Synlett 2013; 24(15): 1968-1972
DOI: 10.1055/s-0033-1339465
letter
© Georg Thieme Verlag Stuttgart · New York

A Remarkable One-Pot Sequential Four-Component Synthesis of Tetrahydroquinazolines via an Isocyanide-Based Multicomponent Reaction

Ahmad Shaabani*
a  Faculty of Chemistry, Shahid Beheshti University, G. C., P. O. Box 19396-4716, Tehran, Iran   Fax: +98(21)29903247    Email: [email protected]
,
Mojtaba Mahyari
a  Faculty of Chemistry, Shahid Beheshti University, G. C., P. O. Box 19396-4716, Tehran, Iran   Fax: +98(21)29903247    Email: [email protected]
,
Morteza Aghaei
a  Faculty of Chemistry, Shahid Beheshti University, G. C., P. O. Box 19396-4716, Tehran, Iran   Fax: +98(21)29903247    Email: [email protected]
,
Sajjad Keshipour
a  Faculty of Chemistry, Shahid Beheshti University, G. C., P. O. Box 19396-4716, Tehran, Iran   Fax: +98(21)29903247    Email: [email protected]
,
Seik Weng Ng
b  Department of Chemistry, University of Malaya, 50603, Kuala Lumpur, Malaysia
› Author Affiliations
Further Information

Publication History

Received: 16 April 2013

Accepted after revision: 21 June 2013

Publication Date:
07 August 2013 (online)


Abstract

A novel one-pot sequential four-component strategy has been developed for the synthesis of tetrahydroquinazolines using either an aliphatic or an acyl halide, an isocyanide, and a 1,3-diamine, in methanol at 60 °C, in good to moderate yields without using a catalyst.

