Replacing Conventional Carbon Nucleophiles with Electrophiles: Nickel-Catalyzed Reductive Alkylation of Aryl Bromides and Chlorides

Abstract

A general method is presented for the synthesis of alkylated arenes by the chemoselective combination of two electrophilic carbons. Under the optimized conditions, a variety of aryl and vinyl bromides are reductively coupled with alkyl bromides in high yields. Under similar conditions, activated aryl chlorides can also be coupled with bromoalkanes. The protocols are highly functional-group tolerant (−OH, −NHTs, −OAc, −OTs, −OTf, −COMe, −NHBoc, −NHCbz, −CN, −SO2Me), and the reactions are assembled on the benchtop with no special precautions to exclude air or moisture. The reaction displays different chemoselectivity than conventional cross-coupling reactions, such as the Suzuki–Miyaura, Stille, and Hiyama–Denmark reactions. Substrates bearing both an electrophilic and nucleophilic carbon result in selective coupling at the electrophilic carbon (R–X) and no reaction at the nucleophilic carbon (R–[M]) for organoboron (−Bpin), organotin (−SnMe3), and organosilicon (−SiMe2OH) containing organic halides (X–R–[M]). A Hammett study showed a linear correlation of σ and σ(−) parameters with the relative rate of reaction of substituted aryl bromides with bromoalkanes. The small ρ values for these correlations (1.2–1.7) indicate that oxidative addition of the bromoarene is not the turnover-frequency determining step. The rate of reaction has a positive dependence on the concentration of alkyl bromide and catalyst, no dependence upon the amount of zinc (reducing agent), and an inverse dependence upon aryl halide concentration. These results and studies with an organic reductant (TDAE) argue against the intermediacy of organozinc reagents.

Nickel-Catalyzed Reductive Couplings

“…Only moderate-to-good yields were obtained for secondary halides. The initial use of phosphine ligand L12 can be avoided under modified Ni/Mn conditions [44]. Concurrently, similar results using cobalt/phosphine catalytic systems were disclosed by Gosmini, which appears to limit to electron-deficient aryl bromides [45].…”

“…1) [44]. Molander and McMillan independently discovered that the Ru and Ni cocatalyzed photoredox arylation conditions could be extended to efficient vinylation of alkyl silicates or alkyl acids [58,59].…”

Recent advances in homogeneous nickel catalysis

“…Later, a range of aryl bromides and chlorides and alkyl bromides were shown to be reactive with zinc as the reducing agent. 76 Though Zn(0) is present, no organozinc species are formed; rather, zinc (or manganese) acts as a reductant directly to the nickel center, accounting for the excellent functional group compatibility.…”

Nickel-Catalyzed Cross-Coupling of Aryl Halides with Alkyl Halides: Ethyl 4-(4-(4-methylphenylsulfonamido)-phenyl)butanoate

“…4–5 A distinguishing feature of this method is that the only organometallic intermediates are catalytic organonickel species – no organozinc or organomanganese reagents are involved. Previous transition metal-catalyzed methods to synthesize alkylated aromatic compounds have relied on the coupling of pre-formed aryl nucleophiles with alkyl electrophiles, 6–8 aryl electrophiles with pre-formed alkyl nucleophiles, 9 or in situ formation of a carbon nucleophile.…”

“…If very deactivated zinc must be used, then brief activation with hydrochloric acid can be effective. 5 …”