Synthesis of trifluoromethyl-1,2,4-triazine- and trifluoromethylpyrimidine- fused uracils

Article abstract of DOI:10.1002/jhet.5570450249

(Chemical Equation Presented) A variety of trifluoromethyl-1,2,4-triazine- and trifluoromethylpyrimidine-fused uracils (9), (12), (15) and (18) were synthesized from trifluoroacetaldehyde ethyl hemiacetal or trifluoroacetic anhydride and corresponding uracil derivatives.

Full text of DOI:10.1002/jhet.5570450249

Mar-Apr 2008
601
Synthesis of Trifluoromethyl-1,2,4-triazine- and
Trifluoromethylpyrimidine-Fused Uracils
Masahiko Takahashi*, Kazuhiko Akiyama, Takumi Suzuki and Hiroshi Inoue
Department of Materials Science, Faculty of Engineering, Ibaraki University, Hitachi, Ibaraki 316-8511, Japan
Received May 17, 2007
O
O
O
O
CF3
O
Me
O
R
Me
O
X
Y
Me
O
N
N
CF3
Me
O
Me
O
N
N
R
N
N
N
N
N
N
N
N
N
N
N
CF3
N
N
N
N
R
N
CF3
Me
Me
Me
Me
Me
X=H, Y=NHNH2
X=H, Y=NH2
R=C6H5, 4-MeC6H4
4-MeOC6H4, 4-ClC6H4
R=C6H5, 4-MeC6H4
R=C6H5, Me, H
4-MeOC6H4, 4-ClC6H4
PhCH2, PhCH2CH2
X=CHO, Y=NH2
A variety of trifluoromethyl-1,2,4-triazine- and trifluoromethylpyrimidine-fused uracils (9), (12), (15)
and (18) were synthesized from trifluoroacetaldehyde ethyl hemiacetal or trifluoroacetic anhydride and
corresponding uracil derivatives.
J. Heterocyclic Chem., 45, 601 (2008).
interesting from the point of view of biological activities
and chemical behavior.
INTRODUCTION
Heterocycles containing fluorine and/or perfluoroalkyl
groups have been target compounds because of their
broad array of biological activities and specific chemical
reactivities [1]. In our previous paper, we described the
synthesis of condensed uracil derivatives having a
trifluoromethyl group, i.e., 5-trifluoromethylpyrido[2,3-d]-
pyrimidine-2,4-diones (1) [2] and 4-trifluoromethyl-
pyrimido[4,5-c]pyridazine-5,7-diones (2) [3] (Figure 1).
Through the course of these studies we have prepared
uracils condensed with trifluoromethyl-1,2,4-triazines (9)
and (12) and with trifluoromethylpyrimidines (15) and (18).
Antibiotic fervenulin (6,8-dimethyl-5,6,7,8-tetrahydro-
pyrimido[5,4-e]-1,2,4-triazine-5,7-dione) (3) [4], toxo-
flavin (4) [5], and isofervenulin (5,7-dimethyl-5,6,7,8-
Several methods for synthesis of 3-substituted
fervenulins have been published: the reaction of 5-
arylazo-6-arylidenehydrazinouracils with dimethylform-
amide diethylacetal [7], the reaction of 6-hydrazino-5-
nitrosouracil with aldehydes [4a,c], cyclization of the
adduct of 6-arylidenhydrazinouracil [8] to diethyl
azodicarboxylate, the cyclization of 6-hydrazono-5-
nitrosouracil [9], and the reaction of 6-amino-5-
nitrosouracil with hydrazones [10]. We have synthesized
3-trifluoromethylfervenulin (9) principally according to
Senga’s method [4a] (Scheme 1). Trifluoroacetaldehyde
hydrazone (7) [3], prepared from 6-hydrazino-1,3-
dimethyluracil (6) and trifluoroacetaldehyde ethyl
hemiacetal, was treated with isopentyl nitrite in ethanol to
give 9 in one step in 44% yield. The 13C nmr spectrum of
9 showed two quartet resonances at δ 119.30 (1JCF=274
Hz) and 153.74 (2JCF=38.0 Hz) ppm due to the
trifluoromethyl carbon and the aromatic C3-carbon,
respectively. The reaction would proceed via nitrosation
to give the intermediate (8) followed by dehydration to 9
as reported in the synthesis of 3-substituted fervenulin
[4a,9a].