 
  • References and Notes

  • 1 Jiang JB, Hesson D, Dusak B, Dexter D, Kang G, Hamel E. J. Med. Chem. 1990; 33: 1721
  • 2 Yale HJ, Kalkstein M. J. Med. Chem. 1967; 10: 334
  • 3 Neil GL, Li LH, Buskirk HH. Cancer Chemother. Pharmacol. 1972; 56: 163
  • 4 Hamel E, Lin CM, Plowman J, Wang HK, Lee KH, Paull KD. Biochem. Pharmacol. 1996; 51: 53
  • 5 Tiwari AK, Mishra AK, Bajpai A, Mishra P, Sharma RK, Pandey VK, Singh VK. Bioorg. Med. Chem. Lett. 2006; 16: 4581
  • 6 Ram VJ, Tripathi BK, Srivastava AK. Bioorg. Med. Chem. 2003; 11: 2439
  • 7 Witt A, Bergman J. Curr. Org. Chem. 2003; 7: 659
  • 8 Touroutoglou N, Pazdur R. Clin. Cancer Res. 1996; 2: 227
  • 9 Jackman AL, Harrap KR, Boyle FT. Invest. New Drugs 1996; 14: 305
  • 10 Sielecki TM, Johnson TL, Liu J, Muckelbauer JK, Grafstrom RH, Cox S, Boylan J, Burton CR, Chen H, Smallwood A, Chang C.-H, Boisclair M, Benfield PA, Trainor GL, Seitz SP. Bioorg. Med. Chem. Lett. 2001; 11: 1157
  • 11 Bonomi PE. Expert Opin. Invest. Drugs 2003; 1395
  • 12 Alaimo RJ, Russell HE. J. Med. Chem. 1972; 15: 335
  • 13 Cooper ER. A, Jackson H. J. Reprod. Fertil. 1973; 34: 445
  • 14 Kuo SC, Lee HZ, Juang JP, Lin YT, Wu TS, Chang JJ, Lednicer D, Paull KD, Lin CM. J. Med. Chem. 1993; 36: 1146
  • 15 Lin CM, Kang G, Roach M, Jiang J, Hesson D, Luduena R, Hamel E. Mol. Pharmacol. 1991; 40: 827
  • 16 Hour MJ, Huang LJ, Kuo SC, Xia Y, Bastow K, Nakanishi Y, Hamel E, Lee KH. J. Med. Chem. 2000; 43: 4479
  • 17 Coskun N. Tetrahedron Lett. 2004; 45: 8973
  • 18 Csütörtöki R, Szatmári I, Koch A, Heydenreich M, Kleinpeter E, Fülöp F. Tetrahedron 2011; 67: 8564
  • 19 Balakumar C, Lamba P, Pran Kishore D, Lakshmi Narayana B, Venkat Rao K, Rajwinder K, Raghuram Rao A, Shireesha B, Narsaiah B. Eur. J. Med. Chem. 2010; 4904
  • 20 Bienayme H, Hulme C, Oddon G, Schmitt P. Chem. Eur. J. 2000; 6: 3321
  • 21 Weber L. Curr. Med. Chem. 2002; 9: 1241
  • 22 Schreiber SL. Science 2000; 287: 1964
  • 23 Dömling A. Chem. Rev. 2006; 106: 17
  • 24 Orru RV, De Greef M. Synthesis 2003; 1471
  • 25 Bienayme H, Hulme C, Oddon G, Schmitt P. Chem. Eur. J. 2000; 6: 3321
  • 26 Zhu J, Bienayme H. Multicomponent Reactions . Wiley-VCH; Weinheim: 2005
  • 27 Shaabani A, Maleki A, Mofakham H, Moghimi-Rad J. J. Org. Chem. 2008; 73: 3925
  • 28 Shaabani A, Rezayan AH, Keshipour S, Sarvary A, Ng SW. Org. Lett. 2009; 11: 3342
  • 29 Shaabani A, Maleki A, Hajishaabanha F, Mofakham H, Seyyedhamzeh M, Mahyari M, Ng SW. J. Comb. Chem. 2009; 12: 186
  • 30 Keshipour S, Shojaei S, Shaabani A. Tetrahedron 2012; 68: 6141
  • 31 Ghadari R, Hajishaabanha F, Mahyari M, Shaabani A, Khavasi HR. Tetrahedron Lett. 2012; 53: 4018
  • 32 Shaabani A, Keshipour S, Shaabani S, Mahyari M. Tetrahedron Lett. 2012; 53: 1641
  • 33 Nef JU. Justus Liebigs Ann. Chem. 1892; 270: 267
