A General and Efficient Synthesis of Azaindoles and Diazaindoles

Abstract

The DBU-mediated cyclization of ortho- (Boc-amino)alkynyl pyridines, -pyridazines, -pyrimidines and -pyrazines efficiently generates azaindoles and diazaindoles, respectively. The reaction proceeds under mild conditions and in high yields. A variety of functional groups are tolerated.Azaindoles (pyrrolopyridines) and related heteroaromatic ring systems are common moieties in pharmaceutically important molecules. A limited number of synthetic routes to access azaindoles are described in the literature. The Madelung indole synthesis has been applied in the preparation of 4-, 5-and 6-azaindoles 1 as well as 4,6-diazaindoles (pyrrolopyrimidines). 2 The 4-, 5-, 6-and 7-azaindole isomers have been generated either by the cyclization of ortho-nitro-alkenylpyridines 3 or the palladium-catalyzed heteroannulation of internal alkynes with ortho-aminoiodopyridines. 4 Recently, the addition of the dianion of 3-amino-4-picoline to carboxylic esters has been reported for the synthesis of 6-azaindoles. 5 However, the most general method used for the synthesis of azaindoles is the cyclization of ortho-amino-alkynyl pyridines. Historically, this transformation has been performed using either transition metal-mediated processes or strong bases. The first copper-mediated cyclization of ortho-amino-alkynyl anilines in the synthesis of an indole was described in 1963. 6 Since then, transition metalmediated conditions have been applied to the synthesis of 5-azaindoles, 7,8 6-azaindoles, 8 7-azaindoles, 8,9 4,5-diazaindoles (pyrrolopyridazines), 10 and 4,6-diazaindoles. 11 These reactions have typically been run at high temperatures (>100°C) in DMF and generate product in moderate yields.Alternatively, strong bases have been employed: cyclizations to give 4-or 5-azaindoles have been performed with NaOEt in EtOH; 12 4-azaindoles have been generated using NaNH 2 in DMF, 13 and 4,7-diazaindoles have been cyclized using methylamine. 14 More recently, t-BuOK or KH in NMP has been used to synthesize various azaindoles and diazaindoles. 15,16 This last method has a more general scope regarding the pattern of ring substitution and functional group tolerability. However, in our hands, variable and moderate yields were observed. This is likely due to the difficult isolation of the polar azaindole products from the reaction mixture. For example, extraction with ethyl acetate or dichloromethane results in a large amount of NMP remaining in the organic layer, while other extraction circumvents this problem, but requires many extractions to isolate the product in good yield. Additionally, the strong basic conditions caused side reactions to occur when certain functional groups were present. Therefore, it was desirable to develop a synthetic method that enabled the cyclization of ortho-(Boc-amino)alkynyl pyridines and diazines using a milder base in a more convenient solvent.Recently, an example was described in the literature using DBU in the base-mediated cyclization of an ortho-(Bocamino)alkynyl pyridine in the synthesis of a 5-azaindole. 17 In thi...

Investigation of Mechanochemical Sonogashira Couplings─From Batch Solution to Continuous Reactive Extrusion through Ball-Milling Optimization

“…We were interested in evaluating this developing technology for the scalable synthesis of pharmaceutically relevant heterocyclic cores via palladium-catalyzed reactions. We chose the Sonogashira reaction, a frequently employed entry into azaindoles and related heterocycles. − The goals of this study were to identify solvent-free mechanochemical reaction conditions that achieved high conversion and purity and to minimize post-reaction manipulations to enable streamlined process manufacturing.…”

Gold catalysis in the synthesis of azaindoles: pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrazines

“…[37][38][39][40][41][42][43][44] Many of them include the use of base [37][38][39] and, despite they give rise to Nunsubstituted compounds, we have tried to accomplish the synthesis of 6a by treating the Nbenzyl-N-[3-(4-methylphenyl)ethynyl-5-phenyl]pyridine-2-ylamine with potassium tert-butoxide ( t BuOK) using N-methylpyrrolidone (NMP) as solvent. 38 No reaction was observed after stirring for 24 h at room temperature and the same result was obtained heating the mixture at 80 ºC.…”