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Chemical transformations determine the structure of a product, and therefore its properties, which in turn affect complex macroscopic functions such as the metabolic stability of pharmaceuticals or the volatility of perfumes. Therefore, reaction selection can influence the success or failure of a candidate molecule to meet a functional objective. The coupling of an amine with a carboxylic acid to form an amide bond is the most popular chemical reaction used for drug discovery.sup.1. However, there are many other ways to connect these two common functional groups together. Here we show computationally that amines and acids can couple via hundreds of hypothetical yet plausible transformations, and we demonstrate experimentally the application of a dozen such reactions. To investigate the contribution of chemical transformations to properties, we developed a string-based notation and used an enumerative combinatorics approach to produce a map of conceivable amine-acid coupling transformations, which can be charted using chemoinformatic techniques. We find that critical physicochemical parameters of the products, such as partition coefficient and polar surface area, vary considerably depending on the transformation chosen. Data mining the amine-acid coupling system produced here should enable reaction discovery, which we demonstrate by developing an esterification reaction found within the mapped space. Complex molecules with distinct property profiles can also be discovered within the amine-acid coupling system, as we show here via the late-stage diversification of drugs and natural products. All possible chemical transformations between amine and carboxylic acid groups are mapped using an automated string-based combinatorics method, showing that the properties and functions of the products vary considerably over all plausible reactions., Author(s): Babak Mahjour [sup.1] , Yuning Shen [sup.1] , Wenbo Liu [sup.1] , Tim Cernak [sup.1] Author Affiliations: (1) Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann [...]

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. Here, we report a formal cross-coupling of alkyl amines and aryl carboxylic acids to form C(sp 3 )-C(sp 2 ) bonds following preactivation 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, and numerous pharmaceuticals are successfully diversified. High-throughput experimentation was leveraged in the development of the reaction and the discovery of performance-enhancing additives such as phthalimide, RuCl 3 , and GaCl 3 . 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 RuCl 3 supports the decarbonylation event, thereby improving reaction selectivity.