Nickel-catalyzed Suzuki\u2013Miyaura cross-couplings of aldehydes

Lin Guo,Luigi Cavallo,Watchara Srimontree,Chen Zhu,Xiangqian Liu,Magnus Rueping,Bholanath Maity

doi:10.1038/s41467-019-09766-x

Abstract

Transition-metal-catalyzed cross-couplings have been extensively used in the pharmaceutical and agrochemical industries for the construction of diverse C–C bonds. Conventional cross-coupling reactions require reactive electrophilic coupling partners, such as organohalides or sulfonates, which are not environmentally friendly and not naturally abundant. Another disadvantage associated with these transformations is the need for an exogenous base to facilitate the key transmetalation step, and this reagent inevitably induces side reactions and limits the substrate scope. Here, we report an unconventional Suzuki-type approach to the synthesis of biaryls, through nickel-catalyzed deformylative cross coupling of aldehydes with organoboron reagents under base-free conditions. The transformation tolerates structurally diverse (hetero)aryl substituents on both coupling partners and shows high reactivity and excellent functional group tolerance. Furthermore, the protocol was carried out on gram scale and successfully applied to the functionalization of complex biologically active molecules. Mechanistic investigations support a catalytic cycle involving the oxidative addition of the nickel into the aldehyde C(acyl)–H bond with subsequent hydride transfer, transmetalation, decarbonylation and reductive elimination processes.

Highlights

Transition-metal-catalyzed cross-couplings have been extensively used in the pharmaceutical and agrochemical industries for the construction of diverse C–C bonds
The development of efficient methods for the selective construction of C–C bonds is of great significance because carbon skeletons exist in numerous biologically active molecules, pharmaceuticals, and functional materials[1]
Protocols using C–O electrophiles are often hampered by the “naphthalene problem” in which only π-extended aromatic frameworks show high reactivity[9,10]; couplings of aromatic carboxylic acids to build biaryl species via decarboxylative pathways are restricted to electron-withdrawing group-containing substrates or a strong oxidant is required[11,12]; the synthesis of biaryl species via the decarbonylative reaction of esters and amides is limited to specific substrates that require an additional step to be synthesized from carboxylic acids[13,14]; and the use of an exogenous base may limit the scope of reagents and substrates[15]

Summary

Introduction

Transition-metal-catalyzed cross-couplings have been extensively used in the pharmaceutical and agrochemical industries for the construction of diverse C–C bonds. Protocols using C–O electrophiles are often hampered by the “naphthalene problem” in which only π-extended aromatic frameworks show high reactivity[9,10]; couplings of aromatic carboxylic acids to build biaryl species via decarboxylative pathways are restricted to electron-withdrawing group-containing substrates or a strong oxidant is required[11,12]; the synthesis of biaryl species via the decarbonylative reaction of esters and amides is limited to specific substrates (phenyl esters and twisted amides) that require an additional step to be synthesized from carboxylic acids[13,14]; and the use of an exogenous base may limit the scope of reagents and substrates[15]. As part of our interest in developing viable protocols for the activation of inert chemical bonds using transition-metal catalysis[19], we report the nickel-catalyzed Suzuki–Miyaura cross coupling of aldehydes with organoboron compounds under base-free conditions (Fig. 1a, right). The catalytic C–C bond formation proceeds smoothly with various aromatic and heteroaromatic aldehydes, providing a useful synthetic strategy that uses aldehydes as unconventional electrophilic coupling partners in cross-coupling reactions that will inspire further exploration

Methods

Results

Conclusion