Sustainable and selective carbene insertion into N–H bonds with a copper-bound recyclable surfactant under micellar conditions†

Abstract

The development of recyclable and water-stable catalysts for sustainable carbene transfer reactions remains challenging due to limited control over reactive intermediates in aqueous media. Herein, we report that micelles enable efficient and selective carbene insertion into the N–H bond using a recyclable copper catalyst under aqueous micellar conditions. We designed a next-generation non-ionic surfactant that forms a micellar nanoreactor to stabilise Cu(i) species and carbene intermediates and enables highly selective carbene insertion into N–H bonds in water under mild conditions. The reactions were performed in an aqueous micellar medium at room temperature (25 °C), avoiding conventional chlorinated solvents, and demonstrated broad substrate scope, including late-stage modification of drug molecules. The system is readily scalable, as demonstrated by 3 gram-scale surfactant synthesis and 1 g-scale catalytic reactions. Importantly, the micellar medium and the organic solvents (EtOAc or MTBE) used for product extraction can be easily recycled multiple times with minimal loss of activity. Therefore, we achieved an E-factor and process mass intensity (PMI) of 0.42 and 1.42, respectively, highlighting their practical utility. Inductively coupled plasma optical emission spectrometry (ICP-OES) analysis of the crude product indicates minimal copper leaching (0.45 ppm), well within the acceptable limits of the International Council for Harmonisation-Guideline for Elemental Impurities (Revision 2) for active pharmaceutical ingredients (APIs). Additionally, spectroscopic and microscopic techniques, such as UV-vis spectroscopy, FT-IR spectroscopy, ESI-MS, X-ray photoelectron spectroscopy (XPS), electron paramagnetic resonance (EPR), confocal laser scanning microscopy (CLSM), fluorescence spectroscopy and time-correlated single-photon counting (TCSPC) investigations, reveal that the micellar environment protects Cu(i) from oxidation while promoting the formation of micelle-confined Fischer-type copper–carbene intermediates within the micellar core, offering fundamental insight into reactivity under nanoconfinement.