CfiEM FEATURE
Heterocycles High growth potential dwdits exploitation by modern methods
A l a n R. Katritzky, University of East Anglia, England
eterocycles are still for many chemists a field to be avoided. The opinion is often advanced, and sometimes really held, that the area is good only for pharmaceutical molecular roulette players and that the true. chemist, above all the physical organic chemist, should not sully himself with the approximations and additional complications (? interests) involved when nitrogen atoms are present. Here, I seek to outline some of the recent advances made in our understanding of heterocyclic chemistry and to suggest the paths along which the field may be further exploited in the next decade.
H
Why heterocyclic
chemistry?
For a variety of complex, fascinating, but, for the present purpose, irrelevant reasons, different brands of chemical research have acquired variable status ratings in different countries. Thus in the U.S. carbonium ions and strained carbocyclic rings are currently among the "with-it" topics, whereas in Britain natural product chemistry has long reigned as queen. The situation has a large factor of a vicious circle about it. The brightest students are drawn to the best professors, and research interest patterns are often formed during Ph.D. or postdoctoral training. Thus, even in the "teach them to swim by throwing them in" environment of the U.S., where the young academic apparently has a wide open choice of his research field, preconditioning too often molds him in a stereotyped image. Why heterocyclic chemistry? I believe that chemists of all ages should give this field more attention for the following reasons: • Above all because the vast field is crammed with interesting problems ripe for exploration with the modem physical and theoretical techniques now available. • Life is heterocyclic: Biochemical mechanisms very frequently involve heterocyclic substrates or heterocyclic enzymes or coenzymes as catalysts. • Every area of carbocyclic chemistry finds another dimension by the introduction of heteroatoms. The threemembered heterocycle diazine CH 2 N 2 , and the stable 80 C&EN APRIL 13, 1970
difluoro derivative CF 2 N 2 , for example, are as fascinating as any strained carbocyclic. • Most complex natural products are heterocycles, and their reactions can only be properly appreciated if those of the constituent parts are understood. • Heterocycles are pre-eminent among dyes and pharmaceuticals and are also important in polymer chemistry. Aliphatic and carbocyclic chemistry were rightly exploited the most fully first, but now we chemists should all pause to consider the advances that have been made and the future potential of the heterocyclic area. New «types of heterocyclic natural products are continually turning up: Recently pyrazole, isoxazole, and oxazole derivatives were described and a tribromopyrrole was also isolated. Herbicides such as praraquat and diquat herald a new agricultural revolution with far-reaching consequences for the future of food production. Until quite recently no modern textbooks covering heterocyclic chemistry were available. However, since 1960 a series of one-volume treatments have appeared; several are now in revised versions. Thus although most chemists above the age of 35 ( and many below it! ) will not have had an adequate undergraduate or graduate course in the subject, they have now a wide variety of selfhelp manuals available. As these books clearly show, heterocyclic chemistry is a logical subject. The wide variety of ring systems and substitution possibilities allows subtle changes in properties to be attained. The field of possible heterocyclic compounds is vast because of the infinite permutations and combinations. Since the chemical and physical properties of the derivatives are logically related to the structure in ways that are becoming better and better understood, chemists who want to avoid scientific obsolescence in the next decade must be familiar with the advances already made and the potential for new discoveries. The future of chemistry, like that of history, is mirrored in the past for those who can read the signs; I hope this article will help readers to assess the possibilities of the subject in their own areas.
Small rings Three- and four-membered rings were for long chemical curiosities, weighted with the deadly ballast of last century strain theories; ethylene oxide and ethylene imide are fre quently not considered heterocyclic compounds at all. E. Schmitz's discovery of cyclodiazomethane, Cl-L
Ν
in 1961 at the German Academy of Sciences, Berlin, shat tered a good many illusions. For long, teachers and texts had eliminated this structure from consideration for "com mon" diazomethane because of "impossibly high" steric strain. In reality, diazirine is, if anything, thermally more stable than diazomethane:
The textbook embarrassment Although β-lactams (four-membered rings) were, somewhat re luctantly, admitted to the ranks of "recognized" chemical com pounds several decades ago, the impossibility of discovering stable a-lactams 1 was confidently asserted in textbooks until very recently. It is now clear that the α-lactam structure is not intrinsically particularly destabilized, relative to open-chain products. The high reactivity is a consequence of low activa tion energies for transformation. When approach to the ring is hindered by bulky groups, the compounds can readily be isolated. In the case of the cyclic azoxy compounds 2, bulky groups probably raise the energy of the unsymmetrical azoxystructure relative to the cyclized form
C .4?
Η To the embarrassment of the writers of many chemical texts, α-lactams
Ν ι
.C-C C
N.
