Synthesis of Pesticides Chemical Structure and Biological Activity Natural Products with Biological Activity. Symposia Papers Presented at the Fourth International Congress of Pesticide Chemistry, Zurich, Switzerland, July 24–28, 1978

330 Pages·1979·10.76 MB·English

by  H. Geissbühler

EXECUTIVE COMMITTEE:
Chairman: E. Knüsli
Members: H. Geissbühler U. Schwieter
J. Egli H. P. Sigg
A. Ehrsam M. Spindler
G. Nussbaumer
INTERNATIONAL UNION OF PURE AND APPLIED CHEMISTRY
IUPAC Secretariat: Bank Court Chambers, 2-3 Pound Way, Cowley Centre,
Oxford OX4 3YF, U.K.
ADVANCES IN
PESTICIDE SCIENCE
Symposia Papers presented at the
Fourth International Congress of Pesticide Chemistry
Zurich, Switzerland, July 24-28, 1978
(In Three Parts)
Part 2
Synthesis of Pesticides
Chemical Structure and Biological Activity
Natural Products with Biological Activity
Editor
H. GEISSBÜHLER
Agrochemicals Division, CIBA-GEIGY Ltd., Basle, Switzerland
Associate Editors
G. T. BROOKS
University of Sussex, Brighton, Sussex, England
P. C. KEARNEY
Agricultural Research Center USDA, Beltsville, Maryland, USA
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First published 1979
British Library Cataloguing in Publication Data
International Congress of Pesticide Chemistry,
4th, Zurich, 1978
Advances in pesticide science.
1. Pesticides — Congresses
I. Title II. Geissbühler, H III. Kearney, PC
IV. Brooks, G T V. International Union of Pure
and Applied Chemistry
668' .65 SB951 78-41084
ISBN 0-08-022349-4
In order to make this volume available as economically
and as rapidly as possible the author's typescript has
been reproduced in its original form. This method un-
fortunately has its typographical limitations but it is
hoped that they in no way distract the reader.
Lithographed by The Nuffield Press Limited, Cowley, Oxford, England.
Editor's Preface
"Advances in Pesticide Science" comprises the plenary and symposia papers
presented at the Fourth International Congress of Pesticide Chemistry, held
in Zurich, Switzerland, in July 1978.
The symposia were organized to serve a special purpose and had a distinct
objective within the framework of the congress programme. In contrast to
workshops and discussion (poster) sessions, which were arranged to be plat-
forms for scientific discussion, the symposia were meant to be the showplaces
of modern pesticide chemistry. In addition to reflecting the present state of
the art, they were to project future directions. Upon termination of a sympo-
sium, the audience was expected to have received a set of new ideas or new
insights into existing problems.
To achieve these goals the chairmen and the authors of invited and contributed
papers were instructed well before the congress to consider the following
suggestions in preparing their sessions or presentations:
- to concentrate on novel (unpublished) or recent data
- to evaluate them critically with regard to their relevance to the practical
development, use, production or regulation of pesticides and growth
regulators
- to mention existing gaps or shortcomings and to project some means for
overcoming them
- to look at the data not from the usual but from a different angle in the
case where the paper (or part of it) had a review-type character.
The Scientific Programme Committee and the editors realized that these aims
were highly ambitious and demanding. In looking at the material published in
the present volumes, a number of papers may not quite reach the envisaged
objectives. However, many others open indeed new vistas and thus provide
original and forward-looking ideas. Therefore; it is hoped that the two
volumes will make a valid contribution to enlarging and improving scientific
knowledge on pesticides and growth regulators.
To preserve the impact and value of the papers, the editors and the Publisher
strove for rapid publication. Numerous people have been involved in reaching
the target date in time. However, those who deserve special mentioning and
thanks are Hanspeter Fischer, Günther Voss, Ruth Reinhard and especially
Max Spindler who worked with perseverance and enthusiasm to successfully
complete the task. The editors wish to apologize for any imperfection of
presentation, which - in the interest of ensuring rapid publication - could
not be corrected without unacceptable delay to the entire publication.
