Advances in Heterocyclic Chemistry

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Contents

CONTRIBUTORS............................................................... vii
.....................................................................
PREFACE ix

Fluoro Heterocycles with Five-Membered Rings

KLAUSBURGER,UWE WUCHERPFENNIG,
A N D E N N OBRUNNER

I . Overview.. ............................................................ 2
11. Direct Introduction. .................................................... 5
111. Introduction of Fluorine and Perfluoroalkyl Groups into Five-Membered
Heterocycles via C yclocondensation Reactions .......................... 14
IV. Introduction of Fluorine, Polyfluoroalkyl, and Perfluoroalkyl Groups into
Five-Membered Heterocycles via Cycloaddition Reactions . . . . . . . . . . . . . . . 28
References. ............................................................ 47

Thiopyrylium, Selenopyrylium, and Telluropyrylium Salts

GIANCARLO DODDIA N D GIANFRANCO ERCOLANI
I. Introduction and Nomenclature .................................. 66
11. Structure and Physic 67
111. Syntheses.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
IV. Reactions.. ........................... 123
V. Practical Applications .................................................. I70
References. . . . . . . . . .................................. 172

Heterocyclic Betaines: Pyridinium (Imidazolium) Azolate Inner Salts

with Several Interannular Linkages
ERMITASALCALDE
I . Introduction.. ...................................................... 198
11. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202

V
vi CONTENTS

111. Structure and Physical Properties ....................................... 222

............................................. 243
250
VI. Conclusions.. .......................................................... 25 1
References. ......... 253

Cycloaddition Reactions of Nitrile Oxides with Alkenes

CHRISTOPHER J . EASTON,C. MERR~CC M. HUGHES,
G. PAULSAVAGE, A N D GREGORY W. SIMPSON
I. Introduction.. ............. ........... 26 1
11. Nitrile Oxide Synthesis 262
111. Mechanism.. .......... ................ 269
IV. Reactivity.. ................................................ 211
V. Regioselectivity ..................... .......................... 213
VI. Stereoselectivity...................................... 211
VII. Uses of Isoxazolines. ................................................... 296
VIII. IntramolecularNitrile Oxide Cycloadditions 306
References. ............................................................ 314

INDEX OF AUTHORS,
CUMULATIVE VOLUMES 1-60 ............................ 329
CUMULATIVE 1-60 ..............................
INDEX OF TITLES,VOLUMES 341
CUMULATIVE
SUBJECT 55-60.. ..............................
INDEX, VOLUMES 353
Contributors

Numbers in parentheses indicate the pages on which the authors' contributions

begin.

Ermitas Alcalde (l97), Laboratorio de Quimica Organica, Facultad de Farmacia,

Universidad de Barcelona, E-08028 Barcelona, Spain
Enno Brunner ( I ) , Organisch-Chemisches Institut der Technischen Universitat
Munchen, 8046 Garching, Germany
Klaus Burger' ( I ) , Organisch-Chemisches Institut der Technischen Universitat
Munchen, 8046 Garching, Germany
Giancarlo Doddi (65), Dipartimento de Chimica, Universita La Sapienza, Piazzale
Aldo Moro, 5, 00185 Roma, Italy
Christopher J. Easton (261), Department of Chemistry, University of Adelaide,
Adelaide, South Australia 5005, Australia
Gianfranco Ercolani (65), Instituto di Chimica Agraria, Universita di Catania, Via
Valdisavoia 5, 95123 Catania, Italy
C. Merncc M. Hughes (261), Department of Chemistry, University of Adelaide,
Adelaide, South Australia 5005, Australia
G. Paul Savage (261), CSIRO Division of Chemicals and Polymers, Private Bag 10,
Rosebank MDC, Victoria 3 169, Australia
Gregory W. Simpson (261), CSIRO Division of Chemicals and Polymers, Private
Bag 10, Rosebank MDC, Victoria 3169, Australia
Uwe Wucherpfennig ( I ) , Organisch-Chemisches Institut der Technischen Univer-
sitat Munchen, 8046 Garching, Germany

'Present affiliation: Organisch-Chemisches Institut der Universitat Leipzig, Talstralle 35,

D-04103 Leipzig, Germany

vii
This Page Intentionally Left Blank
Preface

Volume 60 consists of four chapters and a set of indices.

