It is hard to believe that it is now 50 years since I conceived the concept of periodical volumes of these Advances that would record progress in Heterocyclic Chemistry. In , heterocyclic chemistry was slowly emerging from the dark ages; chemists still depicted purines by the archaic structural designation introduced was it by Emil Fischer? Together with Jeanne Lagowski I had published in a modern text on heterocyclic chemistry, the first that treated this subject in terms of structure and mechanism and attempted to logically cover significant methods of preparation and reactions of heterocyclic compounds as a whole, all in terms of reactivity.
The first two volumes of Advances contained extensive chapters on the tautomerism of various classes of heterocycles. Despite the great influence the precise structure of heterocyclic compounds has on chemical and biological properties we only have to remember base pairing of nucleotides to illustrate this , at that time the literature was replete with incorrectly depicted tautomers. The basis for the position of tautomeric equilibria was usually completely misunderstood.
Although great progress has been made in the last 50 years, there still exist holdouts even among otherwise reputable chemists who persist in depicting 2-pyridone as 2-hydroxypyridine which is a very minor component of the tautomeric equilibrium under almost all conditions. Over the years Advances in Heterocyclic Chemistry has indeed monitored many of the advances in the subject: the series is now boosted by Comprehensive Heterocyclic Chemistry of which the first edition was published in in 8 volumes, followed by the second edition in in 11 volumes and the third in in 15 volumes.
Heterocyclic chemistry has now taken its place as one of the major branches by several criteria the most important of Organic Chemistry. Chemistry has rapidly become the universal language of molecular interactions; it has essentially taken over biochemistry and is rapidly gaining dominance in zoology, botany, physiology and indeed in many branches of medicine.
Chemical structural formulae are quite basic to this progress and have enabled us to rationalize many natural phenomenon and countless reactions both simple and exotic discovered in the laboratory. Now we have reached the milestone of volumes of the series. In place of a single volume we are offering the three volume set 99, and which contain a fascinating variety of reviews covering exciting topics in heterocyclic chemistry. Albert Padwa Emory University starts the volume with a fascinating chapter on the cycloaddition and cyclization chemistry of 2H-azirines, an area in which he has been closely connected with some of the most interesting developments.
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Nuzhat Arshad and Dr. Professor Edmund Lukevics, with Drs Abele and Ignatovich, reviews the chemistry of biologically active silacyclanes covering some lesser known aspects of silicon chemistry and the evidently very wide range of possible structures here. Professor Leonid Belenkii Zelinsky Institute, Moscow has rationalized the orientation of substitution in furan, thiophene, and pyrrole. Finally, Professor Boris Trofimov, together with three colleagues from the Irkutsk Institute of the Russian Academy of Sciences, gives an account recent advances in the chemistry of N-vinylpyrroles obtained from ketones and acetylenes.
Azirines can be regarded as one of the most simple of all heterocyclicsystems, one which is characterized by the presence of two carbon atomsand one nitrogen atom in a three-membered ring containing a p-bond. Interest in thesenitrogen-containing small rings is due to the general influence of ringstrain upon chemical reactivity, to the degree to which the 1H-azirinering, for example, is destabilized by conjugation of the nitrogen lone pairelectrons with the p-bond, and to the potential of derivatives of thesecompounds to act as precursors to more elaborate heterocyclic molecules.
The stabilities and overall profiles of chemical reactivity of theseheterocycles are attributable not only to the combined effects of bondshortening and angle compression, but also to the presence of theelectron-rich nitrogen atom. With 1H-azirines, cyclic delocalization of thelone pair electrons is believed to destabilize the ring to an extent whichprecludes isolation but not detection of the 4p-electron containingantiaromatic ring system.
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Polarization toward the more electronegativenitrogen atom of the 2H-azirine ring results in a shorter CN bond and alonger CC bond, consistent with the dimensions of 2H-azirines foundby single crystal X-ray data 97CEJ The stability of the 2H-azirinering can be attributed not only to the combined effects of bondshortening and angle compression, but also to the presence of theelectron-rich nitrogen atom.
The strain energy associated with theseheterocycles is principally due to deformation of the normal bond anglesbetween the atoms of the ring. The chemistry of 2H-azirines is dominated by processes inwhich the strain of the three-ring system is relieved. They readilyparticipate in cycloaddition reactions as 2p-components and undergoring cleavage on photochemical excitation to give nitrile ylides.
Thesedipoles then undergo a subsequent 1,3-dipolar cycloaddition reactionwith a variety of p-bonds.
