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Synlett 2012; 23(17): 2521-2525
DOI: 10.1055/s-0032-1317297
letter
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Novel 1,4-Benzodiazepine-3,5-dione Derivatives: Reaction of 2-Aminobenzamides under Bargellini Reaction Conditions

Mohammad Mahdavi
a   Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran 14176, Iran   Fax: +98(21)66461178   Email: ashafiee@ams.ac.ir
,
Mehdi Asadi
b   School of Chemistry, University College of Science, University of Tehran, PO Box 14155-6455, Tehran, Iran
,
Mina Saeedi
a   Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran 14176, Iran   Fax: +98(21)66461178   Email: ashafiee@ams.ac.ir
,
Zahra Rezaei
a   Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran 14176, Iran   Fax: +98(21)66461178   Email: ashafiee@ams.ac.ir
,
Hooman Moghbel
b   School of Chemistry, University College of Science, University of Tehran, PO Box 14155-6455, Tehran, Iran
,
Alireza Foroumadi
a   Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran 14176, Iran   Fax: +98(21)66461178   Email: ashafiee@ams.ac.ir
,
Abbas Shafiee*
a   Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran 14176, Iran   Fax: +98(21)66461178   Email: ashafiee@ams.ac.ir
› Author Affiliations
Further Information

Publication History

Received: 15 July 2012

Accepted after revision: 23 August 2012

Publication Date:
21 September 2012 (online)

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Abstract

In this paper, we report on a user-friendly synthesis of 1,4-benzodiazepine-3,5-dione derivatives via Bargellini-type reaction. The corresponding products were obtained using various 2-aminobenzamides under Bargellini reaction conditions, in good yields without unfavorable side reaction.

Key words

Bargellini-type reaction - 1,4-benzodiazepine-3,5-di­ones - 2-aminobenzamides - heterocycles - dichloro epoxide

Supporting Information

    for this article is available online at http://www.thieme-connect.com/ejournals/toc/synlett.
  • Supporting Information
 

