Download PDF
Synlett 2002(1): 0155-0157
DOI: 10.1055/s-2002-19342
LETTER
© Georg Thieme Verlag Stuttgart · New York

A New and Efficient One-pot Synthesis of Pyrido[2,1-f]purine-2,4-diones Starting from 6-Aminouracil Derivatives

María-Jesús Pérez-Pérez*, Eva-María Priego, María-Luisa Jimeno, María-José Camarasa
Instituto de Química Médica (C.S.I.C.), Juan de la Cierva 3, 28006 Madrid, Spain
Fax: +34(91)5644853; e-Mail: mjperez@iqm.csic.es;
Further Information

Publication History

Received 22 October 2001
Publication Date:
01 February 2007 (online)

    Permissions and Reprints All articles of this category

Abstract

A convenient synthesis of pyrido[2,1-f]purine-2,4-diones is described by reaction of 6-aminouracil derivatives with N-bromosuccinimide (NBS) followed by in situ reaction with pyridine or 4-substituted pyridines. A detailed study of the reaction conditions has been performed and a mechanism involving a 5,5-dibromo derivative is proposed.

Key words

heterocycles - tricyclic compounds - pyridines - halogenation - N-bromosuccinimide

    References

  • 1 Cole C. Foster AJ. Freeman S. Jaffar M. Murray P. Stratford IJ. Anti-Cancer Drug Des.  1999,  14:  383 , and references cited therein
    Google Scholar
  • 2 Balzarini J. Esteban-Gamboa A. Esnouf R. Liekens S. Neyts J. De Clercq E. Camarasa MJ. Pérez-Pérez MJ. FEBS Lett.  1998,  438:  91 
    CrossrefGoogle Scholar
  • 3 Hutzenlaub W. Pfleiderer W. Liebigs Ann. Chem.  1979,  1847 
    Google Scholar
  • 4 Müller CE. Geis U. Hipp J. Schobert U. Frobenius W. Pawloski M. Suzuki F. Sandoval-Ramírez J. J. Med. Chem.  1997,  40:  4396 
    CrossrefGoogle Scholar
  • 5 Jacobson KA. In Comprehensive Medicinal Chemistry   Vol. 3:  Emmet JC. Pergamon Press; Oxford: 1990.  p.625 
    Google Scholar
  • 6 Rybar A. Hesek D. Szemes F. Alföldi J. Tegza M. Collect. Czech. Chem. Commun.  1990,  55:  2257 
    Google Scholar
  • 7 Esteban-Gamboa A. Balzarini J. Esnouf R. De Clercq E. Camarasa MJ. Pérez-Pérez MJ. J. Med. Chem.  2000,  43:  971 
    CrossrefPubMedGoogle Scholar
  • 9
  • 10 Gatta F. Del Giudice MR. Borioni A. Mustazza C. J. Heterocycl. Chem.  1994,  31:  81 
    CrossrefGoogle Scholar
  • 11 Priego EM. Camarasa MJ. Pérez-Pérez MJ. Synthesis  2001,  478 
    Article in Thieme ConnectGoogle Scholar
  • 15 The dibromination of 6-amino-1-methyluracil has been proposed in the synthesis of pyrimidin-5-yl sulphides and disulphides: Barker GR. Luthy NG. J. Chem. Soc.  1956,  917 
    Google Scholar
  • 16 Taylor EC. Paudler WW. Cain CK. J. Org. Chem.  1955,  20:  264 
    Google Scholar
  • 17a Peichl E. Kappe T. Arch. Pharm.  1984,  317:  946 
    Google Scholar
  • 17b Kappe T. Khorchid-Zadeh R. Steininger H. Z. Naturforsch.  1975,  30b:  773 
    Google Scholar
  • 19 Scriven EFV. In Comprehensive Heterocyclic Chemistry   Vol. 2:  Katritzky AR. Rees CW. Pergamon; Oxford: 1984.  p.166 
    Google Scholar
8

