Download PDF
Synlett 2008(2): 177-180  
DOI: 10.1055/s-2007-1000872
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Novel and Simple Synthesis of 9H-Pyrimido[4,5-b]indoles under Microwave Irradiation and Solvent-Free Conditions

Mehdi Adib*a, Bagher Mohammadia, Hamid Reza Bijanzadehb
a School of Chemistry, University College of Science, University of Tehran, P.O. Box 14155-6455, Tehran, Iran
Fax: +98(21)66495291; e-Mail: madib@khayam.ut.ac.ir;
b Department of Chemistry, Tarbiat Modarres University, P.O. Box 14115-175, Tehran, Iran
Further Information

Publication History

Received 14 May 2007
Publication Date:
21 December 2007 (online)

    Permissions and Reprints All articles of this category

Abstract

A novel synthesis of 9H-pyrimido[4,5-b]indoles is described from a simple microwave-assisted reaction between oxindoles and aryl nitriles under solvent-free conditions in good to excellent yields.

Key words

9H-pyrimido[4,5-b]indoles - oxindoles - aryl nitriles - solvent-free synthesis - cyclizations - heterocycles

    References and Notes

  • 1 Delia TJ. Hurst DT. In Comprehensive Heterocyclic Chemistry II   Vol. 7:  Katritzky AR. Rees CW. Scriven EVF. Pergamon Press; London: 1996.  Chap. 7. p.229-281  ; and references therein
    Google Scholar
  • 2 Lowinger T, Shimazaki M, Sato H, Tanaka K, Tsuno N, Marx K, Yamamoto M, Urbahns K, Gantner F, Okigami H, Nakashima K, Takeshita K, Bacon KB, Komura H, and Yoshida N. inventors; PCT Int. Appl.,  WO03037898. 
  • 3 Hess S. Muller CE. Frobenius W. Reith U. Klotz KN. Eger K. J. Med. Chem.  2000,  43:  4636 
    CrossrefPubMedGoogle Scholar
  • 4 Coates WJ. inventors; US Patent  5162316. 
  • 5 Monge A. Palop JA. Goni T. Parrado P. Martinez F. Fernandezalvarez E. An. Quim., Ser. C  1988,  84:  38 
    Google Scholar
  • 6 Yuan J, and Hutchison A. inventors; US Patent  6495688. 
  • 7 Glushkov RG. Volskova VA. Magidson OY. Khim.-Farm. Zh.  1967,  1:  25 
    Google Scholar
  • 8 Borovik VP. Shkurko OP. Russ. Chem. Bull.  2002,  51:  2129 
    Google Scholar
  • 9a Dotzauer B. Troschütz R. Synlett  2004,  1039 
    Google Scholar
  • 9b Bernier J.-L. Hénichart J.-P. J. Org. Chem.  1981,  46:  4197 
    Google Scholar
  • 10 Kumar UKS. Yadav AK. Venkatesh C. Ila H. Junjappa H. ARKIVOC  2004,  (viii):  20 
    Google Scholar
  • 11 Zhang YM. Razler T. Jackson PF. Tetrahedron Lett.  2002,  43:  8235 
    CrossrefGoogle Scholar
  • 12 Bundy GL. Banitt LS. Dobrowolski PJ. Palmer JR. Schwartz TM. Zimmermann DC. Lipton MF. Mauragis MA. Veley MF. Appell RB. Clouse RC. Daugs ED. Org. Process Res. Dev.  2001,  5:  144 
    CrossrefGoogle Scholar
  • 13a Molina P. Arques A. Alias A. Vinader MV. Tetrahedron Lett.  1991,  34:  4401 
    CrossrefGoogle Scholar
  • 13b Molina P. Fresneda PM. J. Chem. Soc., Perkin Trans. 1  1988,  1819 
    CrossrefGoogle Scholar
  • 14 Lapachev VV. Stadlbauer W. Kappe T. Monatsh. Chem.  1988,  119:  97 
    CrossrefGoogle Scholar
  • 15 Wright GE. J. Heterocycl. Chem.  1976,  13:  539 
    Google Scholar
  • 16 Eger K. Lanzner W. Rothenhaüsler K. Liebigs Ann. Chem.  1993,  5:  465 
    Google Scholar
  • 17 Microwaves in Organic Synthesis   2nd reprint:  Loupy A. Wiley-VCH; Weinheim: 2004. 
    Google Scholar
  • 19 Full spectroscopic assignment of compound 5a has been made in: Borovik VP. Shakirov MM. Shkurko OP. Vorozhtsov NN. Khim. Geterotsikl. Soedin.  2003,  1531 
    Google Scholar
18

The experiments were performed using a microwave oven (ETHOS 1600, Milestone) with a power of 600 W specially designed for organic synthesis.

