Visible-light-mediated decarboxylative umpolung strategy to carbamoyl/acyl fluorides in buffer medium: Expedient access to unsymmetrical urea/amides and lysine-selective bioconjugation

Abstract

Acyl halides particularly, acyl chlorides are indispensable yet highly reactive electrophile that hydrolyses spontaneously in water or even with aerial moisture. Owing to their distinct reactivities, particulartly stability in aqueous medium, carbamoyl and acyl fluorides. are emerging as a user- and envrironmental-friendly alternatives to their chloride counterparts. For the first time, we have disclosed a photocatalytic decarboxylative fluorination of oxamic acids and α-ketoacids to the corresponding carbamoyl and acyl fluorides in aqueous medium. Remarkably, this decarboxylative fluorination reaction proceeds smoothly with an inexpensive, electrophilic, green fluorinating agent, selectfluor ($2/g) using a catalytic organophotoredox catalyst 4-CzIPN under the visible light irradiation furnishing carbamoyl/acyl fluorides in high yields. Subsequently, they were trapped with amines for the expedient access to unsymmmetrical ureas and amides either in situ or separately under PBS buffer medium (pH ~ 7.4) without any external base. Furthermore, amino acid and late-stage modification of the drug candidates were performed under this mild condition. This metal-free, ambient and aqueous-medium reaction also proceeds smoothly under the renewable sunlight irradiation. Intrigued by the application potential of urea/amide coupling under biocompatible condition, we realized that neutral PBS buffer-mediated mild urea formation at room temperature has potential for the development of in situ click reaction. Gratifyingly, we have demonstrated that the carbamoyl fluoride has an inherent preference towards urea formation with amines in the presence of other nucleophiles in buffer medium at physiological pH which is better chemoselective than sulfur fluoride exchange (SuFEx) click chemistry. Finally, a preliminary lysine-selective bioconjugation with carbamoyl fluoride over serine or cysteine has been demonstrated via competitive experiments and on a nonapeptide urea conjugation. From control experiments, photophysical studies and HOMO-LUMO calculation the involvement of radical pathway for the carbamoyl fluoride formation has been elucidated.