BENZOTRIAZOLE-MEDIATED SYNTHESIS OF

N-ACYLBENZOTRIAZOLES
AND 2H-AZIRINES

By
CHAVON RENEE WILKERSON

A THESIS PRESENTED TO THE GRADUATE SCHOOL

OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT
OF THE REQUIREMENTS FOR THE DEGREE OF
MASTERS OF SCIENCE
UNIVERSITY OF FLORIDA
2003

Copyright 2003
by
Chavon R. Wilkerson

This document is dedicated to Larry Jr., Lauren, Lyndsey, and Johnny Jr..

ACKNOWLEDGMENTS
I thank my parents, Lana and Larry Wilkerson for their love and continuous
support of my career. I thank my sister for her friendship and words of encouragement. I
thank all my friends and family for their support. I thank Professor Alan Katritzky for the
opportunity to learn, study, and practice chemistry under his advisement.

iv

TABLE OF CONTENTS
page
ACKNOWLEDGMENTS ................................................................................................. iv
LIST OF TABLES............................................................................................................. vi
LIST OF FIGURES .......................................................................................................... vii
ABSTRACT.........................................................................................................................x
CHAPTER
1

GENERAL INTRODUCTION ....................................................................................1

1.1 Importance of Heterocyclic Chemistry.................................................................1
1.2 Benzotriazole-Mediated Approach to Heterocyclic Synthesis .............................3

SYNTHESIS OF N-ACYLBENZOTRIAZOLES .....................................................10

2.1 Introduction...........................................................................................................10
2.2 Synthetic Utility Of N-Acylbenzotriazoles...........................................................12
2.3 Results and Discussion .........................................................................................23
2.4 Experimental Methods..........................................................................................26

SYNTHESIS OF 2H-AZIRINES ...............................................................................29

3.1 Introduction...........................................................................................................29
3.2 Synthetic Strategies for 2h-Azirines.....................................................................31
3.3 Benzotriazole Mediated Approach to 2h-Azirines ...............................................37
3.4 Results and Discussion .........................................................................................39
3.3 Conclusion ............................................................................................................45
3.4 Experimental Methods..........................................................................................46

CONCLUSIONS ........................................................................................................50

LIST OF REFERENCES...................................................................................................51
BIOGRAPHICAL SKETCH .............................................................................................60

LIST OF TABLES
page

Table
1.1

Preparation of N-Alkylbenzotriazoles, RBt ...............................................................7

2.1

Synthesis of N-acylbenzotriazoles ...........................................................................25

3.1

2H-azirines 3.28 and their derivatives 3.35, 336, and 3.37......................................45

vi

LIST OF FIGURES
page

Figure
1.1

Heterocycles in living systems ...................................................................................1

1.2

Parent benzotriazole molecule....................................................................................3

1.3

Comparison of benzotriazole as a leaving group to cyano and phenylsulfonyl.........4

1.4

Benzotriazole is activated to -C-H proton loss. .......................................................5

1.5

Benzotriazole has electron donor and electron acceptor abilities. .............................5

1.6

Benzotriazole exists as two isomers of similar stability. ...........................................6

1.7

Reaction of benzotriazole and acid chlorides without base. ......................................7

1.8

Conversion of carboxylate anions into N-acylbenzotriazoles mediated by Nsulfonylbenzotriazole. ................................................................................................8

1.9

Removal of benzotriazolyl group...............................................................................9

2.1

Resonance hybridization of tertiary amides. ............................................................11

2.2

N-acylimidazoles as acylation reagents....................................................................11

2.3

Utility of N-acylbenzotriazoles. ...............................................................................12

2.4

Ring synthesis of substituted 3,4-dihydro-2-pyrones from N- acylbenzotriazoles. .13

2.5

Polycyclic heteroaromatics from N-acylbenzotriazoles ...........................................13

2.6

Formation of butyrolactones from N-acylbenzotriazoles.........................................14

2.7

Simple conversion of N-acylbenzotriazoles to amides.............................................15

2.8

General synthesis of unsymmetrical tetrasubstituted ureas......................................16

2.9

General synthesis of unsymmetrical tetrasubstituted oxamides...............................16

2.10 Trifluoroacetylated N-acylbenzotriazole as a novel protecting group .....................17

vii

2.11 Compounds with the Bt-C-O functionality ..............................................................18

2.12 Synthesis of 1-(benzotriazol-1-yl)alkyl esters by N-acylbenzotriazoles..................18
2.13 Common reactions of carbonyl compounds containing an alpha proton .................19
2.14 C-acylation of ketimines by N-acylbenzotriazoles for the synthesis of
enaminones...............................................................................................................20
2.15 Conversion of sulfones into -keto sulfones by N-acylbenzotriazoles ....................21
2.16 Synthesis of 1,3-diaralyacetones from N-(arylacetyl)benzotriazoles.......................22
2.17 Conversion of arenesulfinate anions into aryl benzyl sulfoxides.............................22
2.18 Formation of N-acylbenzotriazoles ..........................................................................24
2.19 Formation of N-acylbenzotriazole............................................................................25
3.1

Structure of azirines .................................................................................................29

3.2

Synthetic routes to 2H-azirines ................................................................................31

3.3

Example of 2H-azirine formation by a nitrile and carbene ......................................32

3.4

Thermal or photochemical rearrangement of isoxazoles to 2H-azirines..................33

3.5

Ring-contraction of oxazaphospholes to 2H-azirines ..............................................33

3.6

Base-catalyzed elimination of aziridines..................................................................33

3.7

Oxidation of aziridines to 2H-azirines .....................................................................34

3.8

Synthesis of 2H-azirines by thermolysis of vinyl azides .........................................34

3.9

Photolysis of vinyl azides.........................................................................................35

3.10 Pathways to azirines via vinyl azides .......................................................................36

3.11 Neber rearrangement of oximes to produce 2H-azirines..........................................36
3.12 Example of modified Neber reaction .......................................................................37
3.13 Synthesis of ketoxime tosylates ...............................................................................38
3.14 Synthetic approach to 2H-azirines ...........................................................................38
3.15 Synthesis of N-acylmethylbenzotriazoles ................................................................40
3.16 Acylation of benzotriazole .......................................................................................41
viii

3.17 Synthesis of benzotriazole-substituted oximes ........................................................42

3.18 Synthesis of benzotriazole-substituted 2H-azirines ...................................................43
3.19 Substitution of benzotriazole in 2H-azirines ............................................................46

ix

Abstract of Thesis Presented to the Graduate School

of the University of Florida in Partial Fulfillment of the
Requirements for the Degree of Master of Science
BENZOTRIAZOLE-MEDIATED SYNTHESIS OF
N-ACYLBENZOTRIAZOLES
AND 2H-AZIRINES
By
Chavon Renee Wilkerson
August 2003
Chair: Alan R. Katritzky
Major Department: Chemistry
Benzotriazole, a well-known synthetic auxiliary was used in the synthesis of
diverse N-acylbenzotriazoles and 2H-azirines.

N-Acylbenzotriazoles are efficient

acylating reagents as well as intermediates in the synthesis of various important

compounds. The synthesis of five N-acylbenzotriazoles was accomplished. Azirines, the
smallest nitrogen-containing heterocyclic molecules, were synthesized via a Neber
rearrangement of a benzotriazole-substituted oxime p-toluenesulfonate.

The first

example of nucleophilic attack with Grignard reagents on the azirine ring system was
obtained, thus providing novel 2H-azirines.

CHAPTER 1
GENERAL INTRODUCTION
1.1 Importance of Heterocyclic Chemistry
A heterocycle is any organic cyclic compound with a ring containing one or more
carbons and at least one other element, namely O, S, N. About half of the known organic
compounds contain at least one heterocyclic component, thus heterocyclic compounds
are very widely distributed in nature. Their functions are often of fundamental
importance to living systems as they play a vital role in the metabolism of all living cells.
For example, the nucleic acid bases, which are derivatives of the pyrimidine 1.1 and
purine 1.2 ring (Figure 1.1) systems are crucial to the mechanism of replication. Essential
diet ingredients such as thiamin (vitamin B1), riboflavin (vitamin B2), pyridoxyl (vitamin
B6), and ascorbic acid (vitamin C) are heterocyclic compounds. Two of the essential
amino acids, tryptophan and histidine are heterocyclic. The structural complexity of
heterocycles provides an almost limitless series of compounds with a wide range of
physical, chemical, and biological properties. The successful application to many
problems makes for continued interest in their chemistry.
N

NH

1.1

1.2

Figure 1.1 Heterocycles in living systems

Perhaps the most widely studied application of heterocycles is the preparation of
biologically active and medicinally important molecules. The successful treatment of

2
various ailments ranging from malaria to cancer to heart disease is often triggered by the
presence of various heterocyclic compounds in extracts derived from plants, animals, and
insects. Heterocyclic derivatives such as morphine alkaloids, -lactam antibiotics, and
benzodiazepines are just a few familiar examples from various pharmaceuticals featuring
a heterocyclic component[91AG(E)1278].
The ability of mankind to synthetically prepare medicinally important molecules
during the past century has allowed for a continued decrease in the mortality rate from
numerous diseases. However, many diseases, viruses, and infections continue to prosper
among mankind and escape suitable and long-lasting treatments or cures. Teams of
scientists trained in areas like medicinal chemistry, pharmacology, molecular biology,
biochemistry, enzymology and others work tirelessly to find suitable treatments and
cures.
Modern drug discovery focuses on synthesis of specific biomolecular targets,
which invariably contain a heterocyclic component. A key challenge in the synthesis of
such targets continues to be the development of new pathways and improvement of
existing pathways to biologically important molecules. Efforts by many researchers
throughout the world have added tremendously to the knowledge base of heterocyclic
chemistry and have allowed for the development of pharmaceutical, agricultural, and
industrially important products.
Katritzky and co-workers have studied the design of new synthetic reactions,
especially practical, high-yield methods for the synthesis of complex organic molecules
for nearly fifty years[91T2683][98CR409]. The development of superior synthetic
methods and preparation of useful compounds within the Katritzky group is based on the

3
use of a well-known synthetic auxiliary, benzotriazole, to be discussed in the following
section.
1.2 Benzotriazole-Mediated Approach to Heterocyclic Synthesis
Any chemical entity providing support, or serving as an aid in organic synthesis
can be viewed as a synthetic auxiliary. A useful synthetic auxiliary should display
several characteristics. It should be readily introduced at the beginning of the sequence,
remain stable during various synthetic operations, and, if possible, exert an activating
influence on other parts of the molecule. In addition, it must be easy to remove at the end
of the synthetic sequence. Perhaps few other synthetic auxiliaries have consistently
contributed to the development of mild and efficient reaction pathways in organic
synthesis when compared with benzotriazole 1.3.
N

N
N
H

1.3

Figure 1.2 Parent benzotriazole molecule

Major efforts to explore novel and useful aspects of benzotriazole chemistry began
in 1987 when Katritzky and co-workers carried out systematic studies of the properties
and reactions of N-substituents in heterocyclic compounds
[87JCS(P1)781][87JCS(P1)791][87JCS(P1)799]. Since that time, benzotriazole has
proven to be a highly valuable synthetic auxiliary. Five key attributes contribute to the
success of benzotriazole as a desirable synthetic auxiliary:

Introduction and removal from organic compounds easily.

Ability to convey multiple activating influences on molecules to which it is

attached.

Intrinsically unreactive and stable.

Desirable physical and biological properties.

Ready availability.
Additionally, when compared with other well-known activating groups,

benzotriazole displays quite a few advantages. The leaving ability of benzotriazole is

comparable to cyano and sulfonyl[95S1315]. These are good leaving groups only when
activated in one of two alternative ways: i) by an electron donor substituent attached to
the same sp3-hybridized carbon atom, ii) by an electron acceptor as when the group is
attached to an sp2-(or sp-) hybridized carbon atom which also carries an attached double
bond to oxygen or nitrogen. The halogens and tosylate behave as leaving groups in each
case i), ii), and iii) when attached to an unactivated sp3- (or sp2-) hybridized carbon.
Especially in case (i), halogens and tosylates are often so reactive as to be difficult to
isolate. For this reason benzotriazole (Bt) may be compared with a tame halogen
substituent because of its leaving abilities and offers a clear advantage since it forms a
stable, non-volatile anion in solution compared with the unstable halogen and tosylate
and the toxic cyano group. (Figure 1.3)

-Bt is stable
-non-volatile
-reusable

N
N
N

-cyano is volatile, poisonous

-poor leaving group

X
O

R
C
H X

S
O

-lachrymator
-not recoverable

Figure 1.3 Comparison of benzotriazole as a leaving group to cyano and phenylsulfonyl.

Heteroatom-assisted deprotonation of an -hydrogen is well known[86JOC86].
For example, the N-alkyl protons to a nitrogen incorporated in a five-membered
heteroaromatic ring such as N-alkylpyrazole are activated[69CR693]. A benzotriazolyl

5
moiety similarly provides activation to allow for deprotonation of an C-H. Detachment
of a proton in the 1- position of benzotriazole most likely occurs due to the presence of
two electron-attracting, pyridinelike nitrogen atoms which increase the acidity of said
proton (Figure 1.4). This type of activation to proton loss is an extremely important
attribute of benzotriazole as it allows for subsequent reactions with electrophiles to form
a variety of interesting compounds[93JHC1261][93T7445][95JOC6].
electron attracting pyridine-like
N- atoms
N

N
N
R

acidic proton

X= O, N, S

Figure 1.4 Benzotriazole is activated to -C-H proton loss.