Selected data of 3: Mp (CH2Cl2-MeOH): 298-299 °C. MS (EI): m/z = 292 [M+]. 1H NMR (DMSO-d6): δ 5.22 (s, 2 H, CH2Ph), 7.10-7.50 (m, 6 H, H-7, Ph), 7.66 (m, J = 7.1, 1.2 Hz, H-8), 7.75 (d, J = 9.1 Hz, 1 H, H-9), 8.94 (d, J = 6.6 Hz, H-6), 11.35 (br s, 1 H, NH). 13C NMR (DMSO-d6): δ 44.92 (CH2Ph), 101.95 (C-4a), 114.51 (C-7), 116.08 (C-9), 127.11, 127.20, 128.32, 136.71 (C-6, Ph), 130.34 (C-8), 147.08 (C-9a), 150.85 (C-10a), 151.60 (C-2), 154.53 (C-4). Anal. Calcd for C16H12N4O2: C, 65.75; H, 4.14; N, 19.17; found: C, 65.47; H, 4.50; N, 19.35.

12

Selected data of 5: MS (ES, positive mode): m/z = 360, [M + Na+], showing the Br isotopic pattern. 1H NMR (CDCl3): δ 0.97 (t, 3 H, CH 3 CH2), 1.72 (m, 2 H, CH3CH 2 ), 4.00 (m, 2 H, NCH2), 4.97 (br s, 2 H, NH2), 5.28 (s, 2 H, CH2Ph), 7.26-7.43 (m, 5 H, Ph). 13C NMR (CDCl3): δ 11.32 (CH3CH2), 21.11 (CH3 CH2), 44.40 (NCH2), 47.78 (CH2Ph), 73.25 (C-5), 150.40, 150.93 (C-2, C-6), 158.52 (C-4).

13

Selected data of 6: Mp (CH2Cl2-MeOH): 163-165 °C. MS (EI): m/z = 334 [M+]. 1H NMR (CDCl3): δ 0.95 (t, J = 7.5 Hz, 3 H, CH3), 1.69 (m, J = 7.5 Hz, 2 H, CH 2 CH3), 4.01 (pt, J = 7.3 Hz, 2 H, NCH2), 5.37 (s, 2 H, CH2Ph), 7.06 (pt, J = 6.1 Hz, H-7), 7.25-7.52 (m, 5 H, Ph), 7.52 (pt, J = 7.0 Hz, H-8), 7.65 (d, J = 7.0 Hz, 1 H, H-9), 9.04 (d, J = 6.7 Hz, 1 H, H-6). 13C NMR (CDCl3): δ 11.32 (CH3CH2), 21.38 (CH3 CH2), 42.83 (NCH2), 46.67 (CH2Ph), 101.90 (C-4a), 113.90 (C-7), 116.41 (C-9), 127.48 (C-6), 129.87 (C-8), 147.63 (C-9a), 150.69 (C-10a), 151.39 (C-2), 155.01 (C-4). Anal. Calcd for C19H18N4O2: C, 68.25; H, 5.43; N, 19.76; found: C, 68.19; H, 5.12; N, 19.40.

14

Selected data of 7: MS (ES, positive mode): m/z = 416 [M + 1]+, showing the isotopic 2 Br pattern. 1H NMR (CDCl3): δ 0.97 (t, 3 H, CH 3 CH2), 1.67 (m, 2 H, CH3CH 2 ), 3.90 (m, 2 H, NCH2), 5.31 (s, 2 H, CH2Ph), 7.28-7.49 (m, 5 H, Ph), 9.59 (br s, 1 H, NH). 13C NMR (CDCl3): δ 10.94 (CH3CH2), 20.68 (CH3 CH2), 45.38 (NCH2), 48.40 (CH2Ph), 50.58 (C-5), 149.14 (C-2), 156.52 (C-6), 161.05 (C-4).

18

General Experimental Procedure: Synthesis of 3, 9 and 10. N-Bromosuccinimide (NBS) (445 mg, 2.5 mmol) was added into a suspension of 6-amino-1-benzyluracil 1 (217 mg, 1.0 mmol) in dry CH3CN (8 mL) and the mixture was heated at 80 ºC for 1 h till all starting material was transformed into the 5,5-dibromoderivative 8. After cooling to r.t., the corresponding pyridine (5-10 mmol) was added, and the resulting mixture was heated at 80 °C for 6 h. The resulting precipitate, that contains the target compound, was collected by filtration and washed with ethyl ether.