tetrahydropyrimido[4,5-e]-1,2,4-triazine-6,8-dione)
[6] have been prepared by various methods. Introduction
of a trifluoromethyl group into these compounds seems
(5)
O
CF3
O
CF3
R1
O
R
O
Ar
N
N
N
N
R2
N
Ph
N
R
N
O
1
2
Derivatives of isofervenulin (5) have been prepared by
the cyclization of 1-cyano-2-methyl-3-(6-uracilyl)iso-
thiourea derivatives [11], 4-chloro-1,2,4-triazine-3-
carboxylate [6a], 6-amino-5-arylazouracils [12], and 6-
amino-5-nitrosouracil [6c], and from the addition product
of uracil to azodicarboxylate diester [6b]. Photooxidation
of 6-(aminomethylene)amino-5-arylazouracils has also
been studied [13]. We have synthesized 2-substitutd 3-
trifluoromethylisofervenulins starting from the readily
O
N
O
N
Me
N
Me
O
N
N
Me
O
N
N
N
N
N
)
N
N
N
O
N
N
Me
Me
Me
fervenulin (
3
)
toxoflavin (
4
)
isofervenulin (5
Figure 1

602
M. Takahashi, K. Akiyama, T. Suzuki and H. Inoue
Vol 45
compounds [17], and it was prepared by treatment of 6-
aminouracil with phosphorus oxychloride/N,N-
followed by heating with
In order to introduce
Scheme 1
OH
O
O
dimethylformamide
trifluoroacetamide.
F3C
Me
N
CF3
Me
O
a
N
OEt
isopentyl-ONO
trifluoromethyl group into the C7 position of 1,3-
dimethylpyrimido[4,5-d]pyrimidine-2,4-diones (15), the
choice of 6-amino-5-iminomethyluracils (14) as the
starting material seems reasonable (Scheme 3). We have
synthesized 6-substituted 7-trifluoromethyl derivatives
(15) in 28-14% yields by heating a mixture of 14,
trifluoroacetaldehyde ethyl hemiacetal, and a catalytic
amount of p-toluenesulfonic acid in dimethyl sulfoxide.
Trial of the reaction under various conditions resulted in
N
O
N
N
N
NHNH2
H
Me
Me
6
7
O
O
O
N
Me
N
N
CF3
Me
CF3
N
N
N
N
O
N
O
N
N
H
Me
Me
1
no improvement in yields. The H nmr spectra of 15a
showed two absorptions due to C7-H at δ 6.14 (q, 3JHF=5.5
8
9
3
Hz, 0.5 H) and 6.15 (q, JHF=5.5 Hz, 0.5 H) and also two
absorptions due to C4-H at 8.12 (s, 0.5H) and 8.13 (s, 0.5
H). Other products have a similar tendency. There would
be two conformational isomers in these products due to
the interaction between a trifluoromethyl group and a
substituent at the N6 position.
available 6-amino-5-arylazouracils (11) [12] obtained
from 6-amino-1,3-dimethyluracil (10) (Scheme 2).
mixture of 11, trifluoroacetaldehyde ethyl hemiacetal, and
a catalytic amount of p-toluenesulfonic acid in N,N-
A
dimethylformamide was refluxed for 5 hours.
After
purification by column chromatography, the desired
products (12a-d) were obtained in 39-58% yields. Nmr
resonances due to the trifluoromethyl group of 12a were
observed at δ 6.46 (q, JHF=5.6 Hz, C3-H) in the H nmr
2
spectrum along with δ 71.48 (q, JCF=32.2 Hz, C3) and
123.00 (q, 1JCF=289 Hz, CF3) in the 13C nmr spectrum.
Scheme 3
O
O
3
1
R
NH2
Me
O
CHO
NH2
Me
O
R
N
N
N
N
N
NH2
Me
Me
Scheme 2
13
14
O
O
N2+Cl-
OH
OEt
R
Me
O
Me
O
N
R
O
N
N
N
N
F3C
Me
O
R
N
N
N
NH2
N
NH2
Me
Me
N
CF3
Me
10
11
15
OH
OEt
O
14
,
15a: R = C6H5
d: R = 4-ClC6H4
b
e
: R = 4-MeC6H4
: R = PhCH2
c: R = 4-MeOC6H4
F3C
Me
N
N
N
R
f: R = PhCH2CH2
N
O
N
CF3
5-Trifluoromethyl
derivatives
of
pyrimido[4,5-
Me
d]pyrimidine-2,4-diones (18) were obtained from 6-
amino-5-trifluoromethyluracil (17), which was prepared
in 90% yield on treatment of 6-aminouracil (16) with
trifluoroacetic anhydride at room temperature. The
problem of acetylation of 6-aminouracils was discussed in
an early report [18], and trifluoroacetyaltion in our
experiment occurred at the C5 position as was expected.
Heating a mixture of 17, benzamidine hydrochloride or
acetamidine hydrochloride, and sodium hydrogen-
carbonate in dimethylformamide at 130-140°C yielded the
expected products 18a and b in rather low yields (15%
and 20%, respectively), whereas formamidine acetate
gave 18c in 66% yield. Attempted cyclization of 17 to
other derivatives of 18 using reagents such as urea,
12
11,
12a: R = C6H5
: R = 4-MeOC6H4
b: R = 4-MeC6H4
c
d: R = 4-ClC6H4
Next, we turned our attention to uracils condensed with
2-trifluoromethylpyrimidine. Cycloaddition reactions of
6-[(dimethylamino)methylene]aminouracil to heterocum-
ulenes [14] or N-sulfonylimines [15] and the aza-Wittig
reaction of iminophosphorane of 6-aminouracil with
isocyanates [16] are recent synthetic approaches to 1,3-
dimethyluracil condensed with a pyrimidine nucleus.
