Sequential Pyridine Dearomatization–Mizoroki–Heck Cyclization for the Construction of Fused (Dihydropyrido)isoindolinone Ring Systems

Abstract

Acylation of 4-alkylpyridines with 2-iodobenzoyl chlorides under basic conditions results in pyridine dearomatization via formation of 4-alkylidene dihydropyridines. These reasonably stable intermediates are further transformed through Pd-catalyzed Mizoroki–Heck cyclization to afford dihydropyrido-fused isoindolinone products in good yield. This study demonstrates successful harnessing of reactive dearomatized pyridine anhydrobases in metal-catalyzed C–C bond-forming reactions, and provides an efficient entry to isoindolinone ring systems structurally related to several indolizidine alkaloid frameworks.

Recent Strategies in the Nucleophilic Dearomatization of Pyridines, Quinolines, and Isoquinolines

“…In 2018, Pigge and co-workers developed a sequence consisting of pyridine dearomatization followed by Pdcatalyzed Mizoroki−Heck cyclization for the synthesis of fused (dihydropyrido)isoindolinone derivatives (Scheme 172). 245 Different substituents on the lateral chain in the C4-position of the starting pyridines were compatible with the process. Regarding the pyridine ring, aromatic substituents were tested at the C3-and C5-positions with good results, while in the case of the acyl chlorides, different groups could be also incorporated at the C4-position.…”

“…In 2018, Pigge and co-workers developed a sequence consisting of pyridine dearomatization followed by Pd-catalyzed Mizoroki–Heck cyclization for the synthesis of fused (dihydropyrido)isoindolinone derivatives ( Scheme 172 ). 245 To achieve this goal, 4-alkylpyridines 367 were treated with 2-iodo benzoyl chlorides 368 to generate functionalized 1,4-dihydropyridines 369 , suitable to undergo an intramolecular Heck reaction in the presence of Pd 2 (dba) 3 , P( o -tol) 3 and Hünig’s base, affording tricyclic derivatives 370 in good yields, as cis / trans mixtures in the double bond. Different substituents on the lateral chain in the C4-position of the starting pyridines were compatible with the process.…”

C-Sulfonylation of 4-Alkylpyridines: Formal Picolyl C–H Activation via Alkylidene Dihydropyridine Intermediates

“…We are exploring new routes to functionalized alkylpyridines that are predicated upon transient generation of reactive alkylidene dihydropyridine intermediates. − In the course of developing a direct methenylation of 4-alkylpyridines using Eschenmoser’s salt, we attempted to prepare the tosylate of hydroxypropylpyridine 1a . However, under the conditions shown in Scheme the pyridine substrate was found to undergo O-tosylation concomitantly with sulfonylation of the picolyl position, and 3aa was isolated in good yield.…”