Deoxygenative Cross-Coupling of C(aryl)–O and C(amide)═O Electrophiles Enabled by Chromium Catalysis Using Bipyridine Ligand

Abstract

Deoxygenative cross-coupling between unactivated C–O and unsaturated CO electrophiles remains an unsolved challenge in synthetic chemistry. Here, we report the deoxygenative cross-coupling of C–O/CO electrophiles by reaction of unactivated aryl esters with unsaturated amides, enabled by chromium catalysis. Inexpensive and simple CrCl3 salt combined with bipyridine ligand, magnesium reductant, and chlorosilane, shows high reactivity in promoting the deoxygenative coupling between C–O and CO bonds involving hydrogen transfer. This reaction provides a strategy to form pharmaceutically interesting diarylmethylated amines, by forging C­(sp2)–C­(sp3) bonds with impeding the competing ester homocoupling and carbonyl reduction that usually occur under reductive conditions. Mechanistic studies based on high-resolution mass spectrometry analysis and deuterium-labeling experiments indicate that cleavage of ester C–O bonds by Cr and subsequent silylation leads to the formation of arylated silachromate, which regioselectively adds to carbonyls of amides through reductive elimination and deoxygenative hydrogen transfer, resulting in the reductive cross-coupling of C­(aryl)–O and C­(amide)O electrophiles.

Iron‐Catalyzed Reductive C(aryl)—Si Cross‐Coupling of Diaryl Ethers with Chlorosilanes

“…[ 35‐41 ] In particular, the direct functionalization of C(aryl)—O bond of aryl ethers is important for the transformation of oxygen‐rich lignocellulosic plant biomass like lignin to well‐defined aromatic compounds. Despite great interest and recent advance on catalytic C(aryl)—O activation of aryl alkyl ethers [ 42‐52 ] and hydrogenolysis of diaryl ether C(aryl)—O bonds (Scheme 1b), [ 53‐57 ] the chemo‐ and regioselective functionalization of the C(aryl)—O bonds of diaryl ethers, especially highly substituted biaryl ethers relevant to those found in lignin, has remained a challenge. Therefore, the development of a selective and efficient catalysis for tackling this challenge is an attractive research object.…”

Deoxygenative arylation of secondary amides by merging iridium catalysis with electrochemical radical cross-coupling

“…1 However, the inert nature of amides makes their reductive transformation to amines challenging. 2 In the past decade, various highly reactive nucleophiles, such as Grignard reagents, alkyl lithium reagents, etc. , have been employed as functionalization partners to react with activated imines or iminium ions, which are generated from inert amides by electrophilic activation, 3 controlled hydride reduction, 4 or transition metal-catalyzed hydrosilylation (Scheme 1a-i).…”

Suzuki–Miyaura Cross-Coupling of Amides by N–C Cleavage Mediated by Air-Stable, Well-Defined [Pd(NHC)(sulfide)Cl2] Catalysts: Reaction Development, Scope, and Mechanism

“…In the past five years, tremendous progress has been achieved in the activation of amide bonds by transition metals. − Once regarded as chemically inert due to the amide resonance ( n N → π* CO barrier to rotation, 15–20 mol/kcal), the activation of amide N–C acyl bonds has experienced a paradigm shift through ground-state-destabilization mechanism that enables amides to participate in a broad range of generic cross-coupling reactions under mild conditions (Figure a). , This amide bond reactivity platform has captured significant attention due to the prevalence of amides in drug discovery research, agrochemistry, natural products, organic materials, and biochemistry, where amides constitute the most common functional groups across various facets of academic and industrial research. , …”