.46, 77.44, 96.88, 126.04, 129.10, 130.08, 134.76, 160.36; IR (NaCl):
1699, 1539, 1130, 981; HRMS calculated for C12H17N2O2 (M+H) 221.1290; found
221.1288
3-93: 2-bromo-1,2-diphenylethanone

To a 10 mL round bottom flask was added (E) and (Z)-(1-methoxyethene-1,2diyl)dibenzene (50 mg, 0.18 mmol), CHCl3(3 mL), and 1-bromo-1,3-dimethylurea (0.37
mL, 0.22 mmol, 100 mg / mL soln in CDCl3). The solution was heated to reflux for 1h and
then was cooled to room temperature and concentrated in vacuo. The product matched the
60

literature data.

The product was purified by silica gel chromatography; 2: 1 hexane:
1

DCM; Rf = 0.35; Solid; mp = 44-46; 12% Yield; H NMR (CDCl3) δ 6.40 (1H, s), 7.357.61 (8H, m), 7.91-8.01 (2H, m);

13

C NMR (CDCl3) δ 51.1, 128.3, 128.5, 128.6, 128.7,

133.3, 135.4, 190.6.
3-94: 1-bromo-1-phenylpropan-2-one
158

To a 10 mL round bottom flask was added (Z) and (E)-(2-methoxyprop-1-en-1-yl)benzene
(50 mg, 0.24 mmol), CHCl3(3 mL), and 1-bromo-1,3-dimethylurea (0.5 mL, 0.27 mmol,
100 mg / mL soln in CDCl3). The solution was heated to reflux for 1h and then was cooled
to room temperature and concentrated in vacuo. The product has been previously
synthesized.

60

1

The product was purified by silica gel chromatography; 15% Yield; Oil; H

NMR (300 MHz) (CDCl3) δ 1.90 (3H, d, J = 7.0 Hz); 5.30 (1H, q, J = 7 .0 Hz), 7.40-7.60
(3H, m), 8.00 (2H, d, J = 9.0 Hz);

13

C NMR (75 MHz) (CDCl3) δ 20.2, 62.8, 129.1, 129.5,

133.1, 136.2, 198.5.

159

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Bales, B. C.; Horner, J. H.; Huang, X.; Newcomb, M.; Crich, D.;
Greenberg, M. M. J. Am. Chem. Soc. 2001, 123, 3623.

(60)

Podgorsek, A.; Stavber, S.; Zupanab, M.; Iskra, J. Green Chem. 2007, 9,
1212.

164

CHAPTER 4
FUTURE DIRECTIONS FOR SYNTHESIS OF NEW HETEROCYCLES WITH
BROMINE REAGENTS

The Tepe lab is interested in the total synthesis of natural products and their
derivatives as potential new 20S proteasome inhibitors. We are particularly interested in
the Phakellins, Phakellstatins, Nagelamide M, and Palau’amine derivatives

1-3

The total

1

synthesis of Dibromophakellin has been accomplished by Nicole Hewlett. The 5
membered guanidine heterocycle in Dibromophakellin was a key step in the synthesis.
This 5-membered guanidine ring was synthesized by the reaction of NBS, N-boc guanidine,
and enamine 4-3. The reaction presumably occurred first by synthesis of N-bromo, N-boc
guanidine by reaction of N-boc guanidine with NBS. NBS should not brominate the
carbamate nitrogen NH because this is the most electron deficient nitrogen in Nbocguanidine and is the hardest to brominate. Instead one of the other two nitrogens of Nbocguanidine should be brominated to yield compound 4-1 or 4-2. The reaction of 4-1 or
4-2 with an enamine occurred through an SN2’ mechanism based on conversation with our
lab (Scheme 4-1). The reaction of compound 4-2 with enamine 4-3 would yield the
intermediate 4-4 which is equilibrium with compound 4-5. The intermediate 4-4 will react
further to close the guanidine ring through an iminium cation (Scheme 4-1).