Furthermore, benzotriazole possesses both electron-donor and electron-acceptor
properties and, because of this, compounds with an heteroatom (typically N, O, and S)
1.4 attached to a benzotriazole nitrogen can ionize in two ways. Ionization may form the
benzotriazole anion and an immonium, oxonium, or thionium cation 1.5, or result in the
loss of the heteroatom substituent to give 1.6. (Figure 1.5)
N

N
N-

H
X
R

1.5
typically for
X=NR2, OR, SR

N
N
H

X
R

1.4
electron donor and acceptor
properties

+
R

X-

1.6

typically for
X= halogen, OH

Figure 1.5 Benzotriazole has electron donor and electron acceptor abilities.

6
N-Substituted benzotriazoles exist as two isomers: 1- and 2-substituted. They
typically exist in equilibrium (Figure 1.6), with 1.3b of the same order of stability as
1.3a, and often show the same reactivity. For simplification, the isomers will be notated
Bt1= benzotriazol-1-yl (3a), Bt2= benzotriazol-2-yl (3b), and Bt= benzotriazol-1-yl and
benzotriazol-2-yl throughout this presentation.
N

N R

R
1.3a

1.3b

Figure 1.6 Benzotriazole exists as two isomers of similar stability.

Benzotriazole (Bt) groups are easily inserted into a molecule by a variety of
substitution, addition, and three component condensation reactions. Examples of some of
these methods are described below.
1. Displacement from alkyl halides: RX + Bt- R-Bt + XA valuable method involves reaction of benzotriazole with alkyl halides, use of
DMF as the solvent and NaOH as the base resulting in high yields (Table 1.1)
[91RTC369]. Alkylation of benzotriazole with alkyl halides can also be achieved either
in basic media in the presence of a phase-transfer catalyst or in the absence of base by
conventional and microwave heating . Various other methods utilizing displacement from
alkyl halides also exist [93TL2673] [96JHC607] [96JHC203]. In general, reaction of
benzotriazole with primary alkyl halides leads to a mixture of N-1 and N-2 isomers, and
sometimes observation of the quaternization product.
2. Displacement from Acyl Halides: RCOX

Bt- RCOBt + X-

A direct method from benzotriazole and an acid chloride at 80-100C without

solvent allows for the preparation of 1-acylbenzotriazoles in good yields (Figure 1.7). N-

7
Acylbenzotriazoles have also been prepared from reactions of acid chlorides with
i) 1-(trimethylsilyl)-benzotriazole[80JOM141], (ii)1-(tributylstannyl)benzotriazole
[77JOM185], or (iii) 1-(hydroxymethyl)benzotriazole [54JA285][57JOC1022].
Table 1.1 Preparation of N-Alkylbenzotriazoles, RBt
RX
R
MeI
Me
i-PrI
i-Pr
n-Bu
n-Bu
Et(Me)CHBr
Et(Me)CH
PhCH2
PhCH2Br
Ph3CCl
Ph3C
EtOOCCH2Cl
EtOOCCH2
PhCOCH2
PhCOCH2Br

Yield (%)
95
80
86
65
99
100
95
98

heat
BtH

+ RCOCl

RCOBt1
1.7a: R=Me, 70%
1.7b: R=Et, 90%
1.7c: R=n-Bu, 79%
1.7d: R=Ph, 90%

Figure 1.7 Reaction of benzotriazole and acid chlorides without base.

Reaction of 1-(methylsulfonyl)benzotriazole with carboxylic acid anions leads to
the formation of 1-acylbenzotriazoles (Figure 1.8), an activated form of an
acid[00JOC8210]. The 1-acylbenzotriazoles are more stable than the corresponding acid
chlorides and offer a mild, highly efficient way of introducing benzotriazole. The reaction
is believed to involve attack of the acid anion on the sulfonyl group to give a mixed
anhydride. The benzotriazole anion then attacks the carbonyl group of the anhydride to
form the acylbenzotriazole.

Bt1
SO2Me

RCOO-

-Bt

O SO2Me

Bt1
COR

Bt-

Figure 1.8 Conversion of carboxylate anions into N-acylbenzotriazoles mediated by Nsulfonylbenzotriazole.

3. Displacement of OH in Alcohols: ROH + Bt- RBt
This method is particularly valuable for the preparation of those Nalkylbenzotriazoles which cannot conveniently be synthesized from the corresponding
alkyl halides either because they are not readily available or are unstable [93JPO567].
4. Displacement of Alkoxy Group in Acetals, Ketals.: R2C(OR2) + Bt- R2C(OR)Bt
Benzotriazole can displace one of the alkoxy groups in acetals or ketals to give 1(-alkoxyalkyl) benzotriazoles[89JOC6022][91S279]. Generally, only one alkoxy group
of acetals and ketals can be substituted by the Bt group, even when an excess of Bt is
used. However, the presence of a carbonyl group promotes this
reaction[87JCS(P1)791].
It is evident from the above illustrations that benzotriazole is a reagent capable of
being introduced into a variety of organic molecules by many mild and effective
procedures. Moreover, the benzotriazole residue can be removed from molecules just as
easily depending on its environment. The four major ways in which a benzotriazolyl
group is removed from a molecule of type 1.8 are depicted in Figure 1.9. The first three
modes all depend on dissociation to Bt- and a cation 1.8a. This dissociation is assisted by
a suitable heteroatom X, and also by proton or Lewis acid catalysis which helps the
departure of the benzotriazolyl group. Analogous vinylogous activation to benzotriazole

9
loss is also possible. For a comprehensive review of reactions involving the removal of
benzotriazole groups please see Chemical Reviews, 1998, 98, 409.

N
N

Nu
X

H Y

X
Y

Nu-

1. removal by substitution

X+

1.8

-H+

2. removal by elimination

1.8a
H2O

4. removal by ring scission

O
HY

3. removal by hydrolysis

Figure 1.9 Removal of benzotriazolyl group.

The key to the reactivity of benzotriazole is the influence it has on molecules to
which it is attached. The presence of a Bt residue allows it to act as a leaving group,
proton activator, an ambident anion directing group, cation stabilizer, and as both a
radical and anion precursor[98T2647][99JOC3335]. Furthermore, the benzotriazole ring
system is itself intrinsically unreactive, stable, and exhibits desirable physical and
innocuous biological properties. The parent benzotriazole 1.3 is a moderate acid (pKa =
8.2), a non-volatile, crystalline, odorless, and non-toxic reagent. At a cost of just $44 for
500 g (Aldrich), benzotriazole is certainly a user-friendly, mild reagent that has been used
extensively in organic synthesis, particularly to provide access to heterocycles.
Our extensive use of benzotriazole-substituted molecules as versatile synthetic
auxiliaries led us to synthesize some useful N-acylbenzotriazoles (see Chapter 2). We
also developed a novel approach to substituted 2H-azirines via a benzotriazole-mediated
Neber reaction (Chapter 3).

CHAPTER 2
SYNTHESIS OF N-ACYLBENZOTRIAZOLES
2.1 Introduction
Compounds containing carbonyl groups are plentiful in nature. Many play a vital
role in in biological processes. Hormones, vitamins, amino acids, drugs, and flavorings
are just a few carbonyl-containing compounds that affect us daily. Polarization of the
carbonyl group (C=O) with partial negative charge on oxygen and partial positive charge
at carbon renders the carbon atom of a carbonyl group susceptible to nucleophilic attack.
For this reason, carbonyl-containing compounds are used extensively as building blocks
toward complex organic structures. Carboxylic acids are widely available carbonyl
containing compounds due to their stability and low reactivity. The unreactive nature of
carboxylic acids especially toward nucleophilic acyl substitution exists (i) because the
hydroxyl group is a poor leaving group, and (ii) because in basic media the oxygen anion
is an even worse leaving group. Chemists need a useful way to activate carboxylic acids
in order to take advantage of the reactivity of the polarized carbonyl group.
Acyl halides and acid anhydrides are commonly used as activated carboxylic acid
derivatives. However, they are highly reactive and often must be prepared just prior to
reaction with a nucleophile. Additionally, many acid halides are unstable, difficult to
prepare, and/or liquids with unpleasant odors. Thus the availability of suitably
substituted and activated carboxylic acid derivatives is important. Acylazoles are
versatile activated derivatives of carboxylic acids, especially useful for acylations
(introduction of RCO- or ArCO- into a molecule) when the acid chloride could produce
10

11
undesired complications[84CHEC(5)451]. Reactive heterocyclic amides or azolides
implies amides whose amide nitrogen is a member of an aromatic five-membered ring
containing at least two nitrogen atoms, i.e. azoles [62AG(E)351]. N-Acylazoles
contain an electron pair on the ring nitrogen that is part of the aromatic sextet, hence
unlike other tertiary amides there is little contribution from resonance structures of type
2.1 (Figure 2.1) to the resonance hybrid. Consequently the positive nature of the
carbonyl carbon is undiminished.
R
R

N
R

R2

+ R1
N 2
R
O
2.1

Figure 2.1 Resonance hybridization of tertiary amides.

N-Acylimidazoles and N-acylbenzimidazoles have been well developed and
reviewed as powerful acylation reagents[79LA1756][80BCJ1638][98MI1]. They have
been widely involved in reactions that result in the acylation of diverse nucleophiles to
produce aldehydes, ketones, carboxylic acids, carboxylic esters, amides, hydrazides and
anhydrides (Figure 2.2).
ImH + RCOR'
R'MgBr
LiAlH4

RCO2H + ImH
H2O

RCO2R' + ImH

R'OH
R'NH2

RCONHR' + ImH

N
COR

RCHO + ImH

H2NNHR'

RCONHNHR' + ImH

R'CO2H
R'SH

RCO2COR' + ImH

RCOSR' + ImH

ImH=imidazole
Figure 2.2 N-acylimidazoles as acylation reagents

12
2.2 Synthetic Utility Of N-Acylbenzotriazoles
Use of N-acylbenzotriazoles as valuable synthetic intermediates has been welldocumented[1895JA449][72BCJ515][76EJB25][79JPS(A)277][83S327]. Katritzky and
co-workers have demonstrated, especially during the past decade, the great synthetic
utility associated with such compounds. A comprehensive review of their utility is
beyond the scope of this thesis. However, in an effort to convince the reader of how
important N-acylbenzotriazoles are, a short summary is presented.
N-Acylbenzotriazoles have found applications in the preparation of various classes
of compounds. They are most used in organic synthesis as reagents for preparation of
heterocycles (Route A, see section 2.2.1), N-acylation (Route B), O-acylation (Route C),
C-acylation (Route D), and preparation of valuable intermediates (Route E, see section
2.2.6) (Figure 2.3).

O
intermediates

R1CHO

R
R2

heterocycles

A
NHR1R2

R1CH2COR2

Bt

O
R

R 1
O

Bt 1

N R1R2

Figure 2.3 Utility of N-acylbenzotriazoles.

2.2.1 Preparation of Heterocycles
Katritzky and co-workers demonstrated that hetero-olefinic and hetero-aromatic
heterocycles could be obtained from various N-acylbenzotriazoles. Lithiated 1alkylcarbonylbenzotriazoles undergo 1,4-addition to ,-unsaturated aromatic ketones

13
(chalcones) to afford previously unknown 3-alkyl-4,6-diaryl-3,4-dihydropyran-2-ones 2.5
and 2.6 predominantly (or exclusively) as 3,4-trans-isomers, in good yields[02JOC3104]
(Figure 2.4). Dihydropyrones are useful in the development of therapies for the treatment
of viral infections, and diseases, including AIDS [98TA2197] [99TA3659]
[99BMC2217] [00JMC843].
R2

R2
R2

N N

1) LDA, THF -78

O

2)
2.2a: R1=Et
2.2b: R1=n-C6H13
2.2c: R1=i-Pr

R3

R2

R3

OLi

R1

-LiBt

COBt

R3

+
O

R3

2.5

2.4

2.3

R1

R1
O

2.6

Figure 2.4 Ring synthesis of substituted 3,4-dihydro-2-pyrones from Nacylbenzotriazoles.

Aryl isocyanates have been widely used for preparation of various heterocyclic
compounds[65JOC3247][78JOC3231][99JOC925]. Condensations of aryl isocyanates
2.7 with alkanoyl-, acetyl-, aroyl-, heterocyclic and cinnamoylbenzotriazoles led to a
diverse group of polycyclic heteroaromatic compounds[00JOC8069], namely quinolines,
pyrimidino[5,4,-c]quinolines, benz[b]-1,8-naphthyridines, phenanthridines, and
indolo[2,3,-b]quinolines (Figure 2.5).
N

N
N

O
R1

sealed tube
24h

polycyclic heteroaromatics
NHAr

2.7
R1=CH3
=CH2CH3
=1,3,3-trimethylbutyl
=acetoacetyl
=phenyl
=thiophenyl
=cinnamoyl

R2=H
=CH3
=OCH3

NHAr

e.g. quinolines (Ar= p-CH3C6H4)

Figure 2.5 Polycyclic heteroaromatics from N-acylbenzotriazoles

14
Schick and co-workers reported formation of di- and trisubstituted butyrolactones
2.9 by intramolecular cyclization of the organolithium intermediates 2.8, prepared by 1,2addition of lithium enolates of N-acylbenzotriazoles 2.2 to carbonyl
compounds[96LA881][02JOC3104] (Figure 2.6). This reaction was demonstrated for
nonbranched aliphatic (R1=Et, n-C6H13) and arylalkyl (R1=PhCH2) acylbenzotriazoles,
while aliphatic ketones and alkyl or (arylalkyl)aldehydes were used as carbonyl
components.

