A One-Pot, Multicomponent Synthesis of 5′-Amino-2,2′-dioxospiro[indoline-3,3′-pyrrole]-4′-carbonitriles

Abstract

A novel, one-pot, multicomponent synthesis of 5′-amino-2,2′-dioxospiro[indoline-3,3′-pyrrole]-4′-carbonitriles is described. The Knoevenagel condensation reaction between isatin derivatives and malononitrile gave the corresponding cyclic arylmethylidenemalononitriles that, on treatment with isocyanides, afforded 2,2′-dioxospiro-bis-γ-lactams in good to excellent yields.

Key words

isatins - isocyanides - spiro compounds - lactams - multicomponent reactions

• References and Notes

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• 14 Preparation of Spiro[indoline-3,3′-pyrrole] Derivatives 6a–l; Typical Procedure for 6a: A mixture of isatin (1 mmol) and malononitrile (1 mmol) in H₂O–EtOH (1:1, 4 mL) was stirred at 80 °C for 10 min. Cyclohexyl isocyanide (1.1 mmol) and pyridine (1 mmol) were added to the mixture, which was then stirred at 80 °C for 20 h. Upon completion of the reaction, as indicated by TLC, the mixture was cooled to room temperature, brine (5 mL) was added, and the mixture was stirred for 5 min. The product was extracted into EtOAc (3 × 5 mL), followed by drying over Na₂SO₄. After filtration, the solvent was removed under the reduced pressure and the residue was crystallized from EtOAc–n-hexane (1:1) to afford 6a as colorless crystals. Compounds 6e and 6k were purified accordingly. Other p­roducts were purified by column chromatography (EtOAc–n-hexane, 1:4). 5′-Amino-1′-cyclohexyl-1-ethyl-2,2′-dioxo-1′,2′-dihydrospiro[indoline-3,3′-pyrrole]-4′-carbonitrile (6c): Yield: 0.298 g (85%); white crystals; mp 200–202 °C. IR (KBr): 3335, 3297 and 3185 (NH), 2191 (CN), 1735 and 1664 (C=O), 1600, 1453, 1353, 1089, 999, 941, 832, 750, 680, 626 cm^–1. ¹H NMR (300.1 MHz, DMSO-d ₆): δ = 1.05–2.10 [t, J = 7.1 Hz, 3 H, CH₃; m, 10 H, CH(CH ₂)₅], 3.20–3.90 [q, J = 7.1 Hz, 2 H, CH₂; m, 1 H, CH(CH₂)₅], 7.05–7.20 (m, 3 H, 3 × CH), 7.36 (t, J = 7.1 Hz, 1 H, CH), 7.80–7.89 (br. s, 2 H, NH₂). ¹³C NMR (75.5 MHz, DMSO-d ₆): δ = 13.0 (CH₃), 25.0 (CH₂), 25.6 (2 × CH₂), 28.9 and 29.1 (2 × CH₂), 35.1 (CH₂), 53.0 [CH(CH₂)₅], 53.3 (C−C=O), 61.6 (N₂C=C), 109.8 (CH), 117.9 (CN), 123.3 and 123.9 (2 × CH), 127.5 (C), 130.0 (CH), 143.9 (C−N), 160.4 (N₂ C=C), 171.8 and 172.0 (2 × C=O). MS: m/z (%) = 350 (42) [M⁺], 281 (48), 268 (100), 239 (42), 225 (34), 212 (20), 198 (44), 183 (39), 160 (33), 128 (19), 97 (18), 83 (28), 69 (34), 55 (80), 41 (80). Anal. Calcd for C₂₀H₂₂N₄O₂ (350.41): C, 68.55; H, 6.33; N, 15.99. Found: C, 68.49; H, 6.37; N, 15.86. 5′-Amino-1′-cyclohexyl-1-isopropyl-2,2′-dioxo-1′,2′-dihydrospiro[indoline-3,3′-pyrrole]-4′-carbonitrile (6e): Yield: 0.324 g (89%); white crystals; mp 196 °C. IR (KBr): 3343, 3265 and 3191 (NH), 2187 (CN), 1739 and 1667 (C=O), 1598, 1450, 1306, 1230, 1171, 1092, 1001, 937, 808, 743, 677 cm^–1. ¹H NMR (300.1 MHz, DMSO-d ₆): δ = 1.02–2.10 [d (1.39), J = 6.9 Hz, 6 H, C(CH₃)₂; m, 10 H, CH(CH ₂)₅], 3.78–3.90 [m, 1 H, CH(CH₂)₅], 4.49 (sept, J = 6.9 Hz, 1 H, CH), 7.02–7.13 (m, 2 H, 2 × CH), 7.25 (d, J = 6.9 Hz, 1 H, CH), 7.35 (t, J = 6.9 Hz, 1 H, CH), 7.79 (s, 2 H, NH₂). ¹³C NMR (75.5 MHz, DMSO-d ₆): δ = 19.4 and 19.5 [C(CH₃)₂], 25.0 (CH₂), 25.7 (2 × CH₂), 29.0 and 29.2 (2 × CH₂), 44.6 [C(CH₃)₂], 53.0 [CH(CH₂)₅], 53.6 (C−C=O), 61.6 (N₂C=C), 110.9 (CH), 117.9 (CN), 123.0 and 124.1 (2 × CH), 127.8 (C), 129.9 (CH), 143.7 (C−N), 160.4 (N₂ C=C), 171.9 and 172.1 (2 × C=O). MS: m/z (%) = 364 (33) [M⁺], 321 (15), 282 (100), 239 (47), 212 (41), 197 (30), 170 (35), 143 (19), 128 (14), 116 (19), 105 (22), 81 (19), 67 (27), 55 (47), 41 (52). Anal. Calcd for C₂₁H₂₄N₄O₂ (364.44): C, 69.21; H, 6.64; N, 15.37. Found: C, 69.18; H, 6.71; N, 15.30.
• 15 To our knowledge, there are two reports concerning the synthesis of 2-oxo-2′-thioxospiro[indoline-3,3′-pyrrole] derivatives with carbonyl and thiocarbonyl functions located next to the spiro-carbon atom; see ref. 11.