The Formal Cross-Coupling of Amines and Carboxylic Acids to Form sp3–sp2 Carbon–Carbon Bonds

Abstract

Amines and carboxylic acids are abundant building blocks for synthesis that classically are united to form an amide bond. To access new pockets of chemical space we are interested in the development of complementary amine–acid coupling reactions. In particular, the formation of carbon–carbon bonds by formal deamination and decarboxylation would be an impactful addition to the synthesis toolbox. 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. Under nickel-catalyzed reductive cross-coupling conditions, a diversity of simple and complex substrates are united in good to excellent yield. High-throughput experimentation was essential to the development of the reaction, and to the discovery of performance-enhancing additives such as cyclic imides, RuCl3 and GaCl3. Preliminary mechanistic investigations suggest that RuCl3 supports the decarbonylation event, increasing reaction selectivity. Numerous amine or acid containing pharmaceuticals are successfully diversified under the optimized conditions.

Rapid Planning and Analysis of High-Throughput Experiment Arrays for Reaction Discovery

“…Phactor™ facilitates the discovery of new reactivity. Our lab is broadly interested in novel amine-acid coupling reactions 50,51,[53][54][55] and particularly amine-acid C-C coupling reactions 53,55 . As part of our studies, we have been exploring mild benzoic acid decarboxylation methods.…”

“…To follow up on our initial report (ref. 55), the catalysts, four additives, four ligands, and two reductants were tested in Figure 4D, and it was found that 31 was afforded at 47% product/internal standard with NiCl2•glyme as the catalyst, 4,4'-di-tertbutyl-2,2-bipyridine as ligand, zinc as the reductant, and lithium perchlorate as an additive. After additional optimization, the reaction array in Figure 4E was run to test the reaction's scope.…”

“…Figure 4F shows the results of a 12 ligand -eight metal catalyst screen expanding on a recently reported sp 2 -sp 3 decarboxylative deaminative C-C coupling from an acid activated as a twisted amide and an amine activated as a Katritzky salt, optimizing the yield of model product 33. 55 Figures 4G-4I show several ultraHTE reaction arrays. Figure 4G and Figure 4H are two reaction arrays produced towards our aryl amine esterification reaction.…”

“…Reaction discovery and library synthesis campaigns utilizing standard 24-, 96-, 384and 1,536-well experiments are described in detail. [50][51][52][53][54][55]…”

Formation of C(sp2)–C(sp3) Bonds Instead of Amide C–N Bonds from Carboxylic Acid and Amine Substrate Pools by Decarbonylative Cross-Electrophile Coupling

“…The mechanistic challenge to be solved is how to convert an aroyl electrophile to an aryl electrophile; if this could be overcome, coupling to a wide array of alkyl electrophiles should be possible (Scheme ). − …”