  • References and Notes

  • 1 Bargellini G. Gazz. Chim. Ital. 1906; 36: 329
    Search in Google Scholar
  • 2 Korger G. Chem. Ber. 1963; 96: 10
    CrossrefSearch in Google Scholar
  • 3 Corey EJ, Link JO. J. Am. Chem. Soc. 1992; 114: 1906
    CrossrefSearch in Google Scholar
  • 4 Butcher KJ, Hurst J. Tetrahedron Lett. 2009; 50: 2497
    CrossrefSearch in Google Scholar
  • 6 Recent synthetic application of Bargellini reaction: Snowden TS. ARKIVOC 2012; (ii): 24
    Search in Google Scholar
  • 7 Hosseini-Zare MS, Mahdavi M, Saeedi M, Asadi M, Javanshir S, Shafiee A, Foroumadi A. Tetrahedron Lett. 2012; 51: 3448
    Search in Google Scholar
  • 8 Tahghighi A, Razmi S, Mahdavi M, Foroumadi P, Ardestani SK, Emami S, Kobarfard F, Dastmalchi S, Shafiee A, Foroumadi A. Eur. J. Med. Chem. 2012; 50: 124
    CrossrefSearch in Google Scholar
  • 9 Hamadi H, Khoobi M, Hossaini Z, Shafiee A. Mol. Diversity 2011; 15: 35
    CrossrefSearch in Google Scholar
  • 10 Jamalian A, Miri R, Firuzi O, Amini M, Moosavi-Movahedi AA, Shafiee A. J. Iran. Chem. Soc. 2011; 8: 983
    CrossrefSearch in Google Scholar
  • 11 Akbarzadeh T, Fallah-Tafti A, Samadi N, Foroumadi A, Amanlou M, Faramarzi MA, Shafiee A. DARU 2010; 18: 118
    Search in Google Scholar
  • 12 Evans BE, Rittle KE, Bock MG, DiPardo RM, Freidinger RM, Whitter WL, Lundell GF, Veber DF, Anderson PS, Chang RS. L, Lotti VJ, Cerino DJ, Chen TB, Kling PJ, Kunkel KA, Springer JP, Hirshfield J. J. Med. Chem. 1988; 31: 2235
    CrossrefPubMedSearch in Google Scholar
  • 13 Chiu TRosenberg H. C. Trends Pharm. Sci. 1983; 4: 348
    CrossrefSearch in Google Scholar
  • 14 Sternbach LH. J. Med. Chem. 1979; 22: 1
    CrossrefPubMedSearch in Google Scholar
    • 15a Parks DJ, LaFrance LV, Calvo RR, Milkiewicz KL, Gupta V, Lattanze J, Ramachandren K, Carver TE, Petrella EC, Cummings MD, Maguire D, Grasberger BL, Lu T. Bioorg. Med. Chem. Lett. 2005; 15: 765
      CrossrefSearch in Google Scholar
    • 15b Cummings MD, Schubert C, Parks DJ, Calvo RR, LaFrance LV, Lattanze J, Milkiewicz KL, Lu T. Chem. Biol. Drug Des. 2006; 67: 201
      CrossrefSearch in Google Scholar
  • 16 Horton DA, Bourne GT. Chem. Rev. 2003; 103: 893
    CrossrefPubMedSearch in Google Scholar
  • 17 Hulme C, Peng J, Tang SY, Burns CJ, Morize I, Labaudiniere R. J. Org. Chem. 1998; 63: 8021
    CrossrefSearch in Google Scholar
  • 18 Keating TA, Armstrong RW. J. Org. Chem. 1996; 61: 8935
    CrossrefSearch in Google Scholar
  • 19 Kalinski C, Umkehrer M, Ross G, Kolb J, Burdacka C, Hiller W. Tetrahedron Lett. 2006; 47: 3423
