Dipole indole formation

Scheme 17.12. Stepwise decompositions of protonated Aspidosperma alkaloid occurring by either (a) stereochemical D ring cleavage yielding loss of acetamide neutral or (b) ion-dipole complex formation by A-benzyl bond cleavage of the protecting group of the indolic system decomposing into odd-electron product ions. (Adapted with permission from Ref 61.)...

In 1966, Walker, Bednar, and Lumry postulated the formation of a 1 2 excited complex state in the system indole-pentane- butanol [101]. Two years later, Beens and Weller found fluorescence emission at 475 nm from an excited complex composed of two molecules of naphthalene and one of 1,4-dicyanobenzene. They postulated the unsymmetrical structure (DD+ A- ) from the solvent dependence of the wavelength of the peak maximum (high dipole moment in contrast to DAD structure) [102]. Later, several other groups detected such termolecular species. For a review on earlier contributions, see Ref. [103]. 

Isocyanides readily undergo cycloaddition reactions, and these are very valuable in the formation of heterocyclic rings. Reaction of j5-nitrostyrene with an alkyl isocyanide gives a hydroxy indole (146). Reaction proceeds even more readily between tosylmethyl isocyanide (147), in which the methylene is activated, and aryldiazonium compounds. With ketenes, isocyanides give imino lactones. However, with r-butylcyanoketene, the reaction follows a different pathway involving the carbonyl bond of the ketene, to yield 148. A [1 + 3] cycloaddition of an isocyanide to a 1,3-dipole has been used to prepare azetidines. The method has been used for synthesis of a number of azetidines . 

Two possible mechanisms for the formation of product 89 have been proposed. One postulated mechanism involves the oxidation of the indole ring of compound 87, thereby producing the corresponding 3-hydroxy intermediate 90, which then reacts with the dipole 88 to produce the observed product 89 (Scheme 22). Alternatively, nucleophilic addition of the indole nitrogen to the nitrile oxide 89, followed by oxidative ring closure of the resulting intermediate 91 would also account for the formation of the cyclized product 90. The authors favor the dipolar cycloaddition route in which the oxidized indole species 90 is the dipolarophile. The authors claim this mechanism is supported by the observation that when 90 (n = 4) is independently synthesized and isolated, its cycloaddition with dipoles yields identical products. 

Very few reports have been published to date on the reactions of indoles with NNN dipoles. The reaction of fluoroalkanesulfonyl azides 193 with indoles 192 results in the formation of distinct amino, imino or diazo products, 195-198 depending on the choice of solvent and the nature of substituents on the indole ring (Scheme 54). When the indole has a methyl group in the 2 or 3 position, compounds 196 or 195 are obtained, respectively. If the 2 and 3 position are unsubstituted, compounds 197 and 198 are obtained, respectively. In all cases, a dipolar cycloadduct 194 is proposed as an intermediate in the first step in the mechanism of these transformations [85, 86]. 

In another example involving the use of indole as a dipole, Letcher and coworkers [97] have shown that indole A -oxides 247, formed by hydride reduction followed by /n-chloroperbenzoic acid oxidation of the corresponding 3/7 indole derivatives, react with DMAD (61) to initially give the [3+2] cycloadducts (Scheme 67). Further rearrangements of these cycloaddition products, depending on the nature of the substituents at the 2 and 3 positions, lead to the formation of either pyrroles 248-250, oxazole 251 or azepine 252 derivatives. 

Wu and coworkers in 2014 explored a [3 4-2] cycloaddition between substituted indoles and oxyallyl dipoles, derived in situ from dehalogenation via enolization of a-halo ketones. Applying their method toward the synthesis of the echitamine core, they first treated a solution of protected trypt-amine 200 and a-chlorocyclopentanone (199) in trifluoroethanol with sodium carbonate (Scheme 21). These conditions eHcited formation of the... 

Kim demonstrated that the substituted benzotriazoles can afford either indoles or 3-acylindoles depending on the R group (equations 2 and 3) [6]. As might be expected, phen-anthridines accompany the 3-acylindole pathway (up to 30%). This reaction is initiated by formation of an 0-stan-nyl ketyl radical and loss of N. Further cyclization and loss of either t-butyl radical or R CHO affords the indole products. Minakata, Komatsu, and coworkers generated 1,5-dipoles from either 0-staimylmethylated thioanilides or isothiocyanates that cyclize to form indoles (equations 4... 

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