C-H trifluoromethylations of 1,3-dimethyluracil and reactivity of the products in C-H arylations

Article abstract of DOI:10.3987/COM-14-12958

Diverse electrophilic, nucleophilic and radical C-H trifluoromethylations of 1,3-dimethyluracil were systematically studied in order to prepare either 5- or 6-(trifluoromethyl)uracil derivatives. Electrophilic reagents led only to dimeric bis-uracil products, whereas the radical trifluoromethylation by CF ₃SO₂Na in presence of t-BuOOH gave 1,3-dimethyl-5- (trifluoromethyl)uracil (2) in good yield. The 6-(trifluoromethyl)uracil derivative 3 was only prepared in low yield and in a mixture with 2 by Ir-catalyzed borylation followed by treatment with the Togni's reagent. Attempted Pd-catalyzed C-H arylations of 2 in the presence of Cs ₂CO₃ gave mixtures of de-trifluoromethylated products, whereas the reaction with 4-iodotoluene in the presence of CsF gave the desired 6-aryl-5-trifluoromethyluracil derivative 8 in moderate yield and the reaction was not general for other aryl halides.

Full text of DOI:10.3987/COM-14-12958

HETEROCYCLES, Vol. 89, No. 5, 2014
1159
HETEROCYCLES, Vol. 89, No. 5, 2014, pp. 1159 - 1171. © 2014 The Japan Institute of Heterocyclic Chemistry
Received, 7th February, 2014, Accepted, 24th March, 2014, Published online, 4th April, 2014
DOI: 10.3987/COM-14-12958
C-H TRIFLUOROMETHYLATIONS OF 1,3-DIMETHYLURACILAND
REACTIVITY OF THE PRODUCTS IN C-H ARYLATIONS
Miroslava Čerňová,a,b Radek Pohl,b Blanka Klepetářová,b and Michal
Hocek*a,b
a
Department of Organic Chemistry, Faculty of Science, Charles University in
Prague, Hlavova 8, CZ-12843 Prague 2, Czech Republic
b
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the
Czech Republic, Gilead Sciences & IOCB Research Center, Flemingovo nam. 2,
CZ-16610 Prague 6, Czech Republic. e-mail: hocek@uochb.cas.cz
Abstract
–
Diverse electrophilic, nucleophilic and radical C-H
trifluoromethylations of 1,3-dimethyluracil were systematically studied in order to
prepare either 5- or 6-(trifluoromethyl)uracil derivatives. Electrophilic reagents
led only to dimeric bis-uracil products, whereas the radical trifluoromethylation
by
CF3SO2Na
in
presence
(2)
of
in
t-BuOOH
good yield.
gave
The
1,3-dimethyl-5-(trifluoromethyl)uracil
6-(trifluoromethyl)uracil derivative 3 was only prepared in low yield and in a
mixture with 2 by Ir-catalyzed borylation followed by treatment with the Togni's
reagent. Attempted Pd-catalyzed C-H arylations of 2 in the presence of Cs2CO3
gave mixtures of de-trifluoromethylated products, whereas the reaction with
4-iodotoluene
in
the
presence
of
CsF
gave
the
desired
6-aryl-5-trifluoromethyluracil derivative 8 in moderate yield and the reaction was
not general for other aryl halides.
INTRODUCTION
5-(Trifluoromethyl)uracil and –uridine are known as antitumor and antiviral compounds1 and in the past
they were prepared either by heterocyclization2 or by cross-coupling of 5-halogenouracil derivatives with
diverse CF3-M species.3 As fluorinated compounds in general, and trifluoromethyl derivatives of
heterocycles in particular, are of great current interest in medicinal chemistry,4 in recent years, diverse

