Synthesis of Diverse Nitrogen Heterocycles via Palladium‐Catalyzed Tandem Azide–Isocyanide Cross‐Coupling/Cyclization: Mechanistic Insight using Experimental and Theoretical Studies

Abstract

A rapid and elegant tandem azide–isocyanide cross‐coupling/cyclization protocol has been developed based on a nitrene transfer reaction. The palladium‐catalyzed ligand‐free methodology led to the synthesis of three different heterocyclic scaffolds with excellent atom/step/redox economy. Studies based on first‐principles‐based quantum calculations and control experiments unraveled a concerted process of nitrene transfer reaction on isocyanides, ruling out the metallaaziridine intermediate reported earlier. This finding could pave the way for novel applications of nitrene transfer reactions to generate bioactive heterocycles.magnified image

Recent Development in Palladium-Catalyzed Domino Reactions: Access to Materials and Biologically Important Carbo- and Heterocycles

“…A domino azide-isocyanide cross-coupling/​cyclization was independently developed by Pardasani’s and Ding’s groups. Their Pd-catalyzed ligand-free methodology allowed the synthesis of three different types of potentially bioactive heterocycles as benzo­oxazinones (with a C–N and a C–O bond formation), quinazolinones (with the generation of two new C–N bonds), and benzazoles (with a C–N and a C–S bond formation).…”

Transition‐Metal‐Catalyzed Cross‐Coupling and Sequential Reactions of Azides with Isocyanides

“…A Pd(OAc) 2 ‐catalyzed ligand‐free cascade reaction was reported by Sawant and colleagues in 2018 [27] . This methodology was employed to synthesize several types of heterocyclic skeletons by azide−isocyanide cross‐coupling and intramolecular cyclization (Scheme 15).…”

“…A Pd(OAc) 2 -catalyzed ligand-free cascade reaction was reported by Sawant and colleagues in 2018. [27] This methodology was employed to synthesize several types of heterocyclic skeletons by azideÀ isocyanide cross-coupling and intramolecular cyclization (Scheme 15). By detailed experimental and theoretical studies, authors observed that the nitrene transfer to isocyanide was a concerted and turnover-limiting step of the overall route.…”

Recent Advances in Palladium-Catalyzed Isocyanide Insertions

“…Analogously, starting from organic azides, the palladium-catalyzed transfers of nitrenes to isocyanide functionalities can be achieved. In a recent example, Sawant et al reported a ligand-free substrate-dependent synthesis of bicyclic systems from bifunctional arylazide substrates [ 89 , 90 ]. Molecular nitrogen is readily extruded from the azide substrates to generate a palladium-bound nitrene intermediate 184 , which is subsequently transferred to the isocyanide to afford the short-lived carbodiimide 185 , which readily undergoes intramolecular addition ( Scheme 49 ).…”