'M'
\ / Ο
-CN
C - C - CH- C c
Ν Despite these recent advances, the commercial possibilities and synthetic potential of such three-membered heterocycles remain virtually unexplored, except possibly for the use of oxaziridines as the basis of manufacturing hydroxylamine. Meanwhile the field of fused heterocycles with three-membered rings is being opened up: A. G. Hortman and D. A. Robertson of Washington University in 1967 described the azabicyclobutane
and cycloazoxyderivatives
fi
c-c
V
c-c c
containing ierf-butyl groups are isolable crystalline and reasonably stable compounds; other derivatives with threemembered rings recently prepared include aziridinium salts
and L. A. Paquette and his group at Ohio State in the same year published details of the first azabulvalenes, which contain at least a potential CCN ring. In the next few years many more fused three-membered heterocyclic compounds will doubtless be reported. Heterocyclic compounds with four-membered rings still show no sign of receiving the attention they deserve. Glimpses of the fascinating possibilities are revealed by a few recent examples of such derivatives fused to aromatic systems.
and vinylene sulfones:
,Ph
Isomers of diazomethane Diazomethane 1 is an explosive gas that is frequently used as a methylating agent. Its structure was in the past much dis cussed, and the cyclic structure 2 was among those advanced. This was ruled out, however, because it was held to be too sterically strained to exist. In fact cyclodiazomethane 2 is at least as thermally stable as the linear variety 1. A third isomer, isodiazomethane, has recently been shown to possess the isonitrile structure 3
0Ώ-* and by the intriguing new small-membered heterocycles such as
,N CHOISI = N
1
Hzc ||
\ Ν
3
I I A r , O N — CH2 APRIL 13, 1970 C&EN
81
prepared by Ε. C. Taylor at Princeton from ketone hydrazones, but the chemistry of the simple monocyclic com pounds with one or two heteroatoms can only be described as woefully neglected. Here is potential enough for reac tive intermediates and physiological activity. Industrial exploratory groups and grant awarding bodies take note! Five-membered
rings
The chemistry of furans, thiophenes, pyrroles, and some of the azoles belongs to one of the most thoroughly studied areas of heterocyclic chemistry. But among five-membered ring derivatives, there remains plenty of opportunity for novelty, particularly if the potential of the less common heteroatoms is realized. The work of the versatile Romanian chemist A. T. Balaban during the past five years has revealed fascinating pos sibilities of boron-containing five-membered heteroaromatic rings such as:
A big future for diazapentalene? Sa, βα-Diazapentalene is an example of a new heterocyclic sys tem that may have a big future application if synthetic routes can be improved to enable its preparation in quantity. It is aromatic with 10 ττ-electrons and is highly resonance stabilized ( 1 2 others). It is expected to undergo electrophilic substitution readily and might form the basis for new classes of dyestuffs, pharmaceuticals, pesticides, and the like
CD—Q> 1
3a,6a-Diazapentalene
©co§> J. H. Morris (Kingston, Surrey, England) recently pre pared the cyclotetraazaboran system /
\
Η of interest as a stable heterocyclic azole not containing carbon. Syntheses of phospholes
by R. C. Cookson at Southampton, England, and G. Mârkel at Wurtzburg, West Germany, have made this system now comparatively readily accessible. It shows little evidence of aromatic stability. The reaction of PhPLi 2 with o-diiodobenzene to yield
is a stable aromatic ring system that could have a big future if synthetic methods to make it can be streamlined. Other known hetero derivatives of pentalene include tetraazapentalenes and the 2-thia- and 4-aza-pentalene anions. Their stability contrasts with the unknown, antiaromatic hydrocarbon. Returning to azole chemistry, the Russians A. F. Pozharsky, E. A. Zvezdina, and A. M. Simonov of Rostov found that 2-aminobenzimidazole was converted into 2-nitrobenzimidazole by sodium and liquid ammonia. This unexpected oxidation was attributed to the formation of intensely nucleophilic dianions of type
00* which are then oxidized by atmospheric oxygen.