165

Scheme 4-1: Possible mechanism for the synthesis of Dibromophakellin
It may be possible to synthesize the Phakellstatin natural products from the reaction of
enamine 4-3 with N-bromoisourea 4-8 through a SN2’ reaction and ring closure to a 5
membered isourea ring. Hydrolysis of the isourea or deprotection of the benzyl group with
hydogenation would yield the 5-membered urea ring. Similarly, enamine 4-9 and Nbromoguanidine 4-2 could theoretically be used to synthesize Palau’amine type derivatives.
Lastly, enamine 4-10 and N-bromoguanidine 4-2 could be used to synthesize Nagelamide
M (Figure 4-1).

166

Figure 4-1: Synthetic strategy to access important natural products through the SN2’
reaction
Based on the N-bromo imide 3-34 we can design new brominating reagents to
access these biologically significant natural products and proteasome inhibitors. By
analyzing 3-34 previous studies have shown that the two acyl groups can be a benzoyl
group, a methyl ester group or a boc group. If we replace one of the carbonyl oxygen
167

atoms with a NH we will have an N-boc, N-bromomethyl carbamimidate 4-11. N-boc, Nbromomethyl carbamimidate is not a C-2 symmetrical bromine reagent, but if we place
another boc group on that reagent than the new bromine reagent N, N-di-boc, Nbromomethyl carbamimidate 4-14 would be C-2 symmetrical. N-boc, N-bromomethyl
carbamimidate can be transformed into N-boc, N-bromoguanidine 4-12 by replacing the
OMe group with an NH2 group. If, another boc group is placed on N-boc, Nbromoguanidine then we will synthesize N,N-diboc, N-bromoguanidine 4-15, which would
be another C-2 symmetrical bromine reagent. (Figure 4-2).

168

Figure 4-2: Proposed new bromine reagents for the synthesis of new heterocycles
These new bromine reagents may create new synthetic methods to synthesize urea and
guanidine heterocycles. Methyl carbamimidate hydrogen chloride was protected with a
boc group and was successfully brominated with bromoacetate to yield compound 4-11.
The compound 4-11 did not precipitate from a solution of hexane/CCl4, but instead was
isolated by carefully removing the solvent at room temperature in vacuo while the flask
was wrapped in aluminum foil. Compound 4-11 can exist as two different forms because

169

either nitrogen atom could be brominated. When 4-11 was reacted with styrene with
BF3•OEt2 once the bromine forms the bromonium ion with styrene two different products
can be formed. In fact a mixture of regioisomers was formed 4-16. Cyclization of 4-16 to
a 5-membered heterocycle was attempted by heating the crude product neat but did not
form the desired product (Scheme 4-2).

Scheme 4-2: Synthesis of compound 4-16

However, one way to get around a mixture of regioisomers would be to use a C-2
symmetrical bromine agent 4-14 or 4-15. Upon reaction of compound 4-14 with styrene

170

and BF3•OEt2 would yield the intermediate 4-17 which has the potential to synthesize the
isourea compound 4-18. The isourea can undergo reaction with acid and water to yield the
urea 4-19 and further hydrolysis to the diamine 4-20 (Scheme 4-3).

Scheme 4-3: Proposed synthesis of isourea and urea heterocycles.
N,N-di-boc, N-bromoguanidine 4-15 could be a new methodology to form guanidine
heterocycles. Two possible boc guanidine heterocycles 4-22 could be synthesized from the
intermediates 4-21. The boc group could then be removed to synthesize the cyclic
guanidine 4-23 (Scheme 4-4).

171

Scheme 4-4: Proposed synthesis of guanidine heterocyle 4-23.
Perhaps a better way to make an urea heterocycle would be with bromine reagent 4-13.
After addition of 4-13 to styrene compound 4-24 would contain a very acid proton.
Deprotonation with a strong base like NaH should close the ring through a 5-exo-tet ring
closure to yield compound 4-25. The CO2Me groups could be easily hydrolyzed to yield
the urea 4-26 which could be further hydrolyzed to a diamine if desired (Scheme 4-5).

172

Scheme 4-5: Proposed synthesis of urea heterocyle 4-26.

