Heteroarynes

The scope of heteroaryne or elimination-addition type of substitution in aromatic azines seems likely to be limited by its requirement for a relatively unactivated leaving group, for an adjacent ionizable substituent or hydrogen atom, and for a very strong base. However, reaction via the heteroaryne mechanism may occur more frequently than is presently appreciated. For example, it has been recently shown that in the reaction of 4-chloropyridine with lithium piperidide, at least a small amount of aryne substitution accompanies direct displacement. The ratio of 4- to 3-substitution was 996 4 and, therefore, there was 0.8% or more pyridyne participation. Heteroarynes are undoubtedly subject to orientation and steric effects which frequently lead to the overwhelming predominance of... 

Since heteroarynes are thus seen to be subject to strong orientation effects, the detection of the occurrence of the aryne mechanism and the evaluation of the extent of its participation require a special approach. Both the aryne and Sj Arl mechanisms can occur together, and variation of the leaving group on a substrate (e.g., 2-halonaphthalenes) can cause a complete shift from the aryne (2-chloro, -bromo, and -iodo) to the Sj Arl mechanism (2-fluoro) see also Section II, D, 1. 

It should be noted that positional selectivity is never complete even when a clean reaction gives only one isolated product.Reaction occurs at all positions in proportion to the ratio of the rate constants. The difference between a clean reaction (e.g., rate 9 times that of a competing reaction) and one giving a troublesome mixture can be merely a moderate quantitative increase in one rate (e.g., to a 9 7 rate ratio) or a change in both rates (e.g., to a 3 4 ratio). Work such as that of Kauffmann and Boettcher on heteroarynes illustrates the potential of modern forms of chromatography for determining the true proportion of even very minor products. 

Thus, rutroheterocycles are importaru synthoas of five-membered heteroarynes h cyclo idchdQa reacdoas, which are geaedilly chfficidt to be geaerated ... 

The heteroaryne 15. produced by treating 5-aeetyI-10-bromo-5//-dibenz[/>,/]azepine (14) with potassium rm-butoxide (see Section 3.2.1.4.2.), has been trapped by cyclohexa-1,3-diene8 and by furan118 as the [4 + 2] cycloadducts 16 and 17, respectively (see also Section 3.2.1.1.1.1.).118... 

Primary and secondary aliphatic amines, morpholine and 2-methylaziridine and aniline and even the sterically hindered 2.2,6,6-tetramethylpiperidine readily react with 6-bromo-trithiadiazepine 7, in certain cases in the presence of /V./V-diisopropylethylamine, at room temperature by substitution of the bromine atom ammonia, for example, yields trithiadiazepin-6-amine 22 (R1 = R2 = H). There is compelling evidence that these reactions proceed by an elimination-addition mechanism via the heteroaryne, trithiadiazepyne 21.391... 

The heteroaryne 1 is trapped as the Diels-Alder adduct when 6-bromo-l,3/4, 5,2,4-trilhia-diazepine is treated with various dienes in the presence of N./V-diisopropylethylamine or sodium methoxide, e.g. trapping of 1 with furan to give 2.391... 

Benzotrithiadiazepines are formed in the reactions of the heteroaryne 1,3/4,5,2,4-trithiadiazepync 2 with cyclopcntadicnoncs by spontaneous decarbonylation of the initial Diels-Alder adducts. Thus, with phencyclone, the triphenylenotrithiadiazepine 3 is isolated.393... 

In the reaction of 2,3,4,5-tetraphenylcyclopenta-2,4-dienone with trithiadiazepyne 2, two molecules of the latter are involved to yield the [1,4]benzodithiin[2,3-/]trithiadiazepine 6a. A similar reaction of 2-methyl-3,4,5-triphenylcyclopenta-2,4-dienone with the heteroaryne, generated from 6-bromo-l,3A4,5,2,4-trithiadiazepine and AoiV-diisopropylethylamine in refluxing acetonitrile, gives the analog 6b. It is suggested that the benzotrithiadiazepines formed initially decompose to dithioquinones, which add a second molecule of the aryne to yield the products.393... 

Thus, nitroheterocycles are important synthons of five-membered heteroarynes in cycloaddition reactions, which are generally difficult to be generated.38... 

Investigations of six-membered heteroarynes concentrate on didehydropyridines, which will be dealt with exclusively in this section. The influence of the nitrogen lone pair on the stmctural and electronic properties of the benzynes was investigated by Cramer and Debbert. " Relative energies of the six isomeric pyridynes and their singlet-triplet splittings are summarized in Table 16.5. 

The Sn(EA) mechanism involves a preliminary base-promoted elimination to yield a heteroaryne intermediate and the subsequent addition of, e.g., NH3 to yield the substitution product(s).85... 

Dehydroheteroarenes like (10) and (11) have also been proposed as intermediates in nucleophilic substitution.23-25 Some of these reactions were evaluated uncritically and operation of other mechanisms like addition-elimination (AE) and ring opening-ring closure (ANRORC) can now be demonstrated in many such cases. Nevertheless, there is conclusive evidence for heteroaryne intermediacy in some reactions of heterocyclic halides. From the preparative point of view, nucleophilic coupling of such intermediates has found only limited applications.26-28 Reactive intermediates with an additional formal bond between nonadjacent atoms, like (12) and (13), have also been postulated but again hold little synthetic interest. 

Carbanions derived from side chain tertiary amides have also been cyclized to provide isoquinolones and isoindoles (equation 36).125 126 While benzyne intermediacy in the formation of the former is likely, the latter seems to arise through a SrnI reaction pathway. Synthesis of indole from the meta bromo compound (87), on the other hand, clearly involves an aryne cyclization. 27 A more versatile route to indoles is based on intramolecular addition of aminyl anions to arynes (equation 38).128 A somewhat similar dihydroindole preparation constitutes the first step in a synthesis of lycoranes (equation 39).129 The synthesis of (88) also falls in the same category of reactions, but it is noteworthy because only a few examples of ring closure of heteroarynes are mentioned in literature.27 28... 

Accordingly, nine aromatic and two heterocyclic anhydrides were pyrolyzed in admixture with pyridine under standardized conditions, and the relative amounts of aryne or heteroaryne produced were determined by analysis of the reaction products (Fields and Meyerson,... 

Pyrazine-2,3-dicarboxylic anhydride gave no products of the reaction of the corresponding heteroaryne with pyridine however, it gave a small but definite amount of phenylpyrazine with benzene, suggesting the formation of pyrazyne. This anhydride is readily converted by ring opening and rearrangement to succinonitrile (Brown et al., 1966). 

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