Azaindole ring synthesis

CARBAZOLES AND AZAINDOLES 5.2.7.1 Carbazole Ring Synthesis and Annulation... 

The most successful method for preparing azaindoles has been the Madelung synthesis, which involves a base-catalyzed cyclization of o-acylaminotoluenes or picolines. Eighteen azaindoles have been prepared by various modifications of the Madelung ring closure. These are summarized in Table I. 

In a series of papers on the photochemical synthesis of cyclo-pentadiene and pyrrole derivatives, Siis and Moller reported the preparation of indoles which could not be made by the Fischer method. Primarily, these were indoles with electron-withdrawing substituents in the benzene ring. Included was the synthesis of 4-azaindole-3-carboxylic acid (18, Scheme 2). The reaction was extended to the synthesis of the other three azaindoles. ... 

The synthesis of azaindoles by the Fischer indole synthesis has been tried more often than by any other method. It has given varied results, with over thirty successful ring closures of pyridyl- or quinolyl-hydrazones reported. Most of these have led to carboline deriva-... 

The 5//-pyrido[4,3-f ]benzo[/]indole ring system (e.g., 192) represents another type of isoellipticine, and its synthesis has been explored by Bisagni and co-workers (95) (Scheme 33). Azaindole 188 was elaborated by means of conventional lithiation methodology to alcohol 189. A sequence of dehydration, hydrogenation, and chlorination gave 190. Either Vilsmeier-Haack conversion to aldehyde 191 and polyphosphoric acid (PPA) cyclization to the desired ring system 192 or direct cyclization to 192 completed the synthesis. The side chain amines were introduced by heating the components neat to provide 193-195. The methoxyl derivatives 196 and 197 were also synthesized (95). 

The synthesis of new photochromic SPs based on 4-azaindole has been reported. The SPs obtained readily dissolve in polar and nonpolar solvents, and some of them even dissolve in water. The small bathochromic shift of the long-wavelength absorption band of these compounds is due to the stronger EA properties of the pyridine ring as compared to those of a benzene ring. The photosensitivity of azaindoline SPs toward UV radiation proved to be no lower, and in some cases even higher, than the photosensitivity of their indoline analogs. 

This in situ generation of enamines and subsequent Heck cyclization to afford indoles has been adopted by several groups for the synthesis of indoles (and azaindoles) from 2-chloroanilines [337], tricyclic inhibitors of 5 -inosine monophosphate dehydrogenase [145], medium-ring fused indoles [338], and tetrahydrocarbazole in an Organic Synthesis preparation [339]. Some mechanistic insights have been offered [340]. The use of aryl-propynamides and rV-alkynyl-2-haloanilides under Heck conditions affords oxindoles [341] and 2-aminomdoles [342], respectively. An example of the latter is illustrated for 323 to 324. 

Lithiation of 2- and 4-t-butoxycarbonylaminopyridines can only take place at C-3 a neat sequence involving, hrst, ring hthiation to allow introduction of a methyl group and, second, side-chain methyl hthiation (8.10), provides one route to azaindoles (20.16), as illustrated below for the synthesis of 5-azaindole (pyrrolo[3,2-c]pyridine)." ... 

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