N. Zanatta et al. / Tetrahedron Letters 47 (2006) 573–576
575
6. Hudlicky, M. Chemistry of Organofluorine Compounds;
Ellis Horwood: Chichester, 1992.
25 °C, for 8 h. Compounds 9 and 10 were obtained as
dark solids and were recrystallized from a mixture of
hexane/ethyl acetate to give white solids in good yields.
Compound 11 was obtained from the reaction of 6a with
2 equiv of thiophenol and triethylamine in benzene for
8 h at 40 °C. Compounds 12–14 were obtained from
the reaction of 6a with 2 equiv of morpholine, piperi-
dine, and diethylamine, respectively, in dry acetone for
16 h at room temperature. An excess of the nucleophiles
(e.g., 2:1) was used to improve yields. When the reaction
of the pyrimidine 6a with amines was carried out in the
same molar ration, in the presence of triethylamine,
lower yields were obtained and impurities were
observed. Compound 15 was obtained by stirring the
pyrimidine 6a with pyridine, used as solvent, at room
temperature for 48 h. Compound 15 was isolated by
precipitation in dichloromethane and analyzed without
further purification. Compound 16 was obtained by
stirring the pyrimidine 6a with 2 equiv of 2-dimethyl-
aminoethanol in acetone, at room temperature for 4 h.
Compound 11 was oxidized with 3-chloroperoxybenzoic
acid in chloroform to give the disulfonyl 17 in good
yields. All compounds were analyzed by 1H and 13C
NMR, GC–MS, and some representative compounds,
also by elemental analysis.20
7. Pierce, M. E.; Parsons, R. L.; Radesca, L. A.; Lo, Y. S.;
Silverman, S.; Moore, J. R.; Islam, Q.; Choudhury, A.;
Fortunak, J. M. D.; Nguyen, D.; Luo, C.; Morgan, S. J.;
Davis, W. P.; Confalone, P. N.; Chen, C.; Tillyer, R. D.;
Frey, L.; Tan, L.; Xu, F.; Zhao, D.; Thompson, A. S.;
Corley, E. G.; Grobowski, E. J. J.; Reamer, R.; Reider, P.
J. J. Org. Chem. 1998, 63, 8536–8543.
8. Welch, J. T. Tetrahedron 1987, 43, 3123–3197.
9. Souza, F. R.; Fighera, M. R.; Lima, T. T. F.; Bastiani, J.;
Barcellos, I. B.; Almeida, C. E.; Oliveira, M. R.; Bona-
corso, H. G.; Flores, A. E.; Mello, C. F. Pharmacol.,
Biochem. Behav. 2001, 68, 525–530.
10. Schetinger, M. R. C.; Porto, N. M.; Moretto, M. B.;
Morsch, V. M.; Rocha, J. B. T.; Vieira, V.; Moro, F.;
Neis, R. T.; Bittencourt, S.; Bonacorso, H. G.; Zanatta, N.
Neurochem. Res. 2000, 25, 949–955.
11. Rubin, M. A.; Albach, C. A.; Berlese, D. B.; Bonacorso,
H. G.; Bittencourt, S. R. T.; Queiroz, C. M. T.; Maixner,
A. E.; Mello, C. F. Braz. J. Med. Biol. Res. 2000, 33, 1069–
1073.
12. Souza, F. R.; Souza, V. T.; Ratzlaff, V.; Borges, L. P.;
Oliveira, M. R.; Bonacorso, H. G.; Zanatta, N.; Martins,
M. A. P.; Mello, C. F. Eur. J. Pharmacol. 2002, 451, 141–
147.
13. Murray, P. E.; McNally, V. A.; Lockyer, S. D.; Williams,
K. J.; Stratford, I. J.; Jaffar, M.; Freeman, S. Bioorg. Med.
Chem. 2002, 10, 525–530.
In summary, this work showed a simple and efficient
method to obtain the title compounds in two reaction
steps from the halogenated building block approach.
This method shows a clear advantage over the method
reported in the literature where the synthesis of 6-meth-
ylenesubstituted uracil derivatives was obtained in five
reaction steps starting from the 6-methyl uracil.13 This
work also showed that the direct halogenation of the
pyrimidine side methyl group led to a mixture of mono-
and dihalogenated compounds of difficult separation
and, therefore, of limited use to obtain the title
compounds.
14. Zanatta, N.; Madruga, C. C.; Clerice, E.; Martins, M. A.
P. J. Heterocycl. Chem. 1995, 32, 735–738.
15. Gershon, H.; Grefig, A. T.; Scala, A. A. J. Heterocycl.
Chem. 1983, 219–224.