7-Trifluoromethyl-1,3-dimethylpyrimido[4,5-d]pyrimidine-
2,4-dione is the only reported case of our target

Mar-Apr 2008
Trifluoromethylated 1,2,4-triazine- and pyrimidine-fused uracils
603
p-toluensulfonic acid in N,N-dimethylformamide (15 ml) was
refluxed for 5 hours. The reaction mixture was extracted by the
use of water and CHCl3, and the organic layer was separated and
dried over magnesium sulfate. After evaporation of the solvent
the solid residue was separated by column chromatography
(silica gel-chloroform 1:ethyl acetate 1) to give 12a as yellow
prisms, 1.25 g (58%), mp 124-125 °C: ir (potassium bromide):
CO 1722, CO 1678, 1622, 1508, 1223, 1149, 1099 cm-1; 1H nmr
(deuteriochloroform): δ 3.42 (s, 3H, CH3), 3.46 (s, 3H, CH3),
6.46 (q, 3JHF=5.6 Hz, 1H, C3-H), 7.26-7.55 (m, 5H, Ph); 13C nmr
thiourea, amide, thioamide and guanidine resulted in the
formation of an intractable complex mixture probably
because of instability of 17 to heating. During our study,
a 5,5-bis(trifluoromethyl) derivative of this class of
compounds was prepared by the reaction of hexafluoro-
acetone (ethoxycarbonyl)imine with uracil by a Russian
group [19].
Scheme 4
2
(deuteriochloroform): δ 28.54, 29.19, 71.48 (q, JCF=32.2 Hz,
O
1
O
C3), 118.82, 122.66, 123.00 (q, JCF=289 Hz, CF3), 127.01,
Me
O
129.54, 142.65, 147.70, 150.51, 157.79; ms: m/z (%) 339 (M+,
5), 270 (100), 213 (5), 104 (18), 77. Anal. Calcd. for
C14H12N5O2F3: C, 49.56; H, 3.57; N, 20.64. Found: C, 49.59; H,
3.65; N, 20.80.
Me
O
COCF3
NH2
(CF3CO)2O
N
N
N
NH2
N
Me
Me
3-Trifluoromethyl-5,7-dimethyl-2-(4-methylphenyl)-2,3,5,
6,7,8-hexahydropyrimido[4,5-e]-1,2,4-triazine-6,8-dione
(12b). This compound was obtained in a manner similar to that
of 12a by which yellow prisms (39%) were obtained, mp 125-
126 °C (chloroform-hexane); ir (potassium bromide): CO 1724,
CO 1676, 1622, 1500, 1225, 1146, 1097 cm-1; 1H nmr
(deuteriochloroform): δ 2.28 (s, 3H, CH3), 3.41 (s, 3H, CH3),
16
17
H2N
HN
O
CF3
R
Me
N
N
O
N
N
R
3
Me
3.45 (s, 3H, CH3), 6.43 (q, JHF=5.6 Hz, 1H, C3-H), 7.23 (d,
J=9.0 Hz, 2H), 7.42 (d, J=9.0 Hz, 2H); 13C nmr
c: R = H
18a: R = C6H5
b: R = Me
2
(deuteriochloroform): δ 20.93, 28.49, 29.16, 71.71 (q, JCF=32.2
1
Hz, C3), 118.83, 122.26, 123.00 (q, JCF=291 Hz, CF3), 130.06,
In conclusion, trfluoromethyl-1,2,4-triazine- and tri-
fluoromethylpyrimidine-fused uracils, i.e., (9), (12), (15)
and (18) were obtained starting from readily available
uracil derivatives (6), (11), (14) and (17), respectively.
137.27, 140.44, 147.75, 150.57, 157.88. Anal. Calcd. for
C15H14N5O2F3: C, 50.99; H, 3.99; N, 19.82. Found: C, 50.98; H,
4.09; N, 20.01.
