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Synthesis 2006(12): 1971-1974  
DOI: 10.1055/s-2006-942402
PAPER
© Georg Thieme Verlag Stuttgart · New York

A Convenient Method for the Preparation of 4-Hydroxy-2-methyl-1-oxo-1,2-dihydroisoquinoline-3-carboxylic Acid Derivatives

María Mercedes Blanco, María Sol Shmidt, Celia Beatriz Schapira, Isabel Amalia Perillo*
Departamento de Química Orgánica, Facultad de Farmacia y Bioquímica (UBA), Junín 956 (1113), Buenos Aires, Argentina
Fax: +54(11)49648250; e-Mail: iperillo@ffyb.uba.ar;
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Publication History

Received 13 January 2006
Publication Date:
06 June 2006 (online)

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Abstract

An improved method for the synthesis of 4-hydroxy-2-methyl-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid derivatives is described. The synthetic route involves initial phthalic anhydride aminolysis with alkylaminoacetic acid derivatives, further esterification with diazomethane and final heterocyclization of the phthalamic ester intermediates by alkoxide-induced Dieckmann condensation. The best yields are reached for esters and N,N-disubstituted carboxamides.

Key words

heterocycles - isoquinolinones - cyclization - lactams - enols

    References

  • Among others:
  • 1a Khan SR. Mhaka A. Pili R. Isaacs JT. Bioorg. Med. Chem. Lett.  2001,  11:  451 
    CrossrefGoogle Scholar
  • 1b Shi J. Xiao Z. Ihnat MA. Kamat C. Pandit B. Hu Z. Li PK. Bioorg. Med. Chem. Lett.  2003,  13:  1187 
    CrossrefGoogle Scholar
  • 1c 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 ; and references cited therein
    CrossrefGoogle Scholar
  • 1d Brunmark C. Runström A. Ohlsson L. Sparre B. Brodin T. Aström M. Hedlund G. J. Neuroimmunol.  2002,  130:  163 
    CrossrefGoogle Scholar
  • 1e Tsuji K. Spears GW. Nakamura K. Tojo T. Seki N. Sugiyama A. Matsuo M. Bioorg. Med. Chem. Lett.  2002,  12:  85 
    CrossrefGoogle Scholar
  • 1f Folkes A. Brown SD. Canne LE. Chan J. Engelhardt E. Epshteyn S. Faint R. Golec J. Hanel A. Kearney P. Leahy JW. Mac M. Matthews D. Prisbilla MP. Sanderson J. Simon RJ. Tesfai Z. Vicker N. Wang S. Webb RR. Charlton P. Bioorg. Med. Chem. Lett.  2002,  12:  1063 
    CrossrefGoogle Scholar
  • 1g Ukrainets IV. Taran SG. Gorokhova OV. Taran EA. Jaradat NA. Petukhova IY. Chem. Heterocycl. Compd. (Engl. Transl.)  2000,  36:  166 
    CrossrefGoogle Scholar
  • 1h Ukrainets IV. Taran SG. Likhanova NV. Rybakov VB. Gorokhova OV. Jaradat NA. Chem. Heterocycl. Compd. (Engl. Transl.)  2000,  36:  49 
    CrossrefGoogle Scholar
  • 1i Kugalowski JJ. Baker R. Curtis NR. Leeson PD. Mawer IM. Moseley AM. Ridgill MP. Rowley M. Stansfield I. Foster AC. Grimwood S. Hill RG. Kemp JA. Marshall JR. Saywell KL. Tricklebank MD. J. Med. Chem.  1994,  37:  1402 
    CrossrefGoogle Scholar
  • Among others, see:
  • 2a Lombardino JG. J. Heterocycl. Chem.  1970,  7:  1057 
    CrossrefGoogle Scholar
  • 2b Schapira CB. Abasolo MI. Perillo IA. J. Heterocycl. Chem.  1985,  22:  577 ; and references cited therein
    CrossrefGoogle Scholar
