Download PDF
Synthesis 2007(6): 829-834  
DOI: 10.1055/s-2007-965949
PAPER
© Georg Thieme Verlag Stuttgart · New York

Reaction of Isatin-1-acetamides with Alkoxides: Synthesis of Novel 1,4-Dihydro-3-hydroxy-4-oxo-2-quinolinecarboxamides

María Mercedes Blanco, Mónica Dal Maso, María Sol Shmidt, Isabel Amalia Perillo*
Departamento de Química Orgánica, Facultad de Farmacia y Bioquímica, Junín 956, 1113 Buenos Aires, Argentina
Fax: +54(11)49648250; e-Mail: iperillo@ffyb.uba.ar;
Further Information

Publication History

Received 8 August 2006
Publication Date:
20 February 2007 (online)

    Permissions and Reprints All articles of this category

Abstract

The study of the reactivity of a series of isatin-1-acet­amides with hot alkoxides is described. These reactions lead to 1,4-dihydro-3-hydroxy-4-oxo-2-quinolinecarboxamides as main products, and 3-hydroxy-2-oxindoles as well as other minor products. Experimental results indicate that the starting compounds undergo transformation through two principal routes: ring expansion of isa­tin leading to quinoline carboxamides, probably as the result of a ring-opening and ring-closure rearrangement, and reduction of the keto carbonyl group due to the reductive ability of alkoxides.

Key words

4-quinolinones - isatin - alkylation - rearrangement - reduction

    References

  • 1a Gabriel S. Colman J. Ber. Dtsch. Chem. Ges.  1900,  33:  980 , 2630
    CrossrefGoogle Scholar
  • 1b Hill JHM. J. Org. Chem.  1965,  30:  620 
    CrossrefGoogle Scholar
  • 1c Schapira CB. Abasolo MI. Perillo IA. J. Heterocycl. Chem.  1985,  22:  577 
    CrossrefGoogle Scholar
  • 1d Kusel H. Ber. Dtsch. Chem. Ges.  1904,  37:  1971 
    CrossrefGoogle Scholar
  • 1e Findeklee W. Ber. Dtsch. Chem. Ges.  1905,  38:  3542 
    CrossrefGoogle Scholar
  • 1f Caswell LR. Haggard A. Yung DC. J. Heterocycl. Chem.  1968,  5:  865 ; and references cited therein
    CrossrefGoogle Scholar
  • 1g Fowler RG. Caswell LR. Sue LI. J. Heterocycl. Chem.  1973,  10:  407 ; and references cited therein
    CrossrefGoogle Scholar
  • 2a Blanco MM. Lorenzo MG. Perillo IA. Schapira CB. J. Heterocycl. Chem.  1996,  33:  361 ; and references cited therein
    CrossrefGoogle Scholar
  • 2b Blanco MM. Schapira CB. Levin G. Perillo IA. J. Heterocycl. Chem.  2005,  42:  493 
    CrossrefGoogle Scholar
  • 2c Gabriel S. Colman J. Ber. Dtsch. Chem. Ges.  1902,  35:  1358 
    CrossrefGoogle Scholar
  • 3 Blanco MM. Shmidt MS. Perillo IA. ARKIVOC  2005,  (xii):  195 ; and references cited therein
    Google Scholar
  • To the best of our knowledge, the parent acid and its ester, obtained with low yields from the preformed 4-quinolinone nucleus were the only compounds previously described in the literature:
  • 4a Behrman EJ. Kiser RL. Garas WF. Behrman EC. Pitt BM. J. Chem. Res., Synop.  1995,  164 
    Google Scholar
  • 4b Coppini D. Gazz. Chim. Ital.  1950,  80:  36 
    Google Scholar
  • The acid, named as 3,4-dihydroxyquinoline-2-carboxylic was isolated from a MeOH extract of A. aerofoba:
  • 4c Fattorusso E. Forenza S. Minale L. Sodano G. Gazz. Chim. Ital.  1971,  101:  104 
    Google Scholar
  • 5a Sumpter WC. Chem. Rev.  1944,  34:  393 
    CrossrefGoogle Scholar
  • 5b Popp FD. Adv. Heterocycl. Chem.  1975,  18:  1 
    CrossrefGoogle Scholar
  • 5c da Silva JFM. Garden SJ. da C. Pinto A. J. Braz. Chem. Soc.  2001,  12:  273 
    CrossrefGoogle Scholar
  • 6 Ainley AD. Robinson R. J. Chem. Soc.  1934,  1508 
    Google Scholar
  • 7 Putokhin NI. Zh. Obshch. Khim.  1935,  5:  1176 ; Chem. Abstr. 1935, 30, 1055
    Google Scholar
  • Structure of compounds 2 was determined by HMQC and HMBC spectra. Predominance of lactam (4-oxo) over lactim forms (4-hydroxy) is common for 4-quinolinones with a varied substitution pattern:
  • 8a Mphahlele MJ. El-Nahas AM. J. Mol. Struct.  2004,  688:  129 ; and references cited therein
    CrossrefGoogle Scholar
  • 8b de la Cruz A. Elguero J. Goya P. Martínez A. Pfeiderer W. Tetrahedron  1992,  48:  6135 
    CrossrefGoogle Scholar
  • On the other hand, stabilization of C-3 enol hydroxyl is possible through intramolecular hydrogen bonds.
  • Amides derived from 1,2-dihydro-4-hydroxy-2-oxo-3-quinolinecarboxylic acid present an important immuno­-modulator and anti-angiogenic activity, among others:
  • 9a Jönsson S. Andersson G. Fex T. Fristedt T. Hedlund G. Jansson K. Abramo L. Fritzson I. Pekarski O. Runström A. Sandin H. Thuvesson I. Björk A. J. Med. Chem.  2004,  47:  2075 
    CrossrefGoogle Scholar
  • 9b Shi J. Xiao Z. Ihnat M. A. Kamat C. Pandit B. Hu Z. Li P.-K. Bioorg. Med. Chem. Lett.  2003,  13:  1187 
    CrossrefGoogle Scholar
  • 9c Tsuji K. Spears GW. Nakamura K. Tojo T. Seki N. Sugiyama A. Matsuo M. Bioorg. Med. Chem. Lett.  2002,  12:  85 
    CrossrefGoogle Scholar
  • 10a Screttas CG. Cazianis T. Tetrahedron  1978,  34:  933 ; and references cited therein
    CrossrefGoogle Scholar
  • 10b Kleinfelter DC. J. Org. Chem.  1967,  32:  840 ; and references cited therein
    CrossrefGoogle Scholar
  • 11 Ashby EC. Argyropoulos JN. Tetrahedron Lett.  1986,  27:  465 ; and references cited therein
    CrossrefGoogle Scholar
  • 12 Langenbeck W. Ber. Dtsch. Chem. Ges.  1928,  61B:  942 
    Google Scholar
  • 13 Kapadia JG. Shukla YN. Basak SP. Sokoloski EA. Fales HM. Tetrahedron  1980,  36:  2441 
    CrossrefGoogle Scholar