  • 34 Coffinier D, El Kaim L, Grimaud L. Org. Lett. 2009; 11: 1825
  • 35 El Kaim E, Grimaud L, Wagschal S. Synlett 2009; 1315
  • 36 Mossetti R, Pirali T, Tron GC, Zhu J. Org. Lett. 2010; 12: 820
  • 37 Coffinier D, El Kaim L, Grimaud L. Synlett 2010; 2474
  • 38 El Kaim L, Grimaud L, Patil P. Org. Lett. 2011; 13: 1261
  • 39 Walborsky H, Niznik G. J. Org. Chem. 1972; 37: 187
    • 40a Azuaje J, Coelho A, Maatougui AE, Blanco JM, Sotelo E. ACS Comb. Sci. 2011; 13: 89
    • 40b Lim YY, Stei AR. Can. J. Chem. 1971; 49: 2455
    • 40c Gassman PG, Haberman LM. Tetrahedron Lett. 1985; 26: 4971
    • 40d Priestley ES, Decicco CP. Org. Lett. 2000; 2: 3095
  • 41 N-Cyclohexyl-4-oxo-2-phenyl-1,2,3,4-tetrahydro-quinazoline-2-carboxamide (4a) – Typical Procedure To magnetically stirred benzoyl chloride (0.14 g, 1.00 mmol) was added cyclohexyl isocyanide (0.11 g, 1.00 mmol), and the reaction mixture was heated for 2 h at 60 °C. After cooling, MeOH (5 mL) and 2-aminobenzamide were added, and the reaction mixture was stirred for 24 h at 60 °C. After completion of the reaction (TLC), the solvent was removed under vacuum, the residue was crystallized from CH2Cl2n-hexane (3:1), and the product 4a was obtained as a white solid (0.21 g, 60%); yield 0.21 g (60%); mp 222–225 °C. IR (KBr): 3381, 3324, 2932, 2844, 1649, 1612, 1492, 1461 cm–1. 1H NMR (300.13 MHz, DMSO-d 6): δ = 1.08–1.59 (10 H, m, 5 CH2 of c-Hex), 3.52 (1 H, br s, CH of c-Hex), 6.69 (1 H, br s, NH), 6.93 (1 H, br s, NH), 7.25–7.70 (9 H, m, CHAr), 8.41 (1 H, br s, CONH). 13C NMR (75.47 MHz, DMSO-d 6): δ = 24.6, 25.5, 32.4, 48.8, 75.5, 114.7, 115.5, 118.2, 126.8, 127.6, 128.7, 129.0, 134.0, 141.4, 147.2, 163.9, 170.3. MS: m/z (%) = 350 (90) [M+ + 1], 223 (100), 297 (25), 145 (15), 119 (30), 92 (60), 55 (65). Anal. Calcd for C21H23N3O2: C, 72.18; H, 6.63; N, 12.03. Found: C, 72.10; H, 6.58; N, 12.17. 2-(4-Bromophenyl)-N-cyclohexyl-4-oxo-1,2,3,4-tetrahydroquinazoline-2-carboxamide (4b) Yellow powder; yield 0.23 g (54%); mp 242–245 °C. IR (KBr): 3371, 3326, 2922, 2830, 1659, 1622, 1483, 1454 cm–1. 1H NMR (300.13 MHz, DMSO-d 6): δ = 1.14–1.60 (10 H, m, 5 CH2 of c-Hex), 3.50 (1 H, br s, CH of c-Hex), 6.69 (1 H, br s, NH), 6.92 (1 H, br s, NH), 7.28–7.79 (8 H, m, CHAr), 8.53 (1 H, br, CONH). 13C NMR (75.47 MHz, DMSO-d 6): δ = 24.7, 24.8, 32.3, 48.9, 75.1, 114.7, 115.6, 118.3, 122.4, 127.6, 129.1, 129.3, 131.6, 131.8, 134.1, 140.9, 147.0, 163.8, 169.8. Anal. Calcd for C21H22BrN3O2: C, 58.89; H, 5.18; Br, 18.66; N, 9.81. Found: C, 58.75; H, 5.24; N, 9.96. N-Cyclohexyl-2-methyl-4-oxo-1,2,3,4-tetrahydroquinazoline-2-carboxamide (4c) White powder; yield 0.18 g (63%); mp 232–235 °C. IR (KBr): 3413, 3321, 3002, 2923, 2852, 1624, 1580, 1525, 1455 cm–1. 