This work highlights Ni-catalyzed reductive coupling of alkyl acids with alkyl halides, particularly sterically hindered unactivated tertiary alkyl bromides for the production of all carbon quaternary ketones. The reductive strategy is applicable to α-selective synthesis of saturated, fully oxygenated C-acyl glycosides through easy manipulations of the readily available sugar bromides and alkyl acids, avoiding otherwise difficult multistep conversions. Initial mechanistic studies suggest that a radical chain mechanism (cycle B, Scheme 1) may be plausible, wherein MgCl2 promotes the reduction of Ni(II) complexes.

A mild Ni-catalyzed reductive arylation of tertiary alkyl halides with aryl bromides has been developed that delivers products bearing all-carbon quaternary centers in moderate to excellent yields with excellent functional group tolerance. Electron-deficient arenes are generally more effective in inhibiting alkyl isomerization. The reactions proceed successfully with pyridine or 4-(dimethylamino)pyridine, while imidazolium salts slightly enhance the coupling efficiency.

The formation of C-C bonds directly from catalytic reductive cross-coupling of two different electrophiles represents one of the practical synthetic protocols that differs from the conventional nucleophile/electrophile coupling methods. Particularly the reductive coupling of alkyl electrophiles with other electrophiles is still a challenge. This account summarizes the advances of the formation of C(sp 3 )-C(sp 3 ) bonds between two alkyl electrophiles, with emphasis on the control of chemoselectivity that is exceedingly challenging to achieve due to similar structures and reactivities of two unactivated alkyl halides. The coupling of alkyl halides with aryl or acyl electrophiles was also discussed based on the chemistry developed by our group, followed by a brief overview for the reactions of tertiary alkyl halides. In the end, a brief outlook of the challenges in this exciting field was illustrated. Whereas the reaction mechanisms generating alkylalkyl products are proposed to involve reactions of Ni(I) species with alkyl halides to generate Ralkyl-Ni(III)-Ralkyl intermediates through a radical/Ni cage-rebound process, evidence seemingly supports that a radical chain mechanism governs the acylation and arylation of alkyl halides. The latter features a cage-escaped alkyl radical.

A Ni-catalyzed Negishi cross-coupling approach to C-glycosides is described with an emphasis on C-aryl glycosides. The combination of NiCl2/PyBox in N,N'-dimethylimidazolidinone (DMI) enabled the synthesis of C-alkyl glycosides under mild reaction conditions. Moderate yields and beta-selectivities were obtained for C-glucosides, and good yields and high alpha-selectivities were the norm for C-mannosides. For C-aryl glycosides, reactions employing Ni(COD)2/(t)Bu-Terpy in N,N-dimethylformamide (DMF) were typically high yielding and provided C-glucosides with high beta-selectivities (1:>10 alpha:beta) and C-mannosides in moderate alpha-selectivities (3:1 alpha:beta); alpha-C-aryl glycosides could be obtained by the combination of Ni(COD)2/PyBox in DMF (>20:1 alpha:beta). The collective studies suggest that stereochemical control of the C-glycosides is dependent on the substrate and catalysts combination. The Negishi protocol displays excellent functional group tolerance, as demonstrated by its use in the first total synthesis of the natural product salmochelin SX.

This work illustrates the reductive coupling of electron-rich aryl halides with tertiary alkyl halides under Ni-catalyzed cross-electrophile coupling conditions, which offers an efficient protocol for the construction of all carbon quaternary stereogenic centers. The mild and easy-to-operate reaction tolerates a wide range of functional groups. The utility of this method is manifested by the preparation of cyclotryptamine derivatives, wherein successful incorporation of 7-indolyl moieties is of particular interest as numerous naturally occurring products are composed of these key scaffolds. DFT calculations have been carried out to investigate the proposed radical chain and double oxidative addition pathways, which provide useful mechanistic insights into the part of the reaction that takes place in solution.

A Ni-catalyzed reductive approach to the cross-coupling of two unactivated alkyl halides has been successfully developed. The reaction works efficiently for primary and secondary halides, with at least one being bromide. The mild reaction conditions allow for excellent functional group tolerance and provide the C(sp(3))-C(sp(3)) coupling products in moderate to excellent yields.

The Ni-catalyzed reductive coupling of alkyl/aryl with other electrophiles has evolved to be an important protocol for the construction of C-C bonds. This chapter first emphasizes the recent progress on the Ni-catalyzed alkylation, arylation/vinylation, and acylation of alkyl electrophiles. A brief overview of CO2 fixation is also addressed. The chemoselectivity between the electrophiles and the reactivity of the alkyl substrates will be detailed on the basis of different Ni-catalyzed conditions and mechanistic perspective. The asymmetric formation of C(sp(3))-C(sp(2)) bonds arising from activated alkyl halides is next depicted followed by allylic carbonylation. Finally, the coupling of aryl halides with other C(sp(2))-electrophiles is detailed at the end of this chapter.

Zn-mediated reduction of readily accessible dialkyl oxalates derived from tertiary alcohols provides an efficient approach to C−O bond fragmentation and alkyl radical formation. With MgCl 2 as the indispensable additive and Ni as the promoter, trapping the radical with activated alkenes and aryl−Ni intermediates allows for the generation of alkylated and arylated all-carbon quaternary centers.