N N
N

R1

1) LDA or
n-BuLi/HMDS
O

2)
R1=Et

2.2a:
2.2b: R1=n-C6H13
2.2c: R1=i-Pr

R2

R2

-LiBt
Bt

R3
R3

Li

R2

O
O

R3

R1

R1

2.8

2.9

Figure 2.6 Formation of butyrolactones from N-acylbenzotriazoles

Figure 2.6 Formation of butyrolactones from N-acylbenzotriazoles
2.2.2 N-Acylbenzotriazoles as N-Acylating Reagents
The amide linkage underlies the properties of a vast array of organic molecules,
polymers, and materials. It contributes to the unique properties of amino acids, peptides,
-lactams, nucleosides, and alkaloids to name but a few. Common routes to primary,
secondary, and tertiary amides mostly involve the treatment of activated derivatives of
acids, especially acyl halides, acid anhydrides, or esters with ammonia or primary and
secondary amines [89MI1]. Limitations are associated with these methods. Acylations
of ammonia, primary and secondary amines by esters frequently require strongly basic
catalysts and/or high pressure, while reactions of ammonia or amines with acyl halides

15
are highly exothermic. Reactions with acid anhydrides easily form imides with ammonia
and primary amines.
Use of N-acylbenzotriazoles as the acylation reagent for N-acylation offers a clear
advantage over such methods. Treatment of N-acylbenzotriazoles with ammonia,
primary, and secondary amines provides a simple, mild, and general procedure for the
preparation of primary 2.10, secondary 2.11, and tertiary amides 2.12, respectively
[00JOC8210] (Figure2.7).
RCONH2
2.10

NH4OH
RCOBt1

R1NH2

RCONHR1
2.11

R2R3NH

RCONR2R3
2.12

Figure 2.7 Simple conversion of N-acylbenzotriazoles to amides

Preparation of unsymmetrical tetrasubstituted ureas have been the subject of much
attention and synthetic effort due to their applications which include uses as antioxidants
in gasoline, as additives in detergents to prevent carbon deposits, as plant growth
regulators, pesticides, herbicides, HIV-1 protease inhibitors, and other medicinal
preparations [85RCR249] [91AAC2209] [93JMC288]. Diverse unsymmetrical
tetrasubstituted ureas 2.14 were prepared by successive treatment of 1,1carbonylbisbenzotriazole 2.13 with secondary amines under mild conditions[97JOC4155]
(Figure 2.8), further illustrating N-acylbenzotriazoles as efficient N-acylating reagents.

16
O

N N
N

N N
N

N N

R1R2NH

BtH

2.13
R3R4NH

O
4

R N
3
R

R
R

BtH

2.14

Figure 2.8 General

of unsymmetrical
tetrasubstitutedtetrasubsituted
ureas
Figuresynthesis
2.8 General
synthesis of unsymmetrical
ureas
Reaction of 1,1-(1,2-dioxoethane-1,2-diyl)bis-1H-benzotriazole 2.15 with
secondary amines provides tetrasubstituted unsymmetrical oxamides 2.16 [98S153]
(Figure 2.9) which have potential application in the synthesis of -diketones[93TL571],
vicinal diamines[92SC1081], as ligands in organometallic complexes[91TMC92],
chelating agents [94CA9431], polymer additives[95CA314553], HIV-1 protease
inhibitors[96TL1153], Tumor Necrosis Factor inhibitors[94CA30551], and aldose
reductase inhibitors[92CA131072].
O
Bt

Bt
O
2.15

R1R2NH

O
1

R
2

Bt
N
O

R3R4NH

O
1

R
2

N R4

N
O
2.16

Figure 2.9 General synthesis of unsymmetrical tetrasubstituted oxamides

N-Acylation is an efficient method to protect amines. Simple amide derivatives are
usually of no value as protecting groups because the conditions required to remove them
are harsh. The trifluoroacetamide group is exceptionally labile to basic hydrolysis and
therefore useful in the protection of primary and secondary amines[56CB647]. It is
readily cleaved by potassium carbonate in aqueous methanol under conditions that
preserve simple methyl esters[88JOC3108][89JOC2498]. Conventional reagents for

17
trifluoroacetylation all have drawbacks or limitations. For example, trifluoroacetyl
triflate is extremely reactive[79JOC313][87JOC4156], N (trifluoroacetoxy)succinimide is
unstable and has to be stored as a benzene solution in a freezer[88JOC3108], and N(trifluoroacetyl)imidazole is highly moisture sensitive [60AG35]. Katritzky et al.
recently introduced a novel and facile trifluoroacetylating reagent for amines and
alcohols. Reaction of trifluoroacetic anydride with benzotriazole in dry THF provides in
almost quantitative yield (trifluoroacetyl) benzotriazole 2.17 [97JOC726] (Figure 2.10).
In a molecule with both primary amino and secondary amino groups, trifluoroacetylation
only occurred at the primary amino group. The 2-amino-2-phenylethanol molecule,
contains both an amino and a hydroxyl group and is selectively trifluoroacetylated at the
amino group. Thus, (trifluoroacetyl)benzotriazole is a convenient trifluoroacetylation
reagent due to its selectivity, facile preparation, easy handling, and stability.
N

N N
N

N
H

(CF3CO)2O

THF

room temperature

O
CF3

TFA

2.17

Figure 2.10 Trifluoroacetylated N-acylbenzotriazole as a novel protecting group

2.2.3 O-Acylation
Compounds containing the Bt-C-O functionality are versatile intermediates in
organic synthesis [98CR409]. Among such benzotriazole derivatives, 1-(benzotriazol-1yl) alkyl ethers 2.18 (Figure 2.11) have been widely used in the preparation of various
heterocycles[95JOC7612][95JOC7625], -functionalized ketones [95JOC7619]
[97JOC706], amides[88JOC5854], and ethers[89JOC6022] to name but a few. The
corresponding 1-(benzotriazol-1-yl) alkyl esters 2.19 should offer similar synthetic
opportunities. Initial routes to molecules of type 2.19 involved intermediates of low-

18
stability and extreme sensitivity to moisture[91S69]. Thus a more general and useful
synthesis of the 1-(benzotriazol-1-yl) alkyl esters was obtained by use of Nacylbenzotriazoles.
N N

N N
N

O R'

O
O

2.18

R'

2.19
R=H, alkyl, aryl
R'=Aryl, alkyl

Figure 2.11 Compounds with the Bt-C-O functionality

Katritzky and co-workers found that 1-(benzotriazol-1-yl) alkyl esters 2.19 can be
obtained from the direct reaction of the corresponding N-acylbenzotriazole derivatives
2.20 and an aldehyde in excellent yields. The best results are obtained when the reaction

is carried out in acetonitrile at a 0.3 M concentration in the presence of a catalytic amount

of base (Figure 2.12). The method is tolerant to base sensitive moieties such as halosubstituents, nitrile, or esters and is able to provide products unobtainable from
previously published methods. Thus N-acylbenzotriazoles are efficient O-acylating
reagents in their additions to aldehydes to give esters of type 2.19.
O
R

N N
N

K2CO3 (cat)
R'CHO

2.20

R'

MeCN
R

N N
N

2.19

Figure 2.12 Synthesis of 1-(benzotriazol-1-yl)alkyl esters by N-acylbenzotriazoles

2.2.4 C-Acylation
Carbon acylations are synthetically important and have been widely reviewed since
they provide a valuable entry to carbon-carbon bonds[73JOC514] [79MI1] [89OPP179].

19
Monocarbonyl compounds such as ketones and aldehydes and various carboxylic acid
derivatives, which contain alpha protons are converted to resonance-stabilized anions
2.21, generally known as enolate anions, in the presence of base. Metal enolates of

carbonyl compounds undergo reactions with a variety of hetero- and carbon-atom

electrophiles. Such reactions rank alongside addition reactions of carbanionic species to
carbonyl groups as the most important methods of carbon-carbon bond formation for
synthesis of complex systems. Metal enolates normally react with carbon electrophiles at
the alpha position to form products of type 2.22 (Figure 2.13). However, the C and O
modes of reaction may compete. Reactions with certain highly reactive electrophiles
may result in enol derivatives of type 2.23 as the exclusive product[73JOC514].
Versatile synthetic intermediates may be obtained by reactions involving enolate
anions and i) alkyl halides and related reagents (alkylation reactions) [79MI1], ii)
acylating reagents (Claisen and related reactions)[54OR59], iii) carbonyl groups of
aldehydes and ketones (Aldol and related 1,2-additions)[68OR1], iv) ,-unsaturated
carbonyl compounds (Michael and related 1,4-additions) [79MI1].

H acidic alpha H

O
R

H O
R

proton

base

R
electrophile

2.22

or

R
H

O E

R
H
2.23

2.21

Figure 2.13 Common reactions of carbonyl compounds containing an alpha proton

20
Carbon acylation of simple ketone enolates for the synthesis of 1,3-diketones and
1,3-ketoesters has been investigated using a wide variety of acylating reagents including
formates and oxalates[79MI1], acid chlorides[77TL1187], N-acylimidazoles[82LA1891],
methyl methoxymagnesium carbonate[59JA2598], and acyl
cyanides[83TL5425][98TL2249]. The C-acylation potential of 1-acylbenzotriazoles in
the regioselective preparation of -diketones has been examined by Katritzky et
al.[00JOC3679]. Reactions of alkyl and aryl N-acylbenzotriazoles with saturated cyclic
ketones, unsaturated cyclic ketones, and aliphatic ketones in the presence of lithium
diisopropylamide (LDA) and tetrahydrofuran (THF) at -78C resulted in C-acylated
products in excellent yields.
The C-acylation of other intermediates was explored with N-acylbenzotriazoles.
Enaminones 2.26 were obtained by acylation of metalated ketimines 2.25a-c (1eq.) with
LDA (2eq.) in THF at 0C, using N-acylbenzotriazoles 2.24a-f (1eq.) as acylating agents
[00S2029] (Figure 2.14). Enaminones are important synthetic intermediates for the
synthesis of carbazolequinone alkaloids [98JCS(P1)4115], tricyclic
benzo[a]quinolizines[98JOC4936], pyrroles[98TL8263], benzodiazepines[99H803],
isoxazoles[93H1617], and quinolines [93H2805].
O
Bt

2.24a-f
R1

a
b
c
d
e
f

Ph
t-Bu
p-MeOC6H4
p-MeC6H4
ClCH2
styryl

R
R

3
3

R N
2

2.26

2.25a-c
R2

R3

a i-Pr n-Bu
b Ph t-Bu
c c-Pr c-hexyl
Bt = benzotriazolyl

Figure 2.14 C-acylation of ketimines by N-acylbenzotriazoles for the synthesis of

enaminones

21
N-Acylbenzotriazoles have also recently been used in a convenient preparation of
aliphatic, aromatic, and heteroaromatic -keto sulfones 2.27[03JOC1443](Figure 2.15).
-Keto sulfones possess wide-spread synthetic applications as intermediates in the
synthesis of, among others, disubstituted acetylenes[84JA3670], olefins[95T9873],
allenes[95TL7925], vinyl sulfones[98TA2311], and polyfunctionalized 4Hpyrans[97JOC6575]. Reductive elimination of the sulfonyl group provides a nice entry
to ketones[85JOC3846][98T9791][00SC2564]. Some -keto sulfones exhibit fungicidal
activity[99JST113] while others are precursors for optically active -hydroxy sulfones
[01TA513] [99TA1369].
N N O

O
R'

R''

O R''

n-BuLi, THF
R

R'
-78 degrees

S
O

2.27

Figure 2.15 Conversion of sulfones into -keto sulfones by N-acylbenzotriazoles

2.2.5 Preparation of Other Intermediates
In addition to serving as excellent acylating reagents, N-acylbenzotriazoles are key
synthons for generating valuable intermediates. Wang and Zhang presented a facile
synthesis of 1,2-diketones by a samarium diiodide-promoted coupling of two Nacylbenzotriazole molecules [02TL5431]. Unlike acyl chlorides and keto cyanides, the
preparation of which is tedious [55OS112], requires high temperature or the use of toxic
cyanides, N-acylbenzotriazoles are stable crystalline solids, readily available from
carboxylic acids and N-(1-methanesulfonyl) benzotriazole. Thus use of the
benzotriazolyl auxiliary allows for mild reaction conditions as well as easily accessible
starting materials for the preparation of 1,2-diketones.

22
Elimination of benzotriazole from N-(arylacetyl)benzotriazoles under basic
conditions allows for the formation of arylketene intermediates which can subsequently
be used to provide other important intermediates. N-(Arylacetyl)benzotriazoles 2.28 on
treatment with sodium hydride in THF followed by hydrolysis with water gives the
symmetrical ketones 2.30 in good yields[96HAC365](Figure 2.16). The ketones 2.30 are
most likely formed by the intermediate ketenes dimerizing to 2.29, followed by addition
of water and loss of carbon dioxide[47JA2444].

