Azaindole synthesis

Although having been discovered only 20 years ago, the Bartoli indole synthesis has found more and more applications in indole and azaindoles synthesis. Applying the classic Bartoli conditions, nitropyridyl-piperazines were converted into 4-azaindole and 6-azaindole in 17 and 51% yield, respectively. Both azaindoles were prepared as potential S-HTe inhibitors for the indication of schizophrenia. 

Echalier, A., Bettayeb, K., Ferandin, Y, Lozach, O., Clement, M., Valette, A., Liger, F., Marquet, B., Morris, J.C., Endicott, J.A., Joseph, B., and Meijer, L. (2008) Meriolins (3-pyrimidin-4-yl)-7-azaindoles) synthesis, kinase inhibitory activity, cellular effects, and a structure of a CDK2/cycinA/meriolin complex. J. Med. Chem., 51, 737-751. 

Pyrrolo[2,3-c]pyridines — see also 6-Azaindoles reaction with O-mesitylhydroxylamine, 4, 508 synthesis, 4, 516, 522 tautomerism, 4, 502 UV spectra, 4, 501... 

Pyrrolo[3,2-6]pyridines — see also 4-Azaindoles hydrogen exchange, 4, 502 quatemization, 4, 503 synthesis, 4, 527... 

A similar synthesis starting with l-(2-nitrobenzyl)pyrrol-2-aldehyde used ethanol-ethyl acetate as solvent (62). Indoles are prepared in excellent yield by hydrogenation of o-nitrobenzyl ketones over Pd-on-C (i). Azaindoles are correspondingly prepared from nitropyridines (97). 

As with the corresponding section on pyrroles, indole syntheses have been categorized utilizing a systematic approach. Intramolecular approaches (type I) and intermolecular approaches (type II) are classified by the number and location of the new bonds that describe the indole forming step (2 examples shown below). In addition, the synthesis of azaindoles,... 

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

Sakamoto described similar reactions of o-bromoaniline derivatives with (Z)-tributyl-2-ethoxyvinyltin and subsequent cyclization of the coupled product with TsOH to yield, for example, N-acetylindole (29% yield overall) [185], This research group also used this methodology to synthesize a series of azaindoles, an example of which is illustrated below [204]. Halonitropyridines were particularly attractive as coupling partners with tributyl-2-ethoxyvinyltin and precursors to azaindoles. Although the (Z)-isomer of 202 is obtained initially, it isomerizes to the ( )-isomer which is the thermodynamic product. This strategy represents a powerful method for the synthesis of all four azaindoles (l//-pyrrolopyridines). In fact, this method, starting with 2,6-dibromoaniline, is one of the best ways to synthesize 7-bromoindole (96% overall yield) [36]. 

Other indoles that have been prepared using the Sonogashira coupling and cyclization sequence include 5,7-difluoroindole and 5,6,7-trifluoroindole [219], 4-, 5-, and 7-methoxyindoles and 5-, 6-, and 7-(triisopropylsilyl)oxyindoles [220], the 5,6-dichloroindole SB 242784, a compound in development for the treatment of osteoporosis [221], 5-azaindoles [222], 7-azaindoles [160], 2,2-biindolyls [223,176], 2-octylindole for use in a synthesis of carazostatin [224], chiral indole precursors for syntheses of carbazoquinocins A and D [225], a series of 5,7-disubstituted indoles [226], a pyrrolo[2,3-eJindole [226], an indolo[7,6-g]indole [227], pyrrolo[3,2,l-y]quinolines from 4-arylamino-8-iodoquinolines [228], optically active indol-2-ylarylcarbinols [229], 2-alkynylindoles [176], 7-substituted indoles via the lithiation of the intermediate 2-alkynylaniline derivative [230], and a variety of 2,5,6-trisubstituted indoles [231], This latter study employs tetrabutylammonium fluoride, instead of Cul or alkoxide, to effect the final cyclization of 215 to indoles 216 as summarized here. 

Somei adapted this chemistry to syntheses of (+)-norchanoclavine-I, ( )-chanoclavine-I, ( )-isochanoclavine-I, ( )-agroclavine, and related indoles [243-245, 248]. Extension of this Heck reaction to 7-iodoindoline and 2-methyl-3-buten-2-ol led to a synthesis of the alkaloid annonidine A [247]. In contrast to the uneventful Heck chemistry of allylic alcohols with 4-haloindoles, reaction of thallated indole 186 with 2-methyl-4-trimethylsilyl-3-butyn-2-ol affords an unusual l-oxa-2-sila-3-cyclopentene indole product [249]. Hegedus was also an early pioneer in exploring Heck reactions of haloindoles [250-252], Thus, reaction of 4-bromo-l-(4-toluenesulfonyl)indole (11) under Heck conditions affords 4-substituted indoles 222 [250], Murakami described the same reaction with ethyl acrylate [83], and 2-iodo-5-(and 7-) azaindoles undergo a Heck reaction with methyl acrylate [19]. 

The 5-, 6-, and 7-azaindoles were synthesized via the Pd-catalyzed heteroannulation of internal alkynes using orf/w-aminopyridine derivatives in an extention of Larock s indole synthesis [169], LiCl was found to be an essential component in order to obtain regioselectivity, reproducibility and improved yields. 

The one-pot synthesis of 4-azaindole is also initiated by photoirradiation 3-amino-2-chloro-pyridine and acetaldehyde are the starting materials (Fontan et al. 1981 Scheme 7.37). 

Certain 2-amino-3-ketones 193 also serve, via the agency of hydrochloric acid, as intermediates for the synthesis of 7-azaindole derivatives 194 (Scheme 57) (88JOC2740). 

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