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Thermal ring cleavage produces vinyl nitrenesby cleavage of the NC2 bond, which then undergo ring expansionreactions. The theoretical, biological applications, and the syntheticchemistry of 2H-azirines have been extensively explored and a numberof general reviews have appeared 01EJOC, 02OPP Figure 1. Molecular orbital calculations suggest that C—C bond cleavage can actually occur more readily than C 2 —N bond cleavage 78JA C 2 -C 3 cleavage.
Taniguchi and coworkers have shown that the thermal reactivity of 2H-azirines varies with the substitution pattern on the azirine ring 69TL Alkyl and aryl substituents at C 2 were found to increase the stability of the ring. The thermal chemistry of a number of aryl-substituted 2H-azirines often results in the formation of indole derivatives 68TL Thus, heating a sample of 2H-azirine 69 gave 3-phenylindole 72 and dihydropyrazine The formation of 72 was suggested to proceed via a vinylnitrene intermediate which cyclizes and then undergoes a 1,5sigmatropic shift Scheme 20 77H The 2H-azirines obtained from the vapor phase pyrolysis of 4,5disubstituted 1-phthalimido-l,2,3-triazoles 74 have been found to undergo further thermal reactions 71CC Those 2H-azirines which contain a methyl group in the 2-position of the ring are cleaved to nitriles and phthalimidocarbenes, whereas those 2H-azirines which possess a phenyl substituent in the 2-position rearrange to indoles Scheme Unambiguous evidence for a thermal C—C cleavage has been obtained, however, in the vapor phase pyrolysis of several 2H-azirines 76JOC Vapor phase pyrolysis of 2-dimethylamino-2H-azirine 86 proceeds in a similar manner at 1C to give the substituted azadiene 87 in high yield 75JA For example, the thermal transformations observed on thermolysis of 2H-azirine 28 were rationalized in terms of an equilibration of the 2H-azirine with a butadienylnitrene, which subsequently rearranged to the final products.
Other examples of this rearrangement have been reported to occur with ester, acyl and cyano groups 72TL The formation of pyridine 94 was postulated to arise by insertion of the butadienylnitrene into the neighboring allylic methyl group followed by oxidation of the transient dihydropyridine In the absence of factors such as strain, pyrrole formation i. Thermolysis of 2H-azirines bearing an aldehyde or imine substituent at C 2 leads to the formation of isoxazoles and pyrazoles, respectively e. The reverse reaction, thermolysis of an isoxazole to afford a 2H-azirine, has also been reported 69TL Thermolysis of 2H-azirines bearing aromatic substituents i.
However, when only one phenyl group is present on C 2 , the intermediate vinyl nitrene can rearrange to a nitrile 68TL The formation of can be explained in terms of an equilibration of the 2H-azirine with a transient vinylnitrene which subsequently adds to the adjacent p-bond. The initially formed bicycloaziridine rearranges to the 3-azabicyclohexene ring system by means of a 1,3-sigmatropic shift. The thermal behavior of the closely related homoallyl-substituted 2Hazirine has also been studied 77JA Heating a solution of in toluene gave 2-methylbiphenyl and 2,5-dimethylphenylpyridine The formation of these products is explained in terms of vinylnitrene which undergoes a 1,4-hydrogen transfer from the neighboring methylene group to generate azatriene Electrocyclic closure to cyclohexadiene followed by loss of ammonia readily accounts for the formation of the substituted biphenyl derivatives.
The formation of involves an insertion of the vinylnitrene into the vinyl group followed by tautomerization and a subsequent oxidation Scheme It should be noted that the thermal cleavage of the C—C bond of 2Hazirines is less common than C 2 —N bond cleavage and requires substantially higher temperatures 82MI These reactions are believed to proceed via iminocarbene intermediates which undergo a 1,4hydrogen transfer to yield 2-aza-1,3-butadienes.
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Scheme 29 shows an example where electrocyclization of the azabutadiene leads to a dihydroquinoline 76JOC The thermolysis of 3-amino-2H-azirines affords isolable 1-aminoazabutadienes 91AG A similar process involving 3-alkoxy-2H-azirines 86RTC is also given in the same scheme. Cycloadditions also occur with heterocumulenes such as ketenes, ketenimines, isocyanates and carbon disulfide. Methyl 2-aryl-2H-azirinecarboxylates are good dienophiles and they readily react with a variety of dienes to give bicyclic products such as and by cycloaddition across the C—N double bond Scheme The cycloadditions are endo-selective and the dienophile approach takes place from the less hindered face of the 2Hazirine 97S, 98TL, 98JCS P1 The Diels—Alder reactions of a chiral ester of 2H-azirinecarboxylic acid with cyclopentadiene was observed to be highly diastereoselective 99JCS P1 Activation of 3-alkyl and 3-phenyl-2H-azirines by Lewis acids also promotes their participation in hetero Diels—Alder reactions with a variety of dienes.
