Dynamic Kinetic Cross-Electrophile Arylation of Benzyl Alcohols by Nickel Catalysis

Abstract

Catalytic transformation of alcohols via metal-catalyzed cross-coupling reactions is very important, but it typically relies on a multistep procedure. We here report a dynamic kinetic cross-coupling approach for the direct functionalization of alcohols. The feasibility of this strategy is demonstrated by a nickel-catalyzed cross-electrophile arylation reaction of benzyl alcohols with (hetero)­aryl electrophiles. The reaction proceeds with a broad substrate scope of both coupling partners. The electron-rich, electron-poor, and ortho-/meta-/para-substituted (hetero)­aryl electrophiles (e.g., Ar–OTf, Ar–I, Ar–Br, and inert Ar–Cl) all coupled well. Most of the functionalities, including aldehyde, ketone, amide, ester, nitrile, sulfone, furan, thiophene, benzothiophene, pyridine, quinolone, Ar–SiMe3, Ar–Bpin, and Ar–SnBu3, were tolerated. The dynamic nature of this method enables the direct arylation of benzylic alcohol in the presence of various nucleophilic groups, including nonactivated primary/secondary/tertiary alcohols, phenols, and free indoles. It thus offers a robust alternative to existing methods for the precise construction of diarylmethanes. The synthetic utility of the method was demonstrated by a concise synthesis of biologically active molecules and by its application to peptide modification and conjugation. Preliminary mechanistic studies revealed that the reaction of in situ formed benzyl oxalates with nickel, possibly via a radical process, is an initial step in the reaction with aryl electrophiles.

Synthesis of Dibenzyls by Nickel-Catalyzed Homocoupling of Benzyl Alcohols

“…Our previous studies reveal that transesterification between alcohol and DMO proceeded smoothly in the presence of either Ni(0) or Mn. 18 Moreover, without DMO, the reaction of preformed oxalate 3a afforded 2a in 84% GC yield under the standard conditions (Scheme 5, part 1). These results suggest that the homocoupling of alcohols may proceed through the intermediacy of benzyl oxalates.…”

“…The catalytic cycle for this reaction is shown in Scheme 6, which is proposed based on our previous finding 18 and on reported work. Step 1: Transesterification of benzyl alcohols and DMO to form benzylic oxalates, which are highly reactive towards low-valent metals.…”

“…20 Benzyl radicals can be generated either by Ni(0) or Ni(I) species. 18 Alternatively, dimerization of benzyl radicals may also result in the desired products.…”

“…[13][14][15][16][17] Very recently, we found that dimethyl oxalate (DMO) can undergo equilibrium reaction with alcohols, and the formed alkyl oxalates can participate in coupling reactions when generated. 18 Based on this finding, we established a nickel-catalyzed dynamic kinetic cross-electrophile coupling of benzyl alcohols and aryl halides. Herein, we demonstrate a nickel-catalyzed homocoupling of benzyl alcohols by this dynamic kinetic strategy, which offers convenient access to dibenzyls (Scheme 2d).…”

“…19 Reaction at 30 °C did not yield any desired product, probably because the transesterification between alcohol and DMO to form active benzylic oxalate did not proceed at this temperature (entry 11). 18 A low yield was obtained when Zn was used instead of Mn (entry 12). In the absence of a nickel catalyst, the reactions afforded 2a in a low yield of 18% (entry 13).…”