In the first chapter, the chemistry of five-membered ring fluorinated
heterocycles is covered by K. Burger, U. Wucherpfennig, and E. Brunner
of the Technical University of Munich, Germany. Polyfluorohetero-
aromatic compounds were last reviewed in Volume 28 of this series in
1981. The chemistry of polyfluoroheterocycles with six-membered rings
was covered by M. J. Silvester in Volume 59; the necessity of treating the
subject in two different chapters is an indication of the increased impor-
tance that polyfluoroheterocycles have attained over the past decade.
Thiopyrylium, selenopyrylium, and telluropyrylium salts are reviewed
by G. Doddi (Rome, Italy) and G. Ercolani (Catania, Italy). Whereas the
chemistry of the analogous pyrylium salts was the subject of a special
supplementary volume in our series in 1982, no exhaustive previous re-
view of the other chalcogenopyrylium salts has been available.
E. Alcalde of Barcelona, Spain, presents a review of the class of hetero-
cyclic betaines in which the positive charge is located on a pyridinium ring
and the negative charge on an azolium ring. A unified picture of what has
been a somewhat neglected class of highly dipolar heterocycles is pre-
sented.
Finally, C. J . Easton, C. M. M. Hughes, G. P. Savage, and G. W.
Simpson (Adelaide and Melbourne, Australia) review the cycloaddition
reactions of nitrile oxides with alkenes. Although previous reviews of this
subject have appeared, the synthetic potential of this reaction has recently
been the object of intensive study.
Volume 60 is an “index volume” and includes three indices. The author
index and the title index cover the entire series since its inception, and list
in alphabetical order the titles and authors of all the chapters that have

ix
X PREFACE

appeared. However, the subject index covers only Volumes 55 through 60.
Volume 40 contained the cumulative subject index for Volumes 1-40;
Volumes 41-45 were covered in Volume 45, and Volumes 46-53 in Vol-
ume 53. Volume 54, as a monograph volume, contained its own subject
index.
Alan R. Katritzky
 ADVANCES IN HETEROCYCLIC CHEMISTRY, VOL. 60

Fluoro Heterocycles with Five-

Membered Rings
KLAUS BURGER, UWE WUCHERPFENNIG, AND
ENNO BRUNNER
Organisch-Chemisches Institut der Technischen Universitat
Miinchen. 8046 Garching, Germany

I. Overview . . . . . . . . , . , . . . . . . , . . , . . . . . . . . . . . . . . . . . . .. 2
A. Reactivity of Fluorine and Trifluoromethyl Groups . . . . . . . . . . . . . . . . . . 4
B. Strategies for the Introduction of Fluorine and Perfluoroalkyl Groups into
Organic Molecules. . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11. Direct Introduction . . . . . , . . . . . . . . . . . . .

2. Fluorination/Dehydrotluonnation . . . .. . . . .. ....... .. . . . .. ... . . . . . . . . . . 6

3. Electrochemical Fluorination . . . . . . . ........ .. 6
4. Nucleophilic Displacement Reactions . .............. 7
5. Electrophilic Fluorination Reactions . . . . . . . . . . . . . . .. . . . . ........... .. . . . 7
6. Balz-Schiemann Reaction. . . . . . . . . . . . . . . . . . . . . . 8
7. Transformation of Hydroxy and Carbonyl . . . . .Groups
. . . . . . into
. . . .C. .F. .and
. . . CF2
....
Moieties . . . . . . . . . . . . . . . . . . . . . . ............. 8
8. Displacement Reactions of Metallated 89
B. Introduction of Polyfluoroalkyl and Perflu 9
Membered Heterocycles . . . . . . . . . . . . . . . . . . . . . . . . 9
1. Introduction of Trifluoromethyl Grou 99
2. Transformation of Trichloromethyl Groups into Trifluoromethyl 9
Groups . . .......................................... 11
3. Groups . . . . . . . .of. .Carboxylic
Transformation . . . . . . . . . .Groups
... into Trifluoromethyl . . . . Groups.
. . . . . . ...... 1I1I
4. Transformation
3. Introduction of of Carboxylic Groups
Trifluoromethyl Groups intoviaTrifluoromethyl
TrifluoromethylGroups. Copper ...... I 12
I
4. . . . . .via
. . .Trifluoromethyl . . . . . . .. . .
. . . . . . . . . . . . . .Copper
I
5. Introduction
Electrophilic ofTrifluoromethylation
-5. Electrophilic
. .
Trifluoromethyl Groups
-_
.I .- ...... n
Trifluoromethylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
.n .-,
12
13
I3

