Enantioselective synthesis of tetrahydrofuran spirooxindoles via domino oxa-Michael/Michael addition reaction using a bifunctional squaramide catalyst

Abstract

An enantioselective approach for the synthesis of tetrahydrofuran spirooxindoles via domino oxa-Michael/Michael reaction of γ‑hydroxyenones to isatylidene malononitriles, using a cinchona derived bifunctional squaramide catalyst has been developed. The methodology...

Metal-Free Regioselective Oxa-Michael Approach to Access Spirooxindole-Fused Tetrahydrofuran/Tetrahydropyran through [3 + 2]/ [4 + 2] Spirocyclization of Methyleneindolinones with Haloalcohols

“…Colorless liquid, 53 mg, 91% yield, 2.5:1 dr, R f = 0.4, column chromatography on silica gel (nhexane/EtOAc 80:20); 1 H NMR (400 MHz, CDCl 3 ): δ 7.32 (td, J = 7.8, 1.2 Hz, 1H), 7.28 (dd, J = 7.6, 1.0 Hz, 1H), 7.11−7.04 (m, 2H), 4.74 (s, 1H), 4.63 (dd, J = 17.7, 2.5 Hz, 1H), 4.51 (dd, J = 17.7, 2.5 Hz, 1H), 4.43 (dt, J = 8.6, 7.4 Hz, 1H), 4.30 (td, J = 8.8, 5.2 Hz, 1H), 3.83−3.69 (m, 2H), 2.68 (ddd, J = 12.5, 8.7, 7.4 Hz, 1H), 2.26 (dd, J = 4.9, 2.4 Hz, 1H), 2.24−2.14 (m, 1H), 0.71 (t, J = 7.1 Hz, 3H); 13 C { 1 H} NMR (101 MHz, CDCl 3 ): δ 175. 8, 168.2, 141.6, 130.3, 128.8, 123.8, 123.4, 109.1, 84.2,76.8, 72.6, 68.9, 60.9, 56.5, 38.5, 29.7, 13.6 = 3253, 2985, 2963, 2907, 2876, 2291, 2120, 1928, 1756, 1610, 1484, 1462, 1427, 1363, 1319, 1294, 1273, 1254, 1200, 1172, 1124, 1087, 1023, 991, 936, 859, 810, 792, 761, 743, 697, 665, 614, 576 cm −1 .…”

“…4, 142.6, 135.8, 130.6, 128.8, 128.7, 127.9, 127.7, 123.7, 123.0, 109.1, 84.2, 69.0, 60.9, 56.6, 44.3, 39.0, 13.4 = 3409, 3066, 2985, 2931, 1955, 1750, 1708, 1609, 1487, 1464, 1367, 1293, 1272, 1251, 1220, 1198, 1172, 1124, 1091, 1018, 983, 940, 896, 854, 795, 757, 721, 691, 634, 565 ,2-dicarboxylate (3n). Colorless liquid, 33 mg, 58% yield, 2:1 dr, R f = 0.4, column chromatography on silica gel (nhexane/EtOAc 80:20); 1 H NMR (400 MHz, CDCl 3 ): δ 7.85 (d, J = 8.2 Hz, 1H), 7.35−7.29 (m, 1H), 7.28−7.25 (m, 1H), 7.14 (td, J = 7.5, 0.9 Hz, 1H), 4.73 (s, 1H), 4.49−4.38 (m, 1H), 4.29 (td, J = 8.8, 5.7 Hz, 1H), 3.76 (q, J = 7.1 Hz, 2H), 2.74 (ddd, J = 12.6, 8.9, 6.9 Hz, 1H), 2.31−2.23 (m, 1H), 1.66 (s, 9H), 0.78 (t, J = 7.1 Hz, 3H); 13 C { 1 H} NMR (101 MHz, CDCl 3 ): δ 175. 5, 167.…”

“…Colorless liquid, 33 mg, 57% yield, 2:1 dr, R f = 0.4, column chromatography on silica gel (n-hexane/EtOAc 80:20); 1 H NMR (400 MHz, CDCl 3 ): δ 7.42−7.34 (m, 1H), 7.27−7.08 (m, 6H), 6.98 (t, J = 7.5 Hz, 1H), 6.41 (d, J = 7.8 Hz, 1H), 5.59 (s, 1H), 4.50 (dd, J = 15.6, 7.1 Hz, 1H), 4.37 (td, J = 8.5, 5.9 Hz, 1H), 2.87 (s, 3H), 2.73 (ddd, J = 12.5, 8.1, 7.0 Hz, 1H), 2.30−2.12 (m, 1H); 13 C { 1 H} NMR (101 MHz, CDCl 3 ): δ 196. 3, 177.1, 142.7, 136.0, 132.8, 130.0, 128.5, 128.0, 127.7, 124.4, 123.2, 107.7, 88.2, 69.2, 57.0, 39.2, 26.3 = 3450, 3069,3055, 2968, 2882, 2342, 2242, 2161, 1776, 1741, 1697,1614, 1576,1499, 1470, 1446, 1376, 1352, 1315, 1280, 1258, 1238, 1163, 1136, 1106, 1070, 1039, 1016, 971, 884, 865,749,694, 668, 644, 593, 540 2′-one (3v).…”

“…Ethyl 1-Methyl-2-oxo-5′,6′dihydro-2′H, 4′H-spiro[indoline-3,3′-pyran]-2′-carboxylate (5a). Colorless liquid, 59 mg, 95% yield, 9:1 dr, R f = 0.3, column chromatography on silica gel (n-hexane/EtOAc 65:35); 1 H NMR (400 MHz, CDCl 3 ): δ 7.67 (d,J = 7.4 Hz,1H), 7.32 (td, J = 7.8, 1.2 Hz, 1H), 7.05 (td, J = 7.6, 0.8 Hz, 1H), 6.87 (d,J = 7.8 Hz,1H),4.52 (s,1H),4.42 (dd,J = 11.5,4.7 Hz,1H),1H),3.83 (ddd,J = 19.9,12.9,7.5 Hz,2H),3.26 (s,3H),1H),2.14 (ddd,J = 13.3,8.5,3.5 Hz,1H), 1.76−1.67 (m, 2H), 0.85 (t, J = 7.1 Hz, 3H); 13 C { 1 H}NMR (101 MHz, CDCl 3 ): δ 177.7, 168. 3, 143.7, 130.2, 128.5, 125.5, 122.4, 108.0, 79.1, 68.6, 61.0, 49.6, 32.5, 26.5, 20.9, 13.8; HRMS (ESI) calcd for: C 16 H 20 NO 4 : [M + H] + , 290.1387found: 290.1390IR υ ̅ = 3055, 2932, 2856, 1753, 1709, 1610, 1493, 1469, 1375, 1348, 1238, 1204, 1188, 1109, 1071, 1052, 1024, 1003.…”

“…12 Alternatively, the Singh group in 2022 developed organocatalyzed [3 + 2] annulation of isatylidene malononitrile and γ-hydroxyenone. 13 However, further strategies to prepare tetrahydropyran spirooxindoles using methyleneindolinones under mild conditions are still undeveloped. The construction of a spiro quaternary center remains challenging to utilize straightforward and easily accessible reagents, 14 which has attracted enormous interest from chemists.…”