Six-membered
gives an indication of the manifold possibilities for the preparation of further new phosphorus-containing rings. In the heterocyclic chemistry of sulfur, American Cyanamid's E. Klingsberg found in 1966 evidence for "no-bond resonance" in
and the contemporary researches of N. Lozac'h and his coworkers at Caen, France, led him to similar conclusions regarding:
82 C&EN APRIL 13, 1970
2
rings
The exploitation of N-oxide intermediates, initiated by the discovery by E. Ochiai's Tokyo group of the facile 4-nitration of pyridine 1-oxide, gathered pace in the 1950's and shows no sign of slackening, with Japanese chemists still to the fore. Oregon State's V. Boekelheide has specialized in the synthesis of "cyclazines," that is, ring systems of type
in which the heterocyclic atom is embedded within a carbon skeleton. The exploration of aza steroids con tinues by H. O. Huisman in Amsterdam and other workers elsewhere. There are signs of an end to nitrogen's near monopoly of six-membered heteroaromatic rings. Du Pont chemist S. Trofimenko reacted pyrazole with borane and thus formed the first pyrazabole
H2
+
«2 with obvious and immediate possibilities for new types of ladder polymers by providing a method of linking imidazole units of benzobisimidazoles and similar compounds with boron connecting groups. Aromatic boron-nitrogen compounds have been exploited during the past decade at Austin, Tex., by M. J. S. Dewar, for example:
Considerable progress in synthesizing aromatic boronnitrogen compounds has been achieved, but the reactions of these compounds are still largely unexplored. During the past three years, the similar but independent work of the groups of G. Mârkel at Wuerzburg and K. Dimroth at Marburg on phosphabenzenes
Ph
Ph
Ρ
Ph
has made these compounds available in greater quantity and ripe for further exploitation. If they ever achieve 1% of the importance that their nitrogen analogs, the pyridines, now enjoy, they will amply repay their exploiters. Among sulfur-containing six-membered rings, it appears that those with hexavalent sulfur
Ph
but more toilers are required to mine these rich seams. Metal chelates can be considered as heterocyclic compounds and consideration as such is more than a semantic possibil ity. Aromaticlike substitution reactions have been re ported; for example, acetylacetates. Space does not permit discussion of this work here. Medium and large rings The surface is but scratched of this enormous area of medium and large rings. Heteroaromatics with sevenmembered boron-containing rings such as
B-Ph have been reported and attention has been given to the benzene oxide-oxepin valence tautomeric system:
O^o Azacyclooctatetraenes have been prepared and a study of their reactions commenced. Several hetero-analogs of the annulenes have been described. The Cologne group headed by E. Vogel bridged the [10]-annulene ring with oxygen and nitrogen
Z=0 RN The preparation of benzofurans by Sheradsky
α
CH,-R I
is a novel analog, obvious once it was reported, of the familiar Fischer indole synthesis. 6-Nitrostyrenes yield indoles 84 C&EN APRIL 13, 1970
rearrangements
)CH
oH Κ
•€t
CH
NH +
Photochemically the transformation succeeds in 35% yield. This was to be expected as earlier the Zurich group had converted pyrazoles into imidazoles:
n«
G H
H. Wynberg at Groningen, Netherlands, has contributed significantly to this area of phototransformation with his elucidation of the rearrangement of 2- to 3-phenylthiophene. The phenyl group moves loith its ring carbon atom as he demonstrated in 1966 by isotopic labeling:
The mechanism involved the rearrangement
The mechanism presently favored involves the intermediate: • Ph which is again an example of a new general type of molec ular acrobatic. Anotlier remarkable class of rearrangements, also in vestigated in the Netherlands during the past few years at the Agricultural University, Wageningen, is H. J. den Hertog's and M. C. van der Plas' conversions of pyridines into pyrimidines and pyrimidines into triazines. 2,6-Dibromopyridine reacts with sodamide to give 4-amino-2methylpyrimidine by the mechanism shown
H2NWH
Br
N^Br
Br
Ν
Br
•Φ &r
iC
Ring-opening
and aromatic
character
Aromaticity is difficult to define and to measure. We all know what we mean by an aromatic compound: An aromatic compound retains its cyclic conjugation through all sorts of reaction sequences. Perhaps the best quantita tive measure is by nmr ring currents, but just how ap plicable this is to heterocycles is controversial. Anyway, it is becoming increasingly evident that heterocyclic rings can often reversibly lose their aromatic character. Thus the phenomenon of covalent hydration, originally discov ered in the quinazolinium cation
H ^
Br
HISU Η ' ΌΗ
W e have here one of the first instances where a hetero cyclic ring opened between two carbon atoms. Heating the nitro azide gives directly the nitro anthranil
consists of the stabilization of (usually) a polyaza ring by the addition of a molecule of water. It is a widespread phenomenon with important consequences and during the past decade has been extensively investigated by the experienced Australian heterocyclic chemist A. Albert and his colleagues, especially W. L. F. Armarago. A label on the 2-nitrogen atom in 2-aminopyridme is scrambled
*^K ΝΗ„ at 200 °C by a reversible ring-opening of the Dimroth type to a glutaconaldehyde-acid derivative. In Norwich we found in 1965 that the simple looking reaction of 1methoxypyridinium ion
The synthesis of muscazone The "reshuffling" of the ring atoms of five-membered hetero cycles on irradiation is now known to be of widespread occur rence: 1 —> 2 and 3 -> 4 are just two examples. These reac tions are related to the photochemical isomerization of sub stituted benzenes to give "Dewar-benzenes" 5, and benzvalenes 6. The ready conversion of ibotic acid 7 into muscazone 8 was therefore to be anticipated
U—U
Q ^o^cH^-HfoH was accompanied by reversible ring-opening:
Ph s
Ph
s 4
CH3ΟΪ4 (CH=CH) C H - O ; OH
CH3ON =CH (θ4 = C H ^ 0~
I predict that reversible ring-opening of heterocyclic species will be found to be far more common than is presently appreciated, and that such reactions will be come of increasing preparative significance. K. Hafner at Darmstadt blazed this trail back in 1955 by his elegant conversion of pyridine to azulenes: APRIL 13, 1970 C&EN
85
2 υ
Heferocycles also help homocyclic chemists
I
so; Reactions of special synthetic
significance
Heterocyclic intermediates are of the greatest impor tance in the synthesis of other chemical compounds. Isoxazoles have already been exploited in several direc tions with outstanding success. At Harvard, R. B. Wood ward found that peptides could advantageously be syn thesized using isoxazolium salts
He/
Rco2H
ti C
o3§.
