Download PDF
Synthesis 2012(4): 610-618  
DOI: 10.1055/s-0031-1290068
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Highly Efficient and Broad-Scope Protocol for the Preparation of 7-Substituted 6-Halopurines via N 9-Boc-Protected 7,8-Dihydropurines

Vladislav Kotek, Tomáš Tobrman, Dalimil Dvořák*
Department of Organic Chemistry, Institute of Chemical Technology, Prague, Technická 5, 2166 28 Prague 6, Czech Republic
Fax: +42(224)354288; e-Mail: dvorakd@vscht.cz;
Further Information

Publication History

Received 26 October 2011
Publication Date:
03 January 2012 (online)

    Permissions and Reprints All articles of this category

Abstract

9-Boc-6-chloropurine, which can be obtained in high yield, is nearly quantitatively reduced with the THF˙BH3 complex. The obtained 9-Boc-7,8-dihydropurine derivative is more stable compared to the corresponding 9-tritylpurine and can be smoothly N7-alkylated, acylated, or it can serve as an N-nucleophile in conjugate additions. Deprotection with trifluoroacetic acid followed by MnO2 oxidation affords the N7-substituted purines in high yields. The whole sequence of alkylation, deprotection, and oxidation can be done with crude intermediates using chromatography only for the purification of the final N7-substituted purine.

Key words

alkylation - acylation - Michael addition - nucleobases - reduction

    References

  • For a recent review of biologically active purines, see:
  • 1a Rosemeyer H. Chem. Biodiversity  2004,  361 
  • 1b Legraverend M. Grierson DS. Bioorg. Med. Chem.  2006,  14:  3987 
    Search in Google Scholar
  • 2 For a recent review on the synthesis of purine derivatives, see: Legraverend M. Tetrahedron  2008,  64:  8585 
    Search in Google Scholar
  • 3a Duke CC. Liepa AJ. MacLeod JK. Letham DS. Parker CW. J. Chem. Soc., Chem. Commun.  1975,  964 ; and references cited therein
  • 3b Jähne G. Kroha H. Müller A. Helsberg M. Winkler I. Gross G. Scholl T. Angew. Chem., Int. Ed. Engl.  1994,  33:  562 
    Search in Google Scholar
  • 3c Yosief T. Rudi A. Stein Z. Goldberg I. Gravalos GMD. Schleyer M. Kashman Y. Tetrahedron Lett.  1998,  39:  3323 
    Search in Google Scholar
  • 3d Rudi A. Shalom H. Schleyer M. Benayahu Y. Kashman Y. J. Nat. Prod.  2004,  67:  106 
    Search in Google Scholar
  • 3e Rudi A. Aknin M. Gaydou E. Kashman Y. J. Nat. Prod.  2004,  67:  1932 
    Search in Google Scholar
  • 3f Yosief T. Rudi A. Kashman Y. J. Nat. Prod.  2000,  63:  299 
    Search in Google Scholar
  • 3g Jemielity J. Kowalska J. Rydzik AM. Darzynkiewicz E. New J. Chem.  2010,  34:  829 ; and references cited therein
    Search in Google Scholar
  • 4a Leonard NJ. Fujii T. Saito T. Chem. Pharm. Bull.  1986,  34:  2037 
    Search in Google Scholar
  • 4b Fujii T. Saito T. Inoue I. Kumazawa Y. Leonard NJ. Chem. Pharm. Bull.  1986,  34:  1821 
    Search in Google Scholar
  • 4c Garner P. Ramakanth S. J. Org. Chem.  1988,  53:  1294 
    Search in Google Scholar
  • 4d Hocková D. Buděčínský M. Marek R. Marek J. Hol A. Eur. J. Org. Chem.  1999,  2675 
  • 5 Montgomery JA. Hewson K. J. Org. Chem.  1961,  26:  4469 
    Search in Google Scholar
  • 6 Ibrahim N. Legraverend M. J. Org. Chem.  2009,  74:  463 
    Search in Google Scholar
  • 7 Dalby C. Bleasdale C. Clegg W. Elsegood MRJ. Golding BT. Griffin RJ. Angew. Chem., Int. Ed. Engl.  1993,  32:  1696 
    Search in Google Scholar
  • 8 Pappo D. Shimony S. Kashman Y. J. Org. Chem.  2005,  70:  199 
    Search in Google Scholar
  • 9 Keder R. Dvořáková H. Dvořák D. Eur. J. Org. Chem.  2009,  1522 
  • 10a Havelková M. Dvořák D. Hocek M. Synthesis  2001,  1704 
  • 10b Tobrman T. Dvořák D. Org. Lett.  2003,  5:  4289 
    Search in Google Scholar
  • 10c Tobrman T. Dvořák D. Org. Lett.  2006,  8:  1291 
    Search in Google Scholar
  • 10d Tobrman T. Dvořák D. Eur. J. Org. Chem.  2008,  2923 
  • 11 Kotek V. Chudíková N. Tobrman T. Dvořák D. Org. Lett.  2010,  12:  5724 
    Search in Google Scholar
  • 12a Albert A. J. Chem. Soc., Perkin Trans. 1  1981,  2974 
  • 12b Kelly JL. Linn JA. J. Org. Chem.  1986,  51:  5435 
    Search in Google Scholar
  • 12c Pendergast W. Hall WR. J. Heterocycl. Chem.  1989,  26:  1863 
    Search in Google Scholar
  • 13 Rodenko B. Koch M. van der Burg AM. Wanner MJ. Koomen G.-J. J. Am. Chem. Soc.  2005,  127:  5957 
    Search in Google Scholar
  • 16a This formal dehydrohalogenation of 6-chloro-7,8-dihydropurines under basic conditions has already been described, however, without a mechanistic explanation: Kelley JL. Linn JA. J. Org. Chem.  1986,  51:  5435 
    Search in Google Scholar
  • 16b

    We believe that the deprotonated 2a can serve as the source of hydride (similar to NADH), which inter-molecularly reduces the halogen.

  • 17 Koch SS. Chamberlin AR. J. Org. Chem.  1993,  58:  2725 
    Search in Google Scholar
  • 18 Edwards MP. Ley SV. Lister SG. Palmer BD. Williams DJ. J. Org. Chem.  1984,  49:  3503 
    Search in Google Scholar
  • 19 Prasad RN. Robins RK. J. Am. Chem. Soc.  1957,  79:  6401 
    Search in Google Scholar
  • 20 Okamura T. Kikuchi T. Fukushi K. Arano Y. Irie T. Bioorg. Med. Chem.  2007,  15:  3127 
    Search in Google Scholar
  • 21 Gundersen L.-L. Bakkestuen AK. Aasen AJ. Øverås H. Rise F. Tetrahedron  1994,  50:  9743 
    Search in Google Scholar
  • 22 Platzer N. Galons H. Bensaid Y. Miocque M. Bram G. Tetrahedron  1987,  43:  2101 
    Search in Google Scholar
14

However, the use of the 6-iodo-7,8-dihydropurines appeared to be crucial for the Heck reaction, which is under study in our laboratory at present.

15

The use of the DBU as the base was less effective compared to the LiHMDS. Thus, alkylation of 2a with benzyl bromide in DMF in the presence of DBU gave 100% conversion and 60% yield of 3c, while in MeCN full conversion was not achieved.