A Facile and Efficient Synthesis of Oxindole Motifs by Direct Vinylogous Aldol/Mannich Reaction of Isatins/Isatinimines with Furan-2(3H)-one

Abstract

A facile and an efficient direct vinylogous aldol/Mannich reaction of furan-2(3H)-one with isatins or isatinimines has been developed by using DABCO as an organocatalyst at room temperature. The synthetic protocol is atom-economical and provides easy access to a variety of oxindole derivatives. This is the first example of a direct vinylogous aldol/Mannich reaction between isatins/isatinimines and furan-2(3H)-one to afford vinylogous aldol adducts. The substrate scope of the protocol is briefly discussed.

Key words

isatins - isatinimines - furanone - aldol reaction - Mannich reaction

• References and Notes


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• 18 3-(5-Oxo-2,5-dihydrofuran-2-yl)-1,3-dihydro-2H-indol-2-ones 4 and 5; General Procedure DABCO (0.05 equiv) was added to a mixture of the appropriate isatin 1 or isatinimine 3 (1 equiv) and furan-2(3 H)-one (2; 1.2 equiv) in THF (2.5 mL), and the mixture was stirred at 25 °C for 2.5–5 h (Schemes 3 and 4). When the reaction was complete (TLC), the reaction was quenched by adding water, and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were then washed with brine, dried (Na₂SO_4­), and concentrated under reduce pressure. The crude product was purified by column chromatography [silica gel (60–120 mesh), EtOAc–hexane]. Products 4a–i and 5a–h were characterized by means of ¹H NMR, ¹³C NMR, mass, and IR spectroscopy. 1-Butyl-3-hydroxy-3-(5-oxo-2,5-dihydrofuran-2-yl)-1,3-dihydro-2H-indol-2-one (4e) By following the general procedure, the reaction of N-butylisatin (1e; 0.101 g, 0.50 mmol, 1.0 equiv) with furan-2(3H)-one (2; 0.050 mg, 0.60 mmol, 1.2 equiv), and DABCO (0.003 g, 0.025 mmol, 0.05 equiv) gave a pale-yellow solid; yield: 0.136 (95%); mp 133–135 °C. IR (KBr): 3375, 3084, 2927, 2862, 1760, 1700, 1610, 1462, 742 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 0.90 (t, J = 7.3 Hz, 3 H), 1.22–1.40 (m, 2 H), 1.50–1.62 (m, 2 H), 3.58–3.76 (m, 2 H), 5.36 (t, J = 1.5 Hz, 1 H), 6.37 (dd, J = 1.8, 5.8 Hz, 1 H), 6.84 (s, 1 H), 6.99 (t, J = 7.1 Hz, 1 H), 7.04–7.11 (m, 2 H), 7.34 (t, J = 7.5 Hz, 1 H), 8.03 (dd, J = 1.3, 5.8 Hz, 1 H). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 13.5, 19.2, 28.8, 39.0, 75.4, 83.8, 108.8, 121.5, 122.6, 125.2, 125.8, 130.0, 143.2, 154.5, 171.6, 174.6. MS (ESI): m/z = 310 [M + Na]⁺. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₆H₁₇NNaO₄: 310.1055; found: 310.1058. 1-Allyl-3-hydroxy-3-(5-oxo-2,5-dihydrofuran-2-yl)-1,3-dihydro-2H-indol-2-one (4f) By following the general procedure, the reaction of N-allylisatin (1f; 0.093 g, 0.50 mmol, 1.0 equiv) with furan-2(3H)-one (2; 0.050 mg, 0.60 mmol, 1.2 equiv), and DABCO (0.003 g, 0.025 mmol, 0.05 equiv) gave a white solid; yield: 0.127 (94%); mp 142–144 °C. IR (KBr): 3362, 3099, 2930, 1789, 1755, 1708, 1612, 1467, 1377, 1116, 1048, 755 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 4.22–4.42 (m, 2 H), 5.13–5.25 (m, 2 H), 5.39 (t, J = 1.7 Hz, 1 H), 5.77–5.90 (m, 1 H), 6.39 (dd, J = 1.8, 5.6 Hz, 1 H), 6.90 (s, 1 H), 6.92–7.02 (m, 2 H), 7.09 (d, J = 7.3 Hz, 1 H), 7.32 (t, J = 7.7 Hz, 1 H), 8.06 (dd, J = 1.5, 5.6 Hz, 1 H). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 41.2, 75.5, 83.7, 109.2, 116.4, 121.7, 122.7, 125.1, 125.6, 129.9, 131.2, 142.9, 154.5, 171.5, 174.4. MS (ESI): m/z = 294 [M + Na]⁺. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₅H₁₃NNaO₄: 294.0732; found: 294.0736. 1-Allyl-5-fluoro-3-hydroxy-3-(5-oxo-2,5-dihydrofuran-2-yl)-1,3-dihydro-2H-indol-2-one (4g) By following the general procedure, the reaction of 5-fluoro-N-allylisatin (1g; 0.102 g, 0.50 mmol, 1.0 equiv) with furan-2(3H)-one (2; 0.050 mg, 0.60 mmol, 1.2 equiv), and DABCO (0.003 g, 0.025 mmol, 0.05 equiv) gave a white solid; yield: 0.140 (97%); mp 153–155 °C. IR (KBr): 3420, 1756, 1721, 1623, 1489, 999, 762 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆): δ (major) = 4.21–4.43 (m, 2 H), 5.11–5.25 (m, 2 H), 5.41 (t, J = 1.5 Hz, 1 H), 5.76–5.89 (m, 1 H), 6.43 (dd, J = 1.8, 5.6 Hz, 1 H), 6.93–7.02 (m, 2 H), 7.07 (s, 1 H), 7.15–7.22 (m, 1 H), 8.05 (dd, J = 1.5, 5.8 Hz, 1 H); δ (minor) = 3.99–4.06 (m, 2 H), 4.94–4.96 (m, 2 H), 5.58 (t, J = 1.7 Hz, 1 H), 5.76–5.89 (m, 1 H), 6.28 (dd, J = 2.0, 5.8 Hz, 1 H), 6.93–7.02 (m, 2 H), 7.10 (s, 1 H), 7.30–7.34 (m, 1 H), 7.84 (dd, J = 1.5, 5.8 Hz, 1 H). ¹³C NMR (75 MHz, DMSO-d ₆): δ (major) = 41.4, 75.7, 83.6, 110.3, 113.1, 116.2, 116.6, 122.9, 127.5, 131.1, 139.1, 154.4, 159.2, 171.5, 174.3; δ (minor) = 41.4, 76.5, 84.5, 110.3, 112.2, 116.0, 116.8, 121.9, 129.6, 131.1, 138.6, 156.1, 159.9, 172.0, 172.7. MS (ESI): m/z = 312 [M + Na]⁺. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₅H₁₂FNNaO₄: 312.0468; found: 312.0463. tert-Butyl 3-Hydroxy-2-oxo-3-(5-oxo-2,5-dihydrofuran-2-yl)indoline-1-carboxylate (4i) By following the general procedure, the reaction of N-(Boc)isatin (1i; 0.123 g, 0.50 mmol, 1.0 equiv) with furan-2(3H)-one (2; 0.050 mg, 0.60 mmol, 1.2 equiv), and DABCO (0.003 g, 0.025 mmol, 0.05 equiv) gave a white solid; yield: 0.140 (85%); mp 142–144 °C. IR (KBr): 3368, 3113, 2985, 1794, 1754, 1698, 1158 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ (major) = 1.63 (s, 9 H), 5.31 (t, J = 1.7 Hz, 1 H), 6.27 (dd, J = 1.9, 5.7 Hz, 1 H), 7.15 (t, J = 7.4 Hz, 1 H), 7.26 (d, J = 7.9 Hz, 1 H), 7.39 (t, J = 7.5 Hz, 1 H), 7.77 (dd, J = 1.5, 5.7 Hz, 1 H), 7.84 (d, J = 8.1 Hz, 1 H); δ (minor) = 1.62 (s, 9 H), 5.37 (t, J = 1.7 Hz, 1 H), 6.10 (dd, J = 1.9, 5.7 Hz, 1 H), 7.21 (t, J = 7.5 Hz, 1 H), 7.45 (d, J = 6.6 Hz, 1 H), 7.48 (dd, J = 1.4, 5.7 Hz, 1 H), 7.77 (dd, J = 1.5, 5.7 Hz, 1 H), 7.84 (d, J = 8.1 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ (major) = 27.9, 76.0, 84.2, 85.2, 115.4, 123.7, 124.8, 124.6, 125.3, 131.0, 140.0, 148.3, 151.2, 171.5, 173.9; δ (minor) = 29.6, 76.0, 84.2, 85.3, 115.4, 123.6, 124.4, 124.6, 125.3, 131.1, 140.0, 148.3, 151.5, 171.5, 173.9. MS (ESI): m/z = 354 [M + Na]⁺. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₇H₁₇NNaO₆: 354.3098; found: 354.3088. 3-[(3-Chlorophenyl)amino]-3-(5-oxo-2,5-dihydrofuran-2-yl)-1,3-dihydro-2H-indol-2-one (5a) By following the general procedure, the reaction of 3-[(3-chlorophenyl)imino]indolin-2-one (3a; 0.128 g, 0.50 mmol, 1.0 equiv) with furan-2(3H)-one (2; 0.050 mg, 0.60 mmol, 1.2 equiv), and DABCO (0.003 g, 0.025 mmol, 0.05 equiv) gave a pale-brown solid; yield: 0.156 (92%); mp 223–225 °C. IR (KBr): 3335, 2989, 2875, 2819, 1712, 1451, 762 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆): δ (major) = 5.47 (t, J = 1.3 Hz, 1 H), 6.20 (dd, J = 1.6, 8.2 Hz, 1 H), 6.26 (t, J = 1.9 Hz, 1 H), 6.37 (dd, J = 1.8, 5.7 Hz, 1 H), 6.58 (dd, J = 1.2, 7.9 Hz, 1 H), 6.91–6.96 (m, 4 H) , 7.03 (s, 1 H), 7.28–7.31 (m, 1 H), 8.01 (dd, J = 1.3, 5.9 Hz, 1 H) 10.98 (s, 1 H); δ (minor) = 5.51 (t, J = 1.3 Hz, 1 H), 6.22–6.24 (m, 1 H), 6.26 (t, J = 1.9 Hz, 1 H), 6.37 (dd, J = 1.8, 5.7 Hz, 1 H), 6.58 (dd, J = 1.2, 7.9 Hz, 1 H), 6.90–6.95 (m, 4 H) , 6.98 (s, 1 H), 709–7.11 (m, 1 H), 7.66 (dd, J = 1.3, 5.7 Hz, 1 H) 11.02 (s, 1 H). ¹³C NMR (75 MHz, DMSO-d ₆): δ (major) = 65.7, 83.5, 110.3, 112.3, 113.1, 117.2, 121.5, 123.2, 123.6, 125.3, 130.2, 130.3, 133.2, 142.2, 147.0, 153.9, 171.2, 175.6; δ (minor) = 66.6, 84.4, 110.4, 112.0, 112.8, 116.9, 122.3, 123.3, 123.7, 125.1, 130.0, 130.4, 133.1, 141.3, 146.8, 154.0, 171.3, 175.8. MS (ESI): m/z = 363 [M + Na]⁺. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₈H₁₃ClN₂NaO₃: 363.0507; found: 363.0506. 3-(5-Oxo-2,5-dihydrofuran-2-yl)-3-(phenylamino)-1,3-dihydro-2H-indol-2-one (5b) By following the general procedure, the reaction of 3-(phenylimino)indolin-2-one (3b; 0.111 g, 0.50 mmol, 1.0 equiv) with furan-2(3H)-one 2 (0.050 mg, 0.60 mmol, 1.2 equiv), and DABCO (0.003 g, 0.025 mmol, 0.05 equiv) gave a pale-brown solid; yield: 0.139 (91%); mp 235–237 °C. IR (KBr): 3385, 3100, 3075, 1751, 1712, 1615, 1475, 755 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 5.47 (t, J = 1.5 Hz, 1 H), 6.25 (d, J = 7.7 Hz, 2 H), 6.35 (dd, J = 1.6, 5.7 Hz, 1 H), 6.55 (t, J = 7.3 Hz, 1 H), 6.70 (s, 1 H), 6.87–6.95 (m, 5 H), 7.25–7.28 (m, 1 H) , 8.04 (dd, J = 1.3, 5.7 Hz, 1 H), 10.89 (s, 1 H). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 65.9, 83.8, 110.3, 113.8, 117.7, 121.2, 123.0, 124.2, 125.2, 128.7, 129.9, 142.3, 145.6, 154.3, 171.2, 176.2. MS (ESI): m/z = 329 [M + Na]⁺. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₈H₁₄N₂NaO₃: 329.0894; found: 329.0896.> 3-[(4-Methoxyphenyl)amino]-3-(5-oxo-2,5-dihydrofuran-2-yl)-1,3-dihydro-2H-indol-2-one (5d) By following the general procedure, the reaction of 3-[(4-methoxyphenyl)imino]indolin-2-one (3d; 0.126 g, 0.50 mmol, 1.0 equiv) with furan-2(3H)-one (2; 0.050 mg, 0.60 mmol, 1.2 equiv), and DABCO (0.003 g, 0.025 mmol, 0.05 equiv) gave a white solid; yield: 0.139 (83%); mp 170–172 °C. IR (KBr): 3293, 3106, 1754, 1706, 1612, 1512, 821 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆): δ (major) = 3.55 (s, 3 H), 5.47 (t, J = 1.5 Hz, 1 H), 6.22–6.26 (m, 3 H), 6.56 (d, J = 9.0 Hz, 2 H), 6.87–6.95 (m, 4 H), 7.24–7.27 (m, 1 H), 8.05 (dd, J = 1.3, 5.7 Hz, 1 H), 10.77 (s, 1 H); δ (minor) = 3.53 (s, 3 H), 5.32 (t, J = 1.3 Hz, 1 H), 6.17–6.30 (m, 3 H), 6.51 (d, J = 8.8 Hz, 2 H), 6.87–6.95 (m, 4 H), 7.20–7.23 (m, 1 H), 8.02 (dd, J = 1.5, 5.7 Hz, 1 H), 10.80 (s, 1 H). ¹³C NMR (75 MHz, DMSO-d ₆): δ (major) = 55.0, 66.7, 83.9, 110.1, 114.1, 116.3, 121.2, 122.8, 124.4, 125.3, 129.8, 139.1, 142.4, 152.2, 154.4, 171.3, 176.4; δ (minor) = 55.3, 66.2, 83.9, 109.9, 114.0, 115.1, 121.2, 122.6, 124.4, 125.3, 130.0, 139.2, 140.1, 152.3, 154.4, 171.3, 176.4. MS (ESI): m/z = 359 [M + Na]⁺. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₉H₁₆N₂NaO₄: 359.1003; found: 359.1002. 