    CrossrefSearch in Google Scholar
  • 20 Jadidi K, Ghahremanzadeh R, Asgari D, Eslami P, Arvin-Nezhad H. Monatsh. Chem. 2008; 139: 1229
    CrossrefSearch in Google Scholar
  • 21 Ciofi L, Trabocchi A, Lalli C, Menchi G, Guarna A. Org. Biomol. Chem. 2012; 10: 2780
    CrossrefSearch in Google Scholar
  • 22 Gärtner S. Justus Liebigs Ann. Chem. 1904; 332: 226
    CrossrefSearch in Google Scholar
  • 23 Wiklund P, Rogers-Evans M, Bergman J. J. Org. Chem. 2004; 69: 6371
    CrossrefSearch in Google Scholar
  • 24 Osman AN, El-Gendy AA, Omar RH, Wagdy L, Omar AH. Boll. Chim. Farm. 2002; 141: 8
    Search in Google Scholar
  • 25 Synthesis of 1,2-Dihydro-4H-benzo[e][1,4]diazepine-3,5-dione Derivatives – General Procedure A mixture of anhydrous acetone–ethyl methyl ketone (40 mmol, 3 mL) and CHCl3 (60 mmol, 4.6 mL) in the presence of NaOH powder (60 mmol, 2.3 g) was stirred at r.t. for 10 min (in the case of ethylmethyl ketone it should be stirred for 15 min). After this time, 2-aminobenzamide derivatives (2 mmol) were added to the reaction mixture and it continued for the corresponding time, as indicated in Table 1, at the same temperature. Upon completion of reaction the solution was extracted with CHCl3 (3 × 20 mL). The organic layer was separated, dried (Na2SO4), and concentrated in vacuo to yield the crude product which was purified by column chromatography eluting with PE–EtOAc (6:1). 1,2-Dihydro-2,2-dimethyl-4H-benzo[e][1,4]diazepine-3,5-dione (11a) Yield 0.17 g (85%); white crystals; mp 228–230 °C. IR (KBr): 3337 (NH), 1698 (C=O), 1636 (C=O) cm–1. 1H NMR (500 MHz, CDCl3): δ = 1.48 (s, 6 H, CH3), 4.11 (s, 1 H, NH), 6.78 (d, J = 7.6 Hz, 1 H, H9), 7.02 (t, J = 7.6 Hz, 1 H, H7), 7.40 (td, J = 7.6, 1.4 Hz, 1 H, H8), 8.20 (dd, J = 7.6, 1.4 Hz, 1 H, H6), 8.11 (s, 1 H, NH). 13C NMR (125 MHz, CDCl3): δ = 23.5, 56.5, 116.8, 118.6, 120.0, 131.8, 134.0, 146.8, 165.0, 173.6. Anal. Calcd for C11H12N2O2: C, 64.69; H, 5.92; N, 13.72. Found: C, 64.80; H, 6.10; N, 13.55. 2-Ethyl-1,2-dihydro-2-methyl-4H-benzo[e][1,4]diazepine-3,5-dione (11b) Yield 0.18 g (85%); white crystals; mp 160–162 °C. IR (KBr): 3359 (NH), 1698 (C=O), 1645 (C=O) cm–1. 1H NMR (500 MHz, CDCl3): δ = 0.87 (t, J = 7.4 Hz, 3 H, CH2CH3 ), 1.48 (s, 3 H, CH3), 1.75 (dq, J = 14.8, 7.4 Hz, 1 H, CH2 CH3), 1.80 (dq, J = 14.8, 7.4 Hz, 1 H, CH 2CH3), 4.16 (s, 1 H, NH), 6.79 (d, J = 7.5 Hz, 1 H, H9), 7.00 (t, J = 7.5 Hz, 1 H, H7), 7.40 (dt, J = 7.5, 1.3 Hz, 1 H, H8), 8.19 (dd, J = 7.5, 1.3 Hz, 1 H, H6), 8.21 (s, 1 H, NH). 