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Synthesis 2009(10): 1715-1719  
DOI: 10.1055/s-0028-1088057
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Tandem CH-Activation-Imine-Formation Reaction: A New Route to Imidazo[2,1-a]phthalazines

Alexander Heim-Riether*, Kevin R. Gipson
Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, CT 06877, USA
Fax: +1(203)7916072; e-Mail: alexander.heim-riether@boehringer-ingelheim.com;
Further Information

Publication History

Received 14 December 2008
Publication Date:
20 April 2009 (online)

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Abstract

A general and efficient synthesis of imidazo[2,1-a]phthalazines by palladium- and copper-mediated coupling of N-aminoimidazoles with 2-haloaryl aldehydes with concurrent imine formation is described. This new synthesis of the imidazo[2,1-a]phthalazine ring system allows for facile introduction of different substituents around the entire core.

Key words

imidazo[2,1-a]phthalazine - imine formation - CH activation - N-aminoimidazoles - 2-bromoaryl aldehydes

    References

  • 1a Hardtmann GE. inventors; US Patent 3 711  481.  Chem. Abstr. 1973, 78, 84430
  • 1b Razvi M. Ramalingam T. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.  1992,  31:  788 
    Google Scholar
  • 1c Catarzi D. Cecchi L. Colotta V. Conti G. Melani F. Filacchioni G. Martini C. Giusti L. Lucacchini A. Farmaco  1993,  48:  447 
    Google Scholar
  • 2a Castle RN. Takano S. J. Heterocycl. Chem.  1966,  3:  381 
    Google Scholar
  • 2b Barlin GB. Aust. J. Chem.  1986,  39:  1803 
    Google Scholar
  • 2c Mavel S. Thery I. Gueiffier A. Arch. Pharm. Pharm. Med. Chem.  2002,  335:  7 
    Google Scholar
  • 2d Solyom S. Hamori T. Borosy AP. Tarnawa I. Berzsenyi P. Pallagi I. Med. Chem. Res.  2002,  11:  39 
    Google Scholar
  • 2e Shubin KM. Kuznetsov VA. Galishev VA. Tetrahedron Lett.  2004,  45:  1407 
    Google Scholar
  • 2f Kuznetsov VA. Shubin KM. Schipalkin AA. Petrov ML. Tetrahedron  2006,  62:  10018 
    Google Scholar
  • 2g Parenty ADC. Song Y.-F. Richmond CJ. Cronin L. Org. Lett.  2007,  9:  2253 
    Google Scholar
  • 3a Heim-Riether A. Healy J. J. Org. Chem.  2005,  70:  7331 
    Google Scholar
  • 3b

    N-Amination of imidazoles leads to separable regioisomers.

  • 4a For a review, see: Miura M. Nomura M. Top. Curr. Chem.  2002,  219:  211 
    Google Scholar
  • For most recent examples of direct intermolecular Pd-catalyzed arylation of azoles, see:
  • 4b Yokooji A. Okazawa T. Satoh T. Miura M. Nomura M. Tetrahedron  2003,  59:  5685 
    Google Scholar
  • 4c Mori A. Sekiguchi A. Masui K. Shimada T. Horie M. Osakada K. Kawamoto M. Ikeda T. J. Am. Chem. Soc.  2003,  125:  1700 
    Google Scholar
  • 4d Li W. Nelson DP. Jensen MS. Hoerrner RS. Javadi GJ. Cai D. Larsen RD. Org. Lett.  2003,  5:  4835 
    Google Scholar
  • 4e Zificsak CA. Hlasta DJ. Tetrahedron  2004,  60:  8991 
    Google Scholar
  • 4f Park C.-H. Ryabova V. Seregin IV. Sromek AW. Gevorgyan V. Org. Lett.  2004,  6:  1159 
    Google Scholar
  • 4g Alagille D. Baldwin RM. Tamagnan GD. Tetrahedron Lett.  2005,  46:  1349 
    Google Scholar
  • 4h Bellina F. Cauteruccio S. Mannina L. Rossi R. Veil S. J. Org. Chem.  2005,  70:  3997 
    Google Scholar
  • 4i Gracias V. Gasiecki AF. Pagano TG. Djuric SW. Tetrahedron Lett.  2006,  47:  8873 
    Google Scholar
  • 4j Bellina F. Cauteruccio S. Mannina L. Rossi R. Viel S. Eur. J. Org. Chem.  2006,  693 
    Google Scholar
  • 4k Cerna I. Pohl R. Klepetarova B. Hocek M. Org. Lett.  2006,  8:  5389 
    Google Scholar
  • 4l Bellina F. Cauteruccio S. Rossi R. J. Org. Chem.  2007,  72:  8543 
    Google Scholar
  • 4m Hien-Quang D. Daugulis O. J. Am. Chem. Soc.  2007,  129:  12404 
    Google Scholar
  • 4n Yoshizumi T. Tsurugi H. Satoh T. Miura M. Tetrahedron Lett.  2008,  49:  1598 
    Google Scholar
  • 5 Caron S. Massett SS. Bogle DE. Castaldi MJ. Braish TF. Org. Process Res. Dev.  2001,  5:  254 
    CrossrefGoogle Scholar
  • 7a Ohff M. Ohff A. Milstein D. Chem. Commun.  1999,  357 
    Google Scholar
  • 7b For a review on palladacyles, see: Ghedini M. Aiello I. Crispini A. Golemme A. La Deda M. Pucci D. Coord. Chem. Rev.  2006,  250:  1373 
    Google Scholar
  • 8 MeP(t-Bu)2˙HBF4 has been reported to significantly increase yield in CH activation reaction: Wang JX. McCubbin A. Meizhong J. Laufer RS. Mao Y. Crew AP. Mulvihill MJ. Snieckus V. Org. Lett.  2008,  10:  2923 
    CrossrefGoogle Scholar
  • 9 Direct arylations of azoles were performed under ligandless conditions; see reference 4j and: Bellina F. Cauteruccio S. Rossi R. Eur. J. Org. Chem.  2006,  1379 
    CrossrefGoogle Scholar
6

No imine formation was observed under standard coupling conditions without one of the two metals (Pd, Cu) present.

10

Starting 1-aminoimidazoles, except commercially available benzimidazol-1-ylamine, were prepared according to reference 3.