Of six-membered heterocycles

The tautomerism of six-membered heterocycles has been referred to elsewhere (Section 2.01.1), in connection with the variety of aromatic structures available to heterocyclic compounds. In this section we consider the matter in more detail. For a fuller discussion the reader should consult the monograph by Elguero et al. (76AHC(S1)) which thoroughly covers work on the subject up to 1976. 

The Diels-Alder reaction is of wide scope. Not all the atoms involved in ring formation have to be carbon atoms the hetero-Diels-Alder reaction involving one or more heteroatom centers can be used for the synthesis of six-membered heterocycles. The reverse of the Diels-Alder reaction—the retro-Diels-Alder reaction —also is of interest as a synthetic method. Moreover and most importantly the usefulness of the Diels-Alder reaction is based on its 5y -stereospecifi-city, with respect to the dienophile as well as the diene, and its predictable regio-and c ifo-selectivities. °... 

In contrast with the hitherto described silylation-aminations of six-membered heterocycles, silylation-amination of five-membered hydroxy-N-heterocycles such as benzoxazol-2-one 289 with excess benzylamine and HMDS 2, to give 2-benzyla-minobenzoxazole, fails, because of the equilibrium between 2-trimethylsilyloxy-... 

Apart from characterization of the individual types of six-membered heterocycles by routine spectroscopic methods, several cationic cyclic diketiminato-phosphenium ions and 1,8-diamidonaphthalene-derived P-chlorophosphines and phosphenium ions, respectively, were characterized by single-crystal X-ray diffraction studies. The P-halogen- and P-hydroxy-substituted cyclic diketiminato-phosphenium ions 28... 

One of the most important species of six-membered heterocycles is represented by the pyrimidine group. Simple synthetic approaches therefore are of great importance. 

Two types of reaction are known which involve ring contraction of six-membered heterocyclic systems and present mechanistically intriguing problems. One is the ring contraction of the diphenyltriazinone (10) Treatment with chloramine gives a 4,5-diphenyl-w-triazole in high yield. A mechanism (Scheme 26) involving a 2-carboxamidotriazole... 

Ring contractions of six-membered heterocycles have also been reported to yield both reduced (75) <84JA7867> and oxidized (76) <86JCS(Pl)643> forms of thiadiazole (Equations (14) and (15)). 

The reactions and reactivity patterns of heterocyclic compounds are rich and varied they are also in very many instances predictable with a high or complete degree of accuracy. The heterocyclic or natural product chemist can therefore, for example, plan multistage syntheses in the reasonably secure knowledge that individual steps will proceed as expected. The objective of the chapter is to give the general and non-specialist reader a feel for these reactions and reactivity patterns in the area of six-membered heterocycles. 

It is generally observed that a C—H bond which is antiperiplanar to a lone pair of electrons (65) is weakened and susceptible to removal by electrophilic or free-radical oxidizing agents. This provides an explanation for the ready hydroperoxidation of aliphatic ethers, both cyclic and acyclic, by atmospheric oxygen. These considerations, however, go beyond the special area of six-membered heterocyclic reactivity presently considered. 

There are few examples of the preparations of heterocyclic compounds containing two or more heteroatoms which involve cyclization with formation of a bond between two heteroatoms. The best known instances of this type of reaction, all of which are [6 + 0] reactions, are the preparations of benzocinnolines as outlined in equations (l)-(4). A similar type of approach to that outlined in equation (4) has been used for the direct preparation of the di-N-oxide (2) from the dioxime (1 equation 5). The naphthotriazine betaine (4) is obtained as one of the products of the thermal decomposition of the azidoazo compound (3 equation 6). 1,2-Dithiins and their dibenzo derivatives have been prepared by oxidation of appropriate dithiols and related starting materials as outlined in equation (7). All of these reactions are, however, somewhat specialized and there has been essentially no systematic study of the preparation of six-membered heterocycles via formation of a bond between two heteroatoms. 

As with the other procedures for the preparation of six-membered heterocyclic systems which proceed via formation of only one ring bond there are relatively few methods which involve formation of a ring bond y to the heteroatom and which can best be classified as [6 + 0] processes rather than [4 + 2], [3 + 3], etc, processes. Of those which can be so represented, however, a number are important processes which are widely used for the synthesis of saturated, partially saturated and aromatic six-membered heterocyclic systems and their benzo derivatives. Mechanistically, the nucleophile —> electrophile approach is by far the most common, but in contrast to the reactions discussed in the previous three sections, radical cyclizations are of considerable utility here. 

