Synlett 2004(10): 1817-1819  
DOI: 10.1055/s-2004-829561
LETTER
© Georg Thieme Verlag Stuttgart · New York

Methods for the Construction of New Highly Functionalised Guanidines

Eric Wellner, Helena Sandin*, Marie-Louise Swanstein
Active Biotech AB, Department of Drug Discovery, Box 724, 22007 Lund, Sweden
Fax: +46(46)191246; e-Mail: helena.sandin@activebiotech.com;
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Publikationsverlauf

Received 30 April 2004
Publikationsdatum:
15. Juli 2004 (online)

Abstract

In this study, we present a fast and chemoselective protocol to highly functionalised guanidines. Guanidines containing a hydroxy function were constructed in the microwave by regioselective ring opening of epoxides in the presence of ammonium hydroxide giving the primary amines, which then were reacted with isothiouronium salts. Direct coupling of an unsubstituted guanidine with an epoxide in the presence of n-BuLi gave the same product.

    References

  • 1a Kienzle F. Kaiser A. Madhukar SC. Eur. Med. Chem.  1982,  17:  547 
  • 1b Weinhardt K. Wallach MB. Marx M. J. Med. Chem.  1985,  28:  694 
  • 1c Rockway TW. Expert Opin. Ther. Patents  2003,  13:  773 
  • 1d Chiron Corp. . Expert Opin. Ther. Patents  2003,  13:  551 
  • 1e Donnelly LE. Rogers DF. Expert Opin. Ther. Patents  2003,  13:  1345 
  • 1f Lehmann J. Rob B. Liebigs Ann. Chem.  1994,  805 
  • 2a Marmillon C. Bompart J. Calas M. Escale R. Bonnet P.-A. Heterocycles  2000,  53:  1317 
  • 2b Liu F. Lu G.-Y. He W.-J. Mei Y.-H. Zhu L.-G. Synthesis  2001,  4:  607 
  • 2c Bruno O. Brullo C. Ranise A. Schenone S. Bondavalli F. Barocelli E. Ballabeni V. Chiavarini M. Tognolini M. Impicciatore M. Bioorg. Med. Chem. Lett.  2001,  11:  1397 
  • 2d Linney ID. Buck IM. Harper EA. Kalindjian SB. Pether MP. Shankley NP. Watt GF. Wright PT. J. Med. Chem.  2000,  43:  2362 
  • 2e For a micro review see: Manimala JC. Anslyn EV. Eur. J. Org. Chem.  2002,  3909 
  • 3 Sandin H. Swanstein M.-L. Wellner E. J. Org. Chem.  2004,  69:  1571 
  • 4a Plenkiewicz H. Dmowski W. J. Fluorine Chem.  1991,  51:  43 
  • 4b Goessnitzer E. Malli R. Schuster S. Favre B. Ryder S. Arch. Pharm.  2002,  11:  535 
  • 5 Favretto L. Nugent W. Licini G. Tetrahedron Lett.  2002,  43:  2581 
  • 6 Booth RJ. Hodges JC. J. Am. Chem. Soc.  1997,  119:  4882 
  • 8 Fahmy HH. Soliman GA. Arch. Pharmacal. Res.  2001,  24:  180 
  • 9 Chen B.-C. Quinlan SL. Reid JG. Jass PA. Robinson TP. Early WA. Delaney EJ. Humora MJM. Tetrahedron: Asymmetry  1998,  9:  1337 
7

Using protected building blocks (path B), the reaction performed less sluggishly leading to a substantially increase in yield.

10

NMR spectroscopy indicates also the formation of a by-product with unsymmetrical ring substitution. Attempts to isolate this compound failed.

11

The addition of Wang resin ensures the removal of the unreacted isothiouronium salt. This underlines the ambivalent reactivity of the starting material 5 towards alcohols3 and amines under microwave conditions.