Synthesis of Novel Spiro[dihydropyridine-oxindole] Compounds in Water

Abstract

An efficient one-pot synthesis of the biologically important spiro[dihydropyridine-oxindole] scaffold was accomplished simply by the reaction of isatin, 2H-indene-1,3-dione and naphthalen-2-amine in aqueous medium. The scope of this reaction was successfully extended by employing two other reactive ketones (acenaphthylene-1,2-dione and ninhydrin) in place of isatin to access the synthesis of corresponding spirocyclic derivatives.

spirooxindole - isatin - dihydropyridine - acenaphthy­lene-1,2-dione - ninhydrin

References and Notes

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13

General Procedure for the Synthesis of Spiro{1 H -indeno[1,2- b ]benzo[ f ]quinolin-13,3′-indoline}-7,13-dihydro-12,2′-dione Derivatives 4a-e
To a stirred mixture of 2H-indene-1,3-dione (1, 0.146 g, 1 mmol), naphthalen-2-amine 2 (0.143 g, 1 mmol), and an isatin derivatives 3a-e (1 mmol) in a solution of H₂O-EtOH [6 mL, 5:1 (v/v)], was added a catalytic amount of PTSA (monohydrate, 0.1 g). The mixture was stirred at 60 ˚C (oil bath) for about 15 min (as monitored by TLC). After completion, the reaction mixture was filtered and the obtained precipitate washed with hot EtOH (95.5%).

