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

Mehdi Adib; Bagher Mohammadi; Hamid Reza Bijanzadeh

doi:10.1055/s-2007-1000872

LETTER

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

Mehdi Adib*^a, Bagher Mohammadi^a, Hamid Reza Bijanzadeh^b
^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

Abstract

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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

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References

References and Notes

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

<A NAME="RD14607ST-19">19</A> Full spectroscopic assignment of compound 5a has been made in: Borovik VP. Shakirov MM. Shkurko OP. Vorozhtsov NN. Khim. Geterotsikl. Soedin. 2003, 1531

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%.