The heterocyclic isoxazole ring can be opened readily at the N-O bond in two ways, via proton abstraction at the 3-position or by reduction. Both of these reactions have already been used in the synthesis of nonheterocyclic compounds. The proton abstraction occurs particularly readily in quaternized isoxazolium compounds and is the basis of a useful preparation of enolesters 2, which readily acylate amino compounds to form peptide links. The reductive fission of the isoxazole ring has been even more widely applied; the reaction sequence 4 —> 6 is an example
COHHët
O-COR
RMHZ
H C /CONHÉt
OaS
Π C
The potential of benzotriazole Benzyne or dehydrobenzene 3 is a short-lived species that can readily be trapped in the form of its adducts with dienes. The oxidation of 1-aminobenzotriazole 1 yields the intermediate nitrene 2, which loses two molecules of nitrogen smoothly to form benzyne. Substituted benzynes of known orientation have been prepared analogously. 1-Chlorobenzotriazole 4 is a "positive halogen" compound of the same general type as N-bromosuccinimide, but is more stable. It behaves as a useful oxidizing agent, converting, for example, secondary alcohols into ketones; in the process it is reduced to benzotriazole and hydrogen chloride
\ Ν'
Η
M
1
who
extolls the
virtues
of
o> 1
as an oxidizing agent. 86 C&EN APRIL 13, 1970
ce
Ν Ν7 Ν:
NH, and
, RNHCOR
o-CoR.
R'NHCOR which convert carboxylic acids into the activated enol esters enabling the synthesis of the peptides. The isoxazole annulation recently proposed for steroid synthesis by the Columbia natural-product master G. Stork should have a bright future in steroid and terpene chemistry. Easily prepared derivatives are ring-opened by hydrogénation to intermediates which close again to the annulated ketones:
In this manner a potential extra ring may be kept until the reactive grouping is released by reduction. Isoxazoles have also been used in the synthetic route aimed at the corrins by J. W. Cornforth at Sittingbourne, A. Eschenmoser at Zurich, and R. B. Woodward at Harvard. The potential of benzotriazole has attracted the attention of Leicester University's C. W. Rees who uncovered a neat route to benzyne from 1-aminobenzotriazole
/
RNHZ :>•
1-chlorobenzotriazole
1
Ο
Ν
4 ct
Alkynyl thioethers are advantageously prepared 1,2,3-thiadiazoles by the synthetic route indicated
ι\
RLi
from
RBr ArCsCSLi
ArCsCSR
and in 1968, H. H. Wasserman at Yale found that G>cyanoacids were readily available by the dye-photosensi tized autoxidation of oxazoles :
WC(CH Z \CO 2 H
• Free radical, R. A. Abramovitch at Alabama. •Electrophilic substitution, K. Schofield at Exeter, and J. H. Ridd at London. Until fairly recently it was not known whether the difficulty in making pyridines undergo electrophilic sub stitution was a result of the extreme difficulty of attack of an electrophile on the pyridinium cations formed in the acidic media used—Wheland intermediates with two posi tive charges—or because the reactions occurred on the minute concentration of free base species present. At Norwich, during the past two or three years we have shown that the pyridines with activating groups normally do react via doubly charged intermediates,
Me H. A. Slaab and his coworkers at Heidelberg, Germany, have made imidazole a well-known reagent within the past decade. 1-Acylimidazoles, for example, are versatile intermediates for the acylation of a wide range of sub strates. A climax in this research was the preparation of the long-sought formyl chloride HCOC1 using hetero cyclic intermediates. Dihydro-l,3-oxazines form the basis of an excellent synthesis of aldehydes. Dihydro-2,4,6,6tetramethyl-l,3-oxazine can readily be alkylated to yield 2-substituted derivatives, which are converted by borohydride reaction and hydrolysis to the aldehyde, as shown by A. Meyers at New Orleans:
^o-^crig ^,4,6,6l,3-
