A Two-Step Synthesis of Selected 1,2,3,4-Tetrahydroquinoxaline Derivatives from N-Aryl-2-nitrosoanilines and Arylidenecyanoacetic Esters

Abstract

Reaction of N-aryl-2-nitrosoanilines with alkyl arylidenecyanoacetates in the presence of Et 3 N in MeCN leads to substituted 1,2,3,4-tetrahydroquinoxaline derivatives in reasonable yields. The reaction comprises nucleophilic addition of the nitrosoaniline to the Michael acceptor followed by cyclization involving the nitroso group. Since the reactive nitrogen groups in N-aryl-2-nitrosoanilines are of opposite character the reaction is regioselective and additionally it was found to be diastereoselective.The 1,2,3,4-tetrahydroquinoxaline scaffold is present in numerous biologically active and pharmacologically important compounds. 1 As an example compounds A, B, and C have found applications as cholesteryl ester transfer protein inhibitors, 1b vasopressin V2 receptor antagonists, 1c and prostaglandin D2 receptor antagonists, 1d respectively ( Figure 1). Figure 1Retrosynthetic analysis of the 1,2,3,4-tetrahydroquinoxaline skeleton suggests that it could be synthesized directly from appropriate 2-nitrosoaniline with unsaturated electrophile via Michael addition of the amino group to the activated C=C bond followed by aza-aldol reaction, completed by reduction of the hydroxyloamine formed (Scheme 1). Scheme 1

Synthetic route towards 1,2,3,4-tetrahydroquinoxaline/piperidine combined tricyclic ring system

“…The tricyclic system presented in this paper is practically unknown, except for the single lactam structure. 34…”

Synthesis of 1-arylbenzimidazoles and dibenzo[b,e][1,4]diazepines from 2 (arylamino)aryliminophosphoranes

“…The latter, bearing two differently polarized groups, proved to be valuable starting materials in the synthesis of various nitrogen heterocycles. [3][4][5][6][7][8] An attractive transformation of 2-nitrosodiarylamines appeared to be their smooth reaction with triphenylphosphine, first published in 2014, 9 leading to 2-(arylamino)aryliminophosphoranes via a Cadogan-type reaction. These turned out to be versatile and stable equivalents for 1-aryl-1,2-arylenediamines; they reacted with isocyanates, 9 nitrous acid, 10 CS 2 11 and CO 2 12 furnishing 2-aminobenzimidazoles, benzotriazoles, 2-thiobenzimidazoles and 2-benzimidazolones respectively (Scheme 1).…”