3-Bromo-7-azaindole

Bromination of 7-azaindole in chloroform at 0° gave 3-bromo-7-azaindole in 81 % yield. This compound is stable to treatment with sodium iodide in acetone, like 3-bromoindole, and with hot dilute hydrochloric acid, whereas the indole undergoes hydrolysis. 

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]. 

Q. Wu, J.A. Lavigne, Y. Tao, M. DTorio, and S. Wang, Novel blue luminescent/electrolumines-luminescent 7-azaindole derivatives l,3-di(7V-7-azaindolyl)benzene, l-bromo-3,5-di(Y-7-azaindo-lyl)benzene, 1,3,5-tri(/V-7-azaindolyl)benzene, and 4,4 -di(7V-7-azaindolyl)biphenyl, Chem. Mater., 13 71-77 (2001). 

Both, benzo[e] indole and benzo[g]indole can be obtained by the reaction of l-bromo-2-naphthylamine or 2-bromo-l-naphthylamine with CH2COPh in DMSO [61], and CH2COBu-t and CH2COCH(OMe)2 anions in liquid ammonia in variable yields (46-82%) [62]. In addition to this, the photostimulated reaction of vie aminohalo pyridines with the anion of CH2COBu-t or CH2COMe ions leads to azaindoles in high yields (75-95%) [63]. 

Fischer attempted the bromination of apoharmine in dilute sulfuric acid at room temperature and obtained a tetrabromo compound, which he did not characterize further. Treatment of l-benzoyl-2,5-dimethyl-4-azaindole with bromine in acetic acid at 25° gave the 3-bromo-l-benzoyl compound in 60% yield. On oxidation with permanganate it gave the same picolinic acid obtained before. Alkaline hydrolysis gave 3-bromo-2,5-dimethyl-4-azaindole (90%), also obtained by direct bromination of 2,5-dimethyl-4-azaindole in 60 % yield. 

In the synthesis of Vemurafenib (Scheme 26) the 5-bromo-7-azaindole part of 113 is made by a Sonogashira reaction (Scheme 42) [73]. Thus, reaction between pyridine 161 and 2-methyl-but-3-yne-2-ol 162 catalysed by PdCl2(PPh3)2, Cul and Et3N yielded the protected pyridine-acetylene 163 in 93% yield. This was deprotected under basic conditions to yield 164, which was cyclised to 165 using tBuOK in NMP for an overall 62% yield. 

Scheme 42 Sonogashira in the preparation of 5-bromo-7-azaindole, an intermediate towards Vemurafenib...

Buchwald developed a series of biarylphosphine ligands to enable a highly selective Pd-catalyzed Negishi reaction between (hetero)aryl halides 301 and turbo-like isopropylzinc bromide.This reaction worked well on a variety of heterocycles including 5-bromo-7-azaindole (140L4638). 

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