Download PDF
Synthesis 2002(1): 0043-0046
DOI: 10.1055/s-2002-19292
PAPER
© Georg Thieme Verlag Stuttgart · New York

Regioselective Synthesis of Linear and Angular Pyridazine Furocoumarins

José Carlos González-Gómez, Lourdes Santana, Eugenio Uriarte*
Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain
Fax: +34(981)594912; e-Mail: qofuri@usc.es;
Further Information

Publication History

Received 3 August 2001
Publication Date:
04 August 2004 (online)

    Permissions and Reprints All articles of this category

Abstract

With a view to develop a general regioselective route to pyridazine analogues of benzofurocoumarins, the angular compound 3 and the linear compound 9 were synthesized. In both cases the key step in the construction of the fused pyridazine ring was a Diels-Alder reaction of the intermediate dihydrofura-3-ones with 3,6-bis(trifluoromethyl)-1,2,4,5-tetrazine. The furocoumarinone precursor 2 of compound 3 was synthesized in 60% yield by regioselective Fries rearrangement of 7-(chloroacetyloxy)coumarin (1). The benzofuranone 7, the precursor of compound 9, was obtained in a preparatively useful scale and 34% overall yield from ethyl 2,4-dimethoxycinnamate (4) in 3 steps by regioselective Friedel-Crafts chloroacetylation and further cyclization. The coumarin skeleton of compound 9 was completed in the final step by lactonization with BBr3.

Key words

Diels-Alder reactions - electrophilic aromatic substitutions - polycycles - heterocycles - regioselectivity

    References

  • 1 Parrish JA. Stern RS. Pathak MA. Fitzpatrick TB. In The Science of Photomedicine   Reagan JD. Parrish JA. Plenum; New York: 1982.  p.595-624  
  • 2 Dall’Acqua F. Vedaldi D. In CRC Handbook of Organic Photochemistry and Photobiology   CRC Press; Boca Raton, FL: 1995.  p.1341-1350  
  • 3 Pathak MA. In Monograph No. 66   Pathak MA. Dunnick JK. National Institute of Health; Washington: 1984.  p.41-46  
  • 4 Dalla Via L. Marciani-Magno S. Current Med. Chem.  2001,  8:  1405 
    Search in Google Scholar
  • 5 Terán C. Miranda R. Teijeira M. Santana L. Uriarte E. Synthesis  1997,  1384 
    Thieme Connect
  • 6 Via LD. Gia O. Magno SM. Santana L. Teijeira M. Uriarte E. J. Med. Chem.  1999,  42:  4405 
    CrossrefSearch in Google Scholar
  • 7 Santana L. Uriarte E. Dalla Via L. Gia O. Bioorg. Med. Chem. Lett.  2000,  10:  135 
    CrossrefSearch in Google Scholar
  • 8 Advances in DNA-Sequence-Specific Agents   Vol. 3:  Jones GB. Palumbo M. Jai Press; London: 1998. 
  • 9 González JC. Dedola T. Santana L. Uriarte E. Begala M. Copez D. Podda G. J. Heterocycl. Chem.  2000,  37:  907 
    Search in Google Scholar
  • For reviews, see:
  • 10a Boger DL. Chem. Rev.  1986,  86:  781 
    Search in Google Scholar
  • 10b Boger DL. Winreb SM. Hetero Diels-Alder Methodology in Organic Synthesis, Organic Chemistry Monograph Series   Vol. 47:  Academic Press; New York: 1987. 
    Search in Google Scholar
  • 10c Sauer J. In Comprehensive Heterocyclic Chemistry II   Vol. 6:  Katritzky AR. Rees CW. Scriven EFV. Pergamon; London: 1996.  p.901-955  
    Search in Google Scholar
  • 11 Benson SC. Lee L. Yang L. Snayder JK. Tetrahedron  2000,  56:  1165 
    CrossrefSearch in Google Scholar
  • 12 Boger DL. Kochanny MJ. J. Org. Chem.  1994,  59:  4950 
    CrossrefSearch in Google Scholar
  • 13 Wan Z.-K. Woo GHC. Snyder JK. Tetrahedron  2001,  57:  5497 
    CrossrefSearch in Google Scholar
  • 14 Klindert T. Stroetmann I. Seitz G. Höfner G. Wanner KT. Frenzen G. Eckhoff B. Arch. Pharm. (Weinheim)  1997,  330:  163 
    Search in Google Scholar
  • 15 Traven VF. Saharuk II. Kravtchenko DV. Heterocycl. Commun.  1998,  4:  429 
    Search in Google Scholar
  • 16 Kravtchenko DV. Chivisova TA. Traven VF. Russ. J. Org. Chem.  1999,  35:  899 
    Search in Google Scholar
  • 17a Cairns N. Harwood LM. Astles DP. Orr A. J. Chem. Soc., Chem. Commun.  1986,  182 
    Crossref
  • 17b Cairns N. Harwood LM. Astles DP. Tetrahedron Lett.  1988,  29:  1311 
    CrossrefSearch in Google Scholar
  • 17c Zubia E. Rodríguez FL. Massanet GM. Collado IG. Tetrahedron  1992,  48:  4239 
    CrossrefSearch in Google Scholar
  • 18 Ethyl 2,4-dimethoxycinnamate was obtained in 98% yield from 2,4-dimethoxybenzaldehyde by Wittig reaction, following the general procedure reported in: Dubuffet T. Loutz A. Lavielle G. Synth. Commun.  1999,  29:  929 
    Search in Google Scholar
  • 20 Mural A. Sato S. Masamune T. Bull. Chem. Soc. Jpn.  1984,  57:  2286 
    Search in Google Scholar
  • For reviews of the Friedel-Crafts reaction, see:
  • 21a Carbonium Ions   Vol. IV:  Olah GA. Wiley; New York: 1974. 
  • 21b Carbocation Chemistry   Vogel P. Elsevier; Amsterdam: 1985. 
  • 21c Electrophilic Aromatic Substitution   Taylor R. Wiley; New York: 1990.  p.222 
  • 22 McOmie JFW. Watts ML. West DE. Tetrahedron  1968,  24:  2289 
    CrossrefSearch in Google Scholar
  • 23 Barlow MG. Haszeldine RN. Pickett JA. J. Chem. Soc., Perkin Trans 1  1978,  378 
    Crossref
19

Attempts to improve the acylation yield under classical Friedel-Crafts conditions,20,21 using 1-3 equiv of chloroacetyl chloride in refluxing CS2 or CCl4 and 2 equiv of AlCl3, afforded intractable black tars.