Copper‐Catalyzed Domino Synthesis of 2‐Imino‐1H‐imidazol‐5(2H)‐ones and Quinoxalines Involving CC Bond Cleavage with a 1,3‐Dicarbonyl Unit as a Leaving Group

Abstract

Although 2-imino-1H-imidazol-5(2H)-ones have important biological activities in metabolism, their synthesis has rarely been investigated. Quinoxalines as "privileged scaffolds" in medicinal chemistry have been extensively investigated, but the development of novel and efficient synthetic methods remains very attractive. Herein, we have developed two copper-catalyzed domino reactions for the synthesis of 2-imino-1H-imidazol-5(2H)-ones and quinoxalines involving CC bond-cleavage with a 1,3-dicarbonyl unit as a leaving group. The domino sequence for the synthesis of 2-imino-1H-imidazol-5(2H)-ones includes aza-Michael addition, intramolecular cyclization, CC bond-cleavage, 1,2-rearrangement, and aerobic dehydrogenation reaction, whereas the domino sequence for the synthesis of quinoxalines includes aza-Michael addition, intramolecular cyclization, elimination reaction, and CC bond-cleavage reaction. The two domino reactions have significant advantages including high efficiency, mild reaction conditions, and high tolerance of various functional groups.

Oxidative Synthesis of Benzimidazoles, Quinoxalines, and Benzoxazoles from Primary Amines by ortho-Quinone Catalysis

“…When 2-phenethylamine was employed as substrate, the reaction gave an unexpected quinoxaline as the major product (62%) along with the expected benzimidazole as a minor product. Quinoxalines are widely used as building blocks in medicinal chemistry and constitute the framework of natural products . Optimizations in terms of solvents and reaction time did not lead to any improvement on the yield of quinoxaline.…”

The Rise of Carbon‐based Leaving Groups

“…Further use of dibenzoylmethane as the leaving group was demonstrated by An‐Xin Wu and his group in 2014 when they synthesized quinoxalines 9 in mild Lewis acidic conditions (Scheme 7). [28] The formation of 9 involves a domino sequence comprising of aza‐Michael addition on substrate 8 , intramolecular cyclization, dehydration, and C−C bond cleavage.…”

“…Thus, a range of active methylene compounds has been observed as carbon-based leaving groups throughout the New CÀ H, [18,21] CÀ C, [17,32,44] CÀ N, [28,38,45] CÀ O [43] and CÀ S [34] bonds can be formed at the expense of a CÀ C bond, indicating the vast utility of the CÀ C bond cleaving reaction. While a majority of the ChemistrySelect methods involve Lewis acidic environment for the CÀ C bond cleavage, the existence of catalyst-free, metal-free, or solventfree methods is bound to enthuse future research involving carbon-based leaving groups in greener conditions.…”

Investigation and Application of Amphoteric α-Amino Aldehyde: An in Situ Generated Species Based on Heyns Rearrangement

“…We then wondered whether nitrogen could be applied as nucleophile. We reasoned that the aldehyde intermediate could condense with another intramolecular amino group to afford quinoxaline derivatives, assuming that o -phenylenediamine 2i was used as substrate (Scheme ). To our delight, we finally succeeded in preparation of quinoxaline 7 efficiently after optimizing the reaction conditions (Table S4).…”