13C NMR (125 MHz, CDCl3): δ = 7.5, 22.7, 27.9, 60.8, 120.3, 120.6, 133.1, 134.8, 145.5, 164.3, 173.8. Anal. Calcd for C12H14N2O2: C, 66.04; H, 6.47; N, 12.84. Found: C, 65.90; H, 6.55; N, 12.99. 4-Benzyl-1,2-dihydro-2,2-dimethyl-4H-benzo[e][1,4]-diazepine-3,5-dione (11c) Yield 0.23 g (80%); white crystals; mp 100–102 °C. IR (KBr): 3335 (NH), 1698 (C=O), 1650 (C=O) cm–1. 1H NMR (500 MHz, CDCl3): δ = 1.35 (s, 6 H, CH3), 5.03 (s, 2 H, NCH2), 6.80 (s, 1 H, NH), 6.99–7.05 (m, 2 H, H9, H4′), 7.17–7.19 (m, 3 H, H7, H2′, H6′), 7.27–7.37 (m, 3 H, H8, H3′, H5′), 7.98 (d, J = 7.2 Hz, 1 H, H6). 13C NMR (125 MHz, CDCl3): δ = 23.3, 48.5, 56.5, 116.4, 117.9, 119.1, 126.7, 126.9, 128.2, 132.2, 133.9, 138.2, 145.8, 167.6, 176.4. Anal. Calcd for C18H18N2O2: C, 73.45; H, 6.16; N, 9.52. Found: C, 73.30; H, 6.40; N, 10.21. 4-Benzyl-2-ethyl-1,2-dihydro-2-methyl-4H-benzo[e]-[1,4]diazepine-3,5-dione (11d) Yield 0.23 g (75%); white crystals; mp 134–136 °C. IR (KBr): 3467 (NH), 1695 (C=O), 1641 (C=O) cm–1. 1H NMR (500 MHz, CDCl3): δ = 0.78 (t, J = 7.4 Hz, 3 H, CH2CH 3), 1.46 (s, 3 H, CH3), 1.77–1.83 (m, 2 H, CH 2CH3), 4.53 (s, 1 H, NH), 5.13 (d, J = 15.7 Hz, 1 H, NCH2), 5.31 (d, J = 15.7 Hz, 1 H, NCH2), 6.77 (d, J = 8.1 Hz, 1 H, H9), 6.89 (t, J = 7.5 Hz, 1 H, H7), 6.98–7.00 (m, 1 H, H4′), 7.06–7.11 (m, 2 H, H2′, H6′), 7.29–7.39 (m, 3 H, H8, H3′, H5′), 8.11 (d, J = 7.5 Hz, 1 H, H6). 13C NMR (125 MHz, CDCl3): δ = 8.4, 20.3, 28.3, 47.1, 61.2, 118.1, 119.0, 119.6, 126.5, 126.8, 127.7, 129.2, 132.6, 133.2, 134.2, 134.9, 144.7, 167.5, 173.7. Anal. Calcd for C19H20N2O2: C, 74.00; H, 6.54; N, 9.08. Found: C, 73.80; H, 6.35; N, 9.30. 4-(2-Chlorobenzyl)-1,2-dihydro-2,2-dimethyl-4H-benzo[e][1,4]diazepine-3,5-dione (11e) Yield 0.27 g (82%); yellow crystals; mp 130–132 °C. IR (KBr): 3338 (NH), 1697 (C=O), 1622 (C=O) cm–1. 1H NMR (500 MHz, CDCl3): δ = 1.51 (s, 6 H, CH3), 4.37 (s, 1 H, NH), 5.26 (s, 2 H, NCH2), 6.76 (dd, J = 8.2, 1.0 Hz, 1 H, H9), 6.95 (ddd, J = 8.2, 6.5, 1.1 Hz, 1 H, H4′), 7.05 (t, J = 7.0 Hz, 1 H, H7), 7.14–7.17 (m, 2 H, H5′, H6′), 7.34 (dd, J = 6.5, 3.0 Hz, 1 H, H3′), 7.38 (ddd, J = 8.2, 7.0, 1.5 Hz, 1 H, H8), 8.20 (dd, J = 7.0, 1.5 Hz, 1 H, H6). 13C NMR (125 MHz, CDCl3): δ = 24.7, 47.3, 58.0, 118.4, 119.1, 119.9, 126.6, 127.0, 127.9, 129.4, 132.9, 133.5, 134.3, 135.1, 144.8, 167.6, 173.5. MS: m/z (%) = 330 (17) [M + 2]+, 328 (51) [M+], 300 (20), 203 (25), 160 (100). 132 (85), 92 (28), 65 (20). Anal. Calcd for C18H17ClN2O2: C, 65.75; H, 5.21; N, 8.52. Found: C, 65.90; H, 5.45; N, 8.40. 