Stereodivergent Synthesis of 3-Aminooxindole Derivatives Containing Vicinal Tetrasubstituted Stereocenters via the Mannich Reaction

Abstract

A highly enantioselective stereodivergent synthesis of 3-aminooxindole derivatives was accomplished via asymmetric Mannich reaction between 2-substituted benzofuran-3-one and isatin-derived ketimines. Both anti and syn-selective chiral 3,3-disubstituted amino oxindoles bearing two adjacent tetrasubstituted stereogenic centers with high yield and excellent enantioselectivities were obtained using readily available cinchona-alkaloid derived organocatalysts. The control experiment revealed that oxygen atom present in the benzofuran ring played an important role in switching diastereodivergence. The obtained Mannich product was further transformed into a biologically important 2,3-dihydrobenzofuran derivative having three contiguous stereocenters with no loss of enantioselectivity.

Aymmetric Aza-Friedel–Crafts Reaction of Isatin-Derived Ketimines with Indoles Catalyzed by a Chiral Phase-Transfer Catalyst

“…4, 154.4, 150.9, 143.1, 137.2, 136.3, 134.9, 130.1, 129.0, 128.5, 128.1, 124.6, 124.1, 123.6, 122.8, 122.5, 121.5, 121.3, 121.1, 120.5, 112.9, 111.7, 109.5, 77.3, 67.1, 62.2, 44.3, 34.7, 31.3 6, 154.6, 143.8, 137.2, 135.9, 130.1,129.3, 128.5, 128.2, 128.1, 124.5, 124.3, 123.7, 122.7, 121.3, 120.3, 112.1, 111.9, 108.5, 77.4, 67.2, 62.1, 26.6 26.9 = +252.2 (c = 0.5, CHCl 3 ), ee = 87% (Chiralpak IG, hexane/EtOH = 70:30, 254 nm, 1 mL/min, t major = 34.330 min, t minor = 12.063 min); 1 H NMR (400 MHz, DMSO) δ 11.17 (s, 1H), 8.67 (s, 1H), 7.63 (t, J = 37.6 Hz, 1H), 7.51−6.57 (m, 17H), 5.20−4.65 (m, 4H); 13 C{ 1 H} NMR (101 MHz, DMSO) δ 175. 4,160.1, 157.8, 155.4, 139.4, 137.5, 137.2, 136.6, 133.7, 128.9, 128.8, 128.3, 128.1, 127.7, 127.6, 125.1 (d, J = 31.4 Hz), 121.9 (d,J = 16.4 Hz),119.3,115.3 (d,J = 23.1 Hz),112.3,111.8,111.5,110.4,66.2,62.4,43.5;19 3, 154.5, 141.5, 137.2, 135.3, 129.1, 128.8, 128.6, 128.3, 128.2, 128.1, 127.6, 127.1, 124.3, 124.1, 124.0, 123.1, 121.3, 120.6, 111.9, 111.8, 110.6, 77.3, 67.4, 62.2, 44. 1, 154.5,142.0, 137.2, 135.3, 132.0, 128.8, 128.6, 128.3, 128.2, 127.6, 127.1, 126.8, 124.3, 124.0, 123.1, 121.3, 120.6, 115.4, 111.9, 111.9, 111 Hz, 1H), 6.07 (s, 1H), 5.04 (s, 2H), 4.80 (s, 2H); 13 C{ 1 H} NMR (101 MHz, CDCl 3 ) δ 174.9, 154. 5, 142.7, 137.9, 137.2, 135.3, 132.3, 128.8, 128.6, 128.3, 128.2, 127.6, 127.1, 124.3, 124.1, 123.1, 121.4, 120.6, 111.9, 111.8, 111.7, 85.36, 77.3, 67.5, 61.9, 44. 6, 154.6, 140.5, 137.2, 135.9, 132.3, 130.1, 129.5, 128.7, 128.5, 128.1, 127.4, 127.1, 124.5, 124.2, 122.8, 121.4, 112.7, 111.9, 109.4, 77.3, 67.2, 62.3, 44.1, 21.3 ), ee = 84% (Chiralpak OD-H, hexane/EtOH = 80:20, 254 nm, 1 mL/min, t major = 28.302 min, t minor = 33.349 min); 1 H NMR (400 MHz, CDCl 3 ) δ 8.57 (s, 1H), 8.06 (d, J = 7.5 Hz, 1H), 7.30−7.05 (m, 13H), 6.98 (s, 1H), 6.67 (d, J = 7.6 Hz, 1H), 6.52 (d, J = 8.9 Hz, 2H), 6.07 (s, 1H), 5.02 (s, 2H), 4.81 (s, 2H), 3.68 (s, 3H); 13 C{ 1 H} NMR (101 MHz, CDCl 3 ) δ 175.…”