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HETEROCYCLES, Vol. 89, No. 5, 2014
methodologies of trifluoromethylations have been developed, either based on improved Cu or
Pd-catalyzed cross-coupling reactions of (hetero)aryl halides or boronates,5 or based on direct C-H
activations.The C-H trifluoromethylations can proceed either as metal catalyzed (Cu or Pd) reactions with
either electrophilic6 or nucleophilic7 "CF3" species or as radical reactions with CF3· generated either by
photoredox catalysis,8 Fenton oxidation9 or by reaction with peroxides.10 A two-step procedure based on
Ir-catalyzed C-H borylation followed by electrophilic trifluoromethylation has also been reported.11
Recently we have developed regioselective C-H arylations12 of 1,3-dialkyluracils which in the presence of
Pd catalysts proceeded preferentially at position 5, whereas in presence of CuI at position 6. Also other
groups have extensively studied and used these reactions in synthesis of either 6- or 5-substituted uracil
derivatives.13 However, synthesis of 5,6-disubstituted uracils has never been achieved by these reactions.
Based on the above mentioned biological activities of 5-trifluoromethyluracils, the logical continuation of
our project was to attempt the synthesis of uracil derivatives bearing one trifluoromethyl and one aryl
group at positions 5 and 6 by two consecutive C-H activations.
RESULTS AND DISCUSSION
C-H trifluoromethylation of 1,3-dimethyluracil8a,9a or uracil10 has been previously reported by radical
reactions to proceed at position 5 in good yields. Only trace amounts (<1%) of 6-trifluoromethyluracil
was detected using Fenton oxidation. Therefore, we started our study by systematic screening of diverse
trifluoromethylating agents and conditions in analogy to literature (usually C-H trifluoromethylations of
other heterocycles)6,7 in the presence or in the absence of Cu(I) salts in order to see whether the
trifluoromethylation of dimethyluracil (1) proceeds and what is the regioselectivity if formation of either
5- (2) or 6-(trifluoromethyl)-1,3-dimethyluracil (3) (Scheme 1).
Scheme 1
The study started by screening of electrophilic trifluoromethylating agents. The Umemoto's reagent
(S-(trifluoromethyl)dibenzothiophenium trifluoroborate)7a was used in combination with Pd(OAc)2 and/or
CuI or Cu(OAc)2 in the presence or absence of P(C6F5)3 ligand and/or Cs2CO3 or CsF base in DMF or
DCE at 160 °C. No trifluoromethylation reaction was observed under any of these conditions. Only in the
reaction in the presence of Cu(OAc)2 and TFA, formation of unexpected 5,5- (4) and 5-6-dimers (5) of
1,3-dimethyluracil was observed (Scheme 2). This confirms that the C-H activation at positions 5 and 6 is

HETEROCYCLES, Vol. 89, No. 5, 2014
1161
indeed possible but the oxidative dimerization of the heterocycle is preferred over trifluoromethylation.
The Togni's reagent (3,3-dimethyl-1-(trifluoromethyl)-1,2-benziodoxole)6c was also tried in the presence
of CuOAc, CuTC, Pd(OAc)2 or AuCl with P(C6F5)3 or phenanthroline and Cs2CO3 or LiOH.H2O, but no
trifluromethylation was observed either.
Scheme 2
Next, we tested selected nucleophilic trifluoromethylating agents themselves or after generation of
radicals. Rupert's reagent (CF3SiMe3)7a,b was used in a series of experiments in reaction with 1 in the
presence of Pd(OAc)2, PhI(OAc)2, TEMPO and CsF or in the presence of Cu(OAc)2, phenanthroline,
(CH3)3COOC(CH3)3, (t-BuO)2 and NaOt-Bu but no trifluoromethylation was observed. Only, a reaction of
1 with CF3SiMe3 in the presence of Cu(OAc)2, phenanthroline, Ag2CO3 and KF gave the desired
1,3-dimethyl-5-trifluoromethyluracil (2) in moderate yield of 27%. The reaction of 1 with CF3SO2Na in
the presence of CuI and Cs2CO3 did not work. However, the same reagent under radical conditions in the
presence of t-BuOOH at rt (analogy to ref.10) gave the 5-trifluoromethylated uracil 2 in good yield of 67%
(Scheme 3, X-ray structure in Figure 1). No formation of 6-(trifluoromethyl)uracil (3) was observed in
any of the direct C-H activations.
Scheme 3
Another possible way to trifluoromethylated heterocycles is based on Ir-catalyzed C-H borylation
followed by electrophilic trifluoromethylation.11 Therefore, we have tried to perform the C-H borylation
of 1 with bis(pinacolato)diboron under [{Ir(cod)OMe}2] + di-tert-butylbipyridine (dtbpy) catalysis in