16. Strekowski, L.; Wydra, R. L.; Jandra, L.; Harden, D. B. J.
Org. Chem. 1991, 56, 5610–5614.
17. Badawey, E.-S. A. M. J. Heterocycl. Chem. 1996, 1003–
1015.
18. Martins, M. P. P.; Sinhorin, A. P.; Zimmermann, N. E.
K.; Zanatta, N.; Bonacorso, H. G.; Bastos, G. P. Synthesis
2001, 1959–1964.
19. Martins, M. A. P.; Cunico, W.; Pereira, C. M. P.;
Sinhorin, A. P.; Flores, A. F. C.; Bonacorso, H. G.;
Zanatta, N. Curr. Org. Synth. 2004, 1, 391–403.
20. Physical and spectral data of selected compounds:
Compound 6a: Yield 60%. dH (400 MHz, CDCl3): 2.62 (s,
3H, SCH3), 4.52 (s, 2H, CH2Br), 7.80 (s, 1H, H-5); dC
(100 MHz; CDCl3): 14.3 (SCH3), 50.0 (CH2Br), 95.5
(CCl3), 108.7 (C5), 167.0 (C4), 167.9 (C2), 173.3 (C6).
GC–MS (EI, 70 eV) m/z (%): 334 (M+, 1), 290 (30), 255
(100), 219 (40).
Acknowledgements
The authors thank the financial support from the Con-
´
selho Nacional de Desenvolvimento Cientıfico e Tec-
´
nologico—CNPq (Universal Grant No. 477682/01-4),
fellowships (D.C.F.), and fellowships from CAPES
(C.C.M.).
Compound 6b: Yield 70%; mp 54–57 °C (hexane). dH
(400 MHz; CDCl3): 1.83 (d, 3H, CH3), 2.62 (s, 3H, SCH3),
5.03 (qua, 1H, CH), 7.77 (s, 1H, H5). dC (100 MHz;
CDCl3): 14.3 (SCH3), 24.2 (CH3), 57.1 (CHBr), 94.5
(CCl3), 107.6 (C5), 166.9 (C4), 171.8 (C2), 173.2 (C6).
GC–MS (EI, 70 eV) m/z (%): 304 (M+À44, 29) 269 (100),
233 (71).
Compound 6c: Yield 65%. dH (400 MHz; CDCl3): 2.54 (s,
3H, SCH3), 6.50 (s, 2H, CHBr2) 7.60 (s, 1H, H-5). dC
(100 MHz; CDCl3): 14.3 (SCH3), 69.3 (CHBr2), 95.1
(CCl3), 107.1 (C5), 167.9 (C4), 168.5 (C2), 173.6 (C6).
GC–MS (EI, 70 eV) m/z (%): 254 (M+À158, 100), 219
(32).
References and notes
1. Lednicer, D.; Mitscher, L. A. The Organic Chemistry of
Drug Synthesis; Pergamon Press: NY, 1980; Vol. 2, p 79;
Lednicer, D.; Mitscher, L. A. The Organic Chemistry of
Drug Synthesis; Pergamon Press: NY, 1980; Vol. 3, p 152.
2. Botta, M.; Corelli, F.; Maga, G.; Manetti, F.; Renzulli,
M.; Spadari, S. Tetrahedron 2001, 57, 8357–8367.
3. Garg, R.; Gupta, S. P.; Gao, H.; Babu, M. S.; Debnath, A.
K.; Hansch, C. Chem. Rev. 1999, 99, 3525–3601.
4. Botta, M.; Occhionero, F.; Nicoletti, R.; Mastromarino,
P.; Conti, C.; Magrini, M.; Saladino, R. Bioorg. Med.
Chem. 1999, 7, 1925–1931.
5. Filler, R.; Kobayashi, Y.; Yagupolski, L. M. Fluorine in
Biorganic Chemistry; Elsevier: Amsterdam, 1993.
Compound 7a: Yield 60%. dH (400 MHz; CDCl3): 2.61 (s,
3H, SCH3), 4.62 (s, 2H, CH2Br), 7.50 (s, 1H, H5). dC
(100 MHz; CDCl3): 14.0 (SCH3), 44.7 (CH2Br), 109.6
(C-5, 4JC4–F = 2.6), 120.3 (CF3, 1JC–F = 285.0 MHz), 156.7
2
(C-4, JC–F = 36.0 MHz), 167.8 (C2), 174.3 (C6). GC–MS
(EI, 70 eV) m/z (%): 207 (M+À79, 100), 196 (10), 136 (25).