C. Introduction of Trifluoromethoxy and Trifluoromethylthio Groups . . . . . . 13

111. Introduction of Fluorine and Perfluoroalkyl Groups into Five-Membered
Heterocycles via Cyclocondensation Reactions . . . . . . . . . . . . . . . . . . . . . . . . 14
A. [3 + 21 Cyclocondensation Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
I. Condensation Reactions of Fluoro-containing 1,3-Dielectrophilic with
I ,2-Dinucleophilic Building Blocks . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
2. Condensation Reactions of 1,3-Dinucleophiles with Fluoro-containing
1,2-Dielectrophilic Building Blocks . . . . . . . . . . . 17
3. Condensation Reactions of Fluoro-containing I ,3-
Electrophilic with 1,2-Nucleophilic/ElectrophilicBuilding Blocks. . . . . 18
4. Condensation Reactions of 1,3-Nucleophilic/Electrophilic with Fluoro-
containing 1,2-Nucleophilic/ElectrophilicBuilding Blocks. . . . . . . . . . . 19

1
Copyright 0 1994 by Academic Press. Inc.
All rights of reproduction in any form reserved.
2 KLAUS BURGER et al. [Sec. I

5 . Condensation Reactions of Fluoro-containing I ,3-Dielectrophilic with

Fluoro-containing 1,2-Dinulceophilic Building Blocks . 22
6. Reactions of Fluoro-containing 1,3-Nucleophilic/Electr
Fluoro-containing I ,2-Nucleophilic/Electrophilic Buildi 22
B. [4 + I ] Cyclocondensation Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
I . Cyclocondensation Reactions of Fluoro-containing I ,.l-Dielectrophilic
with I ,I-Dinucleophilic Building Blocks . . . . . . . . . . . . . . . . . . . . . . . . 22
2. Cyclocondensation Reactions of 1,4-Dinucleophilic with Fluoro-
23
C. 1.5-Cyclocondensation Reactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
D. Miscellaneous .................. 28
IV. Introduction of FI oalkyl Groups into
Five-Membered Heterocycles via Cycloaddition Reactions . . . . . . . . . . . . . . . 28
A. [ 3 + 2 ] Cycloaddition Reactions . . . . . . . . . 28
I . Introduction of Fluorine-containing Subs
Heterocycles via Fluoro-substituted 1.3-Dipoles . . . . . . . . . . . . . . . . . . 29
2. Introduction of Fluorine-containing Substituents into Five-Membered
Heterocycles via Dipolarophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5
3 . Introduction of Perfluorinated and Polyfluorinated Substituents via
I ,3-Dipoles and Dipolarophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
B. Synthesis of Perfluoroalkyl-substitutedFive-Membered Heterocycles via
[4+ I ] Cycloaddition Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
C. Introduction of Perfluoroalkyl Groups into Five-Membered Heterocycles
via Diels-Alder/Retro Diels-Alder Re 44
D. Introduction of Perfluoroalkyl Groups
via [2 + 2 + I ] Cycloaddition Reactions 4.5
E. Synthesis of PerRuoroalkyl-substitutedFive-Membered Heterocycles via
..................... 46
... 47
References ................................................... 47

1. Overview

Fluorine and/or perfluoroalkyl groups positioned strategically in target

molecules may considerably modify chemical properties, biological activ-
ity, and selectivity [76M13; 79M14; 81AG(E)647; 82MI1, 82MI2; 87MI4,
87T3123; 91MI21. A number of fluoro- and perfluoroalkyl-substitutedphar-
maceuticals, agrochemicals, dyes, and polymers have already been com-
mercialized. The number of patents concerning fluorinated compounds
shows a tendency to grow. Thus, one can anticipate that fluoro-containing
compounds will continue to play a significant role in medicinal and agricul-
tural chemistry as well as in material science (90JOC4448).
The exchange of hydrogen by fluorine does not alter steric bulk much
because of the similarity of the Van der Waals radii (H: I .20 A, F: I .35
A) and may be regarded an isosteric substitution. The postulated quasi-
Sec. I] FLUORO HETEROCYCLES WITH FIVE-MEMBERED RINGS 3

