S. Buscemi et al. / Tetrahedron 62 (2006) 1158–1164
1163
was treated with H2O2 (30%; 1 ml, in two portions) and
stirred at 50–60 8C for 5 h. The mixture was diluted with
water. After evaporation under vacuum to remove the
solvent and acetic acid, crystallization of the residue gave
1b (0.09 g, 47%).
5.6.2. Reaction of 3-Amino-5-methyl-1,2,4-oxadiazole 7
with 1,1,1-trifluoro-2,4-pentandione 8a. Chromatography
of the residue returned 3-amino-5-methyl-1,2,4-oxadiazole
7 (0.15 g, 30%) and gave: 2-amino-4-methyl-6-trifluoro-
methyl-pyrimidine-1-oxide 1c (0.48 g, 50%), 2-(hydroxy-
amino)-6-methyl-4-trifluoromethyl-pyrimidine 14c (0.12 g,
12%) and O-Acetyl-2-(hydroxlamino)-6-methyl-4-trifluoro-
methyl-pyrimidine 13c (0.06 g, 5%).
5.5. Hydrogenation of 2-amino-6-methyl-4-trifluoro-
methyl-pyrimidine-1-oxide (1b)
Compound 1c had mp 214–215 8C (white crystals, from
EtOH); [Found: C, 37.20; H, 3.10; N, 21.70. C6H6F3N3O
requires C, 37.31; H, 3.13; N, 21.76%]; nmax (Nujol) 3366,
Hydrogenation of compound 1b (0.19 g, 1 mmol) was
carried out in the Parr apparatus (40 psi) for 1 h in EtOH
(50 ml), in the presence of palladium-on-charcoal (10%;
0.1 g). The solution was filtered and evaporated under
reduced pressure. The residue was crystallized from water
giving 2-amino-6-methyl-4-trifluoromethyl-pyrimidine 2b
(0.17 g, 95%) mp 128–129 8C (from water) (lit.14 128 8C).
3298, 3238, 1651, 1632 cmK1 1H NMR (250 MHz,
;
DMSO-d6) d 2.39 (3H, s, CH3), 7.13 (1H, s, ArH), 8.06
(2H, exch. with D2O, s, NH2); GC/MS m/z 193 (MC, 100),
177 (25), 130 (15), 69 (37), 43 (51); HRMS (MC1) found
194.0537. C6H6F3N3O 1requires 93.0463,
Compound 14c had mp 135–137 8C (white crystals, from
EtOH); [Found: C, 37.20; H, 3.20; N, 21.70. C6H6F3N3O
requires C, 37.31; H, 3.13; N, 21.76%]; nmax (Nujol) 3298,
5.6. Reaction of 3-Amino-5-methyl-1,2,4-oxadiazole 7
with fluorinated diketones 8a,c and perchloric acid
in acetonitrile. General procedure
1
3229, 1601 cmK1; H NMR (250 MHz, DMSO-d6) d 2.46
(3H, s, CH3), 7.07 (1H, s, ArH), 9.00 (1H, exch. with D2O, s,
NH), 10.09 (1H, exch. with D2O, s, OH); GC/MS m/z 194
(MCC1, 100), 193 (MC, 70), 177 (22), 174 (8), 163 (64),
143 (19), 113 (19), 69 (19), 43 (32); HRMS (MC1) found
194.0528. C6H6F3N3O requires 193.0463.
To a mixture of 3-amino-5-methyl-1,2,4-oxadiazole 7
(0.5 g, 5 mmol) and the appropriate fluorinated diketone
8a (1.04 g, 5 mmol) or 8c (0.77 g, 5 mmol) in acetonitrile
(3 ml), perchloric acid (70%, 2 ml) was added. After 24 h at
rt, the mixture was diluted with water, neutralized with solid
NaHCO3 and then extracted with EtOAc (3!200 ml). The
combined organic layers were dried over Na2SO4 and
evaporated.