N
N

R1R2CHCOCl

Et3N

NaH

N
1

THF

R
O

R2=H

2.27

O
R

R
H

H20

-CO2

O
1

2.29

R1
2.28

Figure 2.16 Synthesis of 1,3-diaralyacetones from N-(arylacetyl)benzotriazoles

Reactions of N-(arylacetyl)benzotriazoles with sodium sulfinates provide a novel
method for generating aryl benzyl sulfoxides 2.33 in high yields (70-90%). The reaction
mechanism involves arylketene intermediates 2.32 formed in the basic elimination of
benzotriazole from the N-(arylacetyl)benzotriazoles[96SL701](Figure 2.17).
O
N
N

weak base
heating

N
O

Ar

=C=O
2.32

Ar

ONa
Ar

Ar

2.33

Ar

2.31

Figure 2.16 Conversion of arenesulfinate anions into aryl benzyl sulfoxides

Figure 2.17 Conversion of arenesulfinate anions into aryl benzyl sulfoxides

23
It is clear that N-acylbenzotriazoles are versatile synthetic intermediates used as C-,
O-, and N-acylating agents as well as precursors to heterocycles and other valuable
synthetic targets. This chapter explores the synthesis of some aliphatic, aromatic, and
heteroaromatic N-acylbenzotriazoles.
2.3 Results and Discussion
Several synthetic methods for N-acylbenzotriazoles are available. Previous
preparations of acylbenzotriazoles have utilized acid chlorides by reaction with i) 1(trimethylsilyl) benzotriazole [80JOM141], ii) 1-(tributylstannyl) benzotriazole
[77JOM185], or iii) 1-(hydroxymethyl) benzotriazole[54JA285] which loses
formaldehyde. Katritzky et al. found that N-acylbenzotriazoles could be obtained in good
yields directly from benzotriazole and acid chloride without using any solvent [92T7817].
For example, 1-benzoyl-, 1-acetyl-, 1-propanoyl-, and 1-pentanoyl-benzotriazole were
prepared in 70-90% yields by an equimolar mixture of benzotriazole and the respective
acid chloride at 80-100C. An even better method utilizing the acid chloride involves
dissolving benzotriazole in dichloromethane at zero degrees followed by dropwise
addition of triethylamine and subsequent addition of the acid chloride. This procedure
allows the use of many different acid chlorides[99JHC777].
Compounds 2.34a (Table 2.1) and 2.34b were both prepared in 98% yield by this
improved method. Compound 2.34a was serendipitously discovered during earlier work
in the Katritzky group. It was found to be a side product formed from reaction of
di(benzotriazol-1-yl)-1-methoxy methane with trimethylacetyl chloride in lithium
diisopropamide at -78C. After its discovery a more practical procedure was found
which involved treatment of trimethylacetyl chloride and benzotriazole with sodium
hydrogen carbonate in tetrahydrofuran for five hours. This method provided yields

24
around 70%. We found that 1-(1H-1,2,3-benzotriazol-1-yl)-2,2-dimethyl-1-propanone
2.34a was more easily obtained in almost quantitative yield by reaction of benzotriazole

with the corresponding acid chloride and triethylamine according to a previously reported
procedure [99JHC777]. Similarly we found that previously unknown 4-fluorobenzoyl-1benzotriazole 2.34b could be obtained in high yields by treatment of the 4-fluorobenzoyl
chloride with benzotriazole and triethylamine followed by an acid-base work up
procedure. Presumably benzotriazole is deprotonated by triethylamine to form a reactive
species 2.35 which then reacts as a nucleophile towards the acyl halide to form the
expected product 2.34(Fig. 2.18).
N
N

N
-

Cl

..
N

O
N N
N

N N
R

OCl

N
R

2.34
a R= t-Bu
b R=4-fluorophenyl

Figure 2.18 Formation of N-acylbenzotriazoles

1-(Methanesulfonyl)benzotriazole 2.35 is a useful reagent for the conversion of
carboxylic acids into their corresponding 1-acylbenzotriazoles 2.34 and for the many
carboxylic acids of which the corresponding acid chlorides are unstable or difficult to
obtain such as the pyridinecarboxylic acids[92T7817]. This procedure involves heating
under reflux an equimolar mixture of the carboxylic acid and 1-(methanesulfonyl)

25
benzotriazole in tetrahydrofuran and in the presence of an equimolar amount of
triethylamine. Based on spectral data, 2-acylbenzotriazoles are not observed. The
mechanism for the formation of acylbenzotriazoles 2.34c-e from 1-methanesulfonyl
benzotriazoles and carboxylic acid is illustrated in Figure 2.19: the carboxylate (formed
in the presence of triethylamine) attacks the sulfur atom of 1-(methanesulfonyl)
benzotriazole followed by the departure of benzotriazole to give the intermediate 2.36.
Then the addition of benzotriazole anion to the carbonyl carbon and elimination of
methanesulfonate gives the final product 2.34.

O
O H

O
R

Bt------- S - - - - - - - o

O S O

O CH3

CH3

..
N

O
R

2.35

-Bt

+Bt
R

N
O

N N

Bt-

O SO2Me
2.36

2.34

Figure 2.19 Formation of N-acylbenzotriazole

Table 2.1 Synthesis of N-acylbenzotriazoles
______________________________________________________________
2.34
R
Yield (%)
______________________________________________________________
t-Bu
98
a
b
4-flurophenyl
98
c
2-furanyl
83
d
1-napthyl
98
e
4-pyridyl
84

26
In summary, we have shown that versatile N-acylbenzotriazoles can be prepared
under mild conditions in high yields for a variety of synthetic purposes.
2.4 Experimental Methods
General Methods
Melting points were determined using a Thomas Hoover capillary Melting Point
Apparatus and are uncorrected. 1H (300 MHz) and 13C (75 MHz) NMR spectra were
recorded on a Varian Gemini-300 spectrometer using deuteriochloroform as solvent with
tetramethylsilane (0 ppm) as the internal reference for 1H nmr and the central line of
deuteriochloroform (77 ppm) as the reference for 13C nmr. Tetrahydrofuran was distilled
under nitrogen immediately prior to use from sodium benzophenone ketyl. All reagents
were purchased from Aldrich and used without further purification.
General Procedure for the Preparation of N-Acylbenzotriazoles 2.34a-b
To a solution of benzotriazole (11.9 g, 0.1 mole) in anhydrous dichloromethane
(200ml) at 0C under nitrogen was added dropwise triethylamine (17 ml, 0.12 mole),
followed by addition of the corresponding acid chloride (0.11 mole). The resulting
mixture was stirred at room temperature for one-two hours. The reaction was quenched
at this temperature with hydrochloric acid (2 N, 100 ml), and the organic phase was
separated and then washed with hydrochloric acid (2 N, 2 x 50 ml) and water (50 ml)
successively. The organic extracts were dried over anhydrous magnesium sulfate,
filtered and evaporated to dryness to give a white powdery solid which was purified by
recrystallization.
1-(1H-1,2,3-Benzotriazol-1-yl)-2,2-dimethyl-1-propanone (2.34a)
This compound was obtained as white needles (98%), m.p. 64.0-66.0C
([99JHC777] mp 68-70C, 71%); 1H nmr (CDCl3): 1.65 (s, 9H), 7.47 (m, 1H), 7.61 (m,

27
1H), 8.10 (m, 1H), 8.32 (d, J = 8.3, 1H); 13C nmr (CDCl3): 27.6, 42.5, 115.0, 119.8,
125.9, 130.2, 132.2, 144.8, 159.6, 177.3
1-(1H-1,2,3-Benzotriazol-1-yl)(4-fluorophenyl)methanone (2.34b)
This compound was obtained as a white solid (98%), m.p. 108.0-110.0C; 1H nmr
(CDCl3): 8.33 (m, 3H), 8.20 (d, J = 8.20 Hz, 1H), 7.71 (t, J = 7.7 Hz, 1H), 7.56 (t, J =
7.6 Hz, 1H), 7.27 (t, J = 7.3 Hz, 2H); 13C nmr (CDCl3): 114.7, 115.6 (d, J = 22.4 Hz),
120.2, 126.3, 127.5, 130.4, 132.3, 134.5 (d, J = 9.1 Hz), 145.6, 164.3, 165.3, 167.7
Preparation of N-(1-Methanesulfonyl)benzotriaozole (2.35)
To an ice-cold solution of benzotriazole (11.9 g, 0.10 mol) and triethylamine (15.2
g, 0.15 mol) in dry toluene (120 mL) was added dropwise methylsulfonyl chloride (9.3
mL, 0.12 mol) in toluene (50 mL). The mixture was stirred overnight (15-20 hours) at
room temperature. Ethyl acetate (150 mL) and water (100 mL) were added. The organic
layer was separated, successively washed with water and brine, and dried over anhydrous
magnesium sulfate. Removal of solvents in vacuo gave a solid, which was recrystallized
from benzene or toluene to afford N-(1-methanesulfonyl)benzotriaozole (18 g, 89%) as
colorless needles: mp 109-111C.
General Procedure for the Preparation of N-Acylbenzotriazoles 2.34c-e
A mixture of aromatic or aliphatic acid (10.0 mmol) and 1(methylsulfonyl)benzotriazole (1.97 g, 10.0 mmol) and triethylamine (2.0 mL, 14.0
mmol) were refluxed in THF (50 ml) overnight (15-20 hours). The solvent was
evaporated and the residue was dissolved in chloroform (100 mL). The organic layer was
washed with water, dried over anhydrous magnesium sulfate, and evaporated to give a

28
crude product, which was recrystallized from an appropriate solvent to give pure N(arylcarbonyl)benzotriazole 2.34c-e.
1H-1,2,3-Benzotriazol-1-yl(2-furanyl)methanone (2.34c) yield 83%; off-white
powder (recrystallized from 4:1 hexane/ethyl acetate); mp 164.0-166.0 C ([00JOC8210]
mp 171-173, 92%); 1H nmr (CDCl3): 8.40 (d, J = 8.4 Hz, 1H), 8.14 (m, 2H), 7.88 (s,
1H), 7.66 (t, J = 7.7 Hz, 1H), 7.51 (t, J = 7.5 Hz, 1H), 6.72 (dd, J = 6.7 H, 6.7 Hz, 1H);
13

C nmr (CDCl3): 113.0, 114.6, 120.1, 124.7, 126.3, 130.4, 132.1, 144.5, 145.5, 148.9,

154.9
1H-(1,2,3)-Benzotriazoly-1-yl)(1-naphthyl)methanone (2.34d) yield 98%; lightbrown solid (recrystallized from benzene); mp 134.0-136.0 C ([00JOC8210] mp 136137 C, 88%); 1H nmr (CDCl3): 8.48 (d, J = 8.5 Hz, 1H), 8.10 (m, 3H), 7.93 (m, 2H),
7.73 (t, J = 7.75 Hz, 1H), 7.55 (m, 4H); 13C nmr (CDCl3): 114.6, 120.3, 124.3, 124.7,
126.4, 126.7, 127.9, 128.7, 129.3, 130.1, 130.5, 130.9, 132.0, 132.9, 133.6, 146.2, 167.6
1H-(1,2,3)-Benzotriazol-1-yl)(4-pyridyl)methanone (2.34e) yield 84%; off-white
solid (recrystallized from chloroform and hexanes); mp 144.0-146.0 C ([00JOC8210]
mp 149-151 C, 84%); 1H nmr (CDCl3): 8.91 (m, 2H), 8.37 (d, J = 8.4 Hz, 1H), 8.17
(d, J = 8.2 Hz, 1H), 8.02 (m, 2H), 7.72 (m, 1H), 7.57 (m, 1H); 13C nmr (CDCl3):
114.7, 120.5, 124.4, 126.9, 130.9, 131.8, 138.6, 145.8, 150.4, 165.3

CHAPTER 3
SYNTHESIS OF 2H-AZIRINES
3.1 Introduction
Azirines have attracted considerable attention in recent years. Interest in these
three-membered nitrogen containing heterocycles arises from the general influence of
ring strain upon chemical reactivity and the potential of their derivatives to act as
precursors to more elaborate molecules. Two isomeric azirines exist, namely 3.1 and 3.2
(Figure 3.1) designated by Chemical Abstract and The Ring Index as 1H-azirine and 2Hazirine, respectively. Alternate names such as 2-azirine for 1H-azirine and 1-azirine for
2H-azirine have been suggested in the literature. The structure, biological applications,
and the synthetic chemistry of these heterocycles have been explored since the mid-1960s
and a number of general reviews on azirines have appeared [83M1] [84CHEC47]
[91AG(E)238][02OPP219].
H
N

1H-azirine
(2-azirine)
3.1

2H-azirine
(1-azirine)
3.2

Figure 3.1 Structure of azirines

The 1H-azirine system represents a cyclic conjugated system with 4- electrons
and according to Huckels rule would not be predicted to be stabilized by electron
delocalization. Simple molecular orbital (MO) calculations on the parent 1H-azirine
systems shows DE 0.00 (N = C + 1.5; C-N = C-C)[68JA2875]. The