  • 2c Kadin SB. Wiseman EH. Nature  1969,  222:  275 
    CrossrefGoogle Scholar
  • 2d Lazer E. Miao CK. Cywin CL. Sorcek R. Wong H.-C. Meng Z. Potocki I. Hoermann M. Snow RJ. Tschantz MA. Kelly TA. McNeil DW. Coutts SJ. Churchill L. Graham V. David E. Grob PM. Engel W. Meier H. Trummlitz G. J. Med. Chem.  1997,  40:  980 
    CrossrefGoogle Scholar
  • Among others, see:
  • 3a Blanco MM. Schapira CB. Levin G. Perillo IA. J. Heterocycl. Chem.  2005,  42:  493 ; and references cited therein
    CrossrefGoogle Scholar
  • 3b Scotese AC, and Santilli AA. inventors; S. African ZA  8000631.  ; Chem. Abstr. 1982, 96, 6706
    CrossrefGoogle Scholar
  • 3c Scotese AC, Morris RL, and Santilli AA. inventors; US Patent  4301281.  ; Chem. Abstr. 1982, 97, 23815
    CrossrefGoogle Scholar
  • 3d Armitage BJ, and Leslie BW. inventors; PCT Int. Appl. WO  9611199.  ; Chem.Abstr. 1996, 125, 114712
    CrossrefGoogle Scholar
  • 3e Nuebling C, Von Deyn W, Theobald H, Westphalen K.-O, Kardorff U, Helmut W, Kappe T, and Gerber M. inventors; Ger. Offen. DE  4227747.  ; Chem. Abstr. 1994, 120, 323554z
    CrossrefGoogle Scholar
  • Among others, see:
  • 4a Toyama M. Otomasu H. Chem. Pharm. Bull.  1985,  33:  5543 
    Google Scholar
  • 4b Alonso-Silva IJ. Pardo M. Soto JL. Heterocycles  1988,  27:  357 
    Google Scholar
  • 4c Beattie JF. Hales NJ. J. Chem. Soc., Perkin Trans. 1  1992,  751 
    Google Scholar
  • 4d Khalaj A. Adibpour N. Heterocycles  1999,  51:  131 
    Google Scholar
  • 5a Suzuki M. Nunami K. Matsumoto K. Yoneda N. Miyoshi M. Synthesis  1978,  461 
    CrossrefGoogle Scholar
  • 5b Nunami K. Suzuki M. Matsumoto K. Miyoshi M. Yoneda N. Chem. Pharm. Bull.  1979,  27:  1373 
    CrossrefGoogle Scholar
  • 5c Miyoshi S, Yoneda N, Matsumoto K, Suzuki M, and Nunami K. inventors; Jpn. Kokai Tokkio Koho  7970285.  ; Chem. Abstr. 1979, 91, 175221
    Crossref
  • 7 Janczewski D. Synoradzki L. Wlostowski M. Synlett  2003,  420 
    Article in Thieme ConnectGoogle Scholar
  • 8 Blanco MM. Perillo IA. Schapira CB. J. Heterocycl. Chem.  1999,  36:  979 ; and references cited therein
    Google Scholar
6

Ease of trans-esterification is related to the presence of an electron-withdrawing group at the α-position to the ester (ref. 7) and it was also observed in Dieckmann cyclizations which lead to hydroxy derivatives of related heterocycles (ref. 8).

9

This fact is related to the acid character of aniline hydrogen in phthalamic ester 2c which would allow its deprotonation in basic medium, thus resulting in a less probable formation of the carbanion necessary for the heterocyclization. A similar behavior was observed in the alkoxide promoted cyclization of compounds structurally related to 2c (ref. 3a).

10

Lombardino (ref. 2a) describes the reaction product as a solid, formula: C17H14N2O3·0.5H2O, mp 195-197 °C.

11

The nonresolved multiplicity of the methylene and methyl signals is related to stereochemical features of this type of amides: partial double bond character of CO-N amide bond and/or the diastereotopicity of the methylene hydrogens associated with the presence of a chiral axis (ref. 4a).