20

Preparation of 2,4-Diphenyl-9 H -pyrimido[4,5- b ]indo­le (5a); General Procedure: A mixture of oxindole (0.13 g, 1 mmol), benzonitrile (0.31 g, 3 mmol), and a catalytic amount of sat. aq NaOH solution was irradiated in a microwave oven at 180 °C for 4 min (progress of the reaction was followed by TLC monitoring minute by minute). Then the reaction mixture was cooled to r.t. and the residue was purified by column chromatography [using n-hexane-EtOAc (4:1) as eluent, Merck silica gel 60 mesh]. The solvent was removed and the product was recrystallized from 95% EtOH.
Selected Data: Compound 5a: colorless crystals; mp 300-302 °C. IR (KBr): 3225 (NH), 1580, 1547, 1482, 1443, 1398, 1365, 1255, 1209, 760, 744, 693 cm-1. 1H NMR (500.1 MHz, DMSO-d 6): δ = 7.21 (t, J = 7.7 Hz, 1 H, CH), 7.52 (t, J = 7.5 Hz, 1 H, CH), 7.53-7.59 (m, 3 H, 3 × CH), 7.60 (d, J = 8.1 Hz, 1 H, CH), 7.65-7.72 (m, 3 H, 3 × CH), 7.83 (d, J = 8.0 Hz, 1 H, CH), 8.04 (dd, J = 1.5, 8.0 Hz, 2 H, 2 × CH), 8.58 (dd, J = 1.5, 8.2 Hz, 2 H, 2 × CH), 12.53 (br, 1 H, NH). 13C NMR (125.8 MHz, DMSO-d 6): δ = 108.91 (C), 111.99 (CH), 118.82 (C), 120.56, 121.78, 127.36, 127.79, 128.47, 128.63, 128.78, 129.93, 130.13 (9 × CH), 138.10, 138.58, 139.38, 157.35, 159.02, 159.29 (6 × C). MS: m/z (%) = 321 (27) [M+], 320 (67) [M+ - 1], 242 (14), 190 (26), 164 (14), 105 (58), 84 (44), 77 (76), 57 (86), 43 (100). Anal. Calcd for C22H15N3 (321.38): C, 82.22; H, 4.70; N, 13.07. Found: C, 82.1; H, 4.8; N, 12.8.
Compound 5c: colorless crystals; mp 295-296 °C. IR (KBr): 3285 (NH), 1587, 1549, 1433, 1397, 1368, 1252, 1214, 1179, 796, 739, 718 cm-1. 1H NMR (500.1 MHz, DMSO-d 6): δ = 2.40, 2.49 (2 × s, 6 H, 2 × Me), 7.20 (t, J = 7.2 Hz, 1 H, CH), 7.36 (d, J = 7.5 Hz, 2 H, 2 × CH), 7.47-7.51 (m, 3 H, 3 × CH), 7.58 (d, J = 7.8 Hz, 1 H, CH), 7.86 (d, J = 7.7 Hz, 1 H, CH), 7.93 (d, J = 7.4 Hz, 2 H, 2 × CH), 8.46 (d, J = 7.6 Hz, 2 H, 2 × CH), 12.45 (br s, 1 H, NH). 13C NMR (125.8 MHz, DMSO-d 6): δ = 20.93, 21.01 (2 × Me), 108.51 (C), 111.78 (CH), 118.89 (C), 120.56, 121.76, 127.20, 127.75, 128.73, 129.08, 129.16 (7 × CH), 135.43, 135.76, 138.95, 139.65, 139.81, 157.21, 159.10, 159.42 (8 × C). MS: m/z (%) = 349 (30) [M+], 348 (100) [M+ - 1], 334 (27), 273 (18), 107 (45), 102 (14), 91 (64), 77 (40), 57 (33). Anal. Calcd for C24H19N3 (349.44): C, 82.49; H, 5.48; N, 12.03. Found: C, 82.3; H, 5.7; N, 11.7.
