Csp2-Csp3 bond formation by ruthenium-catalysed C-H activation

Abstract

The synthesis of Csp2-Csp3 bonds is one of the most synthetically relevant transformations in organic synthesis. Classical methods, such as Friedel-Crafts alkylation chemistry, remain powerful and industrially relevant techniques. In spite of this, they have significant limitations such as the requirement for strong Lewis acids. Transition metal catalysis has become indispensable for the synthesis of Csp2-Csp3 bonds over the last 20 years, with cross-coupling chemistry and more recently photoredox alkylation of arenes becoming commonplace in the literature. C-H activation is among the most powerful and sustainable of the modern synthetic organic chemistry tools available to practitioners. However, several limitations with the field remain and transformations are often performed under harsh conditions and can lead to mixtures of products. Disclosed herein are two mild and regioselective Csp2-Csp3 bond forming reactions achieved through ruthenium-catalysed C-H activation. Chapter 2 focuses on the ruthenium-catalysed alkylation of arenes with secondary alkyl bromides. The electron-rich nature of the key catalytic intermediate enables a regiochemical outcome that had not been observed in ruthenium catalysis at the time of publication. Again, this reaction was demonstrated to be synthetically useful by showcasing many examples of late-stage diversification of pharmaceutical compounds. Chapter 3 focuses on the ruthenium-catalysed alkylation of arenes with primary alkyl bromides. The mild conditions enabled by the cyclometallated pre-catalyst RuBnN are ultimately responsible for the broad scope, including late-stage alkylation of pharmaceuticals. Detailed mechanistic studies were carried out in order to ascertain key features of the reaction.

Date of Award	31 Dec 2021
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Jordi Bures (Supervisor) & Igor Larrosa (Supervisor)