This methodology circumvents the previous requirement of needing an electron-withdrawing carboxyl moiety at the 3-position of the 2H-azirine ring 01TL Several other, less activated dienes, were also be used for this reaction. Without the presence of a Lewis acid, no diastereoselectivity was obtained at room temperature. The dramatic effect observed on the reaction diastereoselectivity upon addition of a Lewis acid to 2H-azirine was explained by a bidentate coordination of the Lewis acid to the 2H-azirine nitrogen and the carbonyl group.
This chelation would lead to hindered rotation around the 2H-azirine carbonyl single bond and thus greater stereoselectivity. The increased reaction rate also indicates coordination of the Lewis acids to the 2H-azirine which leads to a lowering of the LUMO energy level and thus an increased reactivity toward the electron-rich diene Scheme A mixture of diastereomers are formed which implies that an isomerization is taking place about C3 to C4 during the course of the reaction Scheme This cycloaddition represents the first example of a reaction between an activated 2-azadiene with an electron deficient 2H-azirine.
The formation of was rationalized by a stepwise mechanism.
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The initial addition of the fulvene to the activated 2H-azirine generates the zwitterionic intermediate which then cyclizes to pyrindine via intermediate Scheme The structure of was unambiguously assigned by single crystal X-ray structure. Still another example of a bimolecular cycloaddition of the 2H-azirine ring system involves the thermal reaction of with cyclopentadienone to give 3H-azepine 72JOC, 72JA Cheletropic fragmentation of adduct furnishes azanorcaradiene This material undergoes a disrotatory electrocyclic ring opening followed by a 1,5-suprafacial hydrogen shift to give the thermodynamically most stable 3H-azepine ring Scheme A variety of heterocyclic products are produced depending on the structure of the 2H-azirine and tetrazine used and the reaction conditions Scheme The formation of pyrimidine from the reaction of aziridine with 2H-azirine in toluene was rationalized by a 1,3-dipolar cycloaddition across the 2Hazirine p-bond.
This transient intermediate underwent a subsequent ring opening reaction with elimination of HBr leading to dihydropyrimidine and this was followed by aromatization to give the observed product Scheme 41 03TL The reaction of 2H-azirinecarboxylate with diazomethane occurs to produce a 4,5-dihydro-3H-pyrazole derivative The process seemingly involves the reaction of 2H-azirine with diazomethane to give cycloadduct as a transient species which then undergoes a subsequent rearrangement to generate allyl azide This compound participates in a second 1,3-dipolar cycloaddition with diazomethane to give Scheme The interaction of diazomethane with 2H-azirines was reported in 64JOC and represents the first example of a 1,3-dipolar cycloaddition with this ring system.
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This material can exist in equilibrium with its valence tautomer , and allylic azides and are subsequently produced from these triazolines by ring cleavage Scheme Aziridines such as undergo thermal ring opening in a conrotatory manner to generate azomethine ylides. The 4p-electron system of nitrile oxides can also participate in 1,3dipolar cycloaddition with 2H-azirines 71TL A possible mechanism for the formation of the carbodiimide assumes the initial formation of a cycloadduct from a 1,3-dipolar addition between the nitrile oxide and the 2H-azirine.
Ring cleavage of the bicyclic adduct or its valence tautomer is followed by a 1,2-migration of the R group of the nitrile oxide in a Beckmann-type rearrangement to give the carbodiimide Scheme The reactions of 2H-azirines with ketenes and ketenimines represent non-concerted additions and are formally different from the additions to 4p-systems of dienes and 1,3-dipolar compounds 73JOC, 71CB Some photochemical sequences increase molecular complexity more than others, but each seems to provide complex heterocyclic structures in a very efficient manner. Indeed, many of these photoreactions rapidly construct hetero-polycyclic systems that are difficult to produce in other ways.
In contrast to their photochemical behavior, the major thermal reaction of 2H-azirines generally involves C 2 —N bond cleavage to form vinyl nitrenes which further react by either insertion into an adjacent C—H bond or else undergo addition across a neighboring p-bond. It is clear from the above discussion that the chemistry of 2H-azirines is both mechanistically complex and 28 Albert Padwa synthetically useful. No doubt additional work with this fascinating small ring nitrogen heterocycle will be forthcoming in the future.
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