Pd-Catalyzed regioselective intramolecular dehydrogenative C-5 cross coupling in anN-substituted pyrrole-azole system

Abstract

Functionalized polycyclic pyrrole-azole structures possessing fused six membered and seven membered rings were directly synthesized via ligand-enabled, Pd-catalyzed, site selective, intramolecular cross couplings of N-substituted pyrrole-azoles. C5-H activation in the presence of a reactive C2-H remains a challenge that needs to be addressed and this was targeted to be resolved through the present approach by specifically generating the cyclized products with 83-100% selectivity. The featured methodology provides a novel disconnection for the synthesis of pyrrole containing alkaloids and medicinal compounds.

Pd-Catalyzed Decarboxylation and Dual C(sp3)–H Functionalization Protocols for the Synthesis of 2,4-Diarylpyridines

“…Addition of formaldehyde ( S ) to enamine U gives an intermediate V . Next, the Pd-catalyzed intramolecular cross-dehydrogenative coupling of intermediate V leads to the formation of side product 2,6-diphenylpyridine ( 5ba ) via the formation of palladacycle W . Finally, the Pd­(II) species is regenerated back to the catalytic cycle by Cu­(II) in the presence of aerial oxygen (Scheme b).…”

Palladium-catalyzed cross-dehydrogenative coupling of (hetero)arenes

“…The two 5,11-dihydroindolo[3,2-b]carbazoles were then used as intermediates for the preparation of malasseziazole A and malasseziazole C, two naturally occurring alkaloids (isolated from cultures of Malassezia furfur) involved in the pathogenesis of pityriasis versicolor (Scheme 99a). In 2016, Miura and coworkers proposed a more extended protocol for the synthesis 209 of four different families of benzobisbenzofurans by means of two-fold intramolecular CDC reactions of 1,2-, 1,3-and 1,4-diaryloxybenzenes. 211 The protocol, performed on a 0.2 mmol substrate scale, involved the use of highly electrophilic Pd More examples of Pd-catalyzed intramolecular CDC reactions between a heteroarene and an arene have been reported for the synthesis of pentacyclic compounds.…”

“…In the same year, Singh and co-workers described the Pd-catalyzed intramolecular CDC reactions between the C2 position of the 1 H -benzimidazole ring and the α-position of the 1 H -pyrrole ring of 1-(2-(1 H -pyrrol-1-yl)ethyl)-1 H -benzo[ d ]imidazoles and 1-(3-(1 H -pyrrol-1-yl)propyl)-1 H -benzo[ d ]imidazoles, to give 5,6-dihydrobenzo[4,5]imidazo[1,2- a ]pyrrolo[2,1- c ]pyrazines and 6,7-dihydro-5 H -benzo[4,5]imidazo[1,2- a ]pyrrolo[2,1- c ][1,4]diazepines, respectively (Scheme 98). 209 The optimization of the reaction conditions was carried out on the 1-(2-(3-formyl-1 H -pyrrol-1-yl)ethyl)-1 H -benzo[ d ]imidazole as the model substrate, having two not equivalent α-positions on the 1 H -pyrrole ring: the intramolecular CDC could occur on both the C2 and C5 position of the 1 H -pyrrole, thus giving a mixture of two different tetracyclic products. The regioselective CDC at the C5 position could be achieved by using sterically hindered reagents, to block the access of the palladium catalyst to the C2 position and facilitate the C–H bond activation of the C5 position of the 1 H -pyrrole.…”

“…Scheme 98 Synthesis of 5,6-dihydrobenzo[4,5]imidazo[1,2-a]pyrrolo[2,1-c]pyrazines and 6,7-dihydro-5H-benzo[4,5]imidazo[1,2-a]pyrrolo[2,1c][1,4]diazepines via Pd-catalyzed intramolecular CDC reactions of 1-(2-(1H-pyrrol-1-yl)ethyl)-1H-benzo[d]imidazoles and 1-(3-(1H-pyrrol-1-yl) propyl)-1H-benzo[d]imidazoles, reported in 2017 by Singh and co-workers 209. …”

Recent Advances in Functionalization of Pyrroles and their Translational Potential

“…demonstated a proficient methodology for direct access to a progression of polyheterocyclic arenes by means of a palladium‐catalyzed regioselective, intramolecular, dehydrogenative cross‐coupling reaction at the C‐5 position of pyrrole substrates in presence of a similarly reactive C‐2 position (Scheme 41). [52] The electron‐withdrawing group when present, particularly at C‐3 position predominately benefits nucleophillic C5 attack of pyrrole than at the C2 position, and in order to comprehend this electronic impact in deciding the selectivity, alkyl and aryl group were kept at the C‐3 position of pyrrole, which further lessended the selectivity for the C‐5 product.…”