SummaryPd-catalysed C–C bond formation is an essential tool within the pharmaceutical and agrochemical industries. Many of these reactions rely heavily on polar aprotic solvents; however, despite their utility, these solvents are incompatible with the drive towards more sustainable chemical synthesis. Herein, we describe the scope and limitations of an alternative to DMF derived from renewable sources (CyreneTM) in Sonogashira cross-coupling and Cacchi-type annulations.

Amide bonds are one of the underpinning linkages in all living systems and are fundamental within drug discovery. Current methods towards their synthesis frequently rely on the use of dipolar aprotic solvents; however, due to increasingly stringent regulations and growing societal pressures, safe and more sustainable alternatives are highly sought after. Herein, we evaluate the application of the bio-based solvent Cyrene™ in the HATU mediated synthesis of amides and peptides. We found that Cyrene functioned as a competent replacement for DMF in the synthesis of a series of lead-like compounds and dipeptides (25 examples, 63-100%).

A one-pot cascade reaction for the synthesis of 2-BMIDA 6,5-bicyclic heterocycles has been developed using Cu(i)/Pd(0)/Cu(ii) catalysis. 2-Iodoanilines and phenols undergo a Cu(i)/Pd(0)-catalyzed Sonogashira reaction with ethynyl BMIDA followed by in situ Cu(ii)-catalyzed 5-endo-dig cyclization to generate heterocyclic scaffolds with a BMIDA functional group in the 2-position. The method provides efficient access to borylated indoles, benzofurans, and aza-derivatives, which can be difficult to access through alternative methods.

The Suzuki–Miyaura (SM) cross-coupling is the most broadly utilized Pd-catalyzed C–C bond-forming reaction in the chemical industry. A large proportion of SM couplings employ dipolar aprotic solvents; however, current sustainability initiatives and increasingly stringent regulations advocate the use of alternatives that exhibit more desirable properties. Here we describe the scope and utility of the bio-derived solvent Cyrene™ in SM cross-couplings and evaluate its suitability as a reaction medium for this benchmark transformation from discovery to gram scale.