Compound 13c had mp 82–83 8C (white crystals, from
EtOH); [Found: C, 40.80; H, 3.40; N, 17.90. C8H8F3N3O2:
C, 40.86; H, 3.43; N, 17.87%]; nmax (Nujol) 3186,
1
1788 cmK1; H NMR (259 MHz, DMSO-d6) d 2.46 (3H,
5.6.1. Reaction of 3-amino-5-methyl-1,2,4-oxadiazole 7
with 1,1,1,5,5,5-hexafluoro-2,4-pentandione 8a. Chroma-
tography of the residue returned 3-amino-5-methyl-1,2,4-
oxadiazole 7 (0.19 g, 38%) and gave: 2-amino-4,6-
bis(trifluoromethyl)-pyrimidine-1-oxide 1a (0.26 g, 21%),
2-(hydroxyamino)-4,6-bis(trifluoromethyl)-pyrimidine 14a
(0.48 g, 39%), O-Acetyl-2-(hydroxyamino)-4,6-bis(trifluoro-
methyl)-pyrimidine 13a (0.03 g, 2%).
s, COCH3), 2.53 (3H, s, CH3), 7.36 (1H, s, ArH), 11.37 (1H,
exch. with D2O, s, NH); GC/MS m/z 236 (MC1, 100), 193
(11), 162 (6), 44 (24).
5.7. Synthesis of 2-chloro-4,6-bistrifluoromethyl-
pyrimidine 15a
A mixture of 4,6-bis(trifluoromethyl)-1H-pyrimidin-2-
one18(1.5 g, 6.4 mmol) and POCl3 (4.38 g, 3 ml) was
refluxed for 4 h. The mixture was then neutralized with
NaOH 8 M and extracted with Et2O (400 ml). The organic
layer was dried over Na2SO4 and evaporated at rt
Distillation of the residue gave 2-chloro-4,6-bis(trifluoro-
methyl)-pyrimidine 15a (0.7 g, 44%) as a colourless oil;
[Found: C, 28.70; H, 0.40; N, 11.10. C6HClF6N2: C, 28.80;
Compound 1a had mp 137–138 8C (white crystals, from
EtOH); [Found: C, 29.00; H, 1.10; N, 16.90. C8H5F6N3O
require C, 29.16; H, 1.22; N, 17.01%]. nmax (Nujol) 3425,
3325, 3132, 1666, 1651 cmK1 1H NMR (250 MHz,
;
DMSO-d6) d 7.54 (1H, s, ArH), 8.70 (2H, exch. with
D2O, s, NH2); GC/MS m/z 248 (MC1), 247 (58), 231 (5), 69
(10).
1
H, 0.40; N, 11.20%]; H NMR (259 MHz, CDCl3) d 7.51
(1H, s, ArH); MS m/z 252 (MC2, 34), 250 (M, 100), 227
(86).
Compound 14a had mp 97–98 8C (yellowish crystals, from
EtOH); [Found: C, 29.10; H, 1.20; N, 17.00. C6H5F6N3O
requires C, 29.16; H, 1.22; N, 17.01%], nmax (Nujol) 3328,
3280, 1612, 1595 cmK1; 1H NMR (250 MHz, DMSO-d6) d
7.52 (1H, s, ArH), 9.52 (1H, exch. with D2O, s, NH), 11.02
(1H, exch. With D2O, s, OH); GC/MS m/z 247 (MC, 100),
231 (24), 228 (16), 69 (67).
5.8. Synthesis of 2-chloro-6-methyl-4-trifluoromethyl-
pyrimidine 15c19
A sample of 2-amino-6-methyl-4-trifluoromethyl-pyrimidine
2b14 (1.8 g, 10 mmol) was dissolved under good stirring in
concentrated hydrochloric acid (5 ml) at 0 8C to give an
homogenous solution. Sodium nitrite (1.03 g, 15 mmol) was
then added during 30 min at 0 8C. After gas evolution
occurred, the solution was stirred for additional 3 h. The
solution was then neutralized with NaOH 8 M and extracted
with ethyl acetate (3!200 ml). The combined organic
layers were dried over Na2SO4 and evaporated.
Compound 13a had mp 89–90 8C (white crystals, from
EtOH); [Found: C, 33.10; H, 1.70; N, 14.40. C8H5F6N3O2
requires C, 33.23; H, 1.74; N, 14.53%]; nmax (Nujol) 3244,
1799 cmK1; 1H NMR (250 MHz, DMSO-d6) d 2.29 (3H, s,
COCH3), 7.85 (1H, s, ArH), 12.26 (1H, exch. with D2O, s,
NH); GC/MS m/z 290 (MC1, 28), 248 (4), 70 (5), 43 (100).