4-(2-Chlorobenzyl)-2-ethyl-1,2-dihydro-2-methyl-4H-benzo[e][1,4]diazepine-3,5-dione (11f) Yield 0.26 g (75%); yellow crystals; mp 134–136 °C. IR (KBr): 3350 (NH) 1697 (C=O), 1623 (C=O) cm–1. 1H NMR (500 MHz, CDCl3): δ = 0.81 (t, J = 7.4 Hz, 3 H, CH2CH 3), 1.49 (s, 3 H, CH3), 1.80 (dq, J = 14.8, 7.4 Hz, 1 H, CH 2CH3), 1.87 (dq, J = 14.8, 7.4 Hz, 1 H, CH 2CH3), 4.50 (s, 1 H, NH), 5.19 (d, J = 15.7 Hz, 1 H, NCH2), 5.36 (d, J = 15.7 Hz, 1 H, NCH2), 6.77 (d, J = 8.0 Hz, 1 H, H9), 6.92 (t, J = 7.5 Hz, 1 H, H4′), 7.05 (t, J = 8.2 Hz, 1 H, H7), 7.12–7.18 (m, 2 H, H5′, H6′), 7.32–7.39 (m, 2 H, H8, H3′), 8.16 (d, J = 8.2 Hz, 1 H, H6). 13C NMR (125 MHz, CDCl3): δ = 7.5, 27.2, 47.2, 61.3, 119.1, 119.7, 126.6, 127.1, 127.8, 128.6, 129.0, 129.3, 132.8, 133.3, 134.2, 144.7, 167.5, 173.7. Anal. Calcd for C19H19ClN2O2: C, 66.57; H, 5.59; N, 8.17. Found: C, 66.80; H, 5.40; N, 7.95. 4-(4-Methoxybenzyl)-1,2-dihydro-2,2-dimethyl-4H-benzo[e][1,4]diazepine-3,5-dione (11g) Yield 0.24 g (75%); white crystals; mp 120–122 °C. IR (KBr): 3329 (NH), 1694 (C=O), 1609 (C=O) cm–1. 1H NMR (500 MHz, CDCl3): δ = 1.43 (s, 6 H, CH3), 3.77 (s, 3 H, OCH3), 4.42 (s, 1 H, NH), 5.12 (s, 2 H, NCH2), 6.70 (d, J = 8.1 Hz, 1 H, H9), 6.82 (d, J = 8.5 Hz, 2 H, H3′, H5′), 6.91 (t, J = 7.6 Hz, 1 H, H7), 7.31–7.34 (m, 3 H, H8, H2′, H6′), 8.20 (dd, J = 7.6, 1.4 Hz, 1 H, H6). 13C NMR (125 MHz, CDCl3): δ = 24.4, 48.7, 55.1, 57.7, 113.6, 114.1, 118.4, 118.8, 119.4, 129.4, 130.2, 133.4, 134.0, 144.5, 158.5, 167.8, 173.0. Anal. Calcd for C19H20N2O3: C, 70.35; H, 6.21; N, 8.64. Found: C, 70.50; H, 6.44; N, 8.80. 4-(4-Methoxybenzyl)-2-ethyl-1,2-dihydro-2-methyl-4H-benzo[e][1,4]diazepine-3,5-dione (11h) Yield 0.24 g (70%); white crystals; mp 110–111 °C. IR (KBr): 3320 (NH), 1698 (C=O), 1617 (C=O) cm–1. 1H NMR (500 MHz, CDCl3): δ = 0.71 (t, J = 7.4 Hz, 3 H, CH2CH 3), 1.47 (s, 3 H, CH3), 1.67 (dq, J = 14.8, 7.4 Hz, 1 H, CH 2CH3), 1.76 (dq, J = 14.8, 7.4 Hz, 1 H, CH 2CH3), 3.76 (s, 3 H, OCH3), 4.43 (s, 1 H, NH), 5.09 (d, J = 14.0 Hz, 1 H, NCH2), 5.15 (d, J = 14.0 Hz, 1 H, NCH2), 6.71 (d, J = 7.3 Hz, 1 H, H9), 6.81 (d, J = 8.6 Hz, 2 H, H3′, H5′), 6.90 (t, J = 7.3 Hz, 1 H, H7), 7.32 (dt, J = 7.3, 1.5 Hz, 1 H, H8), 7.36 (d, J = 8.6 Hz, 2 H, H2′, H6′), 8.19 (dd, J = 7.3, 1.5 Hz, 1 H, H6). 13C NMR (125 MHz, CDCl3): δ = 7.4, 23.1, 26.9, 48.7, 55.1, 60.9, 113.5, 118.3, 118.8, 119.3, 129.8, 130.2, 133.2, 134.0, 144.3, 158.5, 167.7, 173.1. MS: m/z (%) = 338 (76 [M+], 281 (20), 217 (20), 174 (59), 146 (52), 121 (100), 77 (25). Anal. Calcd for C20H22N2O3: C, 70.99; H, 6.55; N, 8.28. Found: C, 71.15; H, 6.80; N, 8.35. 