Download PDF
Synlett 2011(6): 834-836  
DOI: 10.1055/s-0030-1259909
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Solvent-Free Reaction between Anthranilic Acids and Isocyanides: A Novel Approach for the Synthesis of 2-Unsubstituted 4(3H)-Quinazolinones

Mehdi Adib*a, Morteza Karimzadeha, Mohammad Mahdavia, Ehsan Sheikhia, Peiman Mirzaeib
a School of Chemistry, University College of Science, University of Tehran, PO Box 14155-6455, Tehran, Iran
Fax: +98(21)66495291; e-Mail: madib@khayam.ut.ac.ir;
b Department of Chemistry, Shahid Beheshti University, Tehran, Iran
Further Information

Publication History

Received 5 October 2010
Publication Date:
15 March 2011 (online)

    Permissions and Reprints All articles of this category

Abstract

A novel synthesis of 2-unsubstituted 4(3H)-quinazolinones is described. Heating a mixture of an anthranilic acid and an isocyanide under solvent-free conditions afforded the title compounds in good to excellent yields.

Key words

anthranilic acids - isocyanides - 2-unsubstituted 4(3H)-quinazolinones - solvent-free synthesis - cyclizations - heterocycles

    References and Notes

  • 1a Rewcastle GW. In Comprehensive Heterocyclic Chemistry III   Vol. 8:  Katritzky AR. Ramsden CA. Scriven EFV. Taylor RJK. Elsevier Science; Oxford: 2008.  Chapt. 2. p.117-252  
    Google Scholar
  • 1b Undheim K. Benneche T. In Comprehensive Heterocyclic Chemistry II   Vol. 6:  Katritzky AR. Rees CW. Scriven EVF. Pergamon Press; London: 1996.  Chapt. 2. p.93-231  
    Google Scholar
  • 2 Armarego WLF. Fused Pyrimidines, Part 1: Quinazolines   Interscience; New York: 1967. 
    Google Scholar
  • 3 Cao S.-L. Feng Y.-P. Jiang Y.-Y. Liu S.-Y. Ding G.-Y. Li R.-T. Bioorg. Med. Chem. Lett.  2005,  15:  1915 
    CrossrefGoogle Scholar
  • 4 Kenichi O. Yoshihisa Y. Toyonari O. Toru I. Yoshio I. J. Med. Chem.  1985,  28:  568 
    CrossrefGoogle Scholar
  • 5 Wolfe JF. Rathman TL. Sleevi MC. Campbell JA. Greenwood TD. J. Med. Chem.  1990,  33:  161 
    CrossrefGoogle Scholar
  • 6 Tereshima K. Shimamura H. Kawase A. Tanaka Y. Tanimura T. Kamisaki T. Ishizuka Y. Sato M. Chem. Pharm. Bull.  1995,  43:  2021 
    CrossrefGoogle Scholar
  • 7 Kurogi Y. Inoue Y. Tsutsumi K. Nakamura S. Nagao K. Yohsitsugu H. Tsuda Y. J. Med. Chem.  1996,  39:  1433 
