Pyrrolopyridines synthesis

In pyrrolopyridine synthesis reactions, nitropyridines are less reactive than the corresponding nitropyridone derivatives due to the decreased aromaticity of the pyridone ring. The pyridone is more attractive for nucleophilic attack in the reaction <2002H(58)301> (see Section 10.06.5.3). 

Pyrrolopyridines — see Indolizines Pyrrolo[l,2-a]pyridines — see Indolizines Pyrrolo[2,3]pyridines alkylation, 4, 504 synthesis, 4, 528... 

Knochel and co-workers employed the base-mediated cyclization of 2,6-diamino-3,5-dialkynylpyridines in the synthesis of bis-pyrrolopyridine 95 from bis-acetylene 94 (Equation 21) <2003PS(178)1781, 2003T1571>. 

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]. 

Yamanaka and associates developed a method for the synthesis of 2-butylindole from the Sonogashira adduct of ethyl 2-bromophenylcarbamate and 1-hexyne [65, 66]. Extension of that method to pyridines led to the synthesis of pyrrolopyridines [67]. However, the method was not... 

Vasella and co-workers (72) employed mtinchnone chemistry in the synthesis of several pyrrolopyridines and imidazopyridines as novel inhibitors of p-D-glucosi-dases (Scheme 10.23). Thus, treatment of the lactam glycine (119) with acetic... 

A microwave-assisted synthesis of several isomeric pyrrolopyridines ([2,3-3], [2,3-c], [3,2-3], and [3,2-r ]) has been reported starting from aminohalopyridines <2005S2571>. Intramolecular palladium-catalyzed Heck reactions leading to substituted pyrrolo[3,2-3]pyridines from ketones and aminopyridines have been described <2003JME4702>. 

A recent tutorial review was published covering organometallic chemistry and its uses for synthesis and functionalization of pyrrolopyridines <2007CSR1120>. 

Two complementary routes to the synthesis of pyrido[, y-i/ pyridazines have been developed, the first of which begins by constructing the pyridine ring, and the second by constmcting the pyridazine ring. In addition, ring transformations of pyrrolopyridine, pyridooxazine, pyridopyrimidine, and tetrazine derivatives to the pyrido[x,y-t7 pyridazines have also been reported. 

There are few references to the synthesis of these ring systems from nonheterocyclic compounds. As shown in Scheme 26, reaction of the enaminone (75) with ethyl acrylate generated the highly functionalized pyrrolopyridine derivative (76) which was readily aromatized by mild oxidation <78CPB3080>. 

Yamanaka and associates developed a method for the synthesis of 2-butylindole from the Sonogashira adduct of ethyl 2-bromophenylcarbamate and 1-hexyne [97, 98]. Extension of that method to pyridines led to the synthesis of pyrrolopyridines [99]. However, the method was not applicable to the synthesis of pyrrolo[2,3-6/]pyrimidines. They then developed an alternative route involving an initial S Ar displacement at the 4-position of 4,5-dihalopyrimidine followed by a Sonogashira coupling at the 5-position [100]. Thus, 5-iodopyrimidine 200 was obtained from an S Ar displacement at the 4-position of a 4-chloro-5-iodo-2-methylthiopyrimidine (199). The subsequent Sonogashira reaction of 200 with trimethylacetylene at 80°C resulted in adduct 201, which spontaneously cyclized to pyrrolo[2,3-6/]pyrimidine 202. 

In the earlier work, using bases such as sodium ethoxide, drastic conditions were needed, and the yields were often poor and erratic (68AHC27) examples of the synthesis of pyrrolopyridines (141, 142) and pyrrolo[2,3-(f]pyrimidines (143) by this method are summarized by Scheme 32 (64CPB1024). However, with the use of bases such as butyllithium, much milder conditions can be employed, and good yields obtained even with hindered acyl groups, as in the syntheses of r-butylpyrrolopyridines (144, 145) shown in Scheme 33 (83JOC3401). 

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