One-Pot Synthesis of 1,2-Disubstituted 4-, 5-, 6-, and 7-Azaindoles from Amino-o-halopyridines via N-Arylation/Sonogashira/Cyclization Reaction

Abstract

A direct synthesis of several 1,2-disubstituted 4-, 5-, 6-, and 7-azaindoles from available amino-o-halopyridines is described. This procedure involves a palladium-catalyzed N-arylation followed by a Sonogashira reaction and subsequent cyclization in a one-pot manner, exhibiting a wide scope and compatibility with electron-withdrawing and electron-donating groups. The strategy represents an advancement in azaindole chemistry with a straightforward approach toward 1,2-disubstituted azaindoles, while avoiding complex N-arylations of hindered 2-substituted azaindoles and difficult purification steps of intermediates.

Synthesis of 5- and 6-Azaindoles by Sequential Site-Selective Palladium-Catalyzed C–C and C–N Coupling Reactions

“…19 Recently, Marques and coworkers reported a practical one-pot synthesis of 1,2disubstituted azaindoles from amino-o-halopyridines through tandem C-N coupling/Sonogashira/cyclization reactions. 20 While we were preparing this manuscript, a similar ultrasound-assisted one-pot synthesis of 1,2-diaryl-substituted azaindole derivatives involving three sequential Narylations followed by coupling-cyclization using Pd/C-Cu catalysis was reported. 21 In our own contribution to this Scheme 2 Two-step synthesis of 6-azaindoles.…”

Pd-Catalyzed Functionalization of Aryl Amines on a Soluble Polymer Support

“…24 The reaction conditions were selected according to the literature. 25 Furthermore, experiences with 2e were performed under the same catalytic system, using iodoaniline instead of bromoaniline. However, the desired arylated product was not observed.…”

“…Our group has been studying anilines and aminopyridines as suitable substrates on Pd-catalyzed functionalization reactions as well as on the synthesis of heterocycles such as indole and azaindole. 20,[25][26][27][28] Thus, we next tested the substrates immobilized on PEG-2000 (2b and 2e) under the Sonogashira reaction conditions. We first attempted the indolization reaction on PEG-2000, by testing 3b as starting material in the one-pot Sonogashira-cyclization reaction, which would hopefully lead to a PEG-supported 1,2-disubstituted indole.…”

Investigação de Aminopiridinas Não Halogenadas como Substratos Promissores para a Síntese de Azaindoles

“…Apesar da simplicidade deste protocolo para preparar azaindoles 2-substituídos, este não funcionou quando aplicado a N-arilamino-orto-bromopiridinas, o que limita o acesso aos 1,2-diaril azaindoles. Procedimentos alternativos para sintetizar estas estruturas estão a ser investigados, evitando a difícil N-arilação de azaindoles 2-substituídos [22][23][24].…”