Compound 5f: colorless crystals; mp 320 °C (dec.). IR (KBr): 3260 (NH), 1585, 1543, 1525, 1479, 1440, 1396, 1345, 1255, 1210, 798 cm-1. 1H NMR (500.1 MHz, DMSO-d 6): δ = 7.25 (t, J = 7.5 Hz, 1 H, CH), 7.55 (dd, J = 7.5, 7.7 Hz, 1 H, CH), 7.60 (d, J = 7.7 Hz, 1 H, CH), 7.88 (d, J = 7.9 Hz, 1 H, CH), 7.92 (d, J = 8.5 Hz, 2 H, 2 × CH), 7.95 (d, J = 8.6 Hz, 2 H, 2 × CH), 8.65 (d, J = 8.5 Hz, 2 H, 2 × CH), 8.89 (d, J = 8.6 Hz, 2 H, 2 × CH), 12.05 (br, 1 H, NH). 13C NMR (125.8 MHz, DMSO-d 6): δ = 110.25 (C), 112.11 (CH), 119.71 (C), 120.09, 122.18, 127.64, 127.75, 128.95, 129.14, 131.66 (7 × CH), 136.44, 138.71, 139.98, 147.51, 148.60, 157.69, 158.50, 159.33 (8 × C). MS: m/z (%) = 411 (19) [M+], 410 (100) [M+ - 1], 381 (23), 365 (9), 353 (44), 335 (15), 289 (31), 148 (60), 115 (23), 76 (36). Anal. Calcd for C22H13N5O4 (411.38): C, 64.23; H, 3.19; N, 17.02. Found: C, 64.1; H, 3.3; N, 16.9.
Compound 5g: colorless crystals; mp 276-277 °C. IR (KBr): 3200 (NH), 1575, 1485, 1439, 1402, 1360, 1257, 1220, 1091, 902, 785, 741, 700 cm-1. 1H NMR (500.1 MHz, DMSO-d 6): δ = 7.23 (t, J = 7.9 Hz, 1 H, CH), 7.28 (dd, 3 J FH = 8.8 Hz, 3 J HH = 8.8 Hz, 2 H, 2 × CH), 7.46 (dd, 3 J FH = 8.8 Hz, 3 J HH = 8.7 Hz, 2 H, 2 × CH), 7.55 (dd, J = 7.4, 7.8 Hz, 1 H, CH), 7.67 (d, J = 8.1 Hz, 1 H, CH), 7.94 (d, J = 8.0 Hz, 1 H, CH), 8.17 (dd, 4 J FH = 5.5 Hz, 3 J HH = 8.7 Hz, 2 H, 2 × CH), 8.70 (dd, 4 J FH = 5.7 Hz, 3 J HH = 8.8 Hz, 2 H, 2 × CH), 11.40 (br s, 1 H, NH). 13C NMR (125.8 MHz, DMSO-d 6): δ = 110.16 (C), 112.77 (CH), 115.97 (d, 2 J FC = 22.0 Hz, CH), 116.44 (d, 2 J FC = 22.0 Hz, CH), 120.43 (C), 121.88, 123.15, 128.45 (3 × CH), 131.27 (d, 3 J FC = 8.6 Hz, CH), 132.27 (d, 3 J FC = 8.6 Hz, CH), 135.94 (d, 4 J FC = 3.2 Hz, C), 136.43 (d, 4 J FC = 3.3 Hz, C), 140.25, 158.76, 159.58, 160.18 (4 × C), 164.81 (d, 1 J FC = 245.4 Hz, CF), 165.30 (d, 1 J FC = 245.4 Hz, CF). MS: m/z (%) = 357 (77) [M+], 356 (100) [M+ - 1], 260 (6), 233 (8), 208 (13), 178 (9), 149 (5), 114 (4), 95 (8), 69 (13), 57 (10). Anal. Calcd for C22H13F2N3 (357.36): C, 73.94; H, 3.67; N, 11.76. Found: C, 73.8; H, 3.9; N, 11.6.
Compound 5i: colorless crystals; mp 233-235 °C. IR (KBr): 3140 (NH), 1587, 1539, 1364, 1249, 1210, 1071, 763, 739, 692 cm-1. 1H NMR (500.1 MHz, DMSO-d 6): δ = 7.21 (t, J = 7.5 Hz, 1 H, CH), 7.52 (t, J = 7.7 Hz, 1 H, CH), 7.53-7.57 (m, 2 H, 2 × CH), 7.59 (d, J = 8.0 Hz, 1 H, CH), 7.69-7.73 (m, 2 H, 2 × CH), 7.76 (d, J = 8.0 Hz, 1 H, CH), 7.97 (d, J = 6.7 Hz, 1 H, CH), 8.02 (s, 1 H, CH), 8.46 (d, J = 7.5 Hz, 1 H, CH), 8.48 (s, 1 H, CH), 12.59 (s, 1 H, NH). 13C NMR (125.8 MHz, DMSO-d 6): δ = 109.40 (C), 112.06 (CH), 118.40 (C), 120.87, 121.77, 126.29, 127.30, 127.47, 127.80, 128.50, 129.85, 129.89, 130.39, 130.58 (11 × CH), 133.41, 133.50, 139.31, 139.98, 140.34, 156.99, 157.29, 157.78 (8 × C). MS: m/z (%) = 392 (17) [M+37Cl2], 390 (56) [M+37Cl35Cl], 388 (100) [M+35Cl2], 354 (10), 250 (9), 215 (13), 188 (15), 137 (27), 111 (32), 75 (15). Anal. Calcd for C22H13Cl2N3 (390.27): C, 67.71; H, 3.36; N, 10.77. Found: C, 67.7; H, 3.4; N, 10.5.