1H NMR (300.13 MHz, DMSO-d 6): δ = 1.07–1.70 (10 H, m, 5 CH2 of c-Hex), 1.88 (3 H, s, CH3), 2.89 (1 H, br s, CH of c-Hex), 7.21 (1 H, br s, NH), 7.38 (1 H, br s, NH), 7.55–7.90 (4 H, m, CHAr), 8.60 (1 H, br, CONH). 13C NMR (75.47 MHz, DMSO-d 6): δ = 24.2, 25.0, 25.2, 30.7, 49.7, 78.1, 115.1, 122.3, 124.8, 126.3, 126.8, 128.1, 135.1, 147.4, 155.4, 164.3. Anal. Calcd for C16H21N3O2: C, 66.88; H, 7.37; N, 14.62. Found: C, 66.80; H, 7.43; N, 14.69. N-tert-Butyl-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinazoline-2-carboxamide (4d) White powder; yield 0.20 g (62%); mp 182–184 °C. IR (KBr): 3260, 3191, 2964, 2926, 2837, 1635, 1612, 1511 cm–1. 1H NMR (300.13 MHz, DMSO-d 6): δ = 1.57 (9 H, s, 3 CH3), 6.62 (1 H, br s, NH), 6.65 (1 H, br s, NH), 6.74–7.33 (9 H, m, Ar), 7.89 (1 H, br, CONH). 13C NMR (75.47 MHz, DMSO-d 6): δ = 29.7, 45.7, 80.1, 114.7, 116.2, 118.7, 126.4, 127.3 128.3, 129.1, 133.9, 134.0, 141.0, 154.0, 164.5. Anal. Calcd for C19H21N3O2: C, 70.57; H, 6.55; N, 12.99. Found: C, 70.64; H, 6.61; N, 12.90. N-Cyclohexyl-2-ethyl-4-oxo-1,2,3,4-tetrahydroquinazoline-2-carboxamide (4e) White powder; yield 0.19 g (63%); mp 176–179 °C. IR (KBr): 2983, 2940, 2862, 2825, 1701, 1644, 1618, 1498, 1455 cm–1. 1H NMR (300.13 MHz, DMSO-d 6): δ = 1.08–1.88 (13 H, m, 5 CH2 of c-Hex and CH3), 2.28 (2 H, br, CH 2CH3), 2.90 (1 H, br s, CH of c-Hex), 7.11 (1 H, br s, NH), 7.19 (1 H, br s, NH), 7.36–7.91 (4 H, m, CHAr), 8.55 (1 H, br, CONH). 13C NMR (62.83 MHz, DMSO-d 6): δ = 23.2, 24.7, 25.4, 32.9, 35.2, 48.4, 76.4, 113.9, 114.1, 117.3, 126.9, 131.8, 148.5, 159.2, 167.1. Anal. Calcd for C17H23N3O2: C, 67.75; H, 7.69; N, 13.94. Found: C, 67.69; H, 7.62; N, 14.09. N-tert-Butyl-2-ethyl-4-oxo-1,2,3,4-tetrahydroquinazoline-2-carboxamide (4f) Brown powder; yield 0.18 g (65%); mp 157–159 °C. IR (KBr): 3259, 2968, 2895, 1634, 1613, 1515, 1492, 1385 cm–1. 1H NMR (300.13 MHz, DMSO-d 6): δ = 1.22–1.33 (14 H, br s, 3 CH3 of t-Bu, CH2CH 3 and CH 2CH3), 6.59 (1 H, br s, NH), 6.67 (1 H, br s, NH), 7.17–7.91 (4 H, m, CHAr), 8.10 (1 H, br, CONH). 13C NMR (75.47 MHz, DMSO-d 6): δ = 27.5, 29.4, 51.4, 67.3, 78.4, 114.2, 114.7, 116.8, 127.6, 133.6, 147.6, 158.4, 168.4. MS: m/z (%) = 276 (25) [M+ + 1], 223 (80), 200 (15), 177 (15), 161 (100), 120 (25), 92 (25), 58 (75). Anal. Calcd for C15H21N3O2: C, 65.43; H, 7.69; N, 15.26. Found: C, 65.49; H, 7.74; N, 15.18. N-Cyclohexyl-2-phenyl-1,2,3,4-tetrahydroquinazoline-2-carboxamide (4g) White powder; yield 0.22 g (66%); mp 153–159 °C. IR (KBr): 2940, 2862, 2730, 1675, 1606, 1511, 1442 cm–1. 1H NMR (300.13 MHz, DMSO-d 6): δ = 1.07–1.89 (10 H, m, 5 CH2 of c-Hex), 2.88 (2 H, br, CH2, ArCH2), 3.40 (1 H, br s, CH of c-Hex), 6.63 (1 H, br s, NH), 6.72 (1 H, br s, NH), 7.14–7.24 (9 H, m, Ar), 8.35 (1 H, br, CONH). 