A Facile Method for the Synthesis of 3-(Aminomethylene)oxindoles from Isatylidene Malononitriles and α-Azido Ketones

Abstract

A simple one-pot synthesis of 3-(aminomethylene)oxindoles was achieved by the reaction of α-azido ketones and isatylidene malononitriles via Michael addition followed by the conversion of azides to amines. All the synthesized 3-(aminomethylene)oxindoles exhibited good diastereoselectivity.

Key words

isatylidene malononitriles - azido ketones - oxindoles - 3-(aminomethylene)oxindoles - one-pot synthesis

• References and Notes

• 1a Langer P, Freifeld I, Shojaei H. Chem. Commun. 2003; 3044
• 1b Freifeld I, Shojaei H, Langer P. J. Org. Chem. 2006; 71: 4965
• 1c Freifeld I, Shojaei H, Dede R, Langer P. J. Org. Chem. 2006; 71: 6165
• 2 Marco JL, Grau AM, Martin N, Seoane C. Tetrahedron Lett. 1995; 36: 5393
• 3 Kuthan J. Adv. Heterocycl. Chem. 1983; 34: 146
• 4a Dabiri M, Bahramnnejad M, Baghbanzadeh M. Tetrahedron 2009; 65: 9443
• 4b Lee YR, Hari GS. Synthesis 2010; 453
• 4c Wang LM, Jiao N, Qiu J, Yu JJ, Liu JQ, Guo FL, Liu Y. Tetrahedron 2010; 66: 339
• 4d Yuling L, Hui C, Chunling S, Daqing S, Shunjun J. J. Comb. Chem. 2010; 12: 231
• 4e Zhu S.-L, Ji S.-J, Zhang Y. Tetrahedron 2007; 63: 9365
• 4f Sridhar R, Srinivas B, Madhav B, Reddy VP, Nageswar YV. D, Rao KR. Can. J. Chem. 2009; 87: 1704
• 4g Litvinov YM, Mortikov VY, Shestopalov AM. J. Comb. Chem. 2008; 10: 741
• 4h Rad-Moghadam K, Youseftabar-Miri L. Tetrahedron 2011; 67: 5693
• 5 Trost BM, Brennan MK. Synthesis 2009; 3003
• 6a Treu M, Guertler U, Karner T, Kraemer O, Quant JJ, Zahn SK. WO2008152013 A1, 2008 ; Chem. Abstr. 2009, 150, 55987y
• 6b Treu M, Mantoulidis A, Tontsch-Grunt U. WO2007122219 A1, 2007 ; Chem. Abstr. 2007, 147, 502230v
• 6c Heckel A, Roth GR, Joerg K, Hoerer S, Uphues I. U.S. Patent US20050203104 A1, 2005 ; Chem. Abstr. 2005, 143, 306172f
• 6d Burgdorf LT, Bruge D, Greiner H, Kordowicz M, Sirrenberg C, Zenke F (Merck) WO2006131186 A1, 2006 ; Chem. Abstr. 2006, 146, 62590j
• 7a Tang S, Peng P, Pi S.-F, Liang Y, Wang N.-X, Li J.-H. Org. Lett. 2008; 10: 1179
• 7b Tang S, Peng P, Wang Z.-Q, Tang B.-X, Deng C.-L, Li J.-H, Zhong P, Wang N.-X. Org. Lett. 2008; 10: 1875
• 7c Peng P, Tang B.-X, Pi S.-F, Liang Y, Li J.-H. J. Org. Chem. 2009; 74: 3569
• 8 Miura T, Toyoshima T, Takahashi Y, Murakami M. Org. Lett. 2009; 11: 2141
• 9 Bararjanian M, Hosseinzadeh S, Balalaie S, Bijanzadeh HR, Wolf E. Tetrahedron Lett. 2011; 52: 3329
• 10a Shanthi G, Subbulakshmi G, Perumal PT. Tetrahedron 2007; 63: 2057
• 10b Shanthi G, Perumal PT. Tetrahedron Lett. 2008; 49: 7139
• 10c Lakshmi NV, Thirumurugan P, Perumal PT. Tetrahedron Lett. 2010; 51: 1064
