A general alkyl-alkyl cross-coupling enabled by redox-active esters and alkylzinc reagents

Abstract

Alkyl carboxylic acids are ubiquitous in all facets of chemical science, from natural products to polymers, and represent an ideal starting material with which to forge new connections. This study demonstrates how the same activating principles used for decades to make simple C-N (amide) bonds from carboxylic acids with loss of water can be used to make C-C bonds through coupling with dialkylzinc reagents and loss of carbon dioxide. This disconnection strategy benefits from the use of a simple, inexpensive nickel catalyst and exhibits a remarkably broad scope across a range of substrates (>70 examples).

Figure 1. Development of a Ni-catalyzed decarboxylative alkyl-alkyl cross-coupling

(A) Activation of carboxylic acids in organic synthesis. (B) Potential side-products. (C) Ni-catalyzed cross-coupling of redox-active esters and alkylzinc reagents.

Figure 2. Scope of the Ni-catalyzed decarboxylative alkyl-alkyl cross-coupling

Standard conditions: redox-active ester (1 equiv.), dialkylzinc reagent (2 equiv.), NiCl₂·glyme (20 mol%), L2 (40 mol%), THF:DMF, 25 ºC, 8–14 h. THF=tetrahydrofuran; DMF=dimethylformamide.

Figure 3. Ni-catalyzed decarboxylative alkyl-alkyl coupling in solid phase synthesis

† See Supplementary Materials for experimental details.

Figure 4. Scope of the Ni-catalyzed three-component conjunctive cross-coupling

Standard conditions: redox-active ester (1 equiv.), acceptor (2.5 equiv.), PhZnCl·LiCl complex (3 equiv.), NiCl₂·glyme (20 mol%), L2 (40 mol%), THF:DMF, 25 ºC, 8 h. THF=tetrahydrofuran; DMF=dimethylformamide. All the products shown were obtained in a racemic form.