An interdisciplinary platform for the preparation of active pharmaceutical ingredients through electrophilic aminations

In 2020, amines and related functions accounted for approximately 60% of the World Health Organization’s essential medicines. The development of versatile and efficient amination protocols for the functionalization of simple carbon-backbones is therefore a timely and significant goal. Less common electrophilic nitrogen sources are gaining an increasing attention as efficient alternatives to nitrogen nucleophiles [2]. C-nitroso derivatives, as potent nitrogen-transfer reagents, feature a unique ambivalent electrophilic/nucleophilic profile, the taming of which can unlock their tremendous synthetic potential [3]. Within this context, we have started an interdisciplinary research program for understanding and taming the unique reactivity of C-nitroso species. Our main objective is to exploit their synthetic potential at the fullest for electrophilic aminations toward active pharmaceutical ingredients and converges toward versatile, cost-, time- and resource-effective amination protocols. Our strategy relies on the interplay of computational chemistry (toward inherent reactivity features), machine learning (as a predictive tool to assess feasibility), and automated continuous flow process technology (for accurate control of local process parameters). This innovative methodology was validated via automated kinetic studies under flow conditions leading to a comparable set of experimental and theoretical activation parameters. The versatility of the setup enables both physical organic (through the determination of Mayr reactivity indices) and synthetic (through the synthesis of the corresponding α-aminoketones) experiments, with potential concrete applications for the synthesis of fentanyl and derivatives.