4-[(Furan-2-yl)-methyl]-1,2-dihydro-2,2-dimethyl-4H-benzo[e][1,4]diazepine-3,5-dione (11i) Yield 0.18 g (65%); white crystals; mp 103–105 °C. IR (KBr): 3366 (NH), 1695 (C=O), 1625 (C=O) cm–1. 1H NMR (500 MHz, CDCl3): δ = 1.45 (s, 6 H, CH3), 4.37 (s, 1 H, NH), 5.17 (s, 2 H, NCH2), 6.28–6.29 (m, 2 H, furan), 6.71 (dd, J = 7.6, 0.9 Hz, 1 H, H9), 6.92 (dt, J = 7.6, 0.9 Hz, 1 H, H7), 7.30 (dd, J = 3.0, 1.0 Hz, 1 H, furan), 7.34 (dt, J = 7.6, 1.4 Hz, 1 H, H8), 8.21 (dd, J = 7.6, 1.4 Hz, 1 H, H6). 13C NMR (125 MHz, CDCl3): δ = 24.5, 42.1, 57.8, 108.1, 110.2, 118.2, 118.9, 119.6, 133.5, 134.1, 141.6, 144.6, 151.4, 167.2, 173.2. MS: m/z (%) = 284 (35) [M+], 257 (15), 241 (20), 203 (20), 160 (100), 132 (90), 96 (71), 53 (28). Anal. Calcd for C16H16N2O3: C, 67.59; H, 5.67; N, 9.85. Found: C, 67.66; H, 5.86; N, 10.00. 2-Ethyl-4-[(furan-2-yl)-methyl]-1,2-dihydro-2-methyl-4H-benzo[e][1,4]diazepine-3,5-dione (11j) Yield 0.18 g (60%); white crystals; mp 102–104 °C. IR (KBr): 3336 (NH), 1697 (C=O), 1621 (C=O) cm–1. 1H NMR (500 MHz, CDCl3): δ = 0.73 (t, J = 7.4 Hz, 3 H, CH2CH 3), 1.49 (s, 3 H, CH3), 1.66 (dq, J = 14.8, 7.4 Hz, 1 H, CH 2CH3), 1.80 (dq, J = 14.8, 7.4 Hz, 1 H, CH 2CH3), 4.37 (s, 1 H, NH), 5.09 (d, J = 14.7 Hz, 1 H, NCH2), 5.23 (d, J = 14.7 Hz, 1 H, NCH2), 6.28–6.31 (m, 2 H, furan), 6.72 (d, J = 8.0 Hz, 1 H, H9), 6.91 (t, J = 7.7 Hz, 1 H, H7), 7.31–7.35 (m, 2 H, H8, furan), 8.20 (d, J = 7.7 Hz, 1 H, H6). 13C NMR (125 MHz, CDCl3): δ = 7.3, 23.2, 26.9, 42.1, 61.1, 108.5, 110.2, 118.1, 118.9, 119.5, 133.3, 134.1, 141.5, 144.4, 151.4, 167.1, 173.1. MS: m/z (%) = 298 (65) [M+], 271 (14), 241 (42), 217 (26), 174 (97), 146 (75), 81 (100), 53 (45). Anal. Calcd for C17H18N2O3: C, 68.44; H, 6.08; N, 9.39. Found: C, 68.25; H, 5.90; N, 9.15. 4-(3,5-Dimethoxyphenethyl)-1,2-dihydro-2,2-dimethyl-4H-benzo[e][1,4]diazepine-3,5-dione (11k) Yield 0.26 g (70%); white crystals; mp 125–127 °C. IR (KBr): 3367 (NH), 1687 (C=O), 1634 (C=O) cm–1. 1H NMR (500 MHz, CDCl3): δ = 1.26 (s, 6 H, CH3), 2.88 (t, J = 7.8 Hz, 2 H, NCH2CH 2), 3.85 (s, 6 H, OCH3), 4.13 (t, J = 7.8 Hz, 2 H, NCH 2CH2), 4.45 (s, 1 H, NH), 6.72–6.80 (m, 4 H, H9, H2′, H4′, H6′), 6.90 (t, J = 7.5 Hz, 1 H, H7), 7.32 (t, J = 7.5 Hz, 1 H, H8), 8.12 (d, J = 7.5 Hz, 1 H, H6). 13C NMR (125 MHz, CDCl3): δ = 24.5, 34.9, 48.2, 55.7, 55.8, 57.8, 111.1, 112.1, 118.8, 119.5, 120.7, 132.4, 133.1, 134.0, 144.4, 147.4, 148.6, 168.1, 173.2. Anal. Calcd for C21H24N2O4: C, 68.46; H, 6.57; N, 7.60. Found: C, 68.15; H, 6.30; N, 7.77.