A One‐Pot Dearomative Approach to C4‐Alkylated Tetrahydropyridines and Tetrahydroquinolines

Abstract

A regioselective one-pot approach to the synthesis of C4-alkylated tetrahydropyridines (THPs) and tetrahydroquinolines (THQs) by dearomatization of pyridines and quinolines has been developed. The transformation is achieved by the BF 3 • OEt 2-mediated, C4-selective addition of Grignard reagents, followed by a cascade of enamine protonation and the subsequent Et 3 SiH reduction of the resulting iminium ions. This protocol not only provides a facile synthetic approach to C4-substituted THPs and THQs, but also offers a new strategy for the dearomatization of heteroaromatics.

Recent advances in the dearomative functionalisation of heteroarenes

“…22 Scheme 18 C-2 and C-4 functionalisation of quinolines and pyridines by Lewis acid activation and reaction with carbon nucleophiles. 23,24 Lewis acid activation (Scheme 18). 23,24 The crucial intermediate 56, formed aer C-4 attack of the nucleophile, could be elaborated either by reduction with a hydride source as before or by addition of a second nucleophile (here indole) to obtain difunctionalised products (58) in good yields.…”

“…23,24 Lewis acid activation (Scheme 18). 23,24 The crucial intermediate 56, formed aer C-4 attack of the nucleophile, could be elaborated either by reduction with a hydride source as before or by addition of a second nucleophile (here indole) to obtain difunctionalised products (58) in good yields. Unfortunately, other arene nucleophiles did not participate in the trapping of the transient iminium species.…”

“…In related work, Wang and co-workers demonstrated C-2 and C-4 dearomative functionalisation of pyridines and quinolines using the same principle of nucleophilic dearomatisation through attack of an organometallic reagent under concomitant Lewis acid activation (Scheme 18). 23,24 The crucial intermediate 56, formed aer C-4 attack of the nucleophile, could be elaborated either by reduction with a hydride source as before or by addition of a second nucleophile (here indole) to obtain difunctionalised products (58) in good yields. Unfortunately, other arene nucleophiles did not participate in the trapping of the transient iminium species.…”