29

30
corresponding uncyclized enamine has DE 0.30, suggesting that cyclic conjugation
results in destabilization. Thus the 1H-azirine system has been classified as antiaromatic
[67JA4383][68AG(E)565] and only a limited amount of work has been completed on the
system. Consequently most work on azirines has been directed to the chemistry of 2Hazirines. Similarly, this presentation is focused on the synthesis and reactions of 2Hazirines. Throughout this presentation, the 2H-azirine ring system will be referred to as
such, as 1-azirine, or simply as the azirine.
Due to their high reactivity, 2H-azirines have been explored extensively for various
synthetic purposes[84CHEC47][83MI1]. The dimensions of 2H-azirines have been
determined by single crystal X-ray [91AG(E)238] [92HCA1866] [97EJC1757]
[00K303]. Most accounts report a considerable C-N bond lengthening and C-C bond
shortening when compared to normal open chain congeners and are consistent with
estimated bond lengths from theoretical calculations [87JPC6484][93JA11074]
[98JCU912]. The strain energy associated with these heterocycles is mainly due to
deformation of normal bond angle between the atoms of the ring and has been estimated
at about 48 kcal/mol[91AG(E)238].
Compared with an oxirane or thiirane which have strain energies estimated at
27kcal/mol and 34 kcal/mol respectively, it is clear that 2H-azirines are reactive
heterocycles capable of releasing a considerable amount of energy to drive chemical
processes. The N-lone pair of electrons on the azirine makes it an electron rich pyridinelike nitrogen capable of reactions with electrophiles. The combination of high ring
strain, a reactive -bond resulting from polarization of the C=N bond, and the lone pair

31
on the nitrogen atom allow for reactions where the azirine can act as a nucleophile,
electrophile, dienophile or dipolarophile in cycloaddition reactions.
Current synthetic strategies available for the construction of the three-membered
2H-azirine ring include: (i) intermolecular cycloaddition reactions between nitriles and
carbenes or nitrenes and acetylenes, (ii) ring-contraction of isoxazoles, and
oxazaphospholes, (iii) elimination and oxidation reactions on aziridines, (iv)
intramolecular reactions of N-functionalized imines and vinyl azides (Figure 3.2). All
these methods are discussed in the next section, and representative examples to illustrate
each procedure are mentioned.
LG
N
:N:

iv.

i.

N
N3

iv.

i.

iii.

NX

ii.

Y = C, P

Figure 3.2 Synthetic routes to 2H-azirines

3.2 Synthetic Strategies for 2h-Azirines
Although a few examples are known[97EJC1757], reactions of type (i) (Figure 3.2)
are not widely used as they lack generality and typically proceed with low yields
unsuitable for preparative applications. An example of such a reaction is the [1+2]
cycloaddition reaction between a phosphanylcarbene 3.3 and benzonitrile 3.4 which
affords the corresponding phosphorus-substituted 2H-azirine 3.5 in good yield (Figure

32
3.3)[95AG(E)1246]. However, in spite of its simplicity, no more examples of this
approach have been reported.
PR2
SiMe3

3.3

N
Ph

3.4

Ph

PR2
SiMe3

3.5
(85%)

Figure 3.3 Example of 2H-azirine formation by a nitrile and carbene

Rearrangement or ring contraction of five-membered rings such as isoxazoles,
triazoles, and oxazaphospholes provides an important entry to azirines (Figure 3.2,
route(ii)). Ring-contraction of isoxazoles, and oxazaphospholes has been reported in

numerous studies[66JA1844][67JA6911][70T453]. Thermal or photochemical treatment

of isoxazoles 3.6 produces ring contraction to acyl-2H-azirines 3.7, which sometimes
rearrange to form other heterocycles like oxazoles 3.8 [90JOC4011][90LA403](Figure
3.4). These transformations have proved to be reversible at high temperature or with a
change in the irradiation wavelength. Although the thermal rearrangement of isoxazoles
has produced several azirines with good yields[88TL6067], this synthesis is of limited
preparative value due to the high temperatures usually needed. Ring contraction from
isoxazoles to azirines can also be promoted by iron(II) catalysts. Thus, 5-alkoxy-and 5aminoisoxazoles isomerize to 2H-azirines-2-carboxylic esters and to 2H-azirine-2carboxamides, respectively, in nearly quantitative yield by reaction with FeCl2
[97T10911].
Thermally induced extrusion of phosphane oxide from 1,3,5- and 1,2,-5oxazaphosphole heterocycles also leads to 2H-azirines by ring contraction
[67TL917][79JOC3861][86AG99][86AG(E)85]. Electron-withdrawing substituents at

33
C4 in 1,2,5-oxazaphospholes 3.9 (Figure 3.5) favor formation of the corresponding
keteneimine rather than 2H-azirine 3.10 which is produced in low yields.
R

N
2

3.6

254 nm

3.8

254 nm or heat

N
2

O
R

O
1

R
R

3.7

Figure 3.4 Thermal or photochemical rearrangement of isoxazoles to 2H-azirines

PPh3

R 3 R2 R

heat

Ph3P O N

-Ph3PO
3

3.10

3.9

Figure 3.5 Ring-contraction of oxazaphospholes to 2H-azirines

Rearrangement or modification of three-membered rings, namely aziridines also
provides an entry to 1-azirines. N-Substituted aziridines 3.11 such as N-chloro
[88T4447], N-sulfonyl, N-sulfinyl, and N-acyl derivatives are prone to elimination when
treated with base to give 2H-azirines 3.12 (Figure 3.6). Pyrolysis, light-induced
[93CB2337], and fluoride-induced eliminations of aziridines to azirines are known.
3

R
H

NX

3.11

R
R

base

R
R

3.12

X= Cl, OSO2Ph, SOp-Tol, COPh

R= H, alkyl, aryl

Figure 3.6 Base-catalyzed elimination of aziridines

34
A variation to the elimination reactions is the oxidation of aziridine derivatives.
Zwanenburg et al. found they could obtain chiral azirine carboxylate esters 3.14 with the
Swern reagent (DMSO/(COCl)2/Et3N)[95TL4665]. Oxidation of either the trans-3.13 or
the cis-3.15 isomers afforded 2H-azirine carboxylate 3.14 where the integrity of the
stereogenic center at C-2 is retained (Figure 3.7).

1. DMSO/(COCl)2

R
N
H

CO2R

2. Et3N

N
R

1. DMSO/(COCl)2

H
CO2R

72-86%

2. Et3N
54-70%

3.14

trans-3.13

H
R N
H

CO2R

cis-3.15

Figure 3.7 Oxidation of aziridines to 2H-azirines

The thermal and/or photochemical treatment of vinyl azides can be used for the
construction of 2H-azirines[84MI1](route (iv), Figure 3.2). Smolinsky et al. reported the
first general synthesis of 1-azirines[61JA4483] by the vapor phase thermolysis of vinyl
azides 3.16 (Figure 3.8). They reported moderate yields (50-60%) of 2H-azirines along
with small amounts (5%) of keteneimines, presumably generated by migration of the -R
group of the azide onto the nitrogen atom through a Curtius type rearrangement.
N3

H
3.16

heat
R

H
R N

R = Ph
= o-CH3, C6H4
= n-C4H9

Figure 3.8 Synthesis of 2H-azirines by thermolysis of vinyl azides

The formation of 2H-azirines by thermolysis depends largely on the structure of the
vinyl azide[86JOC3176]. Vinyl azides substituted at the 1-position with aryl, alkoxy,

35
amine, or carboethoxy groups give stable azirines, while hydrogen or carbonyl
substituted afford nitriles or other heterocycles instead of the azirine ring. In some cases,
it is difficult to isolate the 2H-azirines after heating the vinyl azides because of the
thermal instability of the heterocycle. However, the photochemical reaction at low
temperature can in some instances lead to a more efficient synthesis of azirines.
Harvey and Ratts reported the first synthesis of 1-azirines through photolysis. They
obtained azirines 3.19 through photolysis of -azidocrotonates 3.18 which were prepared
by the addition of sodium azide in THF/H20 to the allenic ester 3.17 [66JOC3907](Figure
3.9). They subsequently reported the preparation of a number of 1-azirines[68JA2686].
H

CO2Et

NaN3

3.17

H 3C
N3

CO2Et
R

3.18

light

R
CO2Et

H3C

3.19

Figure 3.9 Photolysis of vinyl azides

The most widely accepted mechanism for photolysis and thermolysis involves the
concerted cyclization-elimination of N2 assisted by the -bond [86JOC3176]
[97JA10291] (route b, Figure 3.10). Formation of a transient vinylnitrene intermediate
(route a, Figure 3.10) by loss of molecular nitrogen from the thermally or photolytically
excited vinyl azide is also a possible mechanism[70MI1]. If the 1-azirine is formed from
singlet nitrene, then the conversion is a symmetry-allowed conrotatory electron
cyclization[69AG(E)797]. A third possible mechanism, involving the formation of a
triazole intermediate, which then loses N2, has also been considered (route c, Figure
3.10).

36

electrocyclic
closure

N:

-N2
..

+N N N :

N3

-N2

c
N

-N2

Figure 3.9 Pathways to azirines via vinyl azides

Figure 3.10 Pathways to azirines via vinyl azides
Intramolecular reactions of N-functionalized imines (route (iv), Figure 3.2)
constitute an important strategy in the synthesis of 2H-azirines. Neber and coworkers
described the first rearrangement of a ketoxime intermediate to an azirine. They found
that in the presence of tosyl chloride and pyridine, the oxime 3.20 is converted via 3.21
into aziridines 3.22, and 1-azirines 3.23 could then be prepared by treating 3.22 with
sodium carbonate [32LA281] [35LA283] (Figure3.11).
H
1

N
R

OH
R

N OTs

3.20

R
3.21

N
1

+N
3.22

NO2

R1 =
O2N

R2 =

N
2

CH3, Ph

H
R

3.23

Figure 3.11 Neber rearrangement of oximes to produce 2H-azirines

Modifications of their method described in Figure 3.11 have been developed in
recent years. Perhaps the most widely used modification involves the reaction of

37
quaternary hydrazonium salts with sodium isoproproxide in isopropanol. For example,
Parcell and then later Nair reported the synthesis of 2,2,-dimethyl-3-phenyl-2H-azirine
3.25 by treatment of isobutyrophenone N,N,N-trimethylhydrazonium iodide 3.24 with

base[63CI(L)1396][68JOC2121](Figure 3.12).
+
N
Ph

3.24

N(CH3)3ICH3
CH3

NaOCH(CH3)2
i-PrOH

Ph

CH3
CH3

3.25

Figure 3.12 Example of modified Neber reaction

Many others have also used this modified Neber reaction towards the synthesis of
substituted 2H-azirines[65JOC579][68BCJ1440][78JOC2029]. Sato et al. reported the
modified Neber reaction is affected by the type of hydrogen that is available on the carbon atom[68BCJ1440]. The reaction generally proceeds in high yields if the hydrogen is tertiary. This is probably related to the fact that the mechanism of the Neber
rearrangement involves the formation of a species resembling a vinylnitrene which
undergoes subsequent cyclization[63JOC2271]. The transition state leading to the azirine
ring would be expected to be lower in energy when the double bond is tetrasubstituted.
3.3 Benzotriazole Mediated Approach to 2h-Azirines
Although the modified Neber reaction is widely used, the traditional approach
starting with ketoxime tosylates like 3.21 is still a favorable and mild way to make 2Hazirines. Zwaneburg and co-workers utilized the traditional Neber reaction in an
asymmetric synthesis of 2H-azirine carboxylic esters[96JA8491]. They found that -keto
esters 3.26 are readily converted into the ketoxime tosylates 3.27 in a two-step procedure
in fair yields followed by treatment of 3.27 with triethylamine in dichloromethane to give

38
the desired azirines (Figure 3.13). This method is limited because the intermediate
ketoximes must be tosylated immediately after their preparation, as otherwise the
competing formation of isoxazolones takes place[70BSF2685][86JOC4037].
O

OR'

OTs

1) NH2OH.HCl, NaOH

2) p-TolSO2Cl, pyridine,CH2Cl2

OR'

3.26

3.27

Figure 3.13 Synthesis of ketoxime tosylates

The presence of electron-withdrawing groups at the -position to N-functionalized
imines seems to be a necessary functional group to facilitate formation of the azirine.
With this in mind, we decided to pursue the synthesis of 2H-azirines using the traditional
Neber approach with benzotriazole as a synthetic auxiliary. We have now developed a
mild and reproducible approach to substituted 2H-azirines utilizing benzotriazole
methodology. The presence of benzotriazole in this synthesis allows for deprotonation of
the methylene protons under mild reaction conditions. Furthermore, the presence of
benzotriazole as an electron-withdrawing group instead of an ester (as in 3.27) or other
base sensitive group allows for a wider variety of reaction conditions.
We envisioned a Neber-type reaction whereby 3.29 (Figure 3.14) served as the key
intermediate in the synthesis of the azirine ring. The presence of benzotriazole and an
aryl group makes the methylene protons doubly activated to proton loss.

