Synthesis of 3,3‐Dichloropiperidines and Further Functionalization via Pd‐Catalyzed Cross‐Coupling Reactions of the Dichloromethylene Moiety

Abstract

A new synthetic methodology for the functionalization of the dichloromethylene moiety in 3,3‐dichloropiperidines via Pd‐catalyzed cross‐coupling reactions is reported. A range of 3,3‐dichloropiperidines was synthesized via a hydride induced cyclization of α,α,δ‐trichloroaldimines or an indium(III) triflate catalyzed alkynylation/cyclization procedure of α,α,δ‐trichloroaldimines. Subsequently, a dehydrochlorination followed by a cross‐coupling with the thus formed vinylic chloride was envisioned. The non‐alkynylated 3,3‐dichloropiperidines could be regioselectively eliminated and by careful choice of solvent and base both of the two regioisomeric vinyl chlorides could be exclusively formed. Palladium‐catalyzed Suzuki cross‐coupling of the thus formed 5‐chloro‐1,2,3,6‐tetrahydropyridines led to C3‐substituted 1,2,3,6‐tetrahydropyridines, which could be easily reduced to 3‐substituted piperidines, generating therapeutic agent (±)‐Preclamol for example. The 2‐alkynyl‐3,3‐dichloropiperidines were regioselectively eliminated giving the cyclic enamine, which was subsequently cross‐coupled in one‐pot. The presence of the alkynyl function, in this case, clearly directs elimination towards enamine structures. Hydrogenation of the resulting, unstable 2‐alkynyl‐3‐substituted‐1,2,3,4‐tetrahydropyridines, yields stable 2,3‐disubstituted piperidines.

Synthesis of isolable β-chloroenamines from N-alkoxylactams with organometallic reagents

“…1 l ,3 In a recent study, Tehrani and co-workers described elimination of 3,3-dichloropiperidines 1 by t -BuOM (M = K, Na) to give β-chloroenamine 2 (Scheme 1(a)). 4 However, corresponding enamine 2 could not be isolated due to lack of stabilization effect by substituents. Thus, a one-pot elimination/cross-coupling protocol was applied to produce β-functionalized piperidines 3 in moderate yield.…”