Hans Geissbühler
Gerald T. Brooks
Philip C. Kearney
xiii
IA - Heterocyclic Chemistry in Pesticide Synthesis
CHAIRMAN: G. KEMPTER
Pädagogische Hochschule "Karl Liebknecht",
Potsdam-Sanssouci, GDR
INTRODUCTION BY THE CHAIRMAN
Ladies and Gentlemen! The decision to include pesticide chemists in the dis-
cussion on pesticide chemistry to a larger extent than before was one of the
main results to come out of the Third International Congress of Pesticide
Chemistry in Helsinki four years ago.
And so I am very glad to welcome you to Main Topic I "Synthesis of Pesti-
cides"which, with its symposiums, workshops and poster sessions, has gained
a place among the seven main topics at the present congress.
There are two reasons for devoting the entire Symposium la to the chemistry
of heterocycles. On the one hand, there has been a very rapid increase in
the number of new heterocyclic skeletons and their derivatives which are
now available for a broad testing The second reason was the fact that most
0
of the heterocyclic compounds are biologically active and are therefore
potential pesticides.
New vistas have been opened for the necessary empirical search for new
biologically active compounds, partly taking into consideration the pheno-
menological aspects of frequent "biocidal structural elements'* (e.g. the
urea and carbamate groups with their thiolo-, thiono-, and dithio-analogs,
the halogène and dihalogene groups in aliphatic acids or attached to the
heterocyclic ring, aliphatically or alicyclic bonded chlorinel
Furthermore, numerous examples are known from the chemistry of naturally
occuring substances and pesticide chemistry (the pyridine ring in pyrithia-
mine instead of the thiazole skeleton in thiamine, adenine, 8-aza-adenine,
pyrazino-imidazole, benzotriazole, and benzothiazole instead of benzimidaz-
ole in vitamine B ; thiabendazole/furidazole/antienitum ; dinoseb/pyrichlor ;
1?
dicamba/picloram), but few studies have been carried out on the concept of
the "iso-Tf-electronic substitution", i.e. on the possibility not only to
change the substituents in already existing biologically active substances,
but also to replace the aromatic skeletons by heterocyclic ones. In this
way novel heterologous congeneric series will become available which may
give a deeper understanding of the USAR (Quantitative Structure Activity
Relationship) by way of determining various physical and biological parame-
ters and their correlation by means of mathematical modelling.
It was in 1968 that A.R.KATRITZKY, in his book "The Principles of Heterocyc-
lic Chemistry", said that one could hardly exaggerate the significance of
the heterocycles and that they, from the industrial point-of-view, played a
particularly dominant role in the pharmaceutical and colour industries· He
went on that, from the academic point-of-view, there are many interesting
systems waiting for a detailed investigation and very many results which
need interpretation. And he added that heterocyclic chemistry was the larg-
est and fastest growing department of organic chemistry.
This has remained the trend to this dayo You, ladies and gentlemen, have
contributed to strengthening the position of heterocyclic chemistry and
today's papers are meant to give you valuable information as well as encour-
agement for your future work«
So let me again welcome all of you, and in particular those who will give
their papers later on «, I am very pleased to have here with us representativ-
es of the two world-famous schools of heterocyclic chemistry in Great
Britain and in Yugoslavia. I do hope that our symposium will meet the aim
to cover a well-defined area which is now under active experimental invest-
igation and which is certainly of very great scientific and potential
practical significance.
