Pd(0)-Catalysed C-H Functionalisations for the Enantioselective Synthesis of N-Heterocycles

Abstract

Transition-metal catalysed enantioselective C–H functionalisations enable rapid increase of molecular complexity via non-classical disconnections. This thesis describes the development of intramolecular Pd(0)-catalysed C-H functionalisations for the asymmetric synthesis of relevant N-heterocyclic scaffolds. Dihydroisoquinolinones were prepared by arylation of corresponding cyclopropane-containing bromobenzamides. Using the cyclopropane arylation approach, an expedient enantioselective route to the beclabuvir ring system was developed. The implementation of chloroacetamides as electrophilic partners provided an enantioselective entry toward four- and five-membered chiral lactams by functionalisation of benzylic or cyclopropane C-H bonds. Cyclisation of the trifluoroacetimidoyl chlorides afforded chiral cyclopropane-fused cyclic CF3-ketimines. The latter represent a convenient platform for the synthesis of trifluoromethylated pyrrolidines. Trifluoroacetimidoyl chlorides from toluidines delivered 2-trifluoromethyl indoles. Simple starting material synthesis coupled with the high efficiency of developed transformations establish Pd(0)-catalysed C-H cyclisations as a practical approach for the preparation of 4- to 7-membered N-heterocycles.