Metallaphotoredox-catalysed sp3–sp3 cross-coupling of carboxylic acids with alkyl halides

Abstract

The long-sought direct formation of a bond between two sp3-hybridized carbon atoms is achieved by the merger of photoredox and nickel catalysis using only simple carboxylic acids and alkyl halides as starting materials. There is a demand in drug discovery and other fields for the molecular complexity associated with compounds featuring sp3–sp3 carbon–carbon bonds, but the direct formation of a bond between two sp3-hybridized carbons has been a greater synthetic challenge than the formation of sp2–sp2 bonds. This paper describes the development of a dual catalytic platform for coupling sp3–sp3 centres that merges photoredox and nickel catalysis and is achieved using only simple carboxylic acids and alkyl halides as starting materials. The new protocol is suitable for many primary and secondary carboxylic acids and has been used to synthesize the pharmaceutical tirofiban in four steps from commercially available building blocks. In the past 50 years, cross-coupling reactions mediated by transition metals have changed the way in which complex organic molecules are synthesized. The predictable and chemoselective nature of these transformations has led to their widespread adoption across many areas of chemical research1. However, the construction of a bond between two sp3-hybridized carbon atoms, a fundamental unit of organic chemistry, remains an important yet elusive objective for engineering cross-coupling reactions2. In comparison to related procedures with sp2-hybridized species, the development of methods for sp3–sp3 bond formation via transition metal catalysis has been hampered historically by deleterious side-reactions, such as β-hydride elimination with palladium catalysis or the reluctance of alkyl halides to undergo oxidative addition3,4. To address this issue, nickel-catalysed cross-coupling processes can be used to form sp3–sp3 bonds that utilize organometallic nucleophiles and alkyl electrophiles5,6,7. In particular, the coupling of alkyl halides with pre-generated organozinc8,9, Grignard10 and organoborane11 species has been used to furnish diverse molecular structures. However, the manipulations required to produce these activated structures is inefficient, leading to poor step- and atom-economies. Moreover, the operational difficulties associated with making and using these reactive coupling partners, and preserving them through a synthetic sequence, has hindered their widespread adoption. A generically useful sp3–sp3 coupling technology that uses bench-stable, native organic functional groups, without the need for pre-functionalization or substrate derivatization, would therefore be valuable. Here we demonstrate that the synergistic merger of photoredox and nickel catalysis enables the direct formation of sp3–sp3 bonds using only simple carboxylic acids and alkyl halides as the nucleophilic and electrophilic coupling partners, respectively. This metallaphotoredox protocol is suitable for many primary and secondary carboxylic acids. The merit of this coupling strategy is illustrated by the synthesis of the pharmaceutical tirofiban in four steps from commercially available starting materials.