57
Heterocyclic Synthesis by Rearrangement
A.J.BOULTON AND A.R. KATRITZKY
University of East Anglia, School of Chemical Sciences,
Norwich NR4 7TJ, England
Abstract - 2-Substituted 7-nitroindazoles are prepared from
4-acylbenzofuroxans, which are in equilibrium with 7-nitro-
anthranils, by condensation with primary amines and rearrangement
of the unisolated intermediate imines. With hydroxylamine and
O-substituted hydroxylamines oxime derivatives are isolated;
these form 2-(oxy-substituted)-7-nitroindazoles on heating·
o_-Azidoaryl alkyl ketoximes form stable 3-alkyl-2-hydroxy-
indazoles on thermolysis· Auwers's 3-aryl-2-hydroxyindazoles
are reassigned as 3-aryl-3-hydroxy structures. Apart from the
7-nitro derivatives, anthranils do not, in general, provide
indazoles on reaction with primary amines·
INTRODUCTION
We describe here some of the synthetic possibilities which have developed
from a rearrangement reaction which we discovered some years ago· (l)
Attention will be concentrated on the recent results we have obtained in the
field of indazoles· But first we present a brief summary of the historical
background of the work·
The work really began for us during a study of the structural and theoretical
problems posed by the benzofuroxan molecule, which has aroused some contro-
versy in the past. (2) This problem was no sooner resolved, in favour of .1
(3), than another was presented· This one arose from a suggestion (4) that
4-nitrobenzofuroxan 2 should be represented as a resonance hybrid, 2 *» 2% ·
N.m.r. spectroscopy showed that this idea was incorrect: the proton spectrum
showed an ABC pattern, not an A2B, which the resonance picture would require.
(5) However, the symmetrical structure attracted us as a possible intermedi-
ate, or transition state, in a reaction involving the interchange of N0
2
structural units, one the 4-nitro group, the other part of the furoxan ring·
We looked for, and found, this reaction, which occurred with moderate facility
in a number of examples. (6) The free energy of activation was in the region
of 25 kcal, mol.-1
Cq> Co
O"
(1)
(2) (2·)
The reaction seemed capable of extension, in that it appeared likely that the
NO2 groups - both of them - ould be replaced by other doubly-bonded struct-
ures· Thus we conceived the general rearrangement of Eq· 1 (l), and realised
it for the following ring interconversions:
(nitroso)benzofuroxan into (nitro)benzofurazan (7)
(arylazo)benzofuroxan into (nitro)benzotriazole (7)
(iminoalkyl)benzofuroxan) into (nitro)indazole (8)
(acyl)benzofuroxan into (nitro)anthranil (8), and the reverse (9)·
58
59
Heterocyclic synthesis
It later transpired that the reaction had been anticipated in Italy: some
nitroso- and arylazo-benzofurazan derivatives had been found by Dal Monte
and co-workers (10) to rearrange to isomeric benzofurazan and benzotriazole
derivatives. More recently, the degenerate 7-acylanthranil rearrangement
has been studied by two groups (11, 12), and 7-acetylindazoles and 7-acetyl-
2,1-benzisothiazoles were generated from the appropriate 7-acylanthranil
derivatives (12).
/B
k^N
(1)
A, X = N, Â-0", CR B, Y = NR, 0, S
The general formulae of Eq. 1 represent 8l different substituent/ring system
combinations, with the potentiality for 9 degenerate and 36 non-degenerate
rearrangements. Firm evidence has been obtained for less than a quarter of
these; evidently there is plenty of scope for further development in this
area.
INDAZOLE SYNTHESES
Our first indazole preparation by a reaction of the above type was of the
2-anilino-substituted compound £, which was formed by thermal decomposition
of the phenylhydrazone 2.. An intermediate furoxan (j*) must be formed, and
this rearranges to the indazole, re-generating the nitro group in the position
ortho to that it originally occupied. The yield was rather poor (11%). (8)
„NHPh
CHo .NNHPh
CH3 .N-NHPh CH *N .