“…Benzyl(S)-(1-benzyl-3-(5-methoxy-1H-indol-3-yl)-2-oxoindolin-3yl)carbamate (4bm): Obtained by flash chromatography on silica gel (DCM/ethyl acetate = 20:1); white solid, 21.7 mg, 84% yield, mp = 136−138 °C, [α] D 26.8 = +330.2 (c = 0.5, CHCl 3 ), ee = 93% (Chiralpak IG, hexane/EtOH = 70:30, 254 nm, 1 mL/min, t major = 13.583 min, t minor = 9.732 min); 1 H NMR (400 MHz, DMSO) δ 10.89 (s, 1H), 8.60 (s,1H),1H),7.28 (d,J = 47.6 Hz,12H),7.06 (s,1H),6.82 (dd,J = 25.1,3.0 Hz,2H),2H), 4.93 (dd, J = 58.0, 14.9 Hz, 4H), 3.73 (d, J = 2.6 Hz, 3H); 13 C{ 1 H} NMR (101 MHz, DMSO) δ 175. 5, 156.2, 155.3, 143.2, 138.3, 137.3, 136.9, 131.7, 129.1, 128.9, 128.8, 128.3, 128.1, 127.6, 127.6, 123.8, 123.6, 122.7, 122.6, 119.7, 112.2, 109.5, 109.4, 95.0, 66.0, 62.1, 55.7, 43.4 Benzyl(S)- (1-benzyl-3-(6-chloro-1H-indol-3-yl)-2-oxoindolin-3yl)carbamate (4bn): Obtained by flash chromatography on silica gel (DCM/ethyl acetate = 20:1); white solid, 22.7 mg, 87% yield, mp = 119−121 °C, [α] D 25.8 = +265.2 (c = 0.5, CHCl 3 ), ee = 84% (Chiralpak IG, hexane/EtOH = 70:30, 254 nm, 1 mL/min, t major = 15.463 min, t minor = 10.137 min); 1 H NMR (400 MHz, CDCl 3 ) δ 8.67 (s, 1H), 7.94 (d,J = 8.6 Hz,1H),3H),12H),6.63 (d,J = 7.2 Hz,1H),6.49 (s,1H),6.01 (s,1H),4.99 (s,2H), 4.82 (s, 2H); 13 C{ 1 H} NMR (101 MHz, CDCl 3 ) δ 175. 6, 154.6, 142.8, 137.6, 135.6, 129.4, 128.7, 128.7, 128.5, 128.2, 128.1, 127.5, 127.0, 124.9, 123.7, 123.1, 122.9, 122.3, 121.0, 112.6, 111.7, 109.7, 77.2, 67.4, 62.1, 44. (d,J = 8.6 Hz,1H),3H),10H),7.04 (dd,J = 25.7,18.2 Hz, 2H), 6.61 (t, J = 21.6 Hz, 1H), 6.48 (d, J = 27.1 Hz, 1...…”

“…5, 156.2, 155.3, 143.2, 138.3, 137.3, 136.9, 131.7, 129.1, 128.9, 128.8, 128.3, 128.1, 127.6, 127.6, 123.8, 123.6, 122.7, 122.6, 119.7, 112.2, 109.5, 109.4, 95.0, 66.0, 62.1, 55.7, 43.4 Benzyl(S)- (1-benzyl-3-(6-chloro-1H-indol-3-yl)-2-oxoindolin-3yl)carbamate (4bn): Obtained by flash chromatography on silica gel (DCM/ethyl acetate = 20:1); white solid, 22.7 mg, 87% yield, mp = 119−121 °C, [α] D 25.8 = +265.2 (c = 0.5, CHCl 3 ), ee = 84% (Chiralpak IG, hexane/EtOH = 70:30, 254 nm, 1 mL/min, t major = 15.463 min, t minor = 10.137 min); 1 H NMR (400 MHz, CDCl 3 ) δ 8.67 (s, 1H), 7.94 (d,J = 8.6 Hz,1H),3H),12H),6.63 (d,J = 7.2 Hz,1H),6.49 (s,1H),6.01 (s,1H),4.99 (s,2H), 4.82 (s, 2H); 13 C{ 1 H} NMR (101 MHz, CDCl 3 ) δ 175. 6, 154.6, 142.8, 137.6, 135.6, 129.4, 128.7, 128.7, 128.5, 128.2, 128.1, 127.5, 127.0, 124.9, 123.7, 123.1, 122.9, 122.3, 121.0, 112.6, 111.7, 109.7, 77.2, 67.4, 62.1, 44. (d,J = 8.6 Hz,1H),3H),10H),7.04 (dd,J = 25.7,18.2 Hz, 2H), 6.61 (t, J = 21.6 Hz, 1H), 6.48 (d, J = 27.1 Hz, 1H),6.00 (s, 1H), 5.01 (s, 2H), 4.84 (s, 2H); 13 C{ 1 H} NMR (101 MHz, CDCl 3 ) δ 175. 5, 154.5, 142.8, 137.9, 135.6, 129.4, 128.7, 128.5, 128.2, 128.1, 127.5, 127.1, 124.8, 123.7, 123.6, 123.4, 122.9, 122.7, 116.5, 114.7, 113.0, 109.7, 77.3, 67.3, 62.0,44. 7, 154.5, 142.9, 137.7, 136.0, 135.8, 132.7, 129.1, 128.7, 128.5, 128.1, 127.4, 127.1, 123.7, 123.5, 122.7, 122.3, 122.2, 121.0, 112.4, 111.7, 109.5, 77.3, 67.2, 62.2, 44.1, 21.7; HRMS (ESI) m/z [M + H] + calcd for C 32 H 28 N 3 O 3 502.2125; found 502.2135.…”