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HETEROCYCLES, Vol. 89, No. 5, 2014
THF. This reaction led to an unseparable mixture of starting compound 1, 5-pinacolatoboryl- (6) and
5,6-bis(pinacolatoboryl)uracil (7) in ca. 2:5:3 ratio. Therefore, the whole reaction mixture was only
evaporated and directly used in the second step in the reaction with the Togni's reagent, in the presence of
CuTC, phenanthroline and LiOH·H2O in air. The two-step sequence then gave
1,3-dimethyl-5-(trifluoromethyl)uracil (2) in 21% and 6-1,3-dimethyl-6-(trifluoromethyl)uracil (3) in 8%.
Any attempted optimization did not improve the yields of the final trifluoromethylated uracils. Since no
6-(pinacolatoboryl)uracil was observed in the reaction mixture after the borylation, the formation of 3
apparently must have resulted from trifluoromethylation (at position 6) and proto-deborylation (at
position 5) of diborylated uracil 7. Altough, no method examined in this paper gave higher yield than the
previously
reported
MacMillan
radical
trifluoromethylation,8a
the
synthesis
of
1,3-dimethyl-5-(trifluoromethyl)uracil (2) by the Baran protocol is also very efficient and it was used for
larger scale synthesis of this compound. On the other hand, the borylation/trifluoromethylation sequence
gave for the first time a trifluoromethylation at position 6 (though in low yield).
Scheme 4
Having sufficient amount of 1,3-dimethyl-5-(trifluoromethyl)uracil (2) in hand, we set up a series of
Pd-catalyzed reactions with 4-iodotoluene to explore the possibility of further C-H arylation at position 6
(Scheme 5, Table 1). At first, the conditions from previously reported C-H arylations of 112 were
attempted. The reaction in the presence of Pd(OAc)2, P(C6F5)3, CuI and Cs2CO3 did not give even a trace
amounts of the desired product 8. Surprisingly, it gave only a mixture of 6-tolyl-1,3-dimethyluracil (9)
and 1,3-dimethyluracil (1) where both products lost the trifluoromethyl group at position 5 (entry 1). The

HETEROCYCLES, Vol. 89, No. 5, 2014
1163
same reaction in the absence of CuI gave the same products in lower yields accompanied by unexpected
phenanthrene-fused uracil 10, as a result of double arylation at positions 5 and 6 followed by oxidative
C-H coupling (entry 2). Also the reaction in presence of pivalic acid and K2CO3 (analogy to ref. 14) led to
formation of de-trifluoromethylated products 9 and 1 (entry 3).
Me
I
Me
O
O
O
O
Me
O
CF3
Me
Me
O
CF
Me
O
3 Pd(OAc)2 (5 mol%)
N
N
N
N
+
+
+ 1
ligand, base,
additive, DMF,
160 °C, 48 h
N
O
N
N
N
Me
Me
9
Me
Me
10
Me
Me
Me
8
2
Scheme 5. C-H arylations of 1,3-dimethyl-5-(trifluoromethyl)uracil (2)
Table 1. C-H arylations of 1,3-dimethyl-5-(trifluoromethyl)uracil (2)
Yield (%)
Entry Ligand
Additive
Base
8
9
10
0
1
1
P(C6F5)3
P(C6F5)3
-
CuI
-
Cs2CO3
Cs2CO3
K2CO3
CsF
0
43
25
18
0
57
30
37
0
2
3a
0
11
0
PivOH
CuI
-
0
4
P(C6F5)3
P(C6F5)3
P(C6F5)3
P(C6F5)3
P(C6F5)3
9
0
5
CsF
0
0
3
0
6
PivOH
CuI
CuI
CsF
5
0
0
0
7
piperidine
DBU
CsF
0
0
0
0
8
9
0
0
0
9
(t-Bu)2PMe·HBF4 CuI
15
25
20
0
0
0
0
10
11
12
-
-
-
CuI
CuTC
-
CsF
0
0
0
CsF
0
0
0
CsF
0
3
0
a 3 mol% Pd(OAc)2, DMA, 110 °C, 24 h
However, when CsF was used as a base in the presence of P(C6F5)3 and CuI, the formation of the desired
5-(trifluoromethyl)-6-tolyluracil 8 (for X-ray structure, see Figure 1) was observed in very low yield and
no CF3 group cleavage was observed (entry 4). The same reaction in the absence of CuI gave the fused
product 10 in low yield (entry 5), whereas the presence of PivOH led to low yield of the desired 8 (entry
6). The reaction in the presence of piperidine as a base did not proceed (entry 7), while the use of DBU

