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Synlett 2002(2): 0255-0258
DOI: 10.1055/s-2002-19760
LETTER
© Georg Thieme Verlag Stuttgart · New York

Novel Procedure for Selective C-Nitrosation of Aminopyrimidine Derivatives Under Neutral Conditions. Scope and Synthetic Applications

Antonio Marchala, Manuel Melguizo*a, Manuel Noguerasa, Adolfo Sáncheza, John N. Lowb
a Departamento de Química Inorgánica y Orgánica, Facultad de Ciencias Experimentales, Universidad de Jaén, 23071-Jaén, Spain
Fax: +34(95)3012141; e-Mail: mmelgui@ujaen.es;
b Department of Chemistry, University of Aberdeen, Meston Walk, Old Aberdeen, Aberdeen, AB24 3UE, Scotland
Further Information

Publication History

Received 16 November 2001
Publication Date:
02 February 2007 (online)

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Abstract

A novel simple method, based on treatment with isoamyl nitrite (IAN) in DMSO without any added acid, to produce selective C(5)-nitrosation of aminopyrimidine derivatives is described. It proved to be suitable for a multigram scale and applicable to a larger range of pyrimidine derivatives, including amino-dialkoxypyrimidines, than the procedures previously known. Its scope is analyzed and some example on the usefulness of the newly prepared substances as intermediates in the synthesis of fused heterobicyclic derivatives of potential biological interest is presented.

Key words

electrophilic aromatic substitutions - heterocycles - C-nitrosation - nucleoside analogues - pyrimidines

    References and Notes

  • 1a Shaw G. In Comprehensive Heterocyclic Chemistry   Vol. 5:  Potts KT. Katritzky AR. Rees CW. Pergamon Press; Oxford: 1984.  p.499 
    Google Scholar
  • 1b Pfleiderer W. In Comprehensive Heterocyclic Chemistry II   Vol. 7:  Ramsdem DA. Katritzky AR. Rees CW. Scriven EFW. Pergamon Press; Oxford: 1996.  p.679 
    Google Scholar
  • 1c Melguizo M. Nogueras M. Sánchez A. J. Org. Chem.  1992,  57:  559 
    Google Scholar
  • 2 Arris CE. Boyle FT. Calvert AH. Curtin NJ. Endicott JA. Garman EF. Gibson AE. Golding BT. Grant S. Griffin RJ. Dewsbury P. Johnson LN. Lawrie AM. Newell DR. Noble MEM. Sausville EA. Schultz R. Yu W. J. Med. Chem.  2000,  43:  2797 
    CrossrefGoogle Scholar
  • 3a Chae M.-Y. Swenn K. Kanugula S. Dolan M. Pegg AE. Moschel RC. J. Med. Chem.  1995,  38:  359 
    CrossrefGoogle Scholar
  • 3b Terashima I. Kohda K. J. Med. Chem.  1998,  41:  503 
    CrossrefGoogle Scholar
  • 4a Gray N. Detivaud L. Doerig D. Meijer L. Curr. Med. Chem.  1999,  6:  859 
    CrossrefGoogle Scholar
  • 4b Walker DH. Curr. Top. Microbiol. Immunol.  1998,  227:  149 
    CrossrefGoogle Scholar
  • 4c Garrett MD. Fattaey A. Curr. Opin. Genet. Dev.  1999,  9:  104 
    CrossrefGoogle Scholar
  • 6 Ritzmann G. Ienaga K. Kiriasis L. Pfleiderer W. Chem. Ber.   1980.  113:  p.1535 
    Google Scholar
  • 7 Moodie RB. O’Sullivan B. J. Chem. Soc., Perkin Trans.  1995,  2:  205 
    Google Scholar
  • Compound 1a was obtained by treatment of 2,4,6-trichloropyrimidine with sodium methoxide according to:
  • 8a Fox JJ. Shugar D. Bull. Soc. Chim. Belg.  1952,  61:  44 
    Google Scholar
  • 8b