    CrossrefGoogle Scholar
  • 8 Kuneš J. Ba˛ant J. Pour M. Waisser K. Šlosárek M. Janota J. Farmaco  2000,  55:  725 
    CrossrefGoogle Scholar
  • 9a Jang CS. Fu FY. Wang CY. Huang KC. Lu G. Thou TC. Science  1946,  103:  59 
    Google Scholar
  • 9b Koepfli JB. Mead JF. Brockman JA. J. Am. Chem. Soc.  1947,  69:  1837 
    Google Scholar
  • 10 Kobayashi S. Ueno M. Suzuki R. Ishitani H. Tetrahedron Lett.  1999,  40:  2175 
    CrossrefGoogle Scholar
  • 11a Bridges AJ. Chem. Rev.  2001,  101:  2541 
    Google Scholar
  • 11b Rewcastle GW. Denny WA. Showalter HDH. Curr. Org. Chem.  2000,  4:  679 
    Google Scholar
  • 11c Bridges AJ. Curr. Med. Chem.  1999,  6:  825 
    Google Scholar
  • 12 Niementowski SV. J. Prakt. Chem.  1895,  51:  564 
    Google Scholar
  • 13a Ballard P. Bradbury RH. Harris CS. Hennequin LFA. Hickinson M. Johnson PD. Kettle JG. Klinowska T. Leach AG. Morgentin R. Pass M. Ogilvie DJ. Olivier A. Warin N. Williams EJ. Bioorg. Med. Chem. Lett.  2006,  16:  1633 
    Google Scholar
  • 13b Gomtsyan A. Bayburt EK. Schmidt RG. Zheng GZ. Perner RJ. Didomenico S. Koenig JR. Turner S. Jinkerson T. Drizin I. Hannick SM. Macri BS. McDonald HA. Honore P. Wismer CT. Marsh KC. Wetter J. Stewart KD. Oie T. Jarvis MF. Surowy CS. Faltynek CR. Lee CH. J. Med. Chem.  2005,  48:  744 
    Google Scholar
  • 13c Rocco SA. Barbarini JE. Rittner R. Synthesis  2004,  429 
    Google Scholar
  • 14a Alexandre FR. Berecibar A. Wrigglesworth R. Besson T. Tetrahedron Lett.  2003,  44:  4455 
    Google Scholar
  • 14b Alexandre FR. Berecibar A. Besson T. Tetrahedron Lett.  2002,  43:  3911 
    Google Scholar
  • 15 Majo VJ. Perumal PT. Tetrahedron Lett.  1996,  37:  5015 
    CrossrefGoogle Scholar
  • 16 Kamal A. Reddy KS. Prasad BR. Babu AH. Ramana AV. Tetrahedron Lett.  2004,  45:  6517 
    CrossrefGoogle Scholar
  • 17 Narasimhulu M. Mahesh KC. Reddy TS. Rajesh K. Venkateswarlu Y. Tetrahedron Lett.  2006,  47:  4381 
    CrossrefGoogle Scholar
  • 18 Khosropour AR. Mohammadpoor-Baltork I. Ghorbankhani H. Tetrahedron Lett.  2006,  47:  3561 
    CrossrefGoogle Scholar
  • 19 Chari MA. Shobha D. Mukkanti K. Catal. Commun.  2006,  7:  787 
    CrossrefGoogle Scholar
  • 20a Shaabani A. Soleimani E. Rezayan AH. Tetrahedron Lett.  2007,  48:  6137 
    Google Scholar
