Applications of Nickel-Catalyzed Cross-Coupling Methods in the Synthesis of Organofluorine Compounds

Author: Liang, Yufan

Year: 2016

Degree: Dissertation (Ph.D.)

Advisor: Fu, Gregory C.

Committee Members: Grubbs, Robert H.; Peters, Jonas C.; Stoltz, Brian M.; Fu, Gregory C.

Option: Chemistry

DOI: 10.7907/Z9CF9N45

Abstract

The applications of nickel-catalyzed cross-coupling strategy to the synthesis of organofluorine compounds are explored in this thesis.

Chapter 2 describes the development of the first enantioselective cross-coupling method using secondary geminal dihalides as electrophiles. This method provides a unique approach for the generation of enantioenriched tertiary alkyl fluorides. These cross-coupling products can be further transformed into a variety of potentially valuable chiral building blocks.

Chapter 3 describes the development of a practical and versatile Negishi alkylation method employing α-halo-α-perfluoroalkyl secondary electrophiles. Target molecules bearing perfluoroalkyl-substituted (including trifluoromethyl-substituted) tertiary carbons can be easily generated from fluorinated electrophiles. Competition experiments and mechanistic studies have been performed to reveal the unique properties of these electrophiles and also prove the existence of alkyl radicals.

Chapter 4 describes the development of an asymmetric Negishi arylation protocol with α-halo-α-trifluoromethyl secondary electrophiles. This study provides a unique approach to construct trifluoromethyl-substituted tertiary stereocenters. The optimized condition can also be directly applied to substrates bearing an array of fluoroalkyl groups.

Chapter 5 details the progress towards the development of an asymmetric alkynylation method employing α-halo-α-trifluoromethyl secondary electrophiles. Preliminary studies also demonstrate that the protocol we developed has the potential to be used for other non-fluorinated secondary electrophiles.

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