3-Trifluoromethyl-2-(4-methoxyphenyl)-5,7-dimethyl-2,3,
5,6,7,8-hexahydropyrimido[4,5-e]-1,2,4-triazine-6,8-dione
(12c). This compound was obtained in a manner similar to that
of 12a by which yellow prisms (49%) were obtained, mp 146-
147 °C (chloroform-hexane); ir (potassium bromide): 1472,
1676, 1620, 1496, 1255, 1228, 1184, 1142 cm-1; 1H nmr
(deuteriochloroform): δ 3.41 (s, 3H, CH3), 3.45 (s, 3H, CH3),
EXPERIMENTAL
All melting points were determined with MRK MEL-TEMP
II and are uncorrected. The ir spectra were measured on a
JASCO FT/IR-420 spectrophotometer. Ms and nmr spectra
were obtained with JEOL JMS DX-300 and JEOL GSX-400,
respectively. Microanalysis was performed with YANACO
CHN-CODER MT-5. Chloroform (carcinogenic) used as a
solvent in the following experiment might easily be substituted
by dichloromethane.
3
6.37 (q, JHF=6.0 Hz, 1H, C3-H), 6.94 (d, J=10.0 Hz, 2H), 7.45
(d, J=10.0 Hz, 2H); 13C nmr (deuteriochloroform): δ 28.48,
2
29.16, 55.62, 72.36 (q, JCF=32.2 Hz, C3), 114.63, 120.90,
1
122.12, 123.00 (q, JCF=289 Hz, CF3), 136.32, 147.74, 150.60,
157.90, 158.75. Anal. Calcd. for C15H14N5O3F3: C, 48.78; H,
3.82; N, 18.96. Found: C, 48.45; H, 3.86; N, 18.92.
3-Trifluoromethyl-6,8-dimethyl-5,6,7,8-tetrahydropyrimido-
[5,4-e]-1,2,4-triazine-5,7-dione (9). A suspension of 7 [3] (250
mg, 1.0 mmol) in ethanol (3 ml) was cooled by ice under
nitrogen and was dropwise added by isopentyl nitrite (129 mg,
1.1 mmoles). The mixture was stirred at room temperature for
21 hours. After evaporation of the solvent, the residue was
recrystallized from chloroform-hexane to give 9 as yellow
needles, 115 mg (44%), mp 130-131 °C; ir (potassium bromide):
CO 1743, CO 1691, 1576, 1294, 1201, 1161 cm-1; 1H nmr
2-(4-Chlorophenyl)-3-trifluoromethyl-5,7-dimethyl-2,3,5,6,
7,8-hexahydropyrimido[4,5-e]-1,2,4-triazine-6,8-dione (12d).
This compound was prepared in a manner to that of 12a by
which yellow prisms (54%) were obtained, mp 151-152 °C
(chloroform-hexane); ir (potassium bromide): CO 1730, CO
1678, 1622, 1518, 1493, 1469, 1415, 1373, 1317, 1223, 1146,
1
1097 cm-1; H nmr (deuteriochloroform): δ 3.42 (s, 3H, CH3),
3
3.46 (s, 3H, CH3), 6.41 (q, JHF=5.5 Hz, 1H, C3-H), 7.41 (d,
J=8.2 Hz, 2H), 7.47 (d, J=8.2 Hz, 2H); 13C nmr (deuterio-
(deuteriochloroform): δ 3.58 (s, 3H, CH3), 3.95 (s, 3H, CH3); 13
C
2
chloroform): δ 28.48, 29.24, 71.30 (q, JCF=32.2 Hz, C3),
1
1
nmr (deuteriochloroform): δ 29.76, 30.35, 119.30 (q, JCF=274
119.83, 122.83 (q, JCF=289 Hz, CF3), 129.63, 132.71, 141.14,
2
Hz, CF3), 131.01, 148.89, 151.52, 153.74 (q, JCF=38.0 Hz, C3),
147.55, 150.38, 157.60. Anal. Calcd. for C14H11N5O2ClF3: C,
44.99; H, 2.97; N, 18.74. Found: C, 45.00; H, 3.14; N, 18.78.
6-Amino-5-[N-(benzyl)iminomethyl]-1,3-dimethyluracil
(14e). This compound was prepared according to the literature
method [16], white needles (52%), mp 167-168 °C (ethanol); ir
(potassium bromide): NH 3286, CO 1707, 1618, 1549, 1495,
157.84; ms: m/z (%) 261 (M+, 61 ), 205 (71), 136 (46), 67 (100).
Anal. Calcd. for C8H6N5O2F3: C, 36.79; H, 2.32; N, 26.82.
Found: C, 36.57; H, 2.48; N, 26.47.
3-Trifluoromethyl-5,7-dimethyl-2-phenyl-2,3,5,6,7,8-hexa-
hydropyrimido[4,5-e]-1,2,4-triazine-6,8-dione (12a). A mixture
of 11a (1.56 g, 6.0 mmoles), trifluoroacetaldehyde ethyl
hemiacetal (1.73 g, 12 mmoles), and a catalytic amount of
1
1450 cm-1; H nmr (deuteriochloroform): δ 3.33 (s, 3H, CH3),
3.37 (s, 3H, CH3), 4.65 (s, 2H, CH2), 5.92 (br s, 1H, NH), 7.24-

604
M. Takahashi, K. Akiyama, T. Suzuki and H. Inoue
Vol 45
1
7.36 (m, 5H, ArH), 8.56 (s, 1H, HC=N). Anal. Calcd. for
C14H16N4O2: C, 61.74; H, 5.93; N, 20.58. Found: C, 61.53; H,
5.87; N, 20.73.
