Delayed catalyst function enables direct enantioselective conversion of nitriles to NH ₂ -amines

Abstract

Accessing enantiomerically enriched amines often demands oxidation-state adjustments, protection and deprotection processes, and purification procedures that increase cost and waste, limiting applicability. When diastereomers can be formed, one isomer is attainable. Here, we show that nitriles, largely viewed as insufficiently reactive, can be transformed directly to multifunctional unprotected homoallylic amines by enantioselective addition of a carbon-based nucleophile and diastereodivergent reduction of the resulting ketimine. Successful implementation requires that competing copper-based catalysts be present simultaneously and that the slower-forming and less reactive one engages first. This challenge was addressed by incorporation of a nonproductive side cycle, fueled selectively by inexpensive additives, to delay the function of the more active catalyst. The utility of this approach is highlighted by its application to the efficient preparation of the anticancer agent (+)-tangutorine.

Recent Developments in C–C Bond Formation Using Catalytic Reductive Coupling Strategies

“…This adds to the imine electrophile furnishing 82 that undergoes subsequent ligand substitution with KOt-Bu to regenerate 83. Catalytic asymmetric reactions of 77 with aldehyde and ketone 48 electrophiles as well as nitriles 49 have also been reported. In the case of nitriles, a silane is also added to the reaction mixture so that the analogous product to that of 79 without the PMP-protecting group is obtained directly.…”

Sulfonate N‐Heterocyclic Carbene–Copper Complexes: Uniquely Effective Catalysts for Enantioselective Synthesis of C−C, C−B, C−H, and C−Si Bonds

“…Nonetheless,t he inherent basicity of am etal alkoxide can at times cause undesirable side reactions and/or complications in functional group tolerance issues. [28]…”

Reductive Arylation of Amides via a Nickel‐Catalyzed Suzuki–Miyaura‐Coupling and Transfer‐Hydrogenation Cascade

“…Buchwald and coworkers have reported ac opper-catalyzed reductive alkylation of symmetric anhydrides to afford enantioenriched secondary alcohols, [15] and more recently the Hoveyda group reported ac opper-catalyzed asymmetric reductive allylation of nitriles to access enantioenriched homoallylic amines (Figure 1b). [16] Together,t hese examples illustrate some of the potential advantages of cascade reactions that add disparate nucleophiles to asingle reactive center of an achiral substrate and uncover synergistic reactivity beyond the capabilities of one reaction manifold. [17] In this manuscript, we describe as ynthetic method for achieving the addition of two different nucleophiles to ac arboxylic acid derivative using nickel catalysis.…”