  • 20b Stockdill JL. Wu X. Danishefsky SJ. Tetrahedron Lett.  2009,  50:  5152 
    Google Scholar
  • 21 Shaabani A. Rezayan AH. Sarvary A. Keshipour S. Khavasi HR. Tetrahedron Lett.  2010,  51:  4091 
    CrossrefGoogle Scholar
  • 22 Wu X. Li X. Danishefsky SJ. Tetrahedron Lett.  2009,  50:  1523 
    CrossrefGoogle Scholar
  • 23 Basso A. Banfi L. Galatini A. Guanti G. Rastrelli F. Riva R. Org. Lett.  2009,  11:  4068 
    CrossrefGoogle Scholar
  • 24a Li X. Yuan Y. Berkowitz WF. Todaro LJ. Danishefsky SJ. J. Am. Chem. Soc.  2008,  130:  13222 
    Google Scholar
  • 24b Hou JL. Ajami D. Rebek J. J. Am. Chem. Soc.  2008,  130:  7810 
    Google Scholar
  • 24c Restorp P. Rebek J. J. Am. Chem. Soc.  2008,  130:  11850 
    Google Scholar
  • 25 Marmet D. Boullanger P. Descotes G. Tetrahedron Lett.  1980,  21:  1459 
    CrossrefGoogle Scholar
  • 26a Adib M. Ansari S. Feizi S. Bijanzadeh HR. Synlett  2010,  921 
    Google Scholar
  • 26b Adib M. Ansari S. Fatemi S. Bijanzadeh HR. Zhu LG. Tetrahedron  2010,  66:  2723 
    Google Scholar
  • 26c Adib M. Ansari S. Feizi S. Asgarian Damavandi J. Mirzaei P. Synlett  2009,  3263 
    Google Scholar
  • 26d Adib M. Mahdavi M. Ansari S. Malihi F. Zhu LG. Bijanzadeh HR. Tetrahedron Lett.  2009,  50:  7246 
    Google Scholar
  • 26e Adib M. Sheibani E. Bijanzadeh HR. Zhu LG. Tetrahedron  2008,  64:  10681 
    Google Scholar
  • 26f Adib M. Sayahi MH. Ziyadi H. Zhu LG. Bijanzadeh HR. Synthesis  2008,  3289 
    Google Scholar
  • 26g Adib M. Mohammadi B. Bijanzadeh HR. Synlett  2008,  3180 
    Google Scholar
  • 26h Adib M. Mohammadi B. Bijanzadeh HR. Synlett  2008,  177 
    Google Scholar
  • 26i Adib M. Sayahi MH. Ziyadi H. Bijanzadeh HR. Zhu LG. Tetrahedron  2007,  63:  11135 
    Google Scholar
  • 27 Adib M. Ansari S. Mohammadi A. Bijanzadeh HR. Tetrahedron Lett.  2010,  51:  30 
    CrossrefGoogle Scholar
  • 29a Dömling A. Chem. Rev.  2006,  106:  17 
    Google Scholar
  • 29b Dömling A. Ugi I. Angew. Chem. Int. Ed.  2000,  39:  3169 
    Google Scholar
  • 29c Ugi I. Isonitrile Chemistry   Academic Press; London: 1971. 
    Google Scholar
  • 29d Walborsky HM. Periasamy MP. In The Chemistry of Functional Groups   Suppl. C:  Patai S. Rappaport Z. Wiley; New York: 1983.  Chapt. 20. p.835-837  
    Google Scholar
28

