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

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 
• 1b Pfleiderer W. In Comprehensive Heterocyclic Chemistry II   Vol. 7:  Ramsdem DA. Katritzky AR. Rees CW. Scriven EFW. Pergamon Press; Oxford: 1996.  p.679 
• 1c Melguizo M. Nogueras M. Sánchez A. J. Org. Chem.  1992,  57:  559 
• 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 
• 3a Chae M.-Y. Swenn K. Kanugula S. Dolan M. Pegg AE. Moschel RC. J. Med. Chem.  1995,  38:  359 
• 3b Terashima I. Kohda K. J. Med. Chem.  1998,  41:  503 
• 4a Gray N. Detivaud L. Doerig D. Meijer L. Curr. Med. Chem.  1999,  6:  859 
• 4b Walker DH. Curr. Top. Microbiol. Immunol.  1998,  227:  149 
• 4c Garrett MD. Fattaey A. Curr. Opin. Genet. Dev.  1999,  9:  104 
• 6 Ritzmann G. Ienaga K. Kiriasis L. Pfleiderer W. Chem. Ber.   1980.  113:  p.1535 
• 7 Moodie RB. O’Sullivan B. J. Chem. Soc., Perkin Trans.  1995,  2:  205 
• 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 
• 8b

  1b was purchased from Adrich.

• 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 
• 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)
• 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  
• 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  
• 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  
• 13a
• 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 
• 13b
• Compound 1j was obtained by Raney-nickel desulfurization from pyrimidine 1i according to:
• Pfleiderer W. Liedek E. Ann.  1958,  612:  163 
• 14a Lythgoe B. Todd AR. Topham A. J. Chem. Soc.  1944,  315 
• 14b Evans RM. Jones PG. Palmer PJ. Stephens EF. J. Chem. Soc.  1956,  4106 
• 15 Zvilichovsky G. Feingers J. J. Chem. Soc., Perkin Trans. 1  1976,  1507 
• 16 Pfleiderer W. Chem. Ber.  1957,  90:  2272 
• 17 Schreider H.-J. Pfleiderer W. Chem. Ber.  1974,  107:  3377 
• 18 Engelmann M. Ber. Dtsch. Chem. Ges.  1909,  42:  177 
• 19 Sánchez A. Nogueras M. López R. Gutiérrez M. Colacio E. Thermochim. Acta  1988,  91:  173 
• 20 Nogueras M. López R. Gutiérrez MD. Sánchez, A. J. Therm. Anal.  1988,  34:  1335 
• 23 Low JN. Marchal A. Nogueras M. Melguizo M. Sánchez A. Acta Crystallogr.  2001,  C57:  178 
• 24 Melguizo M. Nogueras M. Sánchez A. Synthesis  1992,  491 

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.