Compound 5j: colorless crystals; mp 300-302 °C. IR (KBr): 3290 (NH), 1577, 1545, 1480, 1429, 1395, 1365, 1249, 1215, 1085, 1008, 844, 799, 740 cm-1. 1H NMR (500.1 MHz, DMSO-d 6): δ = 7.23 (t, J = 7.5 Hz, 1 H, CH), 7.53 (dd, J = 7.4, 7.8 Hz, 1 H, CH), 7.59 (d, J = 7.8 Hz, 1 H, CH), 7.61 (d, J = 8.5 Hz, 2 H, 2 × CH), 7.76 (d, J = 8.3 Hz, 2 H, 2 × CH), 7.82 (d, J = 8.0 Hz, 1 H, CH), 8.06 (d, J = 8.3 Hz, 2 H, 2 × CH), 8.55 (d, J = 8.5 Hz, 2 H, 2 × CH), 12.59 (s, 1 H, NH). 13C NMR (125.8 MHz, DMSO-d 6): δ = 109.04 (C), 111.97 (CH), 118.51 (C), 120.90, 121.91, 127.70, 128.59, 128.81, 129.48, 130.67 (7 × CH), 134.83, 135.08, 136.76, 137.14, 139.19, 157.10, 157.74, 158.26 (8 × C). MS: m/z (%) = 392 (3) [M+37Cl2], 390 (9) [M+37Cl35Cl], 388 (4) [M+35Cl2], 263 (32), 226 (44), 200 (48), 165 (7), 164 (35), 105 (16), 77 (100), 57 (29), 51 (47). Anal. Calcd for C22H13Cl2N3 (390.27): C, 67.71; H, 3.36; N, 10.77. Found: C, 67.6; H, 3.5; N, 10.7.
Compound 5l: colorless crystals; mp 208-211 °C. IR (KBr): 3100 (NH), 1586, 1536, 1362, 1249, 1210, 1062, 772, 741, 716, 698 cm-1. 1H NMR (500.1 MHz, DMSO-d 6): δ = 7.21 (t, J = 7.4 Hz, 1 H, CH), 7.48 (dd, J = 7.7, 8.2 Hz, 1 H, CH), 7.52 (dd, J = 7.4, 8.3 Hz, 1 H, CH), 7.59 (d, J = 8.0 Hz, 1 H, CH), 7.64 (dd, J = 7.8, 8.7 Hz, 1 H, CH), 7.67 (d, J = 8.0 Hz, 1 H, CH), 7.75 (d, J = 7.9 Hz, 1 H, CH), 7.86 (d, J = 7.8 Hz, 1 H, CH), 8.01 (d, J = 7.4 Hz, 1 H, CH), 8.15 (s, 1 H, CH), 8.50 (d, J = 7.6 Hz, 1 H, CH), 8.63 (s, 1 H, CH), 12.58 (1 H, s, NH). 13C NMR (125.8 MHz, DMSO-d 6): δ = 109.37 (C), 112.04 (CH), 118.38 (C), 120.83, 121.74, 121.92, 121.93, 126.65, 127.77, 127.82, 130.22, 130.63, 130.80, 131.34 (11 × CH), 132.72, 132.74, 139.30, 140.15, 140.53, 156.94, 157.17, 157.64 (8 × C). MS: m/z (%) = 481 (6) [M+81Br2], 479 (85) [M+81Br79Br], 477 (6) [M+79Br2], 400(16), 319 (17), 216 (20), 181 (32), 155 (28), 114 (30), 102 (100), 75 (88), 52 (38). Anal. Calcd for C22H13Br2N3 (479.17): C, 55.15; H, 2.73; N, 8.77. Found: C, 54.9; H, 2.9; N, 8.6.
