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Synthesis 2005(10): 1593-1600  
DOI: 10.1055/s-2005-865306
PAPER
© Georg Thieme Verlag Stuttgart · New York

An Efficient and Convenient Synthesis of Tetrahydrocycloheptapyridines: New Precursors for CNS Agents

Takashi Yoshizumi*, Hiroshi Miyazoe, Yuichi Sugimoto, Hirobumi Takahashi, Osamu Okamoto
Tsukuba Research Institute, Banyu Pharmaceutical Co., ltd., Okubo 3, Tsukuba, Ibaraki 300-2611, Japan
Fax: +81(29)8772027; e-Mail: takashi_yoshizumi@merck.com;
Further Information

Publication History

Received 24 November 2004
Publication Date:
12 April 2005 (online)

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Abstract

Development of a convenient and efficient synthetic route for functionalized tetrahydrocycloheptapyridines was accomplished by stepwise iodomethylation and subsequent radical ring expansion using a Bu3SnH/AIBN reaction system. Thus, 8- or 5-­oxotetrahydroquinolines 4a and 4d and 8- or 5-oxotetrahydroisoquinolines 4b and 4c afforded the 5,6,7,8-tetrahydrocycloheptapyridine-9-ones 3a and 3d and 6,7,8,9-tetrahydrocycloheptapyridine-5-ones 3b and 3c, respectively, in moderate total yields (37-61%). It was also found out that this reaction sequence was applicable to the preparation of other heterocyclic fused cycloheptanones.

Key words

cycloheptanone - hydroxymethylation - iodomethylation - ring expansion - radical reaction

    References

  • 1a Cortizo L. Santana L. Raviña E. Orallo F. Fontenla JA. Castro E. Calleja JM. de Ceballos ML. J. Med. Chem.  1991,  34:  2242 
    CrossrefGoogle Scholar
  • 1b Raviña E. Nergeira J. Cid J. Masaguer CF. Rosa E. Rivas ME. Fontenla JA. Loza MI. Tristán H. Cadavid MI. Sanz F. Lozoya E. Carotti A. Carrieri A. J. Med. Chem.  1999,  42:  2774 
    CrossrefGoogle Scholar
  • 1c Fontenla JA. Osuna J. Rosa E. Castro ME. G-Ferreiro T. Loza-García I. Calleja JM. Sanz F. Rodríguez J. Raviña E. Fueyo J. F-Masaguer C. Vidal A. de Ceballos ML. J. Med. Chem.  1994,  37:  2564 
    CrossrefGoogle Scholar
  • 2 Brea J. Rodrigo J. Carrieri A. Sanz F. Cadavid MI. Enguix MJ. Villazón M. Mengod G. Caro Y. Masaguer CF. Raviña E. Centeno NB. Carotti A. Loza MI. J. Med. Chem.  2002,  45:  54 
    CrossrefGoogle Scholar
  • 3 Forbes IT. Cooper DG. Dodds EK. Douglas SE. Gribble AD. Ife RJ. Lightfoot AP. Meeson M. Campbell LP. Coleman T. Riley GJ. Thomas DR. Bioorg. Med. Chem. Lett.  2003,  13:  1055 
    CrossrefGoogle Scholar
  • 4 Daniela B, Giorgio C, Maria GGA, Mario G, and Silvano R. inventors; Patent WO  0027815.  ; Chem. Abstr. 2000, 132, 347490
  • 5 Indeed, replacement of the benzene ring with a pyridine ring changed the physicochemical properties in the case of an endothelin receptor antagonist we developed, see: Niiyama K. Mase T. Takahashi H. Naya A. Katsuki K. Nagase T. Ito S. Hayama T. Hisaka A. Ozaki S. Ihara M. Yano M. Fukuroda T. Noguchi K. Nishikibe M. Ishikawa K. Bioorg. Med. Chem.  2002,  10:  2461 
    CrossrefGoogle Scholar
  • 6 Masaguer CF. Raviña E. Tetrahedron Lett.  1996,  37:  5171 
    CrossrefGoogle Scholar
  • 7 Casariego I. Masaguer CF. Raviña E. Tetrahedron Lett.  1997,  38:  5555 
    CrossrefGoogle Scholar
  • 8 Pita B. Casariego I. Masaguer CF. Raviña E. Tetrahedron Lett.  2000,  41:  9829 
    CrossrefGoogle Scholar
  • 9a Hasegawa E. Kitazumi T. Suzuki K. Tosaka E. Tetrahedron Lett.  1998,  39:  4059 
    CrossrefGoogle Scholar
  • 9b Chung SH. Cho MS. Choi JY. Kwon DW. Kim YH. Synlett  2001,  1266 
    CrossrefGoogle Scholar
  • 9c Sugi M. Sakuma D. Togo H. J. Org. Chem.  2003,  68:  7629 
    CrossrefGoogle Scholar
  • 9d Bowman WR. Westlake PJ. Tetrahedron  1992,  48:  4027 
    CrossrefGoogle Scholar
  • 9e Chatgilialoglu C. Timokhin VI. Ballestri M. J. Org. Chem.  1998,  63:  1327 
    CrossrefGoogle Scholar
  • 10 Comprehensive Heterocyclic Chemistry   Vol. 2:  Katritzky AR. Rees CW. Pergamon; London: 1984. 
    Google Scholar
  • 12 Newton RF. Reynolds DP. Synth. Commun.  1981,  11:  527 
    CrossrefGoogle Scholar
  • 15 Thummel RP. Lefoulon F. Cantu D. Mahadevan R. J. Org. Chem.  1984,  49:  2208 
    CrossrefGoogle Scholar
  • 16 Glassco W. Suchocki J. George C. Martin BR. May EL. J. Med. Chem.  1993,  36:  3381 
    CrossrefGoogle Scholar
  • 17 Lardenois P. Frost J. Dargazanli G. George P. Synth. Commun.  1996,  26:  2305 
    CrossrefGoogle Scholar
  • 18 Huang Y. Hartmann RW. Synth. Commun.  1998,  28:  1197 
    CrossrefGoogle Scholar
  • 19 Mosti L. Menozzi G. Schenone P. J. Heterocycl. Chem.  1983,  20:  649 
    CrossrefGoogle Scholar
  • 20 Schenone P. Mosti L. Menozzi G. J. Heterocycl. Chem.  1982,  19:  1355 
    CrossrefGoogle Scholar
11

We also conducted bromo- or iodomethylation using other bases (t-BuOK, DBU, and Cs2CO3), but the attempts ended in incomplete conversion or complex mixture.

13

Bromination of 9a using CBr4 and PPh3 resulted in lower yield (45%).

14

The stereochemistry of compounds 10 and 11 was determined by their NOEs. The details are listed in the experimental section.