Condensation of a 1,4-nucleophile-electrophile with a 1,2-electrophile-nucleophile is the most versatile and widely exploited of these nucleophile -+ electrophile reactions for [4 + 2] heterocyclization and a number of classical methods for the preparation of six-membered heterocycles are based on this principle. Representative examples are given in equations (83)-(88). 

Synthetic methods for the preparation of six-membered heterocyclic systems which proceed via the formation of three or four bonds are virtually restricted in application to the monocyclic heterocycles and have been most widely applied to pyridine and pyrimidine derivatives. In principle, reactions which proceed with the formation of three ring bonds can be sub-classified into three groups, namely, those involving [4 + 1 + 1] atom fragments, [3 + 2 + 1] atom fragments and [2 + 2 + 2] atom fragments. 

The most important use of oxiranes for the preparation of six-membered heterocycles is in 1,4-dioxane formation. 1,4-Dioxane, for example, is obtained in excellent yield by treatment of oxirane with dilute sulfuric acid (equation 157), and substituted dioxanes can be prepared in a similar manner. 1,4-Dioxanes can also be conveniently obtained by acid-catalyzed condensation of oxiranes with glycols (equation 158), while use of... 

A number of very important synthetic methods are based on ring interconversions of six-membered heterocyclic systems. As with the transformations of five- into six-membered rings, examples are known of all of the possible atom fragments, but [5 + 1] and [4+2] processes are by far the most important. As described in Chapter 2.02, a number of [6+0] photoisomerizations of diazines have been discovered, but while these are of considerable mechanistic and theoretical importance they are of little preparative significance. 

H-Azepines are more rare than 1H- or 3H-azepines and only a few synthetic approaches have been developed. Of these the two main methods involve the ring expansion of six-membered heterocycles. Early studies revealed that highly substituted 4f/-azepines (269) result from the base-catalyzed ring expansion of 4-(chloromethyl)-l,4-dihydro-pyridines (267 Scheme 37). The reaction was found to be temperature and solvent sensitive, and azepines (268)-(270) have been isolated and characterized. However, later studies (68JCS(C)1675) on cyano derivatives (267 E = CN) show the reaction to be even more... 

Other synthetic routes to benzazepines involving ring expansion of six-membered heterocycles include the action of diazomethane (77CPB321), sulfonium ylides (77H(7)37> or acyl halides (75T1991) on quaternary 3,4-dihydroisoquinolines that of sulfoxonium ylides on quaternary quinolines (74IJC(B)1238) and the zinc-acetic acid reduction of quaternary 1-acyltetrahydroisoquinolines (77BSF893). Photoaddition of acyl- or aryl-nitrenes to the exocyclic alkene bond of 2-methylene-1,2-dihydroquinolines results in ring expansion to... 

The transition metal catalyzed synthesis of six membered heterocycles attracted less attention than the preparation of five membered rings. The majority of examples discussed in this chapter achieves the formation of the ring through the combination of two fragments, forming a carbon-carbon and a carbon-heteroatom bond. 

Transition metal catalyzed insertion reactions offer a variety of alternate approaches for the preparation of six membered heterocyclic rings. Besides intramolecular Heck-couplings, annulation reactions involving the insertion of an acetylene derivative, in most cases accompanied by the incorporation of carbon monoxide constitute the majority of this chapter. Although some of these processes involve the formation of a carbon-heteroatom bond, they are discussed here, while the similar annulation reactions not involving CO insertion are mentioned in Chapter 4.4. 

Besides ring closure reactions proceeding through C-H activation, a major part of this chapter is devoted to the formation of six membered heterocycles in annulation reactions. 

The halogenated derivatives of six membered heterocycles, like their carbacyclic analogues, usually participate readily in coupling reactions that involve the incorporation of an olefin or carbon monoxide. The insertion of carbon monoxide commonly leads to the formation of either a carboxylic acid derivative or a ketone, depending on the nature of the other reactants present. Intermolecular and intramolecular variants of the insertion route are equally popular, and are frequently utilized in the functionalization of heterocycles or the formation of annelated ring systems. 

S Some Results of Calculations of Six-membered Heterocyclic Molecules... 

Finally one can conclude that despite still remaining uncertainties there exist some firmly established aromaticity regularities in series of six-membered heterocycles. They are (1) Increase in the electronegativity of the heteroatom leads to decrease of aromaticity (2) Aromaticity falls with increasing the number of pyridine-like nitrogens in the ring (3) Transition from simple azines to their benzoderivatives is also accompanied by a decrease of aromaticity. 

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