General Procedure for the Preparation of Compounds 3a-l
A mixture of the appropriate anthranilic acid (2 mmol) and isocyanide (2.2 mmol) was stirred at 150 ˚C for 2 h. Progress of the reaction was indicated by TLC monitoring. Next, the reaction mixture was cooled to r.t. and acetone (2 mL) was added, and stirring was continued for 10 min at ambient temperature. The precipitate was filtered and washed with cold acetone (2 mL), and the product was recrystallized from n-hexane-EtOAc (1:1). Compounds 3a-i were purified by this procedure, and compounds 3j-l were purified by column chromatography using n-hexane-EtOAc (3:1) as eluent.
3-Cyclohexyl-4(3 H )-quinazolinone (3a)
Yield 0.41g (90%); colorless crystals; mp 126-127 ˚C. IR (KBr): 1659 (C=O), 1596, 1564, 1468, 1399, 1334, 1240, 1172, 1132, 1024, 956, 894, 805, 766, 695 cm-¹. ¹H NMR (300.1 MHz, CDCl3): δ = 1.20-2.04 [m, 10 H, CH(CH 2)5], 4.77-4.86 [m, 1 H, CH(CH2)5], 7.49 (dd, J = 7.2, 7.4 Hz, 1 H, CH), 7.68 (d, J = 7.6 Hz, 1 H, CH), 7.74 (dd, J = 7.0, 7.9 Hz, 1 H, CH), 8.12 (s, 1 H, CH), 8.31 (d, J = 8.0 Hz, 1 H, CH). ¹³C NMR (75.5 MHz, CDCl3): δ = 25.27, 25.89 and 32.60 (3 × CH2), 53.54 (NCH), 121.93 (C), 126.95, 127.10, 127.24, 134.10 and 143.91 (5 × CH), 147.50 (C), 160.70 (C=O). MS (EI): m/z (%) = 228 (24) [M+], 192 (7), 181 (5), 171 (4), 160 (7), 147 (100), 129 (8), 118 (10), 102 (5), 90 (7), 77 (9), 67 (14), 55 (16), 41 (22). Anal. Calcd for C14H16N2O (228.29): C, 73.66; H, 7.06; N, 12.27. Found: C, 73.6; H, 7.2; N, 12.1.
6-Chloro-3-cyclohexyl-4(3 H )-quinazolinone (3j)
Yield 0.43 g (82%); colorless crystals; mp 137-138 ˚C.
IR (KBr): 1668 (C=O), 1597, 1552, 1465, 1388, 1358, 1320, 1240, 1137, 1072, 1022, 947, 895, 822, 775 cm-¹. ¹H NMR (300.1 MHz, CDCl3): δ = 1.25-1.97 [m, 10 H, CH(CH 2)5], 4.76-4.84 [m, 1 H, CH(CH2)5], 7.60 (d, J = 8.8 Hz, 1 H, CH), 7.63 (dd, J = 2.1, 8.8 Hz, 1 H, CH), 8.11 (d, J = 2.1 Hz, 1 H, CH), 8.26 (s, 1 H, CH). ¹³C NMR (75.5 MHz, CDCl3): δ = 25.22, 25.28, and 32.56 (3 × CH2), 53.59 (NCH), 122.97 (C), 126.30 and 128.95 (2 × CH), 132.88 (C), 134.52 and 144.08 (2 × CH), 146.02 (C), 159.68 (C=O). MS (EI): m/z (%) = 264 (8) [M+ ³7Cl], 262 (22) [M+ ³5Cl], 228 (5), 205 (3), 181 (100), 163 (4), 147 (18), 136 (7), 124 (5), 110 (5), 97 (4), 82 (9), 67 (20), 55 (18), 41 (23). Anal. Calcd for C14H15ClN2O (262.74): C, 64.00; H, 5.75; N, 10.66. Found: C, 63.9; H, 5.7; N, 10.6.
6-Chloro-3-(1,1,3,3-tetramethylbutyl)-4(3 H )-quinazolinone (3l)
Yield 0.44 g (76%); colorless crystals; mp 118-119 ˚C.
IR (KBr): 1662 (C=O), 1592, 1560, 1467, 1362, 1324, 1285, 1219, 1128, 1075, 918, 835, 805, 754, 712 cm-¹. ¹H NMR (500.1 MHz, CDCl3): δ = 0.81 [s, 9 H, C(CH3)3], 1.75 [s, 6 H, C(CH3)2], 2.22 (s, 2 H, CH2), 7.56 (d, J = 8.9 Hz, 1 H, CH), 7.60 (dd, J = 2.2, 8.9 Hz, 1 H, CH), 8.20 (d, J = 2.2 Hz, 1 H, CH), 8.26 (s, 1 H, CH). ¹³C NMR (125.8 MHz, CDCl3): δ = 30.00 [C(CH3)2], 31.24 [C(CH3)3], 31.93 [C(CH3)3], 48.88 (CH2), 64.76 [C(CH3)2], 124.13 (C), 126.23 and 128.55 (2 × CH), 132.66 (C), 134.34 and 144.84 (2 × CH), 145.85 (C), 161.41 (C=O). MS (EI): m/z (%) = 294 (1) [M+ ³7Cl], 292 (3) [M+ ³5Cl], 235 (8), 180 (100), 163 (9), 153 (8), 138 (7), 124 (6), 112 (26), 97 (68), 69 (10), 57 (54), 41 (31). Anal. Calcd for C16H21ClN2O (292.81): C, 65.63; H, 7.23; N, 9.57. Found: C, 65.7; H, 7.4; N, 9.4.