14

Spiro{1 H -indeno[1,2- b ]benzo[ f ]quinolin-13,3′-indoline}-7,13-dihydro-12,2′-dione (4a)
Red powder (0.340 g, 85%); mp 298-300 ˚C. IR (KBr): 3470, 3210, 3050, 1688, 1672, 1618 cm^-¹. ^¹H NMR (400.13 MHz, DMSO-d ₆): δ = 6.67 (1 H, d, J = 8.4 Hz, 1-H), 6.86 (1 H, t, J = 7.2Hz, 4′-H), 6.96 (2 H, t, J = 8.0 Hz, 5′-H and 6′-H), 7.21 (1 H, t, J = 7.6 Hz, 7′-H), 7.26 (1 H, d, J = 6.8 Hz), 7.41 (1 H, t, J = 7.2 Hz), 7.54 (1 H, d, J = 8.8 Hz), 7.55 (1 H, t, J = 8.0 Hz), 7.62 (1 H, t, J = 7.2 Hz), 7.73 (1 H, t, J = 6.8 Hz), 7.88 (1 H, d, J = 8.0 Hz), 8.18 (1 H, d, J = 7.2 Hz), 8.76 (1 H, d, J = 8.4 Hz), 10.36 (1 H, s, NH), 10.65 (1 H, s, NH). ^¹³C NMR (100.6 MHz, DMSO-d ₆): δ = 51.3 (C_spiro), 104.0 (C-12a), 110.0 (C-11a), 120.5, 120.6, 121.1, 122.3, 122.7, 123.9, 125.1, 125.2, 125.4, 127.0, 127.3, 128.7, 128.8, 130.9, 131.8, 132.0, 133.3, 134.2, 136.8, 138.4, 141.9 (C-6a), 156.5 (C-7a), 180.0 (amidic C=O), 189.6 (C=O). MS (EI, 70 eV): m/z (%) = 400(56) [M⁺], 384 (14), 371 (100), 355 (95). Anal. Calcd for C₂₇H₁₆N₂O₂: C, 80.99; H, 4.03; N, 7.00. Found: C, 81.03; H, 4.21; N, 6.89. Spiro{1 H -indeno[1,2- b ]benzo[ f ]quinolin-13,3′-indoline}-7,13-dihydro-5′-nitro-12,2′-dione (4b)
Red powder (0.360, 81%); mp 304 ˚C (decomp.). IR (KBr): 3470, 3240, 1706, 1620, 1527, 1330 cm^-¹. ^¹H NMR (400.13 MHz, DMSO-d ₆): δ = 6.69 (1 H, d, J = 8.8 Hz, 1-H), 7.21 (1 H, d, J = 8.8 Hz, 7′-H), 7.28 (1 H, d, J = 7.2 Hz), 7.43 (1 H, t, J = 7.2 Hz), 7.57 (1 H, t, J = 7.2 Hz), 7.58 (1 H, d, J = 8.8 Hz), 7.65 (1 H, t, J = 7.6 Hz), 7.76 (1 H, t, J = 7.2 Hz), 7.86 (1 H, d, J = 2.0 Hz, 4′-H), 7.91 (1 H, d, J = 8.0 Hz), 8.22 (1 H, dd, J = 8.8, 2.4 Hz), 8.23 (1 H, d, J = 8.4 Hz), 8.82 (1 H, d, J = 8.4 Hz), 10.52 (1 H, s, NH), 11.42 (1 H, s, NH). ^¹³C NMR (100.6 MHz, DMSO-d ₆): δ = 51.4 (C_spiro), 102.7 (C-12a), 110.4 (C-11a), 119.0, 120.7, 120.8, 121.5, 122.5, 124.0, 125.1, 125.7, 126.3, 127.2, 127.6, 128.8, 131.1, 132.1, 132.3, 133.6, 134.2, 136.7, 138.8, 143.2, 148.6 (C-6a), 157.0 (C-7a), 180.4 (amidic C=O), 189.6 (C=O). MS (EI, 70 eV): m/z (%) = 445 (48) [M⁺], 443 (100) [M⁺ - 2], 417 (60) [M⁺ - C=O], 400(89), 399 (75) [417 - H₂O], 369 (76). Anal. Calcd for C₂₇H₁₅N₃O₄: C, 72.80; H, 3.39; N, 9.43. Found: C, 72.76; H, 3.42; N, 9.37.
Spiro[1H-indeno[1,2-b]benzo[f]quinolin-13,3-indoline]-7,13-dihydro-5′-methoxy-12,2′-dione (4c)
Orange powder (0.335 g, 78%); mp 306-308 ˚C. IR (KBr): 3237, 1703, 1684, 1532, 1187, 1175 cm^-¹. ^¹H NMR (400.13 MHz, DMSO-d ₆): δ = 3.56 (3 H, s, OCH₃), 6.56 (1 H, d, J = 2.4 Hz, 4′-H), 6.67 (1 H, d, J = 8.8 Hz, 1-H), 6.79 (1 H, dd, J = 8.4, 2.0 Hz, 6′-H), 6.89 (1 H, d, J = 8.8 Hz, 7′-H), 7.26 (1 H, d, J = 6.8 Hz), 7.41 (1 H, t, J = 7.2 Hz), 7.54 (1 H, d, J = 8.0 Hz), 7.55 (1 H, t, J = 6.4 Hz), 7.61 (1 H, t, J = 7.6 Hz), 7.72 (1 H, t, J = 7.2 Hz), 7.88 (1 H, d, J = 8.0 Hz), 8.17 (1 H, d, J = 7.2 Hz), 8.76 (1 H, d, J = 8.4 Hz), 10.35 (1 H, s, NH), 10.48 (1 H, s, NH). ^¹³C NMR (100.6 MHz, DMSO-d ₆): δ = 51.8 (C_spiro), 55.8 (OCH₃), 102.8 (C-12a), 110.4 (C-11a), 111.7, 113.7, 120.5, 120.6, 121.1, 122.4, 123.9, 125.2, 125.4, 127.0, 127.2, 128.7, 130.9, 131.8, 132.0, 133.4, 134.3, 135.3, 136.8, 139.6, 155.8 (C-6a), 156.6 (C-7a), 179.9 (amidic C=O), 189.6 (C=O). MS (EI, 70 eV): m/z (%) = 430 (98) [M⁺], 402 (100) [M⁺ - C=O], 385 (88). Anal. Calcd for C₂₈H₁₈N₂O₃: C, 78.13; H, 4.21; N, 6.51. Found: C, 78.22; H, 4.33; N, 6.46.
Spiro{1 H -indeno[1,2- b ]benzo[ f ]quinolin-13,3′-indoline}-7,13-dihydro-1′-benzyl-12,2′-dione (4e)
Orange powder (0.387 g, 79%); mp 310 ˚C (decomp.). IR (KBr): 3235, 1686, 1622, 1604, 1526, 1362 cm^-¹. ^¹H NMR (400.13 MHz, DMSO-d ₆): δ = 5.00 (1 H, d, J = 16.0 Hz), 5.13 (1 H, d, J = 16.0 Hz), 6.58 (1 H, d, J = 8.8 Hz, 1-H), 6.91-6.96 (2 H, m), 7.05 (1 H, d, J = 7.2 Hz, 7′-H), 7.21 (1 H, t, J = 7.6 Hz), 7.27-7.45 (6 H, m), 7.51-7.59 (3 H, m), 7.64 (1 H, t, J = 7.6 Hz), 7.75 (1 H, t, J = 7.6 Hz), 7.89 (1 H, d, J = 8.4 Hz), 8.22 (1 H, d, J = 7.2 Hz), 8.79 (1 H, d, J = 8.4 Hz), 10.47 (1 H, s, NH). MS (EI, 70 eV): m/z (%) = 490 (34) [M⁺], 461 (4) [M⁺ - HCO], 399 (100) [M⁺ - benzyl], 371 (86) [399 - C=O]. Anal. Calcd for C₃₄H₂₂N₂O₂: C, 83.25; H, 4.52; N, 5.71. Found: C, 83.12; H, 4.59; N, 5.58.
Due to the very low solubility of compounds 4d and 4e we were unable to obtain their ^¹³C NMR spectra.

