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Synthesis of 3,3-dichloropiperidines and further functionalization via Pd-catalyzed cross-coupling reactions of the dichloromethylene moiety

Tijdschriftbijdrage - Tijdschriftartikel

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 alpha,alpha,delta-trichloroaldimines or an indium(III) triflate catalyzed alkynylation/cyclization procedure of alpha,alpha,delta-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.
Tijdschrift: European journal of organic chemistry
ISSN: 1434-193X
Volume: 99
Pagina's: 95 - 103
Jaar van publicatie:2019
Trefwoorden:A1 Journal article
BOF-publication weight:1
CSS-citation score:1
Authors from:Higher Education