Copper-Catalyzed Cascade Annulation of o-Hydroxyphenyl Propargylamines with Pyrazolin-5-ones to Access Pyrano[2,3-c]pyrazoles

Abstract

An efficient copper-catalyzed cascade annulation of o-hydroxyphenyl propargylamines and pyrazolin-5-ones is described. This methodology leads to the rapid assembly of a series of valuable pyrano­[2,3-c]­pyrazoles with good yields across a wide range of substrates in a simple fashion. This novel reaction involves the formation of alkynyl ortho-quinone methides, a 1,4-conjugate addition, and a subsequent 6-endo cyclization process. The mechanistic elucidation is well supported by control experiment and literature precedents.

Lewis Acid-Catalyzed 1,4-Addition and Annulation of 4-Hydroxy-coumarins with o-Hydroxyphenyl Propargyl Amines: Entry to Regio-Selective Synthesis of Furano[3,2-c]coumarins and Pyrano[3,2-c]coumarins

“…Scheme outlines the proposed mechanism for the formation of 3a and 4a . , Initially, the transient intermediate alkynyl o -QM ( A ) is generated from 1a through the Lewis acid-promoted elimination of piperidine. This piperidine then acts as a base required for the deprotonation of 2a to afford 2-oxo-2 H -chromen-4-olate ( B ), which then attacks the intermediate A via conjugate addition to furnish the intermediate C .…”

“…The title compound was prepared from 2-(1-(piperidin-1-yl)-3-(p-tolyl)prop-2-yn-1-yl)phenol and 7-(dimethylamino)-4-hydroxy-2H-chromen-2-one according to general procedure A and purified by column chromatography (petroleum ether/ethyl acetate 15%, R f = 0.32, KMnO 4 stain) to afford a pale green solid in 82% yield (122 mg); mp 213−215 °C; IR (neat): 3269, 2967, 1894, 1701, 1646, 1510, 1358, 1018, 945 cm −1 ; 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.64 (d, J = 8.8 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.17−7.10 (m, 5H), 7.01 (t, J = 7.2 Hz, 1H), 6.82 (bs, 1H), 6.69−6.62 (m, 2H), 4.04 (bs, 2H), 3.42 (q, J = 7.2 Hz, 4H), 2.32 (s, 3H), 1.12 (t, J = 7.2 Hz, 6H); 13…”

“…In 2021, the same group reported a copper-catalyzed cascade reaction of 2-hydroxynaphthalene-1,4-diones with o -HPPAs, leading to the construction of chromene-fused naphthalene-1,4-dione derivatives (Scheme , eq 2) . In 2022, Wang and Zhao demonstrated the synthesis of pyrano­[2,3- c ]­pyrazole derivatives from the reaction of o -HPPAs and pyrazolin-5-ones via a copper-catalyzed cascade annulation strategy (Scheme , eq 3) . In 2015, Shang et al reported a FeCl 3 -mediated reaction of o -HPPAs with dimedone, followed by p -TsOH-catalyzed cyclization, leading to the construction of dimedone-fused chromene derivatives (Scheme , eq 4) .…”

“…MHz, CDCl 3 ): δ (ppm) 7.64 (d, J = 8.8 Hz, 1H), 7.36−7.29 (m, 3H), 7.28−7.21 (m, 4H), 7.14 (d, J = 8.0 Hz, 1H), 7.01 (t, J = 7.6 Hz, 1H), 6.84 (bs, 1H), 6.68−6.62 (m, 2H), 4.09 (bs, 2H), 3.42 (q, J = 7.2 Hz, 4H), 1.21 (t, J = 7.2 Hz, 6H);13 C{1H} NMR (150 MHz, CDCl 3 ): δ (ppm) 161.4, 159.3, 155.1, 154.6, 152.3, 150.2, 137.5, 131.4, 130.1, 128.8, 128.5, 126.8, 122.1, 121.7, 120.2, 119.9, 117.0, 109.4, 106.4, 101.1, 98.0, 44.9, 32.7, 12.5; HRMS (EI) m/z: [M] f = 0.45, KMnO 4 stain) to afford a pale brown solid in 85% yield (117 mg); mp 202−204 °C; IR (neat): 3349, 3092, 2892, 2556, 2428, 1908, 1821, 1634, 1287, 1026, 944 cm −1 ; 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.76 (d, J = 8.8 Hz, 1H), 7.37−7.29 (m, 3H), 7.27−7.21 (m, https://doi.org/10.1021/acs.joc.3c00213 J. Org. Chem.…”

“…13 C{1H} NMR (100 MHz, CDCl 3 ): δ (ppm) 165.6, 163.4, 157.3, 154.9, 153.8, 148.7, 133.8, 132.2, 130.7, 129.6, 129.5, 128.8, 124.6,…”