Compound 5n: colorless crystals; mp 160-162 °C. IR (KBr): 1579, 1550, 1486, 1439, 1400, 1395, 1250, 1210, 758, 740 cm-1. 1H NMR (500.1 MHz, DMSO-d 6): δ = 3.05 (s, 3 H, Me), 7.20 (t, J = 7.7 Hz, 1 H, CH), 7.49-7.57 (m, 4 H, 4 × CH), 7.62 (d, J = 7.8 Hz, 1 H, CH), 7.64-7.71 (m, 3 H, 3 × CH), 7.92 (d, J = 7.9 Hz, 1 H, CH), 8.00 (d, J = 7.8 Hz, 2 H, 2 × CH), 8.50 (d, J = 7.9 Hz, 2 H, 2 × CH). 13C NMR (125.8 MHz, DMSO-d 6): δ = 40.25 (Me), 107.05 (C), 110.23 (CH), 117.78 (C), 119.18, 120.03, 127.15, 127.55, 127.95, 128.09, 128.45, 129.33, 130.64 (9 × CH), 138.39, 139.14, 139.97, 156.79, 158.64, 159.20 (6 × C). MS: m/z (%) = 335 (100) [M+], 258 (14), 230 (23), 129 (18), 105 (43), 103 (39), 77 (55), 57 (40). Anal. Calcd for C23H17N3 (335.41): C, 82.36; H, 5.11; N, 12.53. Found: C, 82.3; H, 5.2; N, 12.4.
Compound 5q: colorless crystals; mp 303-304 °C. IR (KBr): 3250 (NH), 1585, 1550, 1426, 1360, 1250, 1211, 848, 704 cm-1. 1H NMR (300.1 MHz, DMSO-d 6): δ = 2.37, 2.47 (2 × s, 6 H, 2 × Me), 7.32 (d, J = 8.1 Hz, 2 H, 2 × CH), 7.48 (d, J = 8.2 Hz, 2 H, 2 × CH), 7.51 (d, J = 8.6 Hz, 1 H, CH), 7.61 (dd, J = 1.8, 8.6 Hz, 1 H, CH), 7.88 (d, J = 8.1 Hz, 2 H, 2 × CH), 7.89 (d, J = 1.8 Hz, 1 H, CH), 8.41 (d, J = 8.1 Hz, 2 H, 2 × CH), 12.62 (br s, 1 H, NH). 13C NMR (75.5 MHz, DMSO-d 6): δ = 21.06, 21.14 (2 × Me), 107.77, 112.55 (2 × C), 113.90 (CH), 120.99 (C), 123.89, 127.94, 128.81, 129.21, 129.34, 129.73 (6 × CH), 135.23, 135.48, 137.83, 140.17, 140.18, 157.48, 159.82, 160.11 (8 × C). MS: m/z (%) = 429 (65) [M+81Br], 427 (100) [M+79Br], 413 (9), 273 (26), 192 (21), 107 (15), 91 (42), 78 (35). Anal. Calcd for C24H18BrN3 (428.33): C, 67.30; H, 4.24; N, 9.81. Found: C, 67.2; H, 4.4; N, 9.7.
Compound 5r: colorless crystals; mp 231-232 °C. IR (KBr): 3150 (NH), 1585, 1543, 1391, 1365, 1250, 760, 690 cm-1. 1H NMR (300.1 MHz, DMSO-d 6): δ = 7.42 (t, J = 7.8 Hz, 1 H, CH), 7.44 (d, J = 8.6 Hz, 1 H, CH), 7.56 (dd, J = 1.8, 8.6 Hz, 1 H, CH), 7.61 (t, J = 7.9 Hz, 1 H, CH), 7.63 (d, J = 7.9 Hz, 1 H, CH), 7.73 (d, J = 1.8 Hz, 1 H, CH), 7.85 (d, J = 7.7 Hz, 1 H, CH), 7.93 (d, J = 7.7 Hz, 1 H, CH), 8.09 (s, 1 H, CH), 8.39 (d, J = 7.9 Hz, 1 H, CH), 8.52 (s, 1 H, CH), 12.67 (br s, 1 H, NH). 13C NMR (75.5 MHz, DMSO-d 6): δ = 108.50 (C), 112.83, 114.02, 120.26, 121.99, 122.08 (5 × CH), 124.02, 126.74 (2 × C), 127.84 (CH), 130.22, 130.23 (2 × C), 130.70, 130.96, 131.40 (3 × CH), 133.03, 133.10, 138.04, 139.80, 140.10, 157.02, 157.78, 158.18 (8 × C). MS: m/z (%) = 559 (95) [M+81Br2 79Br], 557 (100) [M+81Br79Br2], 480 (13), 400(56), 192 (9), 181 (14), 155 (17), 79 (21), 57 (20). Anal. Calcd for C22H12Br3N3 (558.07): C, 47.35; H, 2.17; N, 7.53. Found: C, 47.3; H, 2.3; N, 7.5%.