3-[(3-Fluorophenyl)amino]-3-(5-oxo-2,5-dihydrofuran-2-yl)-1,3-dihydro-2H-indol-2-one (5f) By following the general procedure, the reaction of 3-[(3-fluorophenyl)imino]indolin-2-one (3f; 0.120 g, 0.50 mmol, 1.0 equiv) with furan-2(3H)-one (2; 0.050 mg, 0.60 mmol, 1.2 equiv), and DABCO (0.003 g, 0.025 mmol, 0.05 equiv) gave a pale-brown solid; yield: 0.154 (95%); mp 232–234 °C. IR (KBr): 3921, 3109, 3064, 1752, 1712, 1618, 1470, 761 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆): δ (major) = 5.47 (t, J = 1.5 Hz, 1 H), 5.90–5.94 (m, 1 H), 6.13 (dd, J = 1.5, 8.2 Hz, 1 H), 6.32–6.37 (m, 2 H), 6.91–6.97 (m, 4 H), 7.06 (s, 1 H), 7.28–7.31 (m, 1 H), 8.01 (dd, J = 1.3, 5.7 Hz, 1 H), 10.96 (s, 1 H); δ (minor) = 5.51 (t, J = 1.5 Hz, 1 H), 5.95–5.98 (m, 1 H), 6.20 (dd, J = 1.9, 5.9 Hz, 1 H), 6.32–6.37 (m, 2 H), 6.98–7.00 (m, 4 H), 7.09 (s, 1 H), 7.28–7.31 (m, 1 H), 7.65 (dd, J = 1.5, 5.9 Hz, 1 H), 11.00 (s, 1 H). ¹³C NMR (75 MHz, DMSO-d ₆): δ (major) = 65.8, 83.5, 100.0, 103.9, 110.0, 110.4, 121.4, 123.2, 123.7, 125.3, 130.2, 142.2, 147.5, 154.0, 161.7, 163.7, 171.2, 177.7; δ (minor) = 66.7, 84.4, 99.7, 103.5, 109.6, 110.5, 122.3, 123.3, 124.4, 125.2, 130.3, 141.3, 147.7, 152.7, 161.7, 163.7, 171.9, 174.5. MS (ESI): m/z = 347 [M + Na]⁺. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₈H₁₃FN₂NaO₃: 347.0808; found: 347.0807. 3-[(2-Chlorophenyl)amino]-3-(5-oxo-2,5-dihydrofuran-2-yl)-1,3-dihydro-2H-indol-2-one (5g) By following the general procedure, the reaction of 3-[(2-chlorophenyl)imino]indolin-2-one (3g; 0.128g, 0.50 mmol, 1.0 equiv) with furan-2(3H)-one (2; 0.050 mg, 0.60 mmol, 1.2 equiv), and DABCO (0.003 g, 0.025 mmol, 0.05 equiv) gave a white solid; yield: 0.151 (89%); mp 175–177 °C. IR (KBr): 3326, 3087, 3032, 2878, 2816, 1784, 1726, 1468, 751 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 5.80 (t, J = 1.3 Hz, 1 H), 5.81 (t, J = 1.5 Hz, 1 H), 5.84 (dd, J = 1.1, 8.1 Hz, 1 H), 6.40 (dd, J = 1.8, 5.8 Hz, 1 H), 6.64 (t, J = 7.7 Hz, 1 H), 6.86 (t, J = 7.7 Hz, 1 H), 6.95–6.99 (m, 2 H), 7.06 (d, J = 6.9 Hz, 1 H), 7.30–7.33 (m, 2 H), 7.80 (dd, J = 1.3, 5.7 Hz, 1 H), 11.00 (s, 1 H). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 65.6, 83.7, 110.5, 112.9, 119.2, 119.7, 121.7, 123.1, 123.8, 125.0, 127.6, 129.3, 130.2, 140.7, 141.8, 153.6, 171.7, 174.8. MS (ESI): m/z = 363 [M + Na]⁺. HRMS (ESI): m/z [M⁺] calcd for C₁₈H₁₃ClN₂O₃: 341.0685; found: 341.0687