isosterism between CH, and CF, groups (72MII ; 82T871; 87T3123) is

still a controversial issue [92JFC(57)229]. The Van der Waals radii of a
trifluoromethyl group and of a methyl group are 2.7 A / 2 A, whereas the
Van der Waals volumes are 42.6 A3 / 16.8 A’ [90AG(E)1320].The steric
demand of a trifluoromethyl group seems to be close to that of an isopropyl
group.
It has been suggested that there should be little or no effect on bond
length when a methyl group attached to a carbon atom is replaced by
a trifluoromethyl group [83JFC(23)147]. Therefore, this transformation
should result in minimal disruption to an enzyme-substrate complex
[90AG(E)13201.
Important differences in chemical reactivity of fluorinated compounds
are based on the difference in carbon-fluorine (456-486 kJ/mol) and
carbon-hydrogen bond energy (356-435 kJ/mol); on the difference in
electronegativity between fluorine and hydrogen (Pauling scale: 4 / 2. I ) ,
which can gradually alter and even invert reaction behavior of adjacent
centers; and on the ability to participate in hydrogen bonding as an electron
pair donor (87JA8067).
With increasing fluorination the C-C bond length shortens and conse-
quently the bond strength increases. This phenomenon is unique among
halogens (75MI 1). For example, the C-C bond in 1 ,l,l-trifluoroethane
or hexafluoroethane is 59 or 42 kJ/mol more stable than that of ethane,
respectively (73MI 1 ; 75MI2). Therefore, introduction of trifluoromethyl
groups stabilizes molecules. Other properties of the trifluoromethyl group
include electronegativity similar to that of oxygen (65JPC3284) and high
lipophilicity [lipophilicity scale (83MI2; 86JPS987): F < CF, < OCF, <
SCF,] enhancing the absorption rates of drugs, improving their transport
rates in viuo, and helping to permeate certain body barriers.
Fluorine introduced into biologically active molecules can block metab-
olism. The high carbon-fluorine bond energy renders fluorine resistant
to many metabolic transformations (91MI3). In this context 5-fluorouracil
is a typical example: It inhibits the enzyme thymidylate synthase, which
catalyzes methylation of deoxyuridylate to provide deoxythymidylate
(72MI2), an essential component for DNA synthesis. 5-Fluorouracil can
still be transformed into 5-fluorouridylate (and hence is incorporated into
RNA) and is accepted as enzyme substrate. The difference in C-H/
C-F bond energy, however, renders C-methylation at the 5-position
impossible. This makes 5-fluorouracil and its analogues efficient cytotoxic
agents .
Since an increasing number of enzymes have been characterized in
terms of their three-dimensional structure, and since the mechanisms by
which reactions occur at their active sites have been elucidated, it should
4 KLAUS BURGER et a/. [Sec. 1.A

be possible to make a rational design of mechanism-based fluorinated

drugs.

A. REACTIVITYOF FLUORINE
AND TRIFLUOROMETHYL
GROUPS

The high carbon-fluorine bond energy renders the fluorine substituent

a bad leaving group in SN2 reactions and resistant to many metabolic
transformations. By contrast, in addition-elimination processes fluorine
shows superior leaving group ability relative to hydrogen and the other
halogens. These properties have led to the development of very effective
mechanism-based enzyme inhibitors (68MI 1; 73MI2; 76M14; 83MI1;
85MIl; 88MI1; 90MI3).
Although the trifluoromethyl group is often considered to be chemically
inert (53JA4091,53JCS922), it is known to undergo a variety of reactions.
The hydrolytic behavior of a trifluoromethyl group is very much dependent
on its position in a molecule. Trifluoromethyl groups of aromatic com-
pounds undergo hydrolysis, but only in acidic media (47MI1). Trifluoro-
methyl groups attached to carbon atoms possessing acidic hydrogen atoms
are susceptible to hydrolysis in basic media (883614). For this reason
3,3,3-trifluoroalanine is unstable in basic medium at room temperature.
The trifluoromethyl group undergoes hydrolysis to give a carboxylate
(66CB 1944). Trifluoromethyl groups attached to certain positions of het-
erocyclic systems undergo facile base-induced hydrolysis, e.g., the triflu-
oromethyl group in 2-trifluoromethylimidazole (79JOC2902; 80JOC383 1)
(Scheme 1).
Via a similar reaction sequence, consisting of a series of successive
eliminationladdition steps, 5-amino-4-trifluoromethyloxazoles can be
transformed into 5-amino-4-methyloxazoleson treatment with LiAlH,
(90S357). The ability to eliminate fluoride ions from trifluoromethyl and
perfluoroalkyl groups on treatment with bases allows in siru generation of
valuable synthetic fluoro-containing building blocks (8836 14; 90JOC4777).