“…Benzyl(S)-(1-benzyl-3-(7-bromo-1H-indol-3-yl)-2-oxoindolin-3yl)carbamate (4bq): Obtained by flash chromatography on silica gel (DCM/ethyl acetate = 20:1); white solid, 23.7 mg, 84% yield, mp = 115−117 °C, [α] D 26.8 = +85.6 (c = 0.2, CHCl 3 ), ee = 88% (Chiralpak IG, hexane/EtOH = 70:30, 254 nm, 1 mL/min, t major = 33.783 min, t minor = 14.845 min); 1 H NMR (400 MHz, CDCl 3 ) δ 8.54 (s, 1H), 8.02 (d,J = 7.9 Hz,1H),4H),7.16 (dd,J = 28.7,24.1 Hz, 7H), 7.09−6.87 (m, 3H), 6.74−6.59 (m, 3H), 6.04 (s, 1H), 5.02 (s, 2H), 4.88 (s, 2H); 13 C{ 1 H} NMR (101 MHz, CDCl 3 ) δ 175. 3, 154.5, 142.9, 135.8, 129.8, 129.4, 128.7, 128.5, 128.2, 127.4, 127.2, 125.8, 125.3, 124.7, 123.8, 122.9, 121.7, 121.0, 114.2, 109.7, 105.1, 77.4, 67.4, 62.1, 44. ), ee = 94% (Chiralpak IG, hexane/EtOH = 70:30, 254 nm, 1 mL/min, t major = 37.458 min, t minor = 15.292 min); 1 H NMR (400 MHz, CDCl 3 ) δ 8.47 (s, 1H), 7.84 (d,J = 7.8 Hz,1H),7.37 (d,J = 6.5 Hz,3H),09 (m, 7H), 7.00 (m, 4H), 6.62 (s, 3H), 6.08 (s, 1H), 5.01 (s, 2H), 4.85 (s, 2H), 2.33 (s, 3H); 13 C{ 1 H } NMR (101 MHz, CDCl 3 ) δ 175. 6, 154.6, 142.9, 136.8, 136.0, 135.8, 129.1, 128.7, 128.5, 128.1, 127.4, 127.2, 124.1, 123.8, 123.8, 123.4, 122.8, 121.1, 120.6, 119.0, 113.1, 109.6, 77.3, 67.2, 62.3, 44.1, 16.6 = 90−92 °C, [α] D 20 = +67.2 (c = 0.5, CHCl 3 ), ee = 11% (Chiralpak OD-H, hexane/EtOH = 70:30, 254 nm, 1 mL/min, t major = 6.267 min, t minor = 5.652 min); 1 H NMR (400 MHz, CDCl 3 ) δ 9.07 (s, 1H), 8.50 (s,1H),2H),7.57 (d,J = 5.8 Hz,1H),5H),6H),1H),6.95 (d,J = 3.4 Hz,1H),6.74 (dd,J = 7.7,3.5 Hz,1H),6.39 (d,J = 3.4 Hz,1H),2H),4.81 (dd,…”

“…Characterization of Compounds 4a2−4a4. Benzyl(S)-(1benzyl-3-(1-methyl-1H-indol-3-yl)-2-oxoindolin-3-yl)carbamate (4a2): Obtained by flash chromatography on silica gel (hexane/ethyl acetate = 2:1); white solid, 47.65 mg, 95% yield, mp = 155−157 °C, [α] D 20.3 = +276 (c = 1, CHCl 3 ), ee = 90% (Chiralpak OD-H, hexane/ EtOH = 80:20, 254 nm, 1 mL/min, t major = 23.170 min, t minor = 16.510 min); 1 H NMR (400 MHz, CDCl 3 ) δ 8.11 (d,J = 8.0 Hz,1H),7.44 (d,J = 7.1 Hz,1H),14H),1H),6.63 (d,J = 38.5 Hz,2H),6.06 (s,1H),4H),3.65 (s,3H); 13 C{ 1 H} NMR (101 MHz, CDCl 3 ) δ 175. 5, 154.4, 142.9, 137.9, 136.1, 135.9, 129.1, 128.6, 128.5, 128.3, 128.1, 127.3, 127.2, 125.1, 123.7, 122.6, 122.6, 121.7, 120.1, 111.3, 109.7, 109.5, 77.2, 67.1, 62.0, 44.2, 32.9; HRMS (ESI) m/z [M + H] + calcd for C 32 H 28 N 3 O 3 502.2125; found 502.2119.…”