The combination of these bromine reagents with BF3•OEt2 and neutral olefins may
allow for new synthetic methodologies to access urea and guanidine heterocycles.
However, Br-N(CO2Me)2 3-34 failed to add to an electron poor alpha beta unsaturated
olefin. A paper by Wei and coworkers presented a new methodology to make alpha
4

bromo, beta tosyl ketones. We may be able to use compound 3-34 with their reaction
conditions to synthesis an amino alcohol. The key to the methodology by Wei was the
catalyst KI. KI reacted with an alpha beta unsaturated olefin 4-27 by 1,4-addition followed
by abstraction of the bromine from NBS to yield 4-30. This intermediate can then undergo
substitution of the iodide atom with TsNH2 to yield compound 4-31 and succinimide
(Scheme 4-6).

173

Scheme 4-6: Addition of TsNH2 to an alpha beta unsaturated olefin

Based on this mechanism it may be possible to add various bromine reagents to an
alpha-beta unsaturated aldehyde by use of catalytic Iodine source and an organo catalyst.
However, this can only be accomplished if I-Br is not being formed in the reaction of NBS
and KI, which Wei did not mention the possibility of I-Br being formed. The
5

organocatalyst is based on the work by MacMillan. This work has been pursued by Travis
Bethel and use of compound Br-N(CO2Me)2. Formation of the iminium 4-33 by
condensation of the organocatalyst with the aldehyde 4-32 would undergo attack by the
iodide anion to yield an enamine 4-34. The enamine would undergo reaction with BrN(CO2Me)2 to yield compound 4-35. Compound 4-35 has several electrophilic sites but
174

hopefully nucleophilic attack would occur at the alpha or beta position and not at the
iminium carbon to yield compound 4-36. After removing the organocatalyst by workup
and heating compound 4-37 the compound 4-38 should be synthesized. Heating compound
4-47 should result in formation of a carbocation and formation of the trans-diastereomer 438 (Scheme 4-7).

Scheme 4-7: Proposed synthesis of Oxazolidin-2-ones from alpha-beta unsaturated
aldehydes
175

Hopefully this methodology will provide a new methodology to access an amino
alcohol from hydrolysis of compound 4-38. This would not yield the amino alcohol
enantiomerically pure because the oxazoldin-2-one ring formation occurred through a
carbocation as mentioned earlier. However, an organocatalyst methodology with KI may
allow for an enantioselective synthesis of urea and guanidine rings from reaction of an Nbromourea or N-bromoguanidine with alpha beta unsaturated aldehyde or ketone. These
methodologies will hopefully allow the Tepe lab to synthesize new 20S proteasome
inhibitors and new guanidine and urea containing natural products.

176

APPENDIX

177

1

Figure 4-3: H NMR spectrum for compound 2-16
178

Figure 4-4:

13

C NMR spectrum for compound 2-16

179

1

Figure 4-5: H NMR spectrum for compound 2-17

180

Figure 4-6:

13

C NMR spectrum for compound 2-17

181

1

Figure 4-7: H NMR spectrum for compound 2-18
182

Figure 4-8:

13

C NMR spectrum for compound 2-18

183

1

Figure 4-9: H NMR spectrum for compound 2-19 regioisomer 1

184

Figure 4-10:

13

C NMR spectrum for compound 2-19 regioisomer 1

185

1

Figure 4-11: H NMR spectrum for compound 2-19 regioisomer 2

186

Figure 4-12:

13

C NMR spectrum for compound 2-19 regioisomer 2
187

1

Figure 4-13: H NMR spectrum for compound 2-20

188

Figure 4-14:

13

C NMR spectrum for compound 2-20

189

1

Figure 4-15: H NMR spectrum for compound 2-21

190

Figure 4-16:

13

C NMR spectrum for compound 2-21

191

1

Figure 4-17: H NMR spectrum for compound 2-22

192

Figure 4-18:

13

C NMR spectrum for compound 2-22

193

1

Figure 4-19: H NMR spectrum for compound 2-23

194

Figure 4-20:

13

C NMR spectrum for compound 2-23
195

1

Figure 4-21: H NMR spectrum for compound 2-16
196

Figure 4-22:

13

C NMR spectrum for compound 2-16

197

1

Figure 4-23: H NMR spectrum for compound 3-18
198

Figure 4-24:

13

C NMR spectrum for compound 3-18
199

1

Figure 4-25: H NMR spectrum for compound 3-34

200

Figure 4-26:

13

C NMR spectrum for compound 3-34
201

1

Figure 4-27: H NMR spectrum for compound 3-47
202

Figure 4-28:

13

C NMR spectrum for compound 3-47
203

1

Figure 4-29: H NMR spectrum for compound 3-52
204

Figure 4-30:

13

C NMR spectrum for compound 3-52
205

1

Figure 4-31: H NMR spectrum for compound 3-53
206

Figure 4-32:

13

C NMR spectrum for compound 3-53
207

1

Figure 4-33: H NMR spectrum for compound 3-54
208

Figure 4-34:

13

C NMR spectrum for compound 3-54
209

1

Figure 4-35: H NMR spectrum for compound 3-56
210

Figure 4-36:

13

C NMR spectrum for compound 3-56
211

1

Figure 4-37: H NMR spectrum for compound 3-57
212

Figure 4-38:

13

C NMR spectrum for compound 3-57
213

1

Figure 4-39: H NMR spectrum for compound 3-58
214

Figure 4-40:

13

C NMR spectrum for compound 3-58
215

1

Figure 4-41: H NMR spectrum for compound 3-63
216

Figure 4-42:

13

C NMR spectrum for compound 3-63
217

1

Figure 4-43: H NMR spectrum for compound 3-64
218

Figure 4-44:

13

C NMR spectrum for compound 3-64
219

1

Figure 4-45: H NMR spectrum for compound 3-65
220

Figure 4-46:

13

C NMR spectrum for compound 3-65
221

1

Figure 4-47: H NMR spectrum for compound 3-66
222

Figure 4-48:

13

C NMR spectrum for compound 3-66
223

1

Figure 4-49: H NMR spectrum for compound 3-67
224

Figure 4-50:

13

C NMR spectrum for compound 3-67
225

1

Figure 4-51: H NMR spectrum for compound 3-68
226

Figure 4-52:

13

C NMR spectrum for compound 3-68
227

1

Figure 4-53: H NMR spectrum for compound 3-70
228

Figure 4-54:

13

C NMR spectrum for compound 3-70
229

1

Figure 4-55: H NMR spectrum for compound 3-71
230

Figure 4-56:

13

C NMR spectrum for compound 3-71
231

1

Figure 4-57: H NMR spectrum for compound 3-72
232

Figure 4-58:

13

C NMR spectrum for compound 3-72
233

1

Figure 4-59: H NMR spectrum for compound 3-77
234

Figure 4-60:

13

C NMR spectrum for compound 3-77
235

1

Figure 4-61: H NMR spectrum for compound 3-78
236

Figure 4-62:

13

C NMR spectrum for compound 3-78
237

1

Figure 4-63: H NMR spectrum for compound 3-79
238

Figure 4-64:

13

C NMR spectrum for compound 3-79
239

1

Figure 4-65: H NMR spectrum for compound 3-89
240

Figure 4-66:

13

C NMR spectrum for compound 3-89
241

242

1

28.9483
28.7359

Figure 4-67: H NMR spectrum for compound 3-90

243

77.5150

Figure 4-68:

13

C NMR spectrum for compound 3-90
244

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245

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(2)

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Tetrahedron 2008, 64, 10810.

(3)

Wang, S.; Dilley, A. S.; Poullennec, K. G.; Romo, D. Tetrahedron 2006,
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(4)

Wei, J.; Zhang, L.; Chen, Z.; Shi, X.; Cao, J. Org. Biomol. Chem. 2009, 7,
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(5)

Brochu, M. P.; Brown, S. P.; MacMillan, D. W. C. J. Am. Chem. Soc.
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246