R H R R

R H
-HF
+HaO, -HF @C02H

SCHEME
1
Sec. II.AI FLUORO HETEROCYCLES WITH FIVE-MEMBERED RINGS 5

B. STRATEGIES
FORTHE INTRODUCTION
OF FLUORINE
AND
PERFLUOROALKYL
GROUPSINTO ORGANICMOLECULES

There are two fundamentally different strategies by which fluorine and/

or perfluoroalkyl (or polyfluoroalkyl) groups can be introduced into target
molecules: ( a )Direct introduction-by direct substitution of hydrogen by
fluorine and perfluoroalkyl groups in a late step of the reaction sequence
or by functional group transformations in a late step of the reaction se-
quence; and (b) introduction of fluorine and perfluoroalkyl groups by
application of fluorine-containing building blocks, derived from readily
available starting materials.
Although the first approach is more straightforward, provided that suit-
able fluorinating and perfluoroalkylating reagents are available, control of
regio- and stereoselectivity is often difficult to achieve. Because of the
high reactivity of most fluorinating agents, many functional groups already
present in the molecule also may be transformed in an undesired way.
Therefore, they have to be appropriately protected. Protection and depro-
tection of these groups require additional reaction steps. Furthermore,
many of the reagents currently used for direct introduction of fluorine
and perfluoroalkyl groups are expensive, toxic, corrosive, and sometimes
explosive.
Consequently, the building block strategy (78T3; 81MI1) for introduc-
tion of fluorine and perfluoroalkyl groups into organic molecules repre-
sents an attractive alternative concept. The method is often synthetically
more elegant and allows one to introduce fluorine and perfluoroalkyl
groups in a regio- and stereoselective manner into a target molecule.
Since partially fluorinated heterocyclic compounds are important in
both academia and industry the synthetic state of the art has been reviewed
regularly (74MIl; 76MI2; 77MI1; 81AHCl; 91MII).

11. Direct Introduction

A. INTRODUCTION OF FLUORINE
INTO
HETEROCYCLES
FIVE-MEMBERED
1. Radical H / F Substitution

Introduction of fluorine into heterocyclic systems can be achieved using

molecular fluorine. However, direct fluorination is known to be notori-
ously regio- and stereo-unselective. Extensive work is still going on to
overcome these problems (79MI3; 86CRV997; 89M11). In special cases
6 KLAUS BURGER er al. [Sec. 1I.A

2
SCHEME

selective fluorination can be achieved under certain reaction conditions

[86BAU1901; 89JFC(45)99].

2. FluorinationlDehydroJEuorination

Fluorination/dehydrofluorinationis the classical route to perfluoroaro-

matics. However, yields are low, when this method is applied to nitrogen-
containing aromatic systems. In contrast, fluorinated furans
[69JCS(C)2585; 7OJCS(C)2146] and thiophenes [69CC27; 71JCS(C)346,
71JCS(C)352] can be synthesized in good yields on reaction with high-
valency metal fluorides (HVMF) (60MI1) and subsequent dehydrofluori-
nation (Scheme 2).
This route is especially valuable for the transformation of electron-rich
heteroaromatic compounds into their fluorinated analogues, which are
not suitable for the nucleophilic exchange route. The method has been
extended by addition of fluorinated olefins. The fluoroolefins add in a
radical process to the 2-position of tetrahydrofuran, followed by perfluori-
nation to give the perfluorinated 2-alkyl-substituted tetrahydrofurans in
excellent yields [84JFC(25)523;85JFC(29)323](Scheme 3).

3. Electrochemical Fluorination
This fluorination technique is difficult to employ for selective fluorina-
tion and gives high yields only for poly- and perfluorinated compounds
[67MI 1 ; 79CJC2617; 87CL1435; 88JFC(39)435; 89T1423; 90JFC(48)257;
9 1T5491.

SCHEME
3