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HETEROCYCLES, Vol. 89, No. 5, 2014
gave low yield of 8 again (entry 8). Some improvement of the yield was achieved by the use of
(t-Bu)2PMe·HBF4 as ligand precursor to give product 8 in 15%. The best conversion was achieved in the
reaction in the presence of CuI and CsF in the absence of any ligand. Under these conditions, desired
product 8 was isolated in 25% yield (entry 10). The use of copper thiophene-2-carboxylate (CuTC) did
not lead to improvement of the yield (entry 11), whereas the absence of any Cu(I) salt led to formation of
10 (entry 12). Prolongation of reaction time, use of microwave irradiation, various temperatures or change
of solvent (DMA) did not lead to any improvement of the reactivity. Attempted applications of the best
conditions (from entry 10) to the analogous reactions of 2 with iodobenzene or 4-iodoanisole did not lead
to any detectable amounts of 6-arylated products so, apparently, the reaction is not general and C-H
arylations with other aryl halides would require complete re-optimization of the conditions. Also
attempted C-H trifluoromethylation (with CF3SO2Na in the presence of tBuOOH) or C-H borylation
(with
bis(pinacolato)diboron
under
[{Ir(cod)OMe}2]
+
di-tert-butylbipyridine)
of
1,3-dimethyl-6-tolyluracil (6) or isomeric 1,3-dimethyl-5-tolyluracil did not lead to any 5,6-disubstituted
uracil products.
Figure 1. Crystal structures of compounds 2 (CCDC 945178) and 8 (CCDC 945179)
Since the C-H arylation reactions in presence of Cs2CO3 led to loss of the CF3 group, it was interesting to
look into possible mechanism of this C-C bond cleavage. Therefore a model reaction in the absence of
aryl halide and catalyst was performed. Thus, 1,3-dimethyl-5-(trifluoromethyl)pyrimidine-2,4(1H,3H)-
dione (2) was treated with Cs2CO3 in DMF at 160 °C. When the reaction was stopped after 3 h using acid
work up, formation of 1,3-dimethyluracil-5-carboxylic acid 11 was observed, whereas, after prolonged
reaction time, dimethyluracil 1 was observed as the major product (by NMR of the crude mixture). To
verify whether the transformation of CF3 to CO2H is a substitution or a "hydrolysis", the same reaction
13
was performed with K2 CO3 which showed no 13C enrichment of product 11 confirming the CF3
"hydrolysis" hypothesis.