3sc o 3sc*
O
N02 \
o
KM
^
(I) (4) (i>
The way to further indazoles seemed open when some 7-nitroanthranils were
found to rearrange thermally to 4-acylbenzofuroxans. This equilibrium (6 5* £)
was at first thought to favour the anthranils exclusively, since the 3-methyl-
7-nitro compound was apparently overwhelmingly favoured over 4-acetylbenzo-
furoxan (j3a) . (8) However, the corresponding 4-formyl compound (6b) coexists
with the anthranil (£b) to the extent of ç_a. 30%, at equilibrium. (13) Two
other 7-nitroanthranils (£c, £d) were found to be thermodynamically less
stable than the corresponding furoxans (,6c, 6_d) . (13» 14)
R1 R2
CH3 H (fi)
H H (b)
H Cl (ç)
NO,
H OMe (d)
(D
Simple refluxing with aniline converted 7-nitroanthranil (£b) into 7-nitro-
2-phenylindazole, in good yield, but with primary aliphatic amines a different
reaction took place, resulting in a mixture of ethyl 3-nitroanthranilate (when
the experiment was performed in ethanol) and the corresponding amide derived
from the amine. (13) In the reaction with aniline, the prior rearrangement of
60
A. J. Boulton and A. R. Katritzky
the nitroanthranil to the formylbenzofuroxan is certainly necessary, and,
furthermore, in the reactions with aliphatic amines, the fact that the major
product is the ester leads us to believe that the mechanism for this degrada-
tion involves deprotonation from the anthranil C-3, giving rise to a ketene
intermediate (8), which reacts with the solvent, as well as the amine (Scheme
l). Neither the reaction forming the anthranilic acid derivatives (£)ι nor
that forming the indazoles (JjO) , involves a direct attack by a nucleophilic
species at the anthranil 3-C atom, although there are a few literature prece-
dents for anthranils reacting in this way, with other reagents.
CH=0 CH=NR
NO*,
N-R
NO,
X = OEt, NHMe
(12)
SCHEME 1
We were able to prepare indazoles with 2-alkyl substituents, by the simple
expedient of separating and isolating the formylbenzofuroxan, and reacting
that with the amine. In this way a variety of 2-alkylindazoles was made (13);
these are tabulated below. The majority of the examples are derived from the
simplest starting furoxan (èJb), but it was in fact easier to work with the
7-methoxy derivative ((>d) , because this was strongly favoured in the equilib-
rium with the nitroanthranil (£d), which we could never isolate or even
detect.
TABLE I. Indazoles (10) from Benzofuroxans and Amines
Yield (%) m. pt. (
Ph H 74 168-169
Me H 36 145-146
Et H 45 73-74
t-Bu H 66 liquid
CH2Ph H 37 122-123
Ph Cl 71 145-146
Me Cl 28 160-161
Ph OMe 62 183.5
Me OMe 56 153
Next, in an attempt to prepare 2-oxy-substituted indazoles, we treated the
4-formyl-7-methoxybenzofuroxan with hydroxylamine and some of its 0-substit-
uted derivatives. The corresponding oximes could be isolated in these cases,
and their rearrangement to indazoles had to be brought about in a separate
heating stage. In the case of the 0-phenyl derivative (.11; R - ^n» **' = OMe),
only a very small yield of indazole was produced, the majority of the reaction
going by some undetermined decomposition pathway. But the majority of the
oximes, including the O-unsubstituted one, gave 2-hydroxy- or 2-alkoxy-
indazoles (JL2) in reasonable yields (Table II).
61
Heterocyclic synthesis
R \\ N
o o
(11)
TABLE II. Furoxan-aldoximes i±l) and 2-0xy-indazoles (12)
Furoxan aldoximes 2-Oxy-indazoles
R R· Yield (%) m· pt.(°C) Yield (%) m· pt.(°C)
H OMe 59 236-240(d) 32 24l-244(d)
Me OMe 54 120-125(d) 45 83-84
CH Ph OMe 43 123-125(d) 64
2 103-105
Ph OMe 73 127-128U) 4 217-218
72 108-109
Me Cl 66 113-114
A literature search for 2-hydroxy- and 2-alkoxy-indazoles revealed that they
are a very little-investigated group of compounds· The parent 2-hydroxy
compound had been prepared by Bamberger in 1902 by an apparently straight-
forward method - thermal decomposition of the 2-azidobenzaldehyde oxime. But
his paper described a rather odd set of conditions for the reaction, and a
very laborious separation from the various by-products which were formed· (15)
A similar reaction, but under less complicated conditions, was performed many
years later in our own laboratory (Ji -► 14) · (8)
N0
2
CH=NOH
Δ
-»
OMe
(H) (14)
But, even before Bamberger, Auwers had prepared some compounds which he
described as 3-aryl-2-hydroxyindazoles. (l6) The method for making them was
to add a diazotized o-aminobenzophenone to aqueous sodium sulphite* This
produces a sticky red precipitate at once, which turns yellow and redissolves.