13C NMR (75.47 MHz, DMSO-d 6): δ = 24.2, 25.0, 30.6, 41.1, 49.7, 76.6, 117.2, 118.4, 127.4, 126.2, 127.5, 127.6, 128.5, 129.2, 131.3, 150.1, 151.2, 167.9. Anal. Calcd for C21H25N3O: C, 75.19; H, 7.51; N, 12.53. Found: C, 75.12; H, 7.44; N, 12.62. N-Cyclohexyl-2-methyl-1,2,3,4-tetrahydroquinazoline-2-carboxamide (4h) White powder; yield 0.19 g (70%); mp 145–148 °C. IR (KBr): 3425, 3336, 3021, 2936, 1637, 1587, 1500, 1461 cm–1. 1H NMR (300.13 MHz, DMSO-d 6): δ = 1.07–1.70 (10 H, m, 5 CH2 of c-Hex), 1.89 (3 H, s, CH3), 2.89 (1 H, br s, CH of c-Hex), 3.86 (2 H, br, CH2, ArCH2), 6.56 (1 H, br s, NH), 6.69 (1 H, br s, NH), 7.01–7.15 (4 H, m, CHAr), 8.26 (1 H, br, CONH). 13C NMR (75.47 MHz, DMSO-d 6): δ = 24.2, 25.0, 30.7, 38.9, 40.9, 49.7, 82.2, 116.0, 116.6, 117.7, 129.8, 130.9, 147.5, 159.1, 165.2. Anal. Calcd for C16H23N3O: C, 70.30; H, 8.48; N, 15.37. Found: C, 70.39; H, 8.57; N, 15.24. N-Cyclohexyl-2-ethyl-1,2,3,4-tetrahydroquinazoline-2-carboxamide (4i) White powder; yield 0.19 g (66%); mp 149–151 °C. IR (KBr): 3381, 3325, 3014, 2932, 2869, 1648, 1612, 1503 cm–1. 1H NMR (300.13 MHz, DMSO-d 6): δ = 0.84–1.67 (13 H, m, 5 CH2 of c-Hex and CH3), 1.89 (2 H, br s, CH 2CH3), 2.88 (1 H, br s, CH of c-Hex), 3.39 (2 H, br, ArCH2), 6.56 (1 H, br s, NH), 6.70 (1 H, br s, NH), 7.13–7.28 (4 H, m, CHAr), 8.20 (1 H, br, CONH2). 13C NMR (75.47 MHz, DMSO-d 6): δ = 15.6, 24.2, 25.0, 30.6, 40.7, 41.1, 49.7, 77.3, 117.2, 118.4, 127.4, 127.6, 129.3, 131.3, 150.1, 157.3, 164.5. Anal. Calcd for C17H25N3O: C, 71.04; H, 8.77; N, 14.62. Found: C, 71.21; H, 8.64; N, 14.70. (2E,2′E)-2,2′-[Ethane-1,2-diylbis(azan-1-yl-1-ylidene)]bis[2-(4-bromophenyl)-N-cyclohexylacetamide] (8) White powder; yield 0.50 g (78%); mp 202–204 °C. IR (KBr): 3244, 3071, 2093, 2853, 1623, 1553, 1448 cm–1. 1H NMR (300.13 MHz, DMSO-d 6): δ = 1.22–1.84 (20 H, m, 10 CH2 of c-Hex), 2.15–2.21 (4 H, m, 2 CH2), 3.10 (2 H, br s, 2 NH), 3.64–3.75 (2 H, m, 2 CH of c-Hex), 7.16–7.60 (10 H, m, CHAr), 7.74 (2 H, br, CONH). 13C NMR (75.47 MHz, DMSO-d 6): δ = 24.8, 25.5, 32.8, 46.1, 84.6, 125.6, 128.2, 128.4, 141.8, 172.9. MS: m/z = 646 (10) [M+ + 2], 644 (20) [M+], 642 (10) [M+ – 2], 604 (15), 518 (50), 478 (25), 392 (15), 351 (20), 335 (30), 321 (10), 266 (20), 210 (25), 184 (60), 102 (15), 83 (70), 55 (100). Anal. Calcd for C28H38N4, C, 78.10; H, 8.89; N, 13.01. Found: C, 78.01; H, 8.95; N, 13.05. (2E,2′E)-2,2′-[1,2-Phenylenebis(azan-1-yl-1-ylidene)]bis[2-(4-bromophenyl)-N-cyclohexylacetamide] (9) White powder; yield 0.49 g (71%); mp 162–163 °C. IR (KBr): 3338, 3297, 2933, 2878, 2854, 1644, 1514, 1485, 1455 cm–1. 1H NMR (300.13 MHz, DMSO-d 6): δ = 1.24–1.83 (20 H, m, 10 CH2 of c-Hex), 2.82 (4 H, br, 2 CH2), 3.64 (2 H, br s, 2 CH of c-Hex), 7.49–7.66 (8 H, m, CHAr), 7.72 (2 H, br, CONH). 13C NMR (75.47 MHz, DMSO-d 6): δ = 25.0, 25.5, 32.7, 46.6, 48.0, 84.5, 123.0, 128.8, 129.9, 131.0, 175.2. Anal. Calcd for C28H36Br2N4, C, 57.15; H, 6.17; Br, 27.16; N, 9.52. Found: C, 57.10; H, 6.09; N, 9.61.