Copper-Catalyzed Three-Component Cascade Annulation for Divergent Syntheses of Imidazoles and Dihydroimidazoles

Abstract

The first example of divergent N-heterocycle syntheses through a copper-catalyzed three-component reaction of α,β-unsaturated ketoximes, paraformaldehyde, and amines has been documented. In particular, this divergent synthetic strategy was achieved by controlling the reaction conditions to afford the corresponding imidazoles and dihydroimidazoles in moderate to good yields with a broad substrate scope and good functional group compatibility.

An electrochemical tandem Michael addition, azidation and intramolecular cyclization strategy for the synthesis of imidazole derivatives

“…Initially, iodide was oxidized into an iodine radical, which reacted with A to form intermediate B, and then intermediate B was attacked by N 3 − to produce C. Intermediate C was then oxidized to D to give an α-azidoalkyl free radical. Subsequently, releasing N 2 of D formed iminyl free radical E. After the formation of the imino radical, it would abstract a hydrogen atom from the methylene group adjacent to another nitrogen atom to afford α-amino radical F through the process of a [1,5]-H shift. 10 F was then oxidized to carbonium and captured with imine nitrogen to form the cyclization product.…”

“…1). 1 Therefore, the method of developing novel and efficient synthetic imidazole rings continues to receive attention from contemporary synthetic chemists. 2 The classical methods for the synthesis of imidazole derivatives include the Debus–Radziszewski method, 3 which forms a Biside intermediate through the reaction of an α-dicarbonyl compound and dry ammonia and subsequently undergoes the desired cyclization reaction.…”

Synthesis of 2,4,6-Trisubstituted Pyrimidines through Copper-Catalyzed [4 + 2] Annulation of α,β-Unsaturated Ketoximes with Activated Nitriles

“…7 Very recently, we established the copper-catalyzed coupling of α,β-unsaturated ketoxime acetates with the in situ-generated Nsubstituted formaldimine for divergent syntheses of imidazoles and dihydroimidazoles by controlling the reaction conditions. 8 Despite numerous achievements, to the best of our knowledge, the annulation of α,β-unsaturated ketoximes with C�N bonds has not yet been reported, and new protocols for addressing the issue remain urgent and highly desirable.…”

“…In addition, Ellman and our group successfully realized the rhodium­(III)-, cobalt­(III)-, and copper­(I)-catalyzed condensation of α,β-unsaturated ketoximes with activated C=O bonds to access functionalized furans, 2H-1,3-oxazines, and dihydrooxazoles . Very recently, we established the copper-catalyzed coupling of α,β-unsaturated ketoxime acetates with the in situ-generated N -substituted formaldimine for divergent syntheses of imidazoles and dihydroimidazoles by controlling the reaction conditions . Despite numerous achievements, to the best of our knowledge, the annulation of α,β-unsaturated ketoximes with CN bonds has not yet been reported, and new protocols for addressing the issue remain urgent and highly desirable.…”

An HFIP-assisted, cobalt-catalyzed three-component electrophilic C–H amination/cyclization/directing group removal cascade to naphtho[1,2-d]imidazoles

“…9 Paraformaldehyde has also been used as a C-1 source for the synthesis of azacycles through cascade reactions via C–H activation. 10 Although there are several methods for the synthesis of 2-substituted benzimidazoles, 11 the synthesis of 2-unsubstituted benzimidazoles has been achieved only through a Pd-catalyzed intramolecular C–H amination using sophisticated N , N -diphenyl formamidine substrates. 12 An efficient protocol for the one-pot synthesis of 2-unsubstituted benzimidazoles is still lacking.…”