Hz, C7), 94.34, 115.19, 123.28 (q, JCF=290.1 Hz, CF3), 124.70,
135.64, 150.02, 151.87, 153.44, 159.18, 160.59. Anal. Calcd.
for C16H15N4O3F3: C, 52.18; H, 4.11; N, 15.21. Found: C, 52.14;
H, 4.19; N, 15.32.
6-Amino-1,3-dimethyl-5-[N-(2-phenylethyl)iminomethyl]-
uracil (14f). This compound was prepared according to the
literature method [16], white needles (68%), mp 157-158 °C
(ethanol); ir (potassium bromide): NH 3288, CO 1699, 1624,
6-(4-Chlorophenyl)-7-trifluoromethyl-1,3-dimethyl-1,2,3,4,
6,7-hexahydropyrimido[4,5-d]pyrimidine-2,4-dione (15d).
This compound was obtained in a manner similar to that of 15a
by which white powder (21%) was obtained, mp 183-184 °C
(methanol); ir (potassium bromide): CO 1712, CO 1643, 1539,
1483, 1373, 1325, 1282, 1207, 1136, 1093 cm-1; 1H nmr
(deuteriochloroform): δ 3.32 (s, 3H, CH3), 3.42 (s, 3H, CH3),
6.08 (q, JHF=5.3 Hz, 0.5 H, C7-H), 6.09 (q, JHF=5.3 Hz, 0.5 H,
C7-H), 7.26 (d, J=8.8 Hz, 2H), 7.45 (d, J=8.8 Hz, 2H), 8.06 (s,
0.5 H, C5-H), 8.07 (s, 0.5 Hz, C5-H); 13H nmr (deuterio-
1
1545, 1360, 1182 cm-1; H nmr (deuteriochloroform): δ 2.93 (t,
J=7.2 Hz, 2H, CH2), 3.26 (s, 3H, CH3), 3.33 (s, 3H, CH3), 3.71
(t, J=7.2 Hz, 2H), 6.06 (br s, 1H, NH2), 7.18-7.32 (m, 5H, ArH),
8.33 (s, 1H, HC=N). Anal. Calcd. for C15H18N4O2: C, 62.91; H,
6.35; N, 19.57. Found: C, 62.93; H, 6.44; N, 19.85.
3
3
7-Trifluoromethyl-1,3-dimethyl-6-phenyl-1,2,3,4,6,7-hexa-
hydropyrimido[4,5-d]pyrimidine-2,4-dione (15a). A mixture
of 14a [16] (520 mg, 2.0 mmoles), trifluoroacetaldehyde
ethylhemiacetal (640 mg, 4.0 mmoles), and a catalytic amount
of p-toluenesulfonic acid monohydrate in dimethyl sulfoxide (4
ml) was refluxed for 12 hours. The reaction mixture was poured
into a mixed solvent of water and chloroform, and the mixture
was extracted with chloroform. The organic layer was dried
over magnesium sulfate and evaporated to give an oily residue,
which was solidified by addition of methanol. The solid was
collected by filtration and recrystallized from methanol. The
crystals were purified by column chromatography (silica gel- a
mixed solvent of chloroform 1: ethyl acetate 1) to give 15a (190
mg, 28%), light yellow powder, mp 183-184 °C (methanol); ir
(potassium bromide): CO 1712, 1666, 1628, 1597, 1537, 1489,
1308, 1252, 1201, 1174, 1146 cm-1; 1H nmr (deuteriochloro-
2
chloroform): δ 28.68, 29.81, 76.83 (q, JCF=31.2 Hz, C7), 96.26,
124.02 (q, 1JCF=288.5 Hz, CF3), 124.75, 131.17, 134.67, 141.87,
149.67, 152.51, 154.12, 161.21. Anal. Calcd. for C15H12N4O2Cl
F3: C, 48.34; H, 3.25; N, 15.03. Found: C, 48.41; H, 3.37; N,
15.18.