HETEROCYCLES, Vol. 89, No. 5, 2014
1165
O
Cs2CO3
DMF
O
Me
O
CO2Cs
H+
Me
O
CF3
N
N
160 °C, 3 h
O
N
N
N
Me
CO2H
Me
Me
2
N
O
O
Cs2CO3
DMF
Me
11
Me
N
160 °C,
24 h
O
N
(NMR)
Me
1
Scheme 6. 1,3-Dimethyl-5-(trifluoromethyl)pyrimidine-2,4(1H,3H)-dione (2) subjected to reaction with
base
CONCLUSIONS
In conclusion, C-H trifluoromethylation of 1,3-dimethyluracil (1) was systematically studied. While
attempted electrophilic trifluoromethylations led to uracil dimers and nucleophilic trifluoromethylations
did not work or gave low conversions, radical trifluoromethylation with CF3SO2Na in the presence of
tBuOOH (analogy to ref.10) gave 1,3-dimethyl-5-(trifluoromethyl)uracil (2) in good yield. C-H borylation
of 1 gave an unseparable mixture of mono- and diborylated products which upon reaction with the Togni's
reagent gave separable mixture of 2 and 1,3-dimethyl-6-(trifluoromethyl)uracil (3). Attempted C-H
arylation of 2 in presence of Cs2CO3 was difficult due to electron withdrawing effect of the CF3 group on
the pyrimidine ring and was also accompanied by cleavage of the CF3 group due to hydrolysis followed
by decarboxylation. C-H arylations of 2 with tolyl iodide in the presence of a Cu(I) salt and CsF gave the
desired 6-aryl-5-CF3-uracil 8 in moderate yields only and the reaction did not work for other aryl halides.
This study shows possible severe limitations of further derivatizations and reactivity of
trifluoromethyl-derivatives of heterocycles which can undergo number of side-reactions resulting from
reactivity and instability of the CF3 group.
EXPERIMENTAL
1,3-Dimethyluracil (1) and all reagents were purchased from commercial suppliers and used without any
further treatment. Dichloromethane, dry DMF, THF and dichloroethane were used as received from
supplier. Cs2CO3 and CsF are extremely hygroscopic and must be kept away from moisture, therefore

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HETEROCYCLES, Vol. 89, No. 5, 2014
were dried at 500 °C under vacuo for 15 minutes prior to each use. All reactions were carried out in
flame-dried glassware with magnetic stirring. All compounds were fully characterized by NMR
spectroscopy and spectra were recorded on a Bruker Avance II 600 (1H at 600.1 MHz, 13C at 150.9 MHz)
1
13
19
or on a Bruker Avance II 500 (499.8 or 500.0 MHz for H, 125.7 MHz for C and 470.3 MHz for F)
spectrometers. The samples were measured in CDCl3 and chemical shifts (in ppm, δ-scale) were
1
referenced to solvent signal for H and 13C (δ(1H) = 7.26 ppm, δ(13C) = 77.0 ppm) and to external
standard C6F6 (-163 ppm) for 19F (1H decoupling), or in D2O solutions with 1,4-dioxane as internal
standard (δ(1H) = 3.75 ppm, δ(13C) = 69.3 ppm). Coupling constants (J) are given in Hz. 1H and 13C
resonances were assigned using H,C-HSQC and H,C-HMBC spectra. IR spectra (wavenumbers in cm-1)
were recorded on a Bruker Alpha FT-IR spectrometer using ATR technique. Melting points were
determined on a Kofler block and are uncorrected. High resolution mass spectra were measured on a LTQ
Orbitrap XL (Thermo Fisher Scientific) spectrometer using EI or ESI ionization technique. X-ray
diffraction experiment of single crystals was carried out on an Xcalibur X-ray diffractometr with CuKα
(λ=1.54180 Å) at 190 K.
1,3-Dimethyl-5-(trifluoromethyl)pyrimidine-2,4(1H,3H)-dione (2)
To a solution of 1.3-dimethyluracil (1) (70.1 mg, 0.5 mmol, 1.0 equiv) and sodium trifluoromethylsulfinate
(234 mg, 1.5 mmol, 3.0 equiv) in CH2Cl2 (2.0 mL) and water (0.8 mL) at 0 ºC was slowly added
tert-butylhydroperoxide (70% solution in water, 0.34 mL, 2.5 mmol, 5.0 equiv) with vigorous stirring under
an air atmosphere. The reaction was allowed to warm to room temperature and monitored by thin layer
chromatography (hexanes / EtOAc 1:1) until completion. Upon consumption of starting material (4 h), the
reaction was partitioned between CH2Cl2 (4.0 mL) and saturated sodium bicarbonate (4.0 mL). The organic
layer was separated, and the aqueous layer was extracted with CH2Cl2 (3 x 4.0 mL). The organic layers were
dried with magnesium sulfate, concentrated, and isolated by column chromatography on 50 g of silica gel in
eluent hexanes / EtOAc 8:2, in 67% yield, as a white crystals from hexanes / EtOAc, mp 100-102 °C (lit15
mp 101-102 °C). 1H NMR (499.8 MHz, CