Metallaphotoredox-Catalyzed sp3–sp3 Cross-Coupling of Carboxylic Acids with Alkyl Halides

摘要

Over the last half-century, transition metal-mediated cross-coupling reactions have changed the way in which complex organic molecules are synthesized. Indeed, the predictable and chemoselective nature of these transformations has led to their widespread adoption across a vast array of chemical research areas. However, the construction of sp³–sp³ bonds, a fundamental unit of organic chemistry, remains an important yet elusive objective for cross-coupling reaction engineering. In comparison to related procedures with sp²-hybridized species, the development of methods for sp³–sp³ bond formation via transition metal catalysis has been historically hampered by deleterious side-reactions, such as β-hydride elimination with Pd-catalysis, and the reluctance of alkyl halides to undergo oxidative addition^,. To address this issue, a number of research groups have demonstrated the feasibility of nickel-catalyzed cross-coupling processes to form sp³–sp³ bonds that utilize organometallic nucleophiles and alkyl electrophiles^–. In particular, the coupling of alkyl halides with pregenerated organozinc^–, Grignard^,, and organoborane species has been used to furnish diverse molecular structures. However, the poor step and atom economies along with the operational difficulties associated with making, carrying, and using these sensitive coupling partners has hindered their widespread adoption. The prospect of establishing a generically useful sp³–sp³ coupling technology that employs bench-stable, native organic functional groups, without the need for pre-functionalization or substrate derivatization, would therefore be a valuable addition to fields of research that rely on organic molecule construction. 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. The outlined protocol is suitable for a wide array of primary and secondary carboxylic acids and does not require the presence of radical stabilizing groups. The merit of this coupling strategy is illustrated by the expedient synthesis of the pharmaceutical tirofiban in four steps from commercially available starting materials.