6-Benzyl-7-trifluoromethyl-1,3-dimethyl-1,2,3,4,6,7-hexa-
hydropyrimido[4,5-d]pyrimidine-2,4-dione (15e). This
compound was obtained in a manner similar to that of 15a by
which white needles (21%) were obtained, mp 144-145 °C
(ethanol); ir (potassium bromide): CO 1720, CO 1652, 1635,
1506, 1417, 1389, 1171, 1142 cm-1; 1H nmr (deuteriochloro-
form): δ 3.31 (s, 3H, CH3), 3.32 (s, 3H, CH3), 4.59 (d, J=15.2
Hz, 1H, PhCH), 4.70 (d, J=15.2 Hz, 1H, PhCH), 5.54 (q,
3JHF=5.5 Hz, 1H, C5-H), 7.23-7.44 (m, 4H, ArH), 7.95 (s, 1H,
C5-H); 13C nmr (deuteriochloroform): 27.65, 28.79, 58.93, 73.49
3
form): δ 3.32 (s, 3H, CH3), 3.42 (s, 3H, CH3), 6.14 (q, JHF=5.5
3
2
1
Hz, 0.5 H, C7-H), 6.15 (q, JHF=5.3Hz, 0.5 H, C7-H), 7.30-7.50
(q, JCF=31.7 Hz, C7), 91.97, 123.59 (q, JCF=288.5 Hz, CF3),
128.05, 129.28, 129.47, 132.64, 151.97, 153.38, 160.54, 162.67.
Anal. Calcd. for C16H15N4O2F3: C, 54.54; H, 4.30; N, 15.90.
Found: C, 54.53; H, 4.42; N, 15.76.
(m, 5H, ArH), 8.12 (s, 0.5 H, C5-H), 8.12 (s, 0.5 H, C5-H); 13C
2
nmr (deuteriochloroform): δ 27.81, 28.93, 76.00 (q, JCF=31.7
1
Hz, C7), 94.96, 123.28 (q, JCF=289.1 Hz, CF3), 122.59, 127.98,
130.17, 124.57, 149.40, 151.79, 153.44, 160.51; ms: m/z (%)
338 (M+, 2), 269 (100), 212 (11), 104 (11), 77 (44). Anal.
Calcd. for C15H12O2N4F3: C, 53.26; 3.87; H, 3.87; N, 16.56.
Found: C, 53.20; H, 4.00; N, 16.71.
6-(2-Phenylethyl)-7-trifluoromethyl-1,3-dimethyl-1,2,3,4,
6,8-hexahydropyrimido[4,5-d]pyrimidine-2,4-dione (15f).
This compound was obtained in a manner similar to that of 15a
by which white prisms (23%) were obtained, mp 145-147 °C
(ethanol); ir (potassium bromide) CO 1709, CO 1637, 1539,
7-Trifluoromethyl-1,3-dimethyl-6-(4-methylphenyl)-1,2,3,
4,6,7-hexahydropyrimido[4,5-d]pyrimidine-2,4-dione (15b).
This compound was obtained in a manner similar to that of 15a
by which light yellow powder (26%) was obtained, mp 156-157
°C (methanol); ir (potassium bromide): CO 1662, 1630, 1539,
1491, 1375, 1301, 1282, 1248, 1200, 1144 cm-1; 1H nmr
(deuteriochloroform): δ 2.39 (s, 3H, CH3), 3.32 (s, 3H, CH3),
1
1504, 1415, 1381, 1171, 1142, 1101 cm-1; H nmr (deuterio-
chloroform): δ 2.90-3.03 (m, 2H, CH2), 3.26 (s, 3H, CH3), 3.34
3
(s, 3H, CH3), 3.62-3.37 (m, 2H, CH2), 5.51 (q, JHF=5.6 Hz, 1H,
C7-H), 7.13-7.33 (m, 5H, ArH), 7.65 (s, 1H, C5-H); 13C nmr
(deuteriochloroform): 27.60, 28.78, 35.36, 56.31, 74.33 (q,
1
2JCF=31.2 Hz, C7), 92.00, 123.35 (q, JCF=288.5 Hz, CF3),
3
3.42 (s, 3H, CH3), 6.09 (q, JHF=5.5 Hz, 0.5H, C7-H), 6.19 (q,
127.44, 128.54, 128.97, 135.83, 151.57, 151.94, 153.52, 160.34.
Anal. Calcd. for C17H17N4O2F3: C, 55.73; H, 4.69; N, 15.30.
Found: C, 55.70; H, 4.59; N, 15.46.
3JHF=5.5 Hz, C7-H), 7.18-7.27 (m, 4H, ArH), 8.08 (s, 0.5 H, C5-
H), 8.09 (s, 0.5H, C5-H); 13C nmr (deuteriochloroform): δ 21.01,
27.76, 28.91, 76.13 (q, 2JCF=31.0 Hz, C7), 94.57, 122.56, 123.27
6-Amino-5-trifluoroacetyl-1,3-dimethyluracil (17). To
powdered 16 (3.10 g, 20 mmoles) without a solvent was
dropwise added trifluoroacetic anhydride (14 ml, 101 mmoles)
under nitrogen and the mixture was stirred at room temperature
for 24 hours. The mixture was neutralized with 50% aqueous
sodium hydroxide, and the resulting precipitates were collected
by filtration to give 17 (4.50 g, 90%), white prisms, mp 180-181
°C (methanol); ir (potassium bromide): NH 3338, CO 1728,
1618, 1539, 1444, 1221, 1184, 1140 cm-1; 1H nmr (dimethyl
sulfoxide-d6): δ 3.14 (s, 3H, CH3), 3.34 (s, 3H, CH3), 8.79 (br s,
1H, NH), 10.20 (br s, 1H, NH); 13C nmr (dimethyl sulfoxide-d6):
1
(q, JCF = 289.0 Hz, CF3), 130.65, 138.22, 140.13, 149.61,
151.83, 153.46, 160.56. Anal. Calcd. for C16H15N4O2F3: C,
54.55; H, 4.29; N, 15.90. Found: C, 54.58; H, 4.34; N, 16.09.