Then a second, yellow, precipitate appears, and this is the product. It is
very unstable and difficult to purify, but, having been purified it can be
kept under refrigeration for several weeks. The evidence for the structures
of these compounds rested mainly on analytical data, and the fact that they
give 3-arylindazoles on reduction, and 2-aryl-3-indazolinones on rearrange-
ment in alkali· Kametani quite recently has utilised this reaction in order
to prepare the 2-arylindazolinones, and his suggested mechanism for the
2-hydroxyindazole formation, which is closely similar to Auwers's original
proposal, is shown in Scheme 2. (17)
As can be seen, the final step is a most curious one· The 2-sulphonated
compound is a sulphamic acid derivative, and hydroxide ion would not be
expected to displace sulphite at a nitrogen atom; rather, sulphate ion and
the indazole should be formed. It certainly ijs possible to write a reasonable
mechanism for 2-hydroxyindazole formation by this reaction: one simply has to
assume that the diazonium ion reacts with hydroxide first, or with sulphite
ion at the oxygen rather than the sulphur. But we do not believe that these
compounds are 2-hydroxyindazoles at all, for reasons to be explained below.
62
A. J. Boulton and A. R. Katritzky
CO-Ar
NH-NHSOj Na
1
N-OH N-SO^ Na+
SCHEME 2
An attempt to prepare a 3-aryl-2-hydroxyindazole directly, by thermal decom-
position of an £-azidoaryl ketoxime, was unsuccessful. The azide showed a
marked reluctance to evolve nitrogen on heating, and after several hours of
reflux in toluene or xylene the starting compound remained as the predominant
material present, along with many other products in small amount. Photochemi-
cal decomposition gave a similar result, as did the oxime acetate. However, a
2-hydroxy-3-alkylindazole could be made, from the corresponding azido-oxime.
This material was a stable white crystalline solid. Its mass spectrum showed
the parent ion as the base peak. Its infrared spectrum was very unusual: it
showed two strong, very broad, bands with maxima at £a. 2300 and l600 cm."1,
indicative of the presence of a very strong hydrogen bond, in the solid phase.
Qualitatively, the compound is a fairly strong acid. There was also a weak
peak at I63O cm."1, typical of indazoles. (13)
N-OH N-OMe
(1Z)
Diazomethane converted the acid 1%. into a mixture of the 0-methyl (.^6) and
N-methyl i\j) derivatives, and the 0-raethylcompound could also be prepared by
thermolysis of the azido-oxime ()-methyl ether. Qualitatively, the UV spectrum
of _1£ in water resembled that of 1Z rather than that of _16,, suggesting that,
in this medium at least, the N-H tautomer of JJ5, predominates. A drop of
aqueous sodium acetate to the solution of \£ produced a radical change in the
spectrum, now due to that of the anion.
The "2-hydroxy-3-arylindazoles" were very unstable indeed, particularly in
non-polar solutions. The first time we attempted to run the IR spectrum of the
5-chloro-3-phenyl compound in chloroform (which had been carefully purified
and dried), a strong band at l800 cm.""1 was seen, and the cell contents smelt
strongly of COCI2· *n alcohol and ether solutions the compounds are much more
stable. The mass spectrum showed either no parent ion or one <1% of the base
peak (and this was unconfirmed by accurate mass measurements). The IR spectrum
(solid phase) showed a rather pointed, strong band at ca. 3200 cm."1, with no
absorption in the "double bond region" until l600 cm.^ The UV spectrum did
not change on addition of acetate, or of dilute NaOH, although it did change
(reversibly) when made strongly alkaline. This is in agreement with Auwers's
observation that the products are soluble in alkali, and can be re-precipit-
ated on acidification. Significantly, the spectra of the neutral compounds all
showed a weak band (c £a. 150) at about 38Ο nm.
Comparison of these data with those for the 3-alkyl compound (!£) shows almost
no points of resemblance. In fact, we believe that the 3-aryl compounds are
all compatible with their formulation as 2,-hydroxy derivatives (lQ), This