Diastereo‐ and Enantioselective Silver‐Catalyzed [3+3] Cycloaddition and Kinetic Resolution of Azomethine Imines with Activated Isocyanides

Abstract

In contrast to the well‐established [3+2] cycloaddition reactions, the catalytic enantioselective [3+n] (n≥3) cycloaddition reaction of activated isocyanides for the preparation of six‐membered or larger ring systems has remained underdeveloped. Herein, we report the first example of highly diastereo‐ and enantioselective [3+3] cycloaddition of activated isocyanides with azomethine imines. By employing silver catalysis, a wide range of biologically important bicyclic 1,2,4‐triazines were obtained in high yields (up to 99 %) with good to excellent stereoselectivities (up to >20 : 1 dr, 99 % ee). In addition, the same catalytic system could be applied to both the late‐stage functionalization of complex bioactive molecules and the kinetic resolution of racemic azomethine imines, further highlighting its versatility and synthetic utility.

Silver-catalyzed synthesis of nitrogen heterocycles: recent advancements

“…In 2022, Liao and co-workers developed a silver-catalyzed platform for the synthesis of biologically relevant bicyclic 1,2,4-triazines 138 through stereoselective [3 + 3] cycloaddition between azomethine imines 137 and activated isocyanides 50 . 90 This novel stereoselective strategy was achieved at 25 °C in THF for 48 h in the presence of 5 mol% Ag 2 CO 3 52 and 10 mol% ligand (Fig. 6) and afforded the desired products 138 in good to excellent yields with excellent stereoselectivities (Scheme 51).…”

Application of Silver Compounds in Fluoroorganic Synthesis: A Minireview

“…The first experimental example of diastereo-and highly enantioselective silver catalyzed [3 + 3] cycloaddition with kinetic resolution of azomethine imines with activated isocyanides has been recently reported by Liao, Qian and co-workers. [191] The biologically important bicyclic 1,2,4-triazine systems that contains EDG as well as EWG substituents (e. g. FÀ or CF 3 À ) were obtained in high yields (up to 99 %) with very good stereoselectivities (Scheme 38).…”

“…[190] Scheme 38. Silver catalyzed enantioselective [3 + 3] cycloaddition reaction of activated isocyanides for the preparation of six-membered bicyclic 1,2,4triazine systems, [191] 1,2-diphenylethylenediamine phosphine-urea type trifluoromethyl group containing ligand used for preparation of Ag catalyst. Scheme 39.…”

Stereo- and Regiospecific SN2′ Reaction of MBH Adducts with Isocyanoacetates: en Route to Transition-Metal-Free α-Allylation of Isocyanoacetates

“…Being a type of activated methylene compounds, isocyanoacetates have been widely employed as α-nucleophiles to attack electrophiles leading to a variety of nucleophilic addition and cycloaddition. Typical electrophilic acceptors include alkyl (pseudo)­halides, electron-deficient alkenes , and heterocycles, alkynes, cumulated double bonds, imines, carbonyls, , aziridines, nitrones, 1,3-dipoles, aryl diazonium salts and so forth. Morita–Baylis–Hillman (MBH) adducts, which have proven to be a type of versatile electrophiles, however, have never been reported to react with isocyanoacetates to the best of our knowledge.…”