N
R

Bt

3.28

OTs
Bt

3.29
R=aryl

Figure 3.14 Synthetic approach to 2H-azirines

OH
Bt

3.30

O
Bt

3.31

39
3.4 Results and Discussion
A post-doctoral researcher in the Katritzky group, Dr. Mingyi Wang, first began to
study how the azirine ring could be obtained from an intermediate of type 3.29. The key
starting material, substituted or unsubstituted -(benzotriazol-1-yl) acetophenone 3.31
was easily obtained by either method described below. 1-(Trimethylsilylmethyl) azoles
have been prepared by various methods and utilized for a range of synthetic
transformations[86JOC3897][86H240][87JCS(P1)769][87JOC844][80JOM141].
Multigram quantities of 1-(trimethylsilylmethyl) benzotriazole 3.32 (Figure 3.15) are
readily prepared by stirring the sodium salt of benzotriazole and
chloromethyltrimethylsilane in dimethylformamide at room temperature for
approximately 24 hours. Some of the corresponding 2-(trimethylsilylmethyl)
benzotriazole is also formed, but it is an oil and stays in solution. Katritzky et al. found
that desilylation of 3.32 can be effected by treatment with acyl halides to afford ketones
of type 3.31 in yields of about 70% or greater[90HAC21]. Thus, this silicon-containing
N-substituent allows for successful introduction of acyl groups at the -position to the

benzotriazole ring.

40
N

N
N

Cl

Si

DMF

N
N

Na

Si

3.32
RCOCl
THF
reflux

O
3.31
R=H
R=Cl
R=CH3

Figure 3.15 Synthesis of N-acylmethylbenzotriazoles

In the absence of any added base in refluxing toluene or benzene, benzotriazole
replaces the halogen atom of an -halogenated ketone or a carboxylic ester to give the
corresponding N-1-substituted benzotriazole 3.31 as the only isomer[94S597]. The
regiospecific or regioselective alkylation reactions of benzotriazole in the absence of base
can be explained as follows. In dilute solutions, benzotriazole exists completely in the
1H-tautomeric form[51JA4360]. Furthermore, in nonpolar solvents like benzene and
toluene, benzotriazole is largely associated into dimers and higher conglomerates
[42JCS420][55JPC1044]. Thus, a model of dimer 3.33 (Figure 3.16) bonded by
intermolecular hydrogen-bonding can be constructed. It is believed that when a carbonyl
group is present in a suitable position in the halide, formation of hydrogen-bonding
between the dimer 3.33 and the substrate, as indicated by 3.34, along with the high
nucleophilicity of the 1-N position enhances the selectivity for formation of only the N-1substituted benzotriazole derivative. Thus a mixture of -chloroacetophenone and

41
benzotriazole can be refluxed under nitrogen gas in toluene or benzene for 24 hours to
provide compounds of type 3.31. For our purposes, use of (1-trimethylsilylmethyl)
benzotriazole was the preferred method while -chloroketones were used only in the
absence of the silicon-containing intermediate.
N
N --- H
N

N
H --- N

N
N --- H
N

H --- N
3.33

X
3.34

Figure 3.16 Acylation of benzotriazole

The precursor 3.30, easily obtained from reaction of 3.31 with hydroxylamine
hydrochloride in ethanol and 10 % sodium hydroxide, provided oximes as single isomers
in good yields (Figure 3.17). Compound 3.30a was previously prepared in the Katritzky
group while I and a fellow graduate student, Ms. Hongfang Yang, prepared 3.30b for the
first time. Additionally, I prepared the previously unknown compound 3.30c.
With the crystalline benzotriazole-substituted oximes in hand, Dr. Wang first
attempted to prepare oxime tosylates of type 3.29 for further reaction with a suitable base
to obtain the azirine. All efforts to obtain this compound with a reproducible procedure
and satisfactory yields failed. Synthesis of the azirine ring was then attempted by
preparation of 3.29 in situ from the benzotriazole-substituted oxime.

42

R
Bt
O

HO

NH2OH.HCl
10%NaOH
EtOH
reflux

N
Bt

3.31a-c
a, R=H
b, R=Cl
c, R=CH3

3.30a-c

Figure 3.17 Synthesis of benzotriazole-substituted oximes

We developed a reproducible, one-pot procedure which provided benzotriazolesubstituted 2H- azirines in good yields (Figure 3.18). Crystalline oximes 3.30a-c were
dissolved in a 4:1 mixture of chloroform and anhydrous diethyl ether at 0C followed by
10 equivalents of a 10% aqueous KOH solution and a catalytic amount of tetra-nbutylammonium hydrogen sulfate (as a phase transfer catalyst). The mixture was stirred
for about 30 minutes to one hour followed by dropwise addition of a tosyl chloride
solution in ether. While maintaining the reaction temperature at 0C-5 C for 5-6 hours,
the color of the reaction changed from clear to light-yellow to dark red/burgundy. Upon
observation by thin-layer chromatography that all starting oxime 3.30a-c was consumed,
the reaction was quenched. The concentration and amount of aqueous KOH and the
reaction time significantly affected product yields. Optimal conditions were found to be
10 equivalents of 10% KOH and 5-6 hours of reaction time at 0C thus to avoid isolation
of oxime tosylates 3.32a-c.

43

HO

TsO
N

1) 10 eq. 10%KOH, diethyl ether, chloroform

(tetra-n-butylammonium sulfate)

Bt

2) tosyl chloride, diethyl ether

0 deg. Celsius, 5-6h

Bt
R

3.32a-c

3.30a-c

N
Bt
R

3.28a-c

Figure 3.18 Synthesis of benzotriazole-substituted 2H-azirines

The benzotriazole-substituted 2H-azirines 3.28a-c (Table 3.1) were isolated after
column chromatography in yields of 60, 58, and 66%. Carbon-13 NMR spectra of 3.28ac displayed the expected signals characteristic of benzotriazolyl at ca. 146 and 110

ppm, and of the sp3 carbon (C-2) and the sp2 carbon (C-3) of the 2H-azirine ring at ca.
42 and 164, respectively.
With the desired azirines in hand, we proceeded to test the reactivity of the
compounds, especially toward nucleophilic attack. Displacements of benzotriazole by
nucleophiles have been reviewed[94S445]. Most documented reactions of 2H- azirines
with nucleophiles involve nucleophilic addition to the imine bond [84CHEC47]
[99JCS(P1)1305][00SL1843] to produce aziridines instead of retaining the structure of
the azirine. Additionally, no previous nucleophilic replacement of a 3-substituent of 2Hazirines with a C-nucleophile has been reported. Reported successful halide

44
displacements of 2-halo-2H-azirines with nucleophiles have all involved an additional
electron-withdrawing group, e.g. carboxylate, at the 2-position[00TL7217].
We studied the reactivity of 2-(benzotriazol-1-yl)-2H-azirines using organometallic
reagents, phthalimide anion, and sodium benzenethiol as nucleophiles. Treatment of 2(benzotriazol-1-yl)-2H-azirine 3.28a-c with benzylmagnesium chloride or 4methylbenzylmagnesium chloride in the presence of zinc chloride gave the desired
products 3.35a-f in moderate to good yields (Figure 3.19, Table 3.1). Except for 3.35a-f,
no other products were observed in each case.
Compared with 2H-azirines 3.28a-c, the 13C NMR spectra of 3.35a-f revealed the
disappearance of benzotriazole moiety signals, and the appearance of signals
characteristic of benzyl at ca. 33.233.6. The spectral data of 3.35a are also consistent
with that reported[00EJO257]. In the presence of zinc chloride, unfortunately, reactions
of 3.28a-c with other Grignard reagents, both aryl (e.g. phenyl, p-chlorophenyl, p-tolyl)
and alkyl (e.g. phenylethyl, pentyl) failed. In some cases, the reactions did not proceed,
but allowed the recovery of the starting 2-(benzotriazol-1-yl)-2H-azirines. In other cases,
the disappearance of the starting 2-(benzotriazol-1-yl)-2H-azirines resulted in a
complicated mixture.
Following a literature procedure[02JOC66], treatment of 2-(benzotriazol-1-yl)-2Hazirines 3.28a-c with potassium phthalimide and sodium benzenethiol at room
temperature in DMF led to the synthesis of novel 2H-azirine derivatives 3.35a-c and
3.36a in good yields (Figure 3.19, Table 3.1).

45
Table 3.1 2H-azirines 3.28 and their derivatives 3.35, 336, and 3.37
Yield Mp (oC) 13C NMR
Entry R
R'
(%)
3.28a

Ph

60

99-100

42.6 (C-2)

164.6 (C-3)

3.28b

4-ClC6H4

58

158-160

42.4 (C-2)

163.8 (C-3)

3.28c

4-MeC6H4

66

101-102

42.6 (C-2)

164.1 (C-3)

3.35a

Ph

C6H5CH2

66

Oil

40.1 (C-2)

171.6 (C-3)

3.35b

Ph

4-MeC6H4CH2

53

Oil

39.7 (C-2)

171.3 (C-3)

3.35c

4-ClC6H4

C6H5CH2

44

Oil

40.0 (C-2)

170.9 (C-3)

3.35d

4-ClC6H4

4-MeC6H4CH2

66

93-95

39.6 (C-2)

171.0 (C-3)

3.35e

4-MeC6H4

C6H5CH2

71

oil

40.2 (C-2)

171.1 (C-3)

3.35f

4-MeC6H4

4-MeC6H4CH2

50

oil

39.9 (C-2)

171.3 (C-3)

3.36a

Ph

Phthalimido

71

139-140

35.6 (C-2)

165.3 (C-3)

3.36b

4-ClC6H4

Phthalimido

57

182.5184.5

35.7 (C-2)

164.7 (C-3)

3.36c

4-MeC6H4

Phthalimido

79

145-146

35.5 (C-2)

164.8(C-3)

3.37a

Ph

PhS

60

oil

37.6 (C-2)

166.4 (C-3)

3.3 Conclusion
We have developed a methodology for the synthesis of 2-(benzotriazol-1-yl)-2Hazirines under mild conditions, and have disclosed the first example of nucleophilic
substitution reactions of 2H-azirines with organometallic reagents. Novel 2H-azirine
derivatives were thus obtained.

46
C6H4CH2MgBr or
CH3C6H4CH2MgBr

N
R

R'

R
3.35a-f

NaSPh

Bt
3.28a-c

DMF

3.37a

Potassium phthalimide
DMF
N

R
3.36a-c

Figure 3.19 Substitution of benzotriazole in 2H-azirines

3.4 Experimental Methods
Melting points were determined on a MEL-TEMP capillary melting point apparatus
equipped with a Fluke 51 digital thermometer. NMR spectra were taken in CDCl3 (unless
stated otherwise) with tetramethylsilane as the internal standard for 1H (300 MHz) or a
solvent as the internal standard for 13C (75MHz). All anhydrous solvents were distilled
from sodium under nitrogen immediately prior to use. All reactions with air-sensitive
compounds were carried out under an argon or nitrogen atmosphere.
General Procedure for the Oximes 3.30a-c
To a solution of hydroxylamine hydrochloride (30 mmol) in water (50 mL), was
added a solution of benzotriazolylmethylketones 3.31a-c (15 mmol) in ethanol (50 mL)
followed by dropwise addition of 10% NaOH (30 mmol) solution at room temperature.
After addition, the yellow or off-white colored mixture was stirred under reflux
overnight. Upon cooling to room temperature, white crystals of the product formed and
were collected by filtration with no further purification necessary.

47
2-(1H-1,2,3-Benzotriazol-1-yl)-1-(4-chlorophenyl)-1-ethanoneoxime (3.30b)
White needles (91%), mp 226227 C; 1H NMR (DMSO-d6) 12.33 (s, 1H), 8.01 (d,
J = 8.2 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.58 (dd, J = 7.8, 7.0

Hz, 1H), 7.437.37 (m, 3H), 6.10 (s, 2H); 13C NMR (DMSO-d6) 149.9, 144.8, 134.0,
132.8, 128.4, 128.0, 127.4, 124.0, 119.1, 110.4, 41.0. Anal. Calcd for C15H14N4O: C,
67.65; H, 5.31; N, 21.04. Found: C, 67.43; H, 5.47; N, 21.02.
2-(1H-1,2,3-Benzotriazol-1-yl)-1-(4-methylphenyl)-1-ethanoneoxime (3.30c)
White microcrystals (92%), mp 185188 oC; 1H NMR (DMSO-d6) 12.11 (s, 1H),
7.99 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.627.53 (m, 3H), 7.37 (dd, J = 8.0,
7.3 Hz, 1H), 7.12 (d, J = 8.0 Hz, 2H), 6.07 (s, 2H), 2.24 (s, 3H); 13C NMR (DMSO-d6)
150.6, 144.9, 138.8, 132.8, 131.1, 128.9, 127.4, 126.2, 124.0, 119.1, 110.4, 41.0, 20.7.
Anal. Calcd for C14H11ClN4O: C, 58.65; H, 3.87; N, 19.54. Found: C, 58.47; H, 3.92; N,
19.49.
General procedure for 2-(benzotriazol-1-yl)-2H-azirines 3.28b-c.
To a solution of oxime (20 mmol) in a mixture of ethyl ether (150 mL) and
chloroform (50 mL), was added dropwise aqueous KOH (11.2 g KOH dissolved in 50
mL of water) at 0 oC. After the addition of the base solution, the mixture was stirred
vigorously at this temperature for 30 min, and then a catalytic amount of Bu4NHSO4 was
added. A solution of p-toluenesulfonyl chloride (TsCl) in Et2O (50 mL) was added
dropwise at 0 oC. After this addition, the final mixture was stirred at 05 oC for 6h until
the solid reactants disappeared. The reaction mixture was transferred into a separatory
funnel and extracted with ethyl ether. The combined organic layer was washed with water

