Amines and carboxylic acids are abundant synthetic building blocks that are classically united to form an amide bond. To access new pockets of chemical space we are interested in the development of amine–acid coupling reactions that complement the amide coupling. In particular, the formation of carbon–carbon bonds by formal deamination and decarboxylation would be an impactful addition to the synthesis toolbox. Analysis of building blocks in the MilliporeSigma catalog shows amines and carboxylic acids access a complementary chemical space to that of halides and boronates often used in C(sp³)–C(sp²) coupling (Figure 1). Additionally, many drugs contain amines and carboxylic acids that can provide a handle for late-stage diversification.

Here we report a formal cross-coupling of alkyl amines and aryl carboxylic acids to form C(sp³)–C(sp²) bonds following pre-activation of the amine–acid building blocks as a pyridinium salt and N-acyl-glutarimide respectively (Figure 2). Under nickel-catalyzed reductive cross-coupling conditions, a diversity of simple and complex substrates are united in good to excellent yield, and numerous pharmaceuticals are successfully diversified. High-throughput experimentation was leveraged in the development of the reaction, and to the discovery of performance-enhancing additives such as phthalimide, RuCl₃ and GaCl₃. Mechanistic investigations suggest phthalimide may play a role in stabilizing productive Ni complexes rather than being involved in oxidative addition of the N-acyl-imide and that RuCl₃ supports the decarbonylation event, improving reaction selectivity.

<b>Figure 1.</b> Analysis of building block availability from MilliporeSigma.

Figure 1. Analysis of building block availability from MilliporeSigma.

<b>Figure 2.</b> Cross-coupling of amines and carboxylic acids to form C(sp<sup>3</sup>)–C(sp<sup>2</sup>) bonds as a complement to amide coupling.

Figure 2. Cross-coupling of amines and carboxylic acids to form C(sp³)–C(sp²) bonds as a complement to amide coupling.

Eunjae Shim

Appearances