7-Trifluoromethyl-6-(4-methoxyphenyl)-1,3-dimethyl-
1,2,3,4,6,7-hexahydropyrimido[4,5-d]pyrimidine-2,4-dione
(15c) This compound was obtained in a manner similar to that
of 15a by which light yellow powder (14%) was obtained, mp
181-182 °C (methanol); ir (potassium bromide): CO 1716, CO
1
1662, 1635, 1493, 1373, 1250, 1203, 1182, 1136 cm-1; H nmr
(deuteriochloroform): δ 3.14 (s, 3H, CH3), 3.32 (s, 3H, CH3),
3
3.84 (s, 3H, CH3), 6.02 (q, JCHF=5.5 Hz, 0.5H, C7-H), 6.03 (q,
1
δ 27.60, 30.10, 87.96, 117.35 (q, JCF=285.9 Hz, CF3), 149.33,
3JHF=5.3 Hz, 0.5H, C7-H), 6.96 (d, J=9.0 Hz, 2H), 7.24 (d, J=9.0
Hz, 2H), 8.03 (s, 0.5 H, C5-H), 8.04 (s, 0.5 H, C5-H); 13C nmr
158.84, 158.87, 175.83 (q, 2JCF=34.9 Hz, CO). Anal. Calcd. for
C8H8N3O3F3: C, 38.25; H, 3.21; N, 16.73. Found: C, 38.53; H,
3.28; N, 16.74.
2
(deuteriochloroform): δ 27.78, 28.93, 55.63, 76.59 (q, JCF=29.6

Mar-Apr 2008
Trifluoromethylated 1,2,4-triazine- and pyrimidine-fused uracils
605
5-Trifluoromethyl-1,3-dimethyl-7-phenyl-1,2,3,4-tetra-
hydropyrimido[4,5-d]pyrimidine-2,4-dione (18a). A mixture
of 17 (502 mg, 2.0 mmoles), benzamidine hydrochloride (626
mg, 4.0 mmoles), and sodium hydrogen carbonate (168 mg, 2.0
mmoles) in N,N-dimethylformamide (5 ml) was heated at 130°C
for 14 hours. After cooling, the mixture was diluted with
chloroform and extracted with water. The organic layer was
dried over magnesium sulfate and evaporated to dryness. The
solid residue was recrystallized from ethyl acetate to give 18a
(83 mg, 15%), white needles, mp 276-277 °C; ir (potassium
bromide): CO 1736, CO 1689, 1570, 1410, 1356, 1225, 1169
Acknowledgements. We thank Ms. Emiko Aizawa, Mr.
Katsutoshi Saitoh and Mr. Kohichi Nomoto, undergraduate
students, for their assistance in the experiment.
REFERENCES AND NOTES
[1] A recent review: Pace, A.; Buscemi, S.; Vivona, N. Org. Prep.
Proced. Int. 2005, 37, 447. Other reviews are summarized in our previous
papers [2], [3].
[2] Takahashi, M.; Nagaoka, H; Inoue, K. J. Heterocycl. Chem.
2004, 41, 525.
[3] Takahashi, M.; Ogawa, Y.; Inoue, K. Heterocycles, 2006, 68,
1875.
[4a] Ichiba, M.; Nishigaki, S.; Senga, K. Heterocycles, 1977, 6, 1921.
[b] Taylor, E. C.; Sowinski, F. J. Org. Chem. 1975, 40, 2321. [c]
Blankenhorn G.; Pfleiderer, W. Chem. Ber. 1972, 105, 3334. [d] Taylor, E.
C.; Sowinski, F. J. Am .Chem. Soc. 1968, 90, 1374.
1
cm-1; H nmr (deuteriotrifluoroacetic acid): δ 3.97 (s, 3H, CH3),
4.33 (s, 3H, CH3), 7.92-8.89 (m, 5H, ArH). Anal. Calcd. for
C15H11N4O2F3: C, 53.57; H, 3.30; N, 16.67. Found: C, 53.85; H,
3.47; N, 16.75.
