Table Of ContentFUSED PYRIMIDINES
Part I: QUINAZOLINES
Tbis is rbc twen~+rtb wiume (Part r) in tbs Icricr
THE CHEMISTRY HETEROCYCLIC COMPOUNDS
OF
THE CHEMISTRY OF HETEROCYCLIC
COMPOUNDS
A MONOGRAPHS
SERIES OF
ARNOLD WEISSBERGER, Editor
FUSED PYRIMIDINES
E&ed by
J. Brown
I).
Part I
QUINAZOLINES
Armarego
W. L. F.
Deparfment o f Medcal Cbemis/ry,
Tbs John Curiin School of Medcal Reiearch,
The Ausiralian National University, Canberra
With collaboration in part by
GEORGHE. HITCHINGaSn d GERTRUDBE. ELION
WeLhome Researcb Labwatoritv, TrrcRaba, N.Y .
1967
INTERSCIENCE PUBLISHERS
a division John Wiley &
of Sons
- -
New York Sydney
London
First publiehed 1967 by John Wiley & Sons, Ltd.
All Righta
Reserved
Library of Congress Catalog Card Number 67-27306
WILLzdyI DLOWEB AND SONS, LIICITW, WNDON ABD BECCLEB
The Chemistry of Heterocyclic Compounds
The Chemistry of heterocyclic one of the most
compounds ia
complex branches of organic chemistry, It is equally intereating for its
theoretical implications, for the diversity of its synthetic procedures,
and for the physiological and industrial significance of hetermyclic
compounh.
A field of such importance and inthic di6culty should be made
as readily accessible rn possible, and the lack of a modern detsiled and
comprehensive presentation of heterocyolic chemistry is therefore
felt. It is the intention of the present series to fill this gap by
keenly
expert presentations of the varioua branchea of heterocyclic chemistry,
The subdivieions have designed to cover the field in its entirety by
been
monographs which reflect the importance and the interrelations of the
various compounds and accommodate the specific intereats of the
authors.
ARNOLDW EISSSEEWER
Research Labord~es
Eaatnaan H&k Cmpany
Rochter, New Ymk
V
Foreword to Fused Pyrimidines
The
OriginalXy it W ~ Sin tended to present aJ1 the fused pyrimidine
systems in one volume of series. Resurgence of interest in purines
this
and quinazoolines, the development of pteridine chemistry, and the wide
exploration of & great many new fused eyetame mbracing the pyrimid-
ine have made the task impossible.
ring,
fwed pyrimidines will now be covered in four parts, of whioh
The
Dr. Armarego’s &uinazolines is the firat. Others, dealing with Purim,
Pteridiw, and Mkwklanew Fwed Pyrimidines respectively, in
are
active preparation. Eventually, this braoket of volumes bring to
will
the WI%S the expertise of six enthusiastict authors with wide and
diverse exprience in the field.
It is a privilege to assist Dr. Weissberger and the authors in
organizing this projeat and in a memure of uniformity
maintaining
and balance in its parts.
D. J. BROWN
Vii
Preface
The presence of the benzene ring in quinazoline modifiea the
chemistry of the pyrimidine ring in a number of ways. The modifies-
tions are so diverse that description of the chemistry of quinazolines
a
merits monograph. Quinazolines were originally prepared for
a separate
academic interest, and a considerable variety were made because many
synthetic approaches were possible. In the last two decades several
naturally occurring quinazolines were discovered, and many quinazo-
were synthesized for biologicd testing. The antimalarid activity
lines
of the alkaloid febrifugine, for example, led to the preparation of a large
number of different quinazoline derivatives. The neurotoxic activity
the recently discovered tetrodotoxin, a perhydroiminoquinazoline,
of
will undoubtedly stimulate research in this previously unknown claas of
quinazolines.
monograph is intended a, critical review of quinazoline
This aa
chemistry well a compilation of the melting pointa of quinazolines.
&B as
Condensed quinazolines are excluded, with the exception of the thiazolo-
quinazolines (thiopegenes) because the chemistry of these is closely
related to that of the thioquinazolines. The literature is covered com-
pletely from the preparation of the first quinrtzoline in 1869 to the
middle of 1966, and incompletely until mid-1966,
I am grateful the many people who helped me during the
to
months of writing. Drs. G. H. Hitchings and G. B. Elion loaned me a
preliminary account of the chemistry of quinazolines based essentially
on synthetic methods. D. J. Brown has unselfishly guided and
Dr.
inspired me, particularly through the most difficult eections, and to
him
I owe a great debt of gratitude. Professor Adrien Albert carefully
read
several chapters and made constructive criticisms. The following were of
considerable help in discussions, in making available to me information
prior to publication, and in allowing me reproduce some of their
to
published dab: Professors R. D. Brown, A. R. Krttritzky, K. S.
Nwang, Drs. 0.B . Barlin, T. J. Batterham, M. E. C. Biffin, J. W.
Bunting, Gordon Catterall, L. Heffemn, D. D. Perrin, K. RaHmn,
M. N.
J. I. C. Smith, Mr. H. Yamamoto. My wife (who is also organic
and an
ix
1*
Profme
X
chemist) assisted in making the tables, compiling the index, and in
reading the whole manuscript. Finally, thanks are due to
grateful
Miss P. who canied out the tedious task of typing the manuscript
Cope
and to Mre. D. McLeod for library facilities.
W. F.
L. ARMAREQO
The Austpdian National University, Canberra
June 1966
Contents
I. Introdmtion ,.
1.History .
Nomenclature
2. .
3. Charaoter of Quinazolines.
The Dual .
4. General Summary of Quinazoline Chemistry
.
A. Syntheses
.
a. F’rimary Synthesea
b. Secondary Syntheses .
.
B. The Heightened Reactivity of 2- and 4-Alkyl Croups
C. Addition and Substitution Reactions, and Nucleophilic Meta-
.
the& 6
D. N-Oxides , 7
.
E. Tautomerism
. 7
Oxidation Reduction
F. and . 8
G. Rearrtangementa
8
IX. Biol.o gical Activity in QuinazoIines 9
Tables 9
6. .
6. References
10
.
Qubaeoline
II. . 11
$ynthesis of Quinazoline
1. . 11
2. Physical Properties . 13
A. Theoretical Aspects
. 14
Spectra
B. . 14
a. Ultraviolet Spectra
. 14
b. Phosphorescence Spectra
. 15
c. Infrared Spectra . 15
d. Proton Magnetic Resonance Spectre
. 10
e. MMS Spectra . 18
C. Covalent Hydration
19
a, Covalent Hydration in Quinazoline. .
19
Effect of Substituents in the Pyrimidine on Covalent
b. Ring
Hydration . 27
.
(i) Effect of substituents in position 4 27
.
(ii) Effect of aubstituenta in position 2 28
xi
xii Contents
c. Effeot Substituenta in the on Covalent
of . Benzene Ring
Hydration 29
D. Pohrography , 32
. .
3. Chemical Reactivity of Quinazoline 33
.
A. Hydrolysie, Oxidstion, Reduction 33
and .
B. Electrophilic end Nucleophilic Substitution, and Alkylation 34
.
C. Addition Reactions 35
.
4. References 36
.
III. C-Alkyl- and C-Arylquhzo. bes 39
Methods Preparation 39
1. of .
A. Bischler’s Synthesie 39
B. Oxidation of 3,4-Dihydroquinazolis , 41
C. Decarboxylation of Acids , 42
.
D. N’ToIuene-psulphonyly~razinoD erivatives 42
From .
E. From Imidoyl Chlorides and Nitriles . 42
F. Aryl Diazonium Salk and Nitriles 43
From
G. From 4-chloro 4-~anoquinazolineasn d Grignard Reagente 44
or
H. From Chloro- CyanoqUinazolines and Sub&mcee with sn
or .
Active Methylene Gro. up 46
I. Reidel’s Synthesis 48
.
J. Miscellane.o us 48
2. Properties 49
.
A. ahysiceJ Properties 49
.
B. Chemical Properties 60
a. The Heightened Reactivity of. 2- end 4-Methyl Groups . 50
b. Oxidation and Reduction 54
.
c. Eleotrophilic Substitution. 56
.
d. Alkylation
66
e. Reactivity the Substituted Atoms Attached
of Carbon fo.
%. I,m d cw . 58
3. Tables 60
4. References . . 67
OxoquinosoJines 5-, 6-, 7-, and 8-Hydmxyquixutzolines .
IV. and 69
1. 2-0x0quinaz01ines. . 69
A. Prepwation . . 69
B. Properties . . 72
.
2. 3,4- and 1,4-Dihydro-4-oxoquinasolines . 74
A. Preparation of 3,4-Dihydro-4-ox.o quinszolinea . . 74
a. Niementowski’s Synthesis . 74
b. Cyclization of o-Amidobenza.m ides . 78
c. From o-Aminobenzonitriles . 80
d. From Anthranilic Acid Derivatives and Nitriles .. 81
e. From 3,1,4-Benzoxazones (Acyhthranile) and Aminee 83
. .
f. From Isatoic Anhydrides 87
.
g. From Anthranilic Acids and Imidoyl ChIorides 88
or Esters . .
h. From Anthranilic Acids Estere and Imidetes 91
i. Grimmel, Cuenther, and or Synthesis . . 93
Morg.a n’s .
j. Sen and Ray’s Synthwis 94
