Chemistry of Heterocyclic Compounds. Volume 16. The Pyrimidines

796 Pages·21.14 MB·english

by  Brown D.J.

PYRIMIDINES
THE
Tbir is the sixteenth volrtme in thr $me$
THE CHEMISTRY HETEROCYCLIC COMPOUNDS
OF
THE CHEMISTRY OF HETEROCYCLIC
COMPOUNDS
A MONOGRAPHS
SERIES OF
ARN 0 B RG Condti9Jg E d h
LD W EI S S E E R,
THE PYRIMIDINES
D. J. Brown
Tbt AlrJtralian National Univcrsdy
Gnbma
WITH AN ESSAY BY
Mason
S. P.
Tbt University, Exettr, England
1962
INTERSCIENCE PUBLISHERS
P division of
JOHN WILEY & SONS NEW YORK LONDON
Library of Congress Card 6 1-9039
Catalog Number
Copyright 0 1962 by John Wiley CE Sons, Inc.
AU Rights Reserved
the Memory of
To
TREATB ALDWIJNOH NSON
The Chemistry Heterocyclic Compounds
of
The chemistry of heterocyclic compounds is one of the most complex
branches of organic chemistry. It is equally interesting for its theoretical
implications, for the diversity of its synthetic procedures, and €or the
physiological and industrial significance of heterocyclic compounds.
A field of such importance and intrinsic difficulty should be made
as
readily accessible possible, and the lack of a modern detailed and compre-
as
hensive presentation of heterocyclic chemistry is therefore keenly felt. It is
the intention of the present series to fill this gap by expert presentations of
the various branches of heterocyclic chemistry. The subdivisions have been
designed to cover the field in its entirety by monographs which reflect the
importance and the interrelations of the various compounds, and accommo-
date the specific interests of the authors.
Research Laboratories ARNOLDW EISSBERGER
Eastman Kodak Comfiarry
Rochester, N m York
VJI
Preface
This book is intended as a critical review of pyrimidine chemistry with
emphasis on practical rather than theoretical aspects. The literature from the
earliest times to 1960 is used to furnish examples illustrating syntheses,
physical properties, and reactions, but no attempt is made to include all
relevant data. The tables interspersed with the text serve to multiply and
diversify these examples, but are likewise not intended cornpIete cata-
as
lopes. In general, if a simpIe exampIe suflices to make a point, examples
involving more highly substituted pyrimidines are omitted. The more
biological aspects of pyrimidine chemistry, such as the nucleic acids or the
structural requirements for activity in barbiturates, are treated quite briefly,
in particular as adequate reviews by workers in such fields exist.
The tables in the Appendix give ready access to the literature
grouped
and melting points of known simple pyrimidines. All such compounds
described up to the end of 1957 are included, and they are supplemented by
a selection of important or interesting members described thereafter until
mid-1960.
The world-wide appeal of pyrimidine chemistry may be judged by the
following approximate analysis of the origins of the twenty two hundred
references used in the book :
United States of America 36.5%
Germany (East and West) 22.7%
British Commonwealth 19.4%
Japan 8.0%
France and Switzerland
3.0%
Italy and Spain 2.6%
Russia 2.2%
Netherlands and Belgium I .5y0
Eastern Europe 1.3%
China I .3%
Austria 1.1%
Scandinavia and Others 0.4%
It will be redised that the present-day output of pyrimidine papers is
very different to the above, which covers the last 140 years. The United States
IX
X Preface
remains the centre of gravity, but the output of Japan, China, and Eastern
Europe has risen considerably and mainly at the expense of Germany.
Many kind people have helped me enormously during the years of
writing. My friend and former colleague, Dr. S. F. Mason, wrote a learned
essay on pyrimidine spectra for Chapter XIII, a task which would have been
quite beyond me. Professor Adrien Albert carefully read the entire text, a d
made numerous helpful suggestions from his wide knowledge and experience
in heterocyclic work. Dr. J. P. English and Dr. J. H. Clark of American
Cyanamid Company, loaned me a fine card index covering the earlier
pyrimidine literature. Dr. S. Matsuura helped me with Japanese papers.
Dr. J. F. W. McOmie sent me much unpublished material, and Dr. H.
Mautner, Dr. H. B. Vickery, Dr. J. Stangk, Dr. D. I. Magrath, Dr. R. F.
Evans, Dr. E. Spinner, and Dr. N. W. Jacobsen helped in other ways. The
National Academy of Sciences (Dr. H. L. Dryden) kindly gave me Johnson’s
photograph. Mr. J. Harper, Mr. B. T. England, and Mrs. D. McLeod assisted
nobly with the references and in other ways. Miss P. L. Baetons typed most
of the manuscript and among the others who helped in various ways are
Miss M. Bell, Mrs. H. Edmonston. who drew the curves, Mrs. S. M. Schenk,
Mr. H. Satrapa, Mr. F. V. Robinson, Mrs. E. M. Lee, and Miss S. Green.
Professor F. Rergel, F. R. S., generously provided facilities for me at the
Chester Beatty Institute, London, at the proof stage. To these, to the un-
named others, and in particular to my wife for her help and remarkable
patience, I offer my gratitude and thanks.
The Azcstralian National University, Canberra D. J. BROWN
Contents
. ..........................
Chapter I Introduction to the Pyrimidines 1
..................................................
1.History 1
. ..............................................
2 Nomenclature 3
3. The Unique Basis of Pyrimidine Chemistry .................... 5
A . The “Active” 2.. 4.. and 6.Positions ........................ 7
B. The “Aromatic” 5.Position ................................ 8
. ....................
C The Effect of Electron-releasing Groups 8
. ................
D The of Electron-withdrawing Groups 8
. Effect ......................................
E Tautomeric Groups 9
4 . General Summary of Pyrimidine Chemistry .................... 9
A . Electrophilic Substitution ................................ 10
..............................
(1) Nitration and Nitrosation 10
(2) Diazo Coupling ...................................... 11
........................................
(3) Halogenation 11
(4) Sulphonation ........................................ 11
........................
(5) Attack by Chloroform or Chloral 11
............................
(6) Other Electrophilic Attacks 11
. ..........................
B Direct Nucleophilic Substitution 12
. ..................................
C Nucleophilic Metatheses 12
..............................
(1) Replacement of Halogens 13
............
(a) By h i n oa nd Substituted-amino Groups 13
....................
(b) By Methoxy and Similar Groups 13
..............................
(c) By Hydroxy Groups 14
..................
(d) By Methylthio and Related Groups 14
..............................
(e) By Mercapto Groups 14
..................
(fJ By Sulpho and Thiocyanato Groups 15
Replacement of Methoxy, Methylthio. and Methylsulphonyl
(2) ..............................................
Groups 15
D . Other Metatheses ........................................ 16
........................
(I) Hydroxy- to Chloro-pyrimidines 16
....................
(2) Hydroxy- to Mercapto-pyrimidines 16
....................
(3) Mercapto- to Hydroxy-pyrimidines 17
........................
(4) Mercapto- to Amino-pyrimidines 17
........................
(5) Amino- to Hydroxy-pyrimidines 17
..........................
(6) Amino- to Chloro-pyrimidines 18
..............
(7) Replacements of Quaternary Amino Groups 18
XI
XI1 Contents
. ......................................
E Addition Reactions i8
......................................
(1) Quaternization 18
(2) Formation of N.0xides ................................ 19
........................
(3) Addition of Hypobromous Acid 19
....................................
(4) Addition of Water 20
......
(5) Addition of Grignard Reagents and Lithium AUryls 20
. ....................................
F Oxidative Reactions 20
....................................
G. Reductive Reactions 21
..................................
(1) Nuclear Reduction., 21
..........................
(2) Reductive Removal of Groups 22
......................
(3) Reductive Modification of Groups 23
. ..........................
H The Modification of Substituents 24
........................................
(1) AminoGroups 24
......................................
(2) Hydroxy Groups 25
....................................
(3) Mercapto Groups 25
......................................
(4) Methyl Groups 26
. ................................
I A Radical Reaction 26
. Free ..........................
5 Physical Properties of Pyrimidines.. 26
. ....................................
A Electronic Structures 27
. ....................................
B Ionization Constants 27
C. Spectra ................................................ 28
D . DipoleMoments ........................................ 28
. ..........................................
E Polarography 28
. ..............................
F Solubility and Melting Point 29
. ........................
Chaptu The Principal Synthetic Method 31
II
1. General Scope .............................................. 31
2 . Use p-Dialdehydes ........................................ 32
. of ..................................
3 Use p-Aldehydo Ketones 34
4 . Use ooff &Diketones ........................................ 36
. ....................................
5 Use of 8-Aldehydo Esters 38
A. Aldehydo Esters with Thioureas .......................... 38
. ........................
B The Davidson-Baudisch Synthesis 38
C . The of or-Ethoxymethylene Esters ...................... 39
6 . Use of BU-sKe eto Esters ........................................
48
A. Keto Esters with Thioureas .............................. 48
B. Keto Esters with Amidines .............................. 49
. ..............................
C Keto Esters with Guanidines 49
. ....................
D Keto Esters with Urea and Derivatives 50
7 . Use of 8-Diesters (Malonic Esters) ............................ 51
A . Malonic Esters and Amidines .............................. 52
. ..........
B Malonic Esters with Urea and its Alkyl Derivatives 52
C . Malonic Esters with Thiourea Derivatives .............. 54
. and ......
D Malonic Esters with Guanidine and its My1D erivatives 55
. ..................................
8 Use of 8-Aldehydo Nitriles 59
. ............................
A Aldehydo Nitriles with Ureas 59
B . Aldehydo NitriIes with Thioureas .......................... 60