    1b was purchased from Adrich.
    Google Scholar
  • 1c was prepared by treatment of 4-amino-2,6-dichloropyrimidine with sodium methoxide according to:
  • Bretschneider H. Klötzer W. Spiteller G. Monatsh. Chem.  1961,  92:  128 
    Google Scholar
  • 10 All the new prepared compounds were fully characterized by spectroscopic methods (IR, UV/Vis, MS, 1H and 13C NMR) and elemental analysis (C ± 0.3, H ± 0.3, N ± 0.4%). A relevant feature of the 2-amino-4,6-dialkoxy-5-nitroso-pyrimidines 2b,g,h is the particularly broad 13C NMR signal (δ = 161-164 ppm in DMSO) for carbons C(4) and C(6) as a consequence of the free rotation of the nitroso group that makes these carbon atoms chemically equivalent. A similar observation on benzene nitroso derivatives can be found in: Lipilin DL. Churakov AM. Ioffe SL. Strelenko YA. Tartakovsky VA. Eur. J. Org. Chem.  1999,  29 ; On the other hand, all the 6-amino-5-nitroso-pyrimidine derivatives show a strong intramolecular hydrogen bonding between the 5-nitroso oxygen atom and the neighbor 6-NH hydrogen, which blocks the free rotation of the nitroso group and results in a large downfield shifting for the 4(6)-NH proton NMR signals (10-13 ppm in DMSO)
    CrossrefGoogle Scholar
  • 12a Brown DJ. The Pyrimidines, In The Chemistry of Heterocyclic Compounds   Vol. 52:  Taylor EC. Weissberger A. John Wiley & Sons; New York: 1994.  p.305-306  
    Google Scholar
  • 12b Brown DJ. The Pyrimidines, In The Chemistry of Heterocyclic Compounds   Suppl. I:  Taylor EC. Weissberger A. John Wiley & Sons; New York: 1970.  p.102-103  
    Google Scholar
  • 12c Brown DJ. The Pyrimidines, In The Chemistry of Heterocyclic Compounds   Suppl. II:  Taylor EC. Weissberger A. John Wiley & Sons; New York: 1985.  p.147-150  
    Google Scholar
  • 13a
    Google Scholar
  • Compound 1h was obtained by treatment of 2-amino-4,6-dimethoxypyrimidine (1b) with benzyl chloride and potassium hydroxide in toluene at 80 ºC. Compound 1i was prepared by treatment of 6-amino-2-methylthiopyrimidin-4(3H)-one with dimethyl sulfate/NaOH according to:
  • Johns CO. Hendrix BM. J. Biol. Chem.  1951,  20:  153 
    Google Scholar
  • 13b
    Google Scholar
  • Compound 1j was obtained by Raney-nickel desulfurization from pyrimidine 1i according to:
  • Pfleiderer W. Liedek E. Ann.  1958,  612:  163 
    Google Scholar
  • 14a Lythgoe B. Todd AR. Topham A. J. Chem. Soc.  1944,  315 
    Google Scholar
  • 14b Evans RM. Jones PG. Palmer PJ. Stephens EF. J. Chem. Soc.  1956,  4106 
    Google Scholar
  • 15 Zvilichovsky G. Feingers J. J. Chem. Soc., Perkin Trans. 1  1976,  1507 
    CrossrefGoogle Scholar
  • 16 Pfleiderer W. Chem. Ber.  1957,  90:  2272 
    Google Scholar
  • 17 Schreider H.-J. Pfleiderer W. Chem. Ber.  1974,  107:  3377 
    Google Scholar
  • 18 Engelmann M. Ber. Dtsch. Chem. Ges.  1909,  42:  177 
    Google Scholar
  • 19 Sánchez A. Nogueras M. López R. Gutiérrez M. Colacio E. Thermochim. Acta  1988,  91:  173 
    Google Scholar
  • 20 Nogueras M. López R. Gutiérrez MD. Sánchez, A. J. Therm. Anal.  1988,  34:  1335 
    Google Scholar
  • 23 Low JN. Marchal A. Nogueras M. Melguizo M. Sánchez A. Acta Crystallogr.  2001,  C57:  178 
    Google Scholar
  • 24 Melguizo M. Nogueras M. Sánchez A. Synthesis  1992,  491 
    Article in Thieme ConnectGoogle Scholar
5

Melguizo, M.; Marchal, A.; Nogueras, M.; Sánchez, A.; Low, J. ”Aminolysis of Methoxy Groups in Pyrimidine Derivatives. Activation by 5-Nitroso Group", J. Heterocycl. Chem. in press.

9

When the reaction was performed under the same conditions but in the presence of a catalytic amount of acetic or trifluoroacetic acid, a complex mixture of colored compounds, synthetically useless, was obtained.

11

Compound 1d was obtained by selective O6-alkylation of 6-amino-2-methoxypyrimidin-4(3H)-one under Mitsunobu conditions (i-PrOH/DEAD/Ph3P) in acetonitrile; 1e was prepared by treatment of 6-amino-2-methoxypyrimidin-4(3H)-one with benzyl chloride and potassium carbonate in DMSO; 1f and 1g were prepared by nucleophilic substitution with sodium benzylate in benzyl alcohol from 4-amino-2,6-dichloropyrimidine and 2-amino-4,6-dichloropyrimidine, respectively.

21

The 1H and 13C NMR signals of the newly formed species coincided with those of an original sample of isoamyl alcohol. On the other hand, the broad signal at 3.69 ppm assigned to H2O traces present in DMSO-d 6 moved to 5.70 ppm (broad signal) assigned to the alcohol exchangeable proton.

22

A study on the nucleophilic substitution of methoxide groups of compounds 2 by different amines is currently under preparation in our laboratory and will be the subject of another report in near future. The easy substitution by the bulky 1-adamantylamino group is here anticipated in order to illustrate the synthetic potential of the products prepared by the nitrosation procedure described here.