15

Spiro{1 H -indeno[1,2- b ]benzo[ f ]quinolin-13,1′(2′ H )-acenaphthylene}-7,13-dihydro-12,2′-dione (9)
Brick red powder (0.352 g, 81%); mp 284-286 ˚C. IR (KBr): 3295, 1702, 1684, 1620, 1586, 1525 cm^-¹. ^¹H NMR (400.13 MHz, DMSO-d ₆): δ = 6.27 (1 H, d, J = 8.8 Hz, 1-H), 7.17 (1 H, d, J = 6.8 Hz), 7.34 (1 H, d, J = 6.8 Hz), 7.38-7.40 (2 H, m), 7.57 (1 H, t, J = 7.2 Hz), 7.62 (1 H, t, J = 8.6 Hz), 7.64 (1 H, t, J = 8.4 Hz), 7.74-7.91 (3 H, m), 8.02 (1 H, d, J = 8.4 Hz), 8.12 (1 H, d, J = 6.8 Hz), 8.22 (1 H, d, J = 7.6 Hz), 8.41 (1 H, d, J = 8.4 Hz), 8.82 (1 H, d, J = 8.8 Hz), 10.45 (1 H, s, NH). ^¹³C NMR (100.6 MHz, DMSO-d ₆): δ = 57.2 (C_spiro), 105.3 (C-12a), 120.6 (C-11a), 121.2, 121.9, 122.4, 123.18, 123.22, 124.0, 125.1, 125.2, 125.6, 127.1, 127.3, 128.7, 129.4, 129.9, 130.4, 131.0, 132.0, 132.1, 132.5, 132.7, 133.3, 134.1, 136.7, 136.8, 141.9 (C-6a), 158.7 (C-7a), 189.9 (C=O), 209.8 (C=O). MS (EI, 70 eV): m/z (%) = 435 (82) [M⁺], 407 (78) [M⁺ - C=O], 406 (100) [M⁺ - HC=O]. Anal. Calcd for C₃₁H₁₇NO₂: C, 85.50; H, 3.93; N, 3.22. Found: C, 85.61; H, 4.11; N, 3.14.


Spiro{1 H -indeno[1,2- b ]benzo[ f ]quinolin-13,2′-indene}-7,13-dihydro-12,1′,3′-trione (10) Red powder (0.326 g, 79%); mp 286-288 ˚C. IR (KBr): 3303, 1740, 1697, 1624, 1587, 1524, 1250 cm^-¹. ^¹H NMR (400.13 MHz, DMSO-d ₆): δ = 6.63 (1 H, d, J = 8.4 Hz, 1-H), 7.28 (1 H, d, J = 7.2 Hz), 7.45 (1 H, t, J = 7.2 Hz), 7.58 (1 H, t, J = 8.4 Hz), 7.59 (1 H, t, J = 8.4 Hz), 7.66 (1 H, t, J = 7.6 Hz), 7.76 (1 H, t, J = 7.2 Hz), 7.93 (1 H, d, J = 8.4 Hz), 8.15-8.19 (4 H, m), 8.20 (1 H, d, J = 7.2 Hz), 8.78 (1 H, d, J = 8.8 Hz), 10.58 (1 H, s, NH). ^¹³C NMR (100.6 MHz, DMSO-d ₆): δ = 57.5 (C_spiro), 118.1 (C-12a), 120.9 (C-11a), 121.6, 122.4, 123.4, 124.0, 124.4 (2 CH), 124.6, 125.8, 127.5, 127.7, 128.9, 131.4, 132.3, 132.8, 133.5, 133.7, 136.5, 137.5 (2 CH), 142.8 (2 C), 157.9 (C-7a), 189.6 (C=O), 200.6 (2 C=O). MS (EI, 70 eV): m/z (%) = 413 (87) [M⁺], 397 (60), 385 (65) [M⁺ - C=O], 384 (100) [M⁺ - HC=O], 369 (54), 356 (45) [384 - C=O]. Anal. Calcd for C₂₈H₁₅NO₃: C, 81.35; H, 3.66; N, 3.39. Found: C, 81.39; H, 3.73; N, 3.32.

16 Wang XS. Zhang MM. Zeng ZS. Shi DQ. Tu SJ. Wei XY. Zong ZM. J. Heterocycl. Chem.  2006,  43:  989