48
and dried over MgSO4. The residue on removal of solvents was purified by column
(hexane-ethyl acetate) to give the desired products 3.28a-c.
1-[3-(4-Chlorophenyl)-2H-aziren-2-yl]-1H-1,2,3-benzotriazole (3.28b)
Yellow prism (58%), mp 158160 C; 1H NMR 8.10 (d, J = 8.5 Hz, 2H), 8.06 (d,
J = 8.7 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.5 Hz, 2H), 7.52 (t, J = 7.6 Hz,

1H), 7.39 (dd, J = 8.0, 7.3 Hz, 1H), 5.17 (s, 1H); 13C NMR 163.8, 146.2, 140.9, 132.9,
131.7, 130.0, 127.9, 124.3, 121.6, 120.2, 109.7, 42.4. Anal. Calcd for C14H9ClN4: C,
62.58; H, 3.38; N, 20.85. Found: C, 62.81; H, 3.34; N, 20.84.
1-[3-(4-Methylphenyl)-2H-aziren-2-yl]-1H-1,2,3-benzotriazole (3.28c)
Yellow microcrystals (66%), mp 101102 C; 1H NMR 8.078.02 (m, 3H), 7.69
(d, J = 8.2 Hz, 1H), 7.507.44 (m, 3H), 7.37 (dd, J = 7.8, 7.4 Hz, 1H), 5.18 (s, 1H), 2.5
(s, 3H). 13C NMR 164.1, 146.1, 145.6, 132.8, 130.6, 130.2, 127.7, 124.2, 120.3, 120.1,
109.9, 42.6, 22.0. Anal. Calcd for C15H12N4: C, 72.56; H, 4.87; N, 22.57. Found: C,
72.63; H, 4.96; N, 24.46.
General procedure for 2H-azirine 3.35a-d.
Under N2, activated Mg powder (2 mmol) was added into a dried two-necked flask
equipped with a condenser and magnetic stirrer. Then 5 mL of Et2O was added. With the
starting of the stirrer, 34 drops of a solution of the bromide (2 mmol) in 5 mL of Et2O
was added by syringe, and several minutes later, the remaining bromide solution was
added dropwise. The mixture was heated and refluxed slowly for 1h. Upon cooling to 18
o

C (ice-salt bath), ZnCl2 solution (1.0 M, 2.0 mL) was added, and 3040 minutes later, a

solution of starting material (0.5 mmol) in 5 mL of toluene was added at this temperature.
After these additions, the final mixture was stirred at 18 oC to room temperature

49
overnight (around 24 h). TLC showed almost no starting material. The reaction was
quenched with water, and the reaction mixture was diluted with Et2O, washed with water,
and dried over MgSO4. The residue on removal of solvents was purified by column
(hexane-ethyl acetate) to give the desired products 3.35a-f.
2-Benzyl-3-phenyl-2H-azirine (3.35a)
Oil (70%);14 1H NMR 7.777.75 (m, 2H), 7.557.47 (m, 3H), 7.317.21 (m, 5H),
3.06 (dd, J =14.6, 5.1, 1H), 2.76 (dd, J = 14.6, 5.1 Hz, 1H), 2.51 (t, J = 5.1 Hz, 1H); 13C
NMR 171.6, 139.3, 132.8, 129.3, 129.0, 128.9, 128.5, 126.3, 125.5, 40.1, 33.2.
2-(4-Methylbenzyl)-3-phenyl-2H-azirine (3.35b)
Oil (70%); 1H NMR 7.867.83 (m, 2H), 7.657.55 (m, 3H), 7.25 (d, J = 8.0 Hz,
2H), 7.18 (d, J = 8.0 Hz, 2H), 3.08 (dd, J = 14.6 4.9 Hz, 1H), 2.77 (dd, J = 14.6, 5.3 Hz,
1H), 2.55 (t, J = 5.1 Hz, 1H), 2.40 (s, 3H); 13C NMR 171.7, 136.2, 135.8, 132.8, 129.4,
129.2, 129.0, 128.8, 125.6, 39.7, 33.4, 21.0. Anal. Calcd for C16 H15N: C, 86.84; H, 6.83;
N, 6.33. Found: C, 86.53; H, 7.24; N, 6.20.
2-[3-(4-Chlorophenyl)-2H-aziren-2-yl]-1H-isoindole-1,3(2H)-dione (3.36b)
Yellow needles (57%), mp 182.5184.5 C; 1H NMR 8.03 (d, J = 8.4 Hz, 2H),
7.857.81 (m, 2H), 7.757.72 (m, 2H), 7.60 (d, J = 8.4 Hz, 2H), 4.27 (s, 1H). 13C NMR
167.9, 164.7, 139.9, 134.4, 131.8, 131.5, 129.5, 123.5, 123.3, 35.7. HRMS (FAB) Calcd
for C16H9N2O2 [M+]: 296.0353. Found: 296.0351.

CHAPTER 4
CONCLUSIONS
An exploration of the synthetic utility of benzotriazole was undertaken.
Benzotriazole is readily introduced into molecules, influences reactivity and selectivity in
many reactions, and is easily removed from molecules. Our extensive use of
benzotriazole-substituted molecules as versatile synthetic auxiliaries led us to synthesize
some useful N-acylbenzotriazoles and novel 2H-azirines.
Diverse N-acylbenzotriazoles were prepared using different procedures. The
presence of benzotriazole does not limit, but in fact expands the variety of reaction
conditions available for the synthesis of important organic intermediates. NAcylbenzotriazoles are valuable intermediates in the synthesis of heterocycles, other
intermediates, N-, C-, and O-acylated products.
A general, reproducible method for the synthesis of benzotriazole-substituted 2Hazirines has been developed starting from N-acylmethylbenzotriazoles. Nucleophilic
displacement of benzotriazole by diverse nucleophiles, namely carbon, nitrogen and
sulfur was achieved.

50

LIST OF REFERENCES
The reference citation system employed throughout this thesis is that from
Comprehensive Heterocyclic Chemistry II (vol.1) Pergamon Press, 1996 (Eds. Katritzky,

A.R.; Rees, C.W. and Scriven, E.)

Each time a reference is cited, a number and letter code appear in brackets, for
example [03ABC000]. The first two digits denote the year of the twentieth century, the
letter code is an abbreviation for the journal or book cited and the last digits represent the
page number. Additional notes to this reference system are as follows:
(ii)

References are listed consecutively by year, alphabetically by the journal code

and then by page number.

(iii)

Each reference code is followed by the conventional literature citation complete

with the name of the authors.

(iv)

Journals which are published in more than one part, or more than one volume per
year, include in the abbreviation cited the appropriate part or volume number.

(v)

Books and journals which are less commonly used are called MI for
miscellaneous.

[1895JA449]

Mixter, W.G. J. Am. Chem. Soc. 1895, 17, 449

[32LA281]

Neber, P.W.; Burgard, A. Liebigs Ann. Chem. 1932, 493, 281

51

52
[35LA283]

Neber, P.W.; Huh, G. Liebigs Ann. Chem. 1935, 515, 283

[47JA2444]

Sauer, J.C. J. Am. Chem. Soc. 1947, 69, 2444

[54JA285]

Gaylord, N. J. Am. Chem. Soc. 1954, 76, 285.

[54OR59]

Houser, C.R.; Swamer, F.W.; Adams, J.T. Org. React. 1954, 8, 59

[55OS112]

Oakwood, T.S.; Weisberger, C.A. Org. Synth. 1955, 3, 112

[56CB647]

Weygand, F.; Geiger, R.Chem. Ber. 1956, 89, 647

[57JOC1022]

Gaylord, N.; Naughton J.M. J. Org. Chem. 1957, 22, 1022.

[59JA2598]

Stiles, M. J. Am. Chem. Soc. 1959, 81, 2598

[61JA4483]

Smolinsky, G. J. Am. Chem. Soc. 1961, 83, 4483

[62AG(E)351]

Staab, H.A. Angew. Chem. Int. Ed. Eng. 1962, 1, 351

[63CI(L)1396]

Parcell, R. F. Chem. Ind. (London) 1963, 1396

[63JOC2271]

House, H.O.; Berkowitz, W. F. J. Org. Chem. 1963, 28, 2271

[65JOC579]

Morrow, D.F.; Butler, M.E.; Huang, E.C.Y. J. Org.Chem. 1965,

30, 579

[65JOC3247]

Sheehan, J.C.; Daves, G.D., Jr. J. Org. Chem. 1965, 30, 3247

[66JA1844]

Ullman, E.F.; Singh, B. J. Am. Chem. Soc. 1972, 94, 1199

[66JOC3907]

Harvey, G.R.; Ratts, K.W. J. Org. Chem. 1966, 31, 3907

[67JA4383]

Breslow, R., Brown, J., and Gajewski, J.J. 1967, J. Am.Chem. Soc.,
89, 4383

[67JA6911]

Singh, B.; Ullman, E.F.; J. Am. Chem. Soc. 1967, 89, 6911

[68AG(E)565]

Breslow, R. Angew. Chem. Int. Ed. Engl. 1968, 7, 565

[68BCJ1440]

Sato, S. Bull. Chem. Soc. Jpn. 1968, 41, 1440

[68JA2686]

Hassner, A.; Fowler, F.W. J. Org. Chem. 1968, 33, 2686

[68JA2875]

Fowler, F.W., Hassner, A. J. Am. Chem. Soc. 1968 90, 2875

[68JOC2121]

Nair, V. J. Org. Chem. 1968, 33, 2121

[69CR693]

Mallan, J.M.; Bebb, R. L. Chem. Rev. 1969, 69, 693.

53
[70BSF2685]

Jacquier, R.; Petrus, C.; Petrus, F.; Verducci, J. Bull. Soc. Chim.
Fr. 1970, 7, 2685

[70T453]

Nishiwaki, T.; Kitimura, T.; Nakano, A. Tetrahedron 1970, 26,

453

[72BCJ515]

Tsujimoto, K.; Ohashi, M.; Yonezawa, T. Bull. Chem. Soc. Jpn.

1972, 45, 515

[73JOC514]

House, H.O.; Auerbach, R.A.; Gall, M.; Peet, N.P. J. Org. Chem.
1973, 38, 514

[76EJB25]

Reboud-Ravaux, M.; Ghelis, C. Eur. J. Biochem. 1976, 65, 25

[77JOM185]

Gassend, R.; Maire, J.C.; Pommier, C. J. Organometallic Chem.

1977, 137, 185

[78JOC2029]

Padwa, A.; Carlsen, P.H.J. J. Org. Chem. 1978, 43, 2029

[78JOC3231]

Ohtsukay, Y. J. Org. Chem. 1978, 43, 3231

[79JOC313]

Forbus, T.R., Jr.; Martin, J.C. J. Org. Chem. 1987, 52, 4156

[79JOC3861]

Hassner, A.; Alexanian, V. J. Org. Chem. 1979, 44, 3861

[79JPS(A)277]

Ferruti, P.; Tanzi, M.C.; Vaccaroni, F.J. J. Polym. Sci., Polym.

Chem. Ed. 1979, 17, 277

[79LA1756]

Walter, W.; Radke, M.; Liebigs Ann. Chem. 1979, 11, 1872

[79MI1]

Caine, D. In Carbon-Carbon Bond Formation; Augustine, R.L.,

Ed.; Marcel Dekker: New York, 1979, p. 250

[80BCJ1638]

Keumi, T.; Saga, H.; Kitajima, H.; Bull. Chem. Soc. Jpn. 1980, 53,
1638

[80JOM141]

Gasparani, J.P.; Gassend, R. J. Organometallic Chem. 1980, 188,

141

[82LA1891]

Sucrow, W.; Brockmann, R.; Liebigs Ann. Chem. 1982, 1891

[83MI1]

Nair, V. In Heterocyclic Compounds; Hassner, A.; Ed.; John Wiley

and Sons: New York, 1983; Vol.42, Part 1, p.215-332

[83S327]

Butula, I.; Zorc, B.; Ljubic, M.; Karlovic, G. Synthesis, 1983, 327

[83TL5425]

Mander, L.N.; Sethi, S.P. Tetrahedron Lett. 1998, 39, 5425

54
[84CHEC47]

Padwa, A.; Woolhouse, A.D. In Comprehensive Heterocyclic

Chemistry; Katritzky, A.R.; Rees, C.W., Eds.; Pergamon Press:
Oxford, 1984; Vol.7, p.47-93

[85JOC3846]

Kurth, M.J.; OBrien, M.J.; J. Org. Chem. 1985, 50, 3846

[85RCR249]

Vishnyakova, T.P.; Golubeva, I.A.; Slebova, E.V. Russ. Chem.

Rev. (Engl. Transl.) 1985, 54, 249

[86H240]

Tsuge, O.; Matsuda, K.; Kanemasa, S. Heterocycles, 1986, 24, 240

[86JOC3176]

Hassner, A.; Wiegand, N.H.; Gottlieb, H.E. J. Org. Chem. 1986,

51, 3176

[86JOC3897]

Shimizu, S.; Ogata, M. J. Org. Chem. 1986, 51, 3897

[86JOC4037]

Katritzky, A.R.; Barczynski, P.; Ostercamp, D.L.; Yousuf, T.I. J.

Org. Chem. 1986, 51, 4037

[86JOU86]

Borovikova, G.S.; Levchenko, E.S.; Kaniskaya, E.T. J. Org. Chem.