• 10d Babu TH, Joseph AA, Muralidharan D, Perumal PT. Tetrahedron Lett. 2010; 51: 994
• 10e Nandakumar A, Thirumurugan P, Perumal PT, Vembu P, Ponnuswamy MN, Ramesh P. Bioorg. Med. Chem. Lett. 2010; 20: 4252
• 10f Kiruthika SE, Lakshmi NV, Banu BR, Perumal PT. Tetrahedron Lett. 2011; 52: 6508
• 10g Lakshmi NV, Josephine GA. S, Perumal PT. Tetrahedron Lett. 2012; 53: 1282
• 11 Crystallographic data for compound 5c in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplemental publication number CCDC 840032. 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]]
• 12 General Procedure for the Synthesis of Oxyindolyl Enaminone: To a stirred solution of isatylidene malononitrile 1 (1.0 mmol) and α-azido ketone 2 (1.25 mmol) in EtOH (5 mL), was added piperidine (1.0 mmol). Stirring was continued at r.t. for appropriate times as mentioned in Table 2. After the reaction was complete as indicated by TLC, solvent was removed under vacuum and the crude product was purified by column chromatography on silica gel (Merck, 100–200 mesh, EtOAc–PE, 25:75). (Z)-3-(1-Amino-2-oxo-2-phenylethylidene)indolin-2-one (5a): brown solid; mp 246–248 °C. IR (KBr): 3413, 3260, 2925, 1665, 1616, 1461, 1324, 1210, 1005, 783, 724, 669, 581, 513 cm^–1. ¹H NMR (500 MHz, DMSO-d ₆ + CDCl₃): δ = 6.45 (d, J = 7.65 Hz, 1 H, ArH), 6.52 (t, J = 7.65 Hz, 1 H, ArH), 6.75–6.78 (m, 2 H, ArH), 7.42 (d, J = 7.65 Hz, 2 H, ArH), 7.65 (t, J = 7.65 Hz, 1 H, ArH), 7.72 (br s, 1 H, D₂O exchangeable, NH), 7.99 (d, J = 7.65 Hz, 2 H, ArH), 9.01 (br s, 1 H, D₂O exchangeable, NH), 9.81 (s, 1 H, D₂O exchangeable, NH). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 94.2, 109.4, 117.9, 120.4, 122.9, 123.6, 129.3, 130.1, 134.0, 135.1, 136.8, 154.5, 171.1, 192.0. Anal. Calcd for C₁₆H₁₂N₂O₂: C, 72.72; H, 4.58; N, 10.60. Found: C, 72.82; H, 4.56; N, 10.62. HRMS (ESI): m/z calcd for C₁₆H₁₂N₂O₂: 265.0972 [M + H]⁺; found: 265.0977. (Z)-3-(1-Amino-2-oxo-2-phenylethylidene)-1-(prop-2-ynyl)indolin-2-one (5c): orange solid; mp 220–222 °C. IR (KBr): 3407, 3285, 2931, 1665, 1616, 1464, 1352, 724, 679, 583 cm. ¹H NMR (500 MHz, DMSO-d ₆): δ = 3.18 (s, 1 H, ≡CH), 4.62 (s, 2 H, CH₂), 6.46 (d, J = 7.65 Hz, 1 H, ArH), 6.68 (t, J = 7.65 Hz, 1 H, ArH), 6.96 (t, J = 7.65 Hz, 1 H, ArH), 7.00 (d, J = 7.65 Hz, 1 H, ArH), 7.59 (t, J = 7.65 Hz, 2 H, ArH), 7.73 (t, J = 7.65 Hz, 1 H, ArH), 8.00 (d, J = 7.65 Hz, 2 H, ArH), 8.64 (br s, 1 H, D₂O exchangeable, NH), 8.99 (br s, 1 H, D₂O exchangeable, NH). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 28.0, 73.9, 78.9, 91.4, 108.6, 117.0, 121.1, 121.9, 123.4, 129.6, 129.7, 130.1, 133.5, 135.5, 155.5, 167.2, 191.5. Anal. Calcd for C₁₉H₁₄N₂O₂: C, 75.48; H, 4.67; N, 9.27. Found: C, 75.44; H, 4.63; N, 9.23. HRMS (ESI): m/z calcd for C₁₉H₁₄N₂O₂: 303.1128 [M + H]⁺; found: 303.1142. (Z)-Ethyl 2-[3-(1-Amino-2-oxo-2-phenylethylidene)-2-oxoindolin-1-yl]acetate (5d): pale orange solid; mp 230–232 °C. IR (KBr): 3404, 3294, 2924, 1714, 1668, 1624, 1496, 1365, 728, 588 cm^–1. ¹H NMR (500 MHz, DMSO-d ₆): δ = 1.18 (t, J = 6.05 Hz, 3 H, Me), 4.12 (q, J = 7.65 Hz, 2 H, CH₂), 4.63 (s, 2 H, CH₂), 6.46 (d, J = 7.65 Hz, 1 H, ArH), 6.66 (t, J = 5.35 Hz, 1 H, ArH), 6.91 (t, J = 6.10 Hz, 2 H, ArH), 7.60 (t, J = 7.65 Hz, 2 H, ArH), 7.74 (t, J = 7.65 Hz, 1 H, ArH), 8.00 (d, J = 2 H, ArH), 8.61 (br s, 1 H, D₂O exchangeable, NH), 8.90 (br s, 1 H, D₂O exchangeable, NH). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 14.6, 41.0, 61.5, 92.0, 108.7, 117.4, 121.3, 122.3, 123.8, 130.1, 134.0, 135.9, 137.4, 155.7, 168.5, 169.0, 192.0. Anal. Calcd for C₂₀H₁₈N₂O₄: C, 68.56; H, 5.18; N, 8.00. Found: C, 68.52; H, 5.16; N, 8.06. HRMS (ESI): m/z calcd for C₂₀H₁₈N₂O₄: 351.1339 [M + H]⁺; found: 351.1345. (Z)-3-(1-Amino-2-oxo-2-phenylethylidene)-1-benzyl-indolin-2-one (5e): brown solid; mp 233–235 °C. IR (KBr): 3410, 3281, 3057, 1663, 1619, 1464, 741, 700, 600 cm^–1. ¹H NMR (500 MHz, DMSO-d ₆): δ = 5.00 (s, 2 H, CH₂), 6.46 (d, J = 8.4 Hz, 1 H, ArH), 6.62 (t, J = 3.85 Hz, 1 H, ArH), 6.84 (d, J = 7.65 Hz, 2 H, ArH), 7.27–7.37 (m, 5 H, ArH), 7.59 (t, J = 7.65 Hz, 2 H, ArH), 7.73 (t, J = 7.65 Hz, 1 H, ArH), 8.02 (d, J = 7.65 Hz, 2 H, ArH), 8.61 (br s, 1 H, D₂O exchangeable, NH), 9.00 (br s, 1 H, D₂O exchangeable, NH). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 42.6, 92.1, 109.0, 117.4, 121.2, 122.4, 123.8, 127.5, 127.7, 129.1, 130.1, 130.2, 134.0, 135.9, 137.9, 137.9, 155.7, 168.6, 192.1. Anal. Calcd for C₂₃H₁₈N₂O₂: C, 77.95; H, 5.12; N, 7.90. Found: C, 77.89; H, 5.18; N, 7.92. HRMS (ESI): m/z calcd for C₂₃H₁₈N₂O₂: 355.1441 [M + H]⁺; found: 355.1457. (Z)-3-(1-Amino-2-oxo-2-phenylethylidene)-5-methyl-indolin-2-one (5g): orange solid; mp 210–212 °C. IR (KBr): 3423, 3154, 1665, 1618, 1481, 1326, 791, 718, 671, 587 cm^–1. ¹H NMR (500 MHz, DMSO-d ₆): δ = 1.94 (s, 3 H, Me), 6.20 (s, 1 H, ArH), 6.65–6.68 (m, 2 H, ArH), 7.58 (t, J = 7.65 Hz, 2 H, ArH), 7.72 (t, J = 7.65 Hz, 1 H, ArH), 7.98 (d, J = 7.65 Hz, 2 H, ArH), 8.33 (br s, 1 H, D₂O exchangeable, NH), 9.01 (br s, 1 H, D₂O exchangeable, NH), 10.32 (s, 1 H, D₂O exchangeable, NH). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 21.5, 93.3, 109.4, 118.2, 123.2, 124.4, 128.9, 130.0, 130.1, 134.1, 134.9, 135.8, 154.9, 170.8, 192.2. Anal. Calcd for C₁₇H₁₄N₂O₂: C, 73.37; H, 5.07; N, 10.07. Found: C, 73.41; H, 5.11; N, 10.03. HRMS (ESI): m/z calcd for C₁₇H₁₄N₂O₂: 279.1128 [M + H]⁺; found: 279.1133. (Z)-3-[1-Amino-2-(naphthalen-2-yl)-2-oxoethylidene]-1-(prop-2-ynyl)indolin-2-one (5i): bright orange solid; mp 246–248 °C. IR (KBr): 3410, 3297, 3054, 2931, 1669, 1619, 1468, 1357, 1278, 1183, 669, 582 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 2.23 (t, J = 2.3 Hz, 1 H, ≡CH), 4.63 (d, J = 2.3 Hz, 2 H, CH₂), 5.61 (br s, 1 H, D₂O exchangeable, NH), 6.69–6.74 (m, 2 H, ArH), 7.00–7.05 (m, 2 H, ArH), 7.53 (t, J = 8.05 Hz, 1 H, ArH), 7.63 (t, J = 8.05 Hz, 1 H, ArH), 7.86–7.94 (m, 3 H, ArH), 8.14 (d, J = 8.55 Hz, 1 H, ArH), 8.57 (s, 1 H, ArH), 9.1 (br s, 1 H, D₂O exchangeable, NH). ¹³C NMR (125 MHz, CDCl₃-d ₆): δ = 28.7, 71.9, 77.7, 95.6, 108.6, 119.0, 121.8, 121.9, 123.8, 124.5, 127.4, 128.0, 129.6, 129.9, 130.2, 132.5, 134.0, 136.6, 137.1, 153.4, 168.5, 191.7. Anal. Calcd for C₂₃H₁₆N₂O₂: C, 78.39; H, 4.58; N, 7.95. Found: C, 78.43; H, 4.63; N, 7.91. HRMS (ESI): m/z calcd for C₂₃H₁₆N₂O₂: 353.1285 [M + H]⁺; found: 353.1290. (Z)-3-[1-Amino-2-(4-chlorophenyl)-2-oxoethylidene]-indolin-2-one (5k): orange solid; mp 236–238 °C. IR (KBr): 3317, 3158, 2925, 2854, 1664, 1614, 1469, 1359, 1279, 1182, 785, 749, 477 cm^–1. ¹H NMR (500 MHz, DMSO-d ₆): δ = 6.38 (d, J = 7.65 Hz, 1 H, ArH), 6.59 (t, J = 7.65 Hz, 1 H, ArH), 6.79 (d, J = 7.65 Hz, 1 H, ArH), 6.85 (t, J = 7.65 Hz, 1 H, ArH), 7.65 (d, J = 8.45 Hz, 2 H, ArH), 7.99 (d, J = 8.45 Hz, 2 H, ArH), 8.38 (br s, 1 H, D₂O exchangeable, NH), 9.02 (br s, 1 H, D₂O exchangeable, NH), 10.47 (s, 1 H, D₂O exchangeable, NH). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 79.6, 93.4, 109.7, 117.5, 120.6, 123.9, 130.3, 131.9, 132.8, 137.1, 140.8, 154.4, 170.6, 191.1. Anal. Calcd for C₁₆H₁₁ClN₂O₂: C, 64.33; H, 3.71; N, 9.38. Found: C, 64.39; H, 3.67; N, 9.32. (Z)-Ethyl 2-{3-[1-Amino-2-(4-chlorophenyl)-2-oxoethylidene]-2-oxoindolin-1-yl}acetate (5l): bright orange solid; mp 221–223 °C. IR (KBr): 3347, 3194, 2925, 1743, 1663, 1613, 1469, 1368, 1275, 1174, 1092, 1016, 754, 593, 539 cm^–1. ¹H NMR (500 MHz, DMSO-d ₆): δ = 1.18 (t, J = 7.3 Hz, 3 H, Me), 4.12 (q, J = 6.85 Hz, 2 H, CH₂), 4.63 (s, 2 H, CH₂), 6.45 (d, J = 7.65 Hz, 1 H, ArH), 6.68 (t, J = 7.65 Hz, 1 H, ArH), 6.89–6.93 (m, 2 H, ArH), 7.67 (d, J = 8.4 Hz, 2 H, ArH), 8.0 (d, J = 7.6 Hz, 2 H, ArH), 8.59 (br s, 1 H, D₂O exchangeable, NH), 8.94 (br s, 1 H, D₂O exchangeable, NH). ¹³C NMR (125 MHz, DMSO-d ₆): 14.6, 41.0, 61.5, 92.0, 108.7, 117.4, 121.4, 122.1, 123.9, 130.3, 131.9, 132.7, 137.5, 140.9, 155.0, 169.0, 191.0. Anal. Calcd for C₂₀H₁₇ClN₂O₄: C, 62.42; H, 4.45; N, 7.28. Found: C, 62.48; H, 4.51; N, 7.21. HRMS (ESI): m/z calcd for C₂₀H₁₇ClN₂O₄: 385.0950 [M + H]⁺; found: 385.0955
• 13 McEwen WE, Conrad WE, VanderWerf CA. J. Am. Chem. Soc. 1952; 74: 1168