5-Trifluoromethyl-1,3,7-trimethyl-1,2,3,4-tetrahydro-
pyrimido[4,5-d]pyrimidine-2,4-dione (18b). This compound
was obtained as described above for 18a and was separated by
column chromatography (silica gel-ethyl acetate 1: hexane 1) to
give 18b (20%), white crops, mp 120-121 °C; ir (potassium
[5] Yoneda, F.; Shinomura, K.; Nishigaki, S. Tetrahedron Lett. 1971,
851.
[6a] Bach, A.; Jiang, X.; MacKenna, J.; Prasad, K.; Repic, O.; Shieh,
W.–C. J. Heterocycl. Chem. 2004, 41, 637. [b] Taylor E. C.; Sowinski, F. J.
Org. Chem. 1975, 40, 2329. [c] Yoneda, F.; Nagamatsu, T.; Ogiwara, K.;
Kanahori, M.; Nishigaki, S.; Taylor, E. C. Chem. Pharm. Bull. 1978, 26, 367.
[7] Nishigaki, S.; Ichiba, M.; Fukami, K.; Senga, K. J. Heterocycl.
Chem. 1982, 19, 769.
1
bromide): CO 1726, CO 1682, 1574, 1414, 1392, 1161 cm-1; H
nmr (deuteriochloroform): δ 2.84 (s, 3H, CH3), 3.48 (s, 3H,
CH3), 3.73 (s, 3H, CH3); 13C nmr (deuteriochloroform): δ 26.60,
1
28.84, 30.23, 103.33, 120.02 (q, JCF=274.8 Hz, CF3), 150,43,
[8] Yoneda, F.; Sakuma, Y.; Nagamatsu, T.; Mizumoto, S. J. Chem.
Soc., Perkin Trans. 1 1976, 2398.
2
155.32 (q, JCF=37.5 Hz, C5), 156.95, 157.85, 171.67. Anal.
[9a] Pfleiderer W.; Blankenhorn, G.. Tetrahedron Lett. 1969, 4699.
[b] Yoneda, F.; Kawamura, M.; Nagamatsu, T.; Kuretani, K.; Hoshi, A.; Iigo,
M. Heterocycles, 1976, 4, 1503 .
[10] Yoneda, F.; Kanahori, M.; Ogiwara, K.; Nishigaki, S. J.
Heterocycl. Chem. 1970, 7, 1443.
Calcd. for C10H9N4O2F3: C, 43.80; H, 3.31; N, 20.44. Found: C,
43.79; H, 3.39; N, 20.27.
5-Trifluoromethyl-1,3-dimethyl-1,2,3,4-tetrahydropyrimido-
[4,5-d]pyrimidine-2,4-dione (18c) A mixture of 17 (251 mg,
1.0 mmoles) and formamidine acetate (208 mg, 2.0 mmoles) in
N,N-dimethylformamide (3 ml) was heated with stirring at
140°C for 3 hours. After cooling, water was added to the
reaction mixture and the resulting precipitates were collected by
filtration to give 18c (173 mg, 66%), white crops, mp 182-183
°C (ethyl acetate); ir (potassium bromide): CO 1730, CO 1676,
[11] Lee, I. Y.; Kim, S. Y.; Lee, J. Y.; Yu, C-M.; Lee, D. H.; Gong, Y-
D. Tetrahedron Lett. 2004, 45, 9319.
[12] Yoneda, F.; Higuchi, M. J. Heterocycl. Chem. 1980, 17, 1365.
[13] Yoneda F.; Higuchi, M. Chem. Pharm. Bull. 1977, 25, 2794.
[14] Prajapati D.; Thakur, A. J. Tetrahedron Lett. 2005, 46, 1433.
[15] Gohain, M.; Prajapati, D.; Gogoi, B. J.; Sandhu, J. S. Synlett,
2004, 1179.
[16] Molina, P.; Vilaplana, M. J.; Perez, J. Tetrahedron, 1990, 46,
7855.
[17] Hirota, K.; Kitada, Y.; Sajiki, H.; Maki, Y. Synthesis, 1984, 589.
[18] Shim, J. L.; Niess, R.; Broom, A. D. J. Org. Chem. 1972, 37, 578.
[19] Sokolov, V. B.; Aksinenko, A. Y. Russian Chem. Bull. 2005, 54,
1518; Chem. Abstr. 2006, 145, 336018u.
1
1581, 1496, 1402, 1338 cm-1; H nmr (deuteriochloroform): δ
3.49 (s, 3H, CH3), 3.75 (s, 3H, CH3), 9.21 (s, 1H, C7-H); 13C
nmr (deuteriochloroform): δ 29.00, 30.43, 106.03, 119.98 (q,
1JCF=275 Hz, CF3), 150.16, 155.74 (q, 2JCF=38.0 Hz, C5), 156.69,
157.85, 160.20. Anal. Calcd. for C9H7N4O2F3: C, 41.54; H,
2.71; N, 21.54. Found: C, 41.60; H, 2.83; N, 21.68.