USSR Engl. Trans. 1986, 22, 86

[87JCS(P1)769]

Katritzky, A.R.; Vazquez de Miguel, L.M.; Aurrecoechea, J.M. J.

Chem. Soc. Perkin Trans. 1 1987, 769

[87JCS(P1)781]

Katritzky, A.R. J. Chem. Soc. Perkin. Trans. 1 1987, 781.

[87JCS(P1)791]

Katritzky, A.R. J. Chem. Soc. Perkin. Trans. 1 1987, 791.

[87JCS(P1)799]

Katritzky, A. R.; Rachwal, S.; Rachwal, B. J. Chem. Soc. Perkin.

Trans. 1 1987, 799

[87JOC844]

Katritzky, A.R.; Kuzmierkiewicz, W.; Aurrecoechea, J.M. J. Org.

Chem. 1987, 52, 844

[87JPC6484]

Mo, O., de Pay, J.L.G., Yanez, M., J. Phys. Chem., 1987, 91, 6484

[88JOC3108]

Bergeron, R.J.; McManis, J.S. J. Org. Chem. 1997, 62, 726

[88JOC5854]

Katritzky, A.R.; Drewniak, M.; Lue, P. J. Org. Chem. 1989, 54,

5854

[88T4447]

Guillemin, J.C.; Dennis, J.-M.; Lasne, M.-C.; Ripoll, J.-L.

Tetrahedron 1988, 44, 4447

[88TL6067]

Lipshutz, B.H.; Reuter, D.C. Tetrahedron Lett 1988, 29, 6067

[89JOC6022]

Katritzky, A.R.; Rachwal, S.; Rachwal, B. J. Org. Chem. 1989, 54,

6022.

55
[89MI1]

Vogel, A. Practical Organic Chemistry: Langman Scientific &

Technical and Wiley: New York, 1989; p. 708

[89OPP179]

Black, T.H. Org. Prep. Proced. Int. 1989, 21, 179

[90HAC21]

Katritzky, A.R.; Lam, J.N. Heteroatom Chemistry, 1990, 21

[90JOC4011]

Sauers, R.R.; Hadel, L.M. J. Org. Chem. 1990, 55, 4011

[90LA403]

Himbert, G.; Kuhn, H.; Barz, M. Liebigs Ann. Chem. 1990, 403

[91AAC2209]

Kempf, D.J.; Marsh, K.C.; Paul, D.A. J. Antimicrob. Agent.

Chemother. 1991, 35, 2209

[91AG(E)238]

Heimgartner, H., Angew. Chem. Int. Ed. Engl., 30, 238 (1991)

[91AG(E)1278]

Hirschmann, R. Angew. Chem., Int. Ed. Engl. 1991, 30, 1278.

[91RTC369]

Katritzky, A.R.; Kuzmierkiewicz, W.; Greenhill, J.V. Recl. Trav.

Chim. Pays-Bas 1991, 369

[91S69]

Katritzky, A.R.; Rachwal, S.; Rachwal, B. Synthesis, 1991, 69

[91S279]

Katritzky, A.R.; Bayyuk, S.I.; Rachwal, S. Synthesis 1991, 279

[91T2683]

Katritzky, A.R.; Rachwal, S.; Hitchings, G.J. Tetrahedron 1991,

47, 2683.

[91TMC92]

Quaeyhaegens, F.J.; Desseyn, H.O. Transition Met. Chem. 1991,

16, 92

[92CA131072]

Britain, D.R.; Brown, S.P.; Cooper, A.L. Chem. Abstr. , 1992, 117,
131072

[92HCA1866]

Villalgordo, J.M., Heimgartner, H. Helv. Chim. Acta, 1992, 75,

1866

[92SC1081]

Nutaitis, C.F. Synth. Commun. 1992, 22, 1081

[92T7817]

Katritzky, A.R.; Shobana, N. et al. Tetrahedron 1992, 48, 7817

[93CB2337]

Maier, G.; Schmidt, C. Chem Ber, 1993, 126, 2337

[93H1617]

Maeba, I.;Ito, Y.; Wakimura, M.;Ito, C. Heterocycles 1993, 36,

1617

[93JA11074]

Alcami, M.; Mo, O.; Yanez, M. J. Am. Chem. Soc. 1993, 115,
11074

56
[93JHC1261]

Katritzky , A.R.; Szajda, M.; Lam, J.N. J. Heterocyl. Chem. 1993,

30, 1261

[93JMC288]

Getman, D.P.; Decrescenzo, G.A.; Heintz, R.M.; et al. J. Med.

Chem. 1993, 36, 288

[93JPO567]

Katritzky, A.R.; Zhang, G.-F.; Fan, W.-Q.; Wu, J.; Pernak, J. J.

Phys. Org. Chem. 1993, 567.

[93T7445]

Katrtitzky, A.R.; Lang, H.; Lan, X. Tetrahedron 1993, 49, 7445.

[93TL571]

Mueller-Westerhoff, U.T.; Zhou, M. Tetrahedron Lett. 1993, 34,

571

[93TL2673]

Molina, A.; Vaquero, J.J.; Garcia, J.L.; Alvarez, J. Tetrahedron

Lett. 1993, 34, 2673

[94CA9431]

Speranza, G.P.; Champion, D.H.; Plishka, M.J. Chem. Abstr. 1994,

121, 9431

[94CA30551]

Christensen, S.B. Chem. Abstr. 1994, 120, 30551

[94S445]

Katritzky, A.R.; Lan, X; Fan, W.-Q. Synthesis 1994, 445

[95AG(E)1246]

Alcaraz, G., Wecker, U., Baceiredo, A., Dahan, F., Bertrand, G.

Angew. Chem. Int. Ed. Engl. 1995, 34, 1246

[95CA314553]

Macleay, R.E.; Kmiec, J.P.; Stein, D.L. Chem. Abstr, 1995, 122,
314553

[95JOC6]

Katritzky, A.R.; Jiang, J. J. Org. Chem. 1995, 60, 6.

[95JOC7612]

Katritzky, A.R.; Lang, H. J. Org. Chem. 1995, 60, 7612

[95JOC7619]

Katritzky, A.R.; Lang, H.; Wang, Z. J. Org. Chem. 1995, 60, 7619

[95JOC7625]

Katritzky, A.R.; Zhang, G.; Jiang, J.; J. Org. Chem. 1995, 60, 7625

[95S1315]

Katritzky, A.R.; Wu, H.; Xie, L. Synthesis 1995, 1315.

[95TL4665]

Gentilucci, L.; Zwanenburg, B.; Grijzen, Y.; Thijs, L. Tetrahedron

Lett. 1995, 36, 4665

[96HAC365]

Katritzky, A.R.; Soleiman, M.; Yang, B. Heteroatom Chemistry

1996, 7, 365

[96JA8491]

Zwanenburg, B.; Verstappen, M.M.H,; Ariaans, G.J.A. J. Am.

Chem. Soc. 1996, 118, 8491

57
[96JHC203]

Schulze, K.; Ernst, S. J. Heterocycl. Chem. 1996, 33, 203.

[96JHC607]

Katritzky, A.R.; Yang, B. J. Heterocyl. Chem. 1996, 33, 607.

[96LA881]

Wedler, C.; Kleiner, K.; Kunath, A.; Schick, H. Liebigs Ann.

Chem. 1996, 881

[96SL701]

Katritzky, A.R.; Yang, B.; Qian, Y. Synlett 1996, 701

[96TL1153]

Jadhav, P.K.; Man, H.-W. Tetrahedron Lett. 1996, 37, 1153

[97EJC1757]

Piquet, V., Baceiredo, A., Gornitzka, H., Dahan, F., Bertrand, G. J.

Eur. Chem., 1997, 3, 1757

[97JA10291]

Suarez, P.; Sordo, T.L. J. Am. Chem. Soc. 1997, 119, 10291

[97JOC706]

Katritzky, A.R.; Feng, O.; Lang, H. J. Org. Chem. 1997, 62, 706

[97JOC4155]

Katritzky, A.R.; Pleynet, D.P.M.; Yang, B.; J. Org. Chem. 1997,

62, 4155

[97JOC6575]

Marco, J.L. J. Org. Chem. 1997, 62, 6575

[97T10911]

Aurricchio, S.; Bini, A.; Pastormerlo, E.; Truscello, A.M.

Tetrahedron 1997, 53, 10911

[98CR409]

Katritzky, A.R.; Lan, X.; Yang, J.Z.; Denisko, O.V. Chem. Rev.
1998, 98, 409

[98JCS(P1)4115]

Murphy, W.S.; Bertrand, M. J. Chem. Soc. Perkin Trans. 1 1998,

4115

[98JCU912]

Calvo-Cosada, S., Quirante, J.J., Suarez, D., Sordo, T.L. J.

Comput. Chem., 1998, 19, 912

[98JOC4936]

Kirschbaum, S.; Waldman, H. J. Org. Chem. 1998, 63, 4936

[98MI1]

Staab, H.A.; Bauer, H.; Schneider, K.M. In Azolides in Organic

Synthesis and Biochemistry; Wiley-VCH: Germany, 1998; p.129

[98S153]

Katritzky, A.R.; Levell, J.R.; Pleynet, D.P.M. Synthesis 1998, 153

[98T9791]

Sengupta, S.; Sarma, D.S.; Mondal, S. Tetrahedron 1998, 54, 9791

[98TA2197]

Soriente, A.; De Rosa, M.; Dovinola, P. Tetrahedron: Asymmetry,

10, 1999, 2197

[98TA2311]

Sengupta, S.; Sarma, D.S.; Mondal, S. Tetrahedron: Asymmetry,

1995, 51, 9873

58

[98TL2249]

Tang, Q.; Sen. S.E. Tetrahedron Lett. 1998, 39, 2249

[98TL8263]

Trautwein, A. W.; Jung, G. Tetrahedron Lett. 1998, 39, 8263

[99BMC2217]

Prasad, J.V.N.; Markoski, L.J.; Boyer, F.E. Bio & Med. Chem.
Lett. 1999, 9, 2217

[99H803]

Nishimura, N.; Koyano, Y.; Sugiura, M.; Maeba, I. Heterocycles

1999, 51, 803

[99JHC777]

Katritzky, A.R.; Pastor, A.; Voronkov, M.V. J. Heterocycl. Chem.

1999, 36, 777

[99JOC925]

Shi, C.; Zhang, Q.; Wang, K.K. J. Org. Chem. 2000, 65, 8069

[99JCS(P1)1305]

Alves, M.J.; Gilchrist, T.L.; Sousa, J.H. J. Chem. Soc., Perkin

Trans. 1 1977, 877

[99JST113]

Wolf, W.M.; J. Mol. Struct. 1999, 474, 113

[99TA1369]

Bentus, P.; Phansavath, P.; Ratovelomanana-Vidal, V. et al.

Tetrahedron: Asymmetry 1999, 10, 1369

[99TA3659]

De Rosa, M.; DellAglio, R.; Soriente, A. Tetrahedron: Asymmetry

1999, 10, 3659

[00JMC843]

Boyer, F.E.; Prasad, J.V.N.; Domagala, J.M. J. Med. Chem. 2000,

43, 843

[00JOC3679]

Katritzky, A.R.; Pastor, A. J. Org. Chem. 2000, 65, 3679

[00JOC8069]

Katritzky, A.R.; Huang, T.B.; Voronkov, M.V. J. Org. Chem.

2000, 65, 8069

[00JOC8210]

Katritzky, A.R.; He, H.Y.; Suzuki, K. J. Org. Chem. 2000, 65,

8210

[00K303]

Peters, K., Peters, E.-M., Hergenrother, T., Quast, H.,

Kristallografiya, 2000, 215, 303

[00S2029]

Katritzky, A.R.; Fang, Y.; Donkor, A.; Xu, J. Synthesis 2000, 2029

[00SC2564]

Guo, H.; Zhang, Y. Synth. Commun. 2000, 30, 2564

[01TA513]

Gotor, V.; Rebolledo, F.; Liz, R. Tetrahedron: Asymmetry 2001,

12, 513

59
[02JOC3104]

Katritzky, A.R.; Denisko, O.V. J. Org. Chem. 2002, 67, 3104

[02OPP219]

Palacios, F.; Ochoa de Retana, A.M.; de Marigorta, E. M.; de los

Santos, J.M. Org. Prep. Proc. Int. 2002, 34, 219

[02TL5431]

Wang, X.; Zhang, Y. Tetrahedron Lett. 2002, 43, 5431

[03JOC1443]

Katritzky, A.R.; Abdel-Fattah, A.A.A.; Wang, M. J. Org. Chem.

2003, 68, 1443

BIOGRAPHICAL SKETCH
Chavon R. Wilkerson was born and raised in the suburbs of Detroit, Michigan, by
her loving and supportive parents. They encouraged her to pursue a college career in her
field of choice---chemistry. As an undergraduate student at North Carolina Agricultural
& Technical State University, Chavon immersed herself in her studies. She was awarded
a prestigious National Institutes of Health scholarship which exposed her to many
opportunities available in biomedical research. Her participation in the scholarship
program and her continued interest in chemical research led her to pursue a graduate
education at the University of Florida. After obtaining the Master of Science degree from
the University of Florida, Chavon plans to continue her career in scientific research.

60