Copper-Catalyzed Oxidative [3 + 2]-Annulation of Quinoxalin-2(1H)-one with Oxime Esters toward Functionalized Pyrazolo[1,5-a]quinoxalin-4(5H)-ones as Opioid Receptor Modulators

Abstract

Pyrazolo­[1,5-a]­quinoxalin-4­(5H)-one derivatives as novel opioid receptor modulators have been synthesized via copper-catalyzed oxidative [3 + 2]-annulation of quinoxalin-2­(1H)-one and oxime-O-acetates. This hydrazine-free C–C and N–N bond formation strategy starts with the generation of C2N1 synthon using oxime acetate, which reacts in a [3 + 2] manner with quinoxalin-2­(1H)-one, followed by oxidative aromatization. The synthesized compounds were tested against opioid receptors, of which eight compounds exhibited an antagonistic effect with EC50 < 5 μM at various opioid receptors. Molecular docking studies were performed to identify the binding of active pyrazolo­[1,5-a]­quinoxalin-4­(5H)-one ligands with hKOR protein. Docking results indicated that compounds 3d and 3g participate in hydrogen bonding with the hydroxyl group of T111 of the active site pocket residue.

Regioselective Synthesis of Phenanthridines via Pd(II)-Catalyzed Annulative C(sp2)–H Activation

“…The titled compound was prepared and purified by silica-gel column chromatography (10% EtOAc/hexane) to yield 1b as a white solid (456 mg, 81%); m.p: 55–57 °C; R f = 0.5 (20% EtOAc/hexane); 1 H NMR (400 MHz, CDCl 3 ): δ 8.95 (s, 1H (O-H)), 7.64–7.61 (m, 2H), 7.40–7.37 (m, 3H), 2.30 (s, 3H); 13 C­{ 1 H} NMR (100 MHz, CDCl 3 ): δ 156.2, 136.7, 129.4, 128.7, 126.2, 12.4; HRMS (ESI) m / z : [M + H] + calcd for C 8 H 10 NO 136.0762, found 136.0759 …”

“…7, 129.4, 128.7, 126.2, 12.4; HRMS (ESI) m/z: [M + H] + calcd for C 8 H 10 NO 136.0762, found 136.0759. 15 (E)-1-Phenylethan-1-one O-Methyl Oxime (1c). The titled compound was prepared and purified by silica-gel column chromatography (12% EtOAc/hexane) to yield 1c as a colorless oil (32 mg, 89%); R f = 0.5 (20% EtOAc/hexane); 1 H NMR (400 MHz, CDCl 3 ): δ 7.65 −7.62 (m, 2H), 7.38−7.33 (m, 3H), 3.99 (s, 3H), 2.22 (s, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ 154.…”

“…In one of our recent findings, we could successfully utilize the oxime acetates and quinoxalinones to construct pyrazoloquinoxalinone in a highly regioselective manner. 15 In continuation, we envisioned utilizing oxime esters with aryl acyl peroxides to construct phenanthridines via palladium-catalyzed decarboxylative ortho C(sp 2 )−H activation/N-arylation (Figure 2c). The potential of aryl acyl peroxides in decarboxylative arylation is well explored.…”

“…Considering the inherent reactivity of oxime esters, , we became interested in developing new methods to construct diversely functionalized heterocycles. In one of our recent findings, we could successfully utilize the oxime acetates and quinoxalinones to construct pyrazoloquinoxalinone in a highly regioselective manner . In continuation, we envisioned utilizing oxime esters with aryl acyl peroxides to construct phenanthridines via palladium-catalyzed decarboxylative ortho C­(sp 2 )–H activation/N-arylation (Figure c).…”

Swapping Copper‐Catalytic Process: Selective Access to Pyrazoles and Conjugated Ketimines from Oxime Acetates and Cyclic Sulfamidate Imines

“…illustrated an appealing tactic for synthesizing 1,3‐disubstituted pyrazoles from oxime acetates, amines and formaldehyde catalyzed by CuBr in the presence of base at 120 °C. Furthermore, Huang [16b] and Srivastava [16c] groups also independently developed novel Cu(I)‐catalyzed [3+2] annulation reactions of oxime acetates with quinoxalin‐2‐(1 H )‐ones/in situ produced 3,4‐dihydroisoquinolines as imine precursors using α‐Fe 2 O 3 as an oxidant that afforded important classes of fused‐pyrazoles. Moreover, Huang et al.…”