A Facile, One-Pot Synthesis of Functionalized Spiro-Oxindoles via Vinylogous Aldol Reaction of Vinyl Malononitriles with Isatin Derivatives in Aqueous ­Media

Abstract

A novel, one-pot approach to functionalized spirocyclic oxindoles has been developed by using vinyl malononitriles and isatin derivatives via vinylogous aldol reaction in aqueous media catalyzed by triethylamine.

Key words

isatin - vinyl malononitrile - vinylogous aldol condensation - one-pot tandem reaction - spirocyclic oxindoles

References and Notes

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14

General Procedure for the Synthesis of Spiro-Oxindole 3c: To a stirred solution of vinyl malononitrile 2a (1 mmol) and Et₃N (1 mmol) in H₂O-EtOH (1:1; 10 mL) at r.t., was added isatin 1c (1 mmol) and stirring was continued for about 25 min. After the reaction was complete as indicated by TLC, the solvent mixture was evaporated under vacuo. The crude product, on chromatographic purification over silica gel (Merck; 100-200 mesh; EtOAc-hexane, 3:7), yielded the desired spiro-oxindole in 87% as a single diastereomer.
Spectral Data of Spiro-Oxindole 3c (Table 2, entry 3): Yield: 87%; off-white solid; mp 196 ˚C. ^¹H NMR (500 MHz, DMSO-d ₆): δ = 0.37 (q, J = 13 Hz, 1 H), 1.37 (m, 2 H), 1.57 (m, 1 H), 1.88 (m, 1 H), 2.04 (m, 1 H), 2.83 (d, J = 9.9 Hz, 1 H), 4.32 (ABq, J = 16.8 Hz, 2 H), 5.16 (t, J = 9.15 Hz, 2 H), 5.46 (s, 1 H), 5.80 (m, 1 H), 7.03 (s, 2 H, D₂O exchangeable), 7.06 (d, J = 7.65 Hz, 1 H), 7.09 (d, J = 7.65 Hz, 1 H), 7.13 (d, J = 7.65 Hz, 1 H), 7.37 (t, J = 7.65 Hz, 1 H). ^¹³C NMR (125 MHz, DMSO-d ₆): δ = 21.3, 22.9, 24.7, 38.1, 42.3, 60.9, 81.9, 110.4, 114.5, 117.9, 118.7, 123.9, 125.1, 125.3, 125.5, 131.3, 131.7, 143.3, 162.1, 171.2. IR (KBr): 3403, 3311, 3242, 3198, 2195, 1706, 1636, 1422, 1377, 763 cm^-¹. MS (ESI): m/z = 334 [M + 1]. Anal. Calcd for C₂₀H₁₉N₃O₂: C, 72.05; H, 5.74; N, 12.60. Found: C, 71.09; H, 5.61; N, 12.53.

15

Crystallographic data for compound 3d in this paper have been deposited with the Cambridge Crystallographic Data centre as supplemental publication No. CCDC 761167. Copies of the data can be obtained, free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: [phone] or email: [e-mail]]

16

Spectral Data of Compound 6 (Table 2, entry 17): Yield: 75%; yellow solid; mp 192 ˚C. ^¹H NMR (500 MHz, DMSO-d ₆): δ = 0.15 (q, J = 12.2 Hz, 1 H), 1.11 (m, 1 H), 1.35 (m, 2 H), 1.81 (m, 1 H), 1.98 (m, 1 H), 2.95 (s, 1 H), 5.48 (s, 1 H), 6.97 (s, 2 H, D₂O exchangeable), 7.45 (d, J = 6.9 Hz, 1 H), 7.72 (t, J = 7.65 Hz, 1 H), 7.85 (t, J = 7.65 Hz, 1 H), 8.05 (dd, J = 6.9, 8.4 Hz, 2 H), 8.33 (d, J = 8.4 Hz, 1 H). ^¹³C NMR (125 MHz, DMSO-d ₆): δ = 21.3, 23.2, 24.6, 38.0, 61.0, 85.2, 114.3, 119.0, 122.5, 123.3, 126.2, 127.3, 129.5, 129.8, 130.3, 130.7, 133.8, 134.5, 142.5, 162.9, 198.3. IR (KBr): 3421, 3322, 3194, 2927, 2193, 1713, 1632, 1581, 1010, 783 cm^-¹. MS (ESI): m/z = 329 [M + 1]. Anal. Calcd for C₂₀H₁₉N₃O₂: C, 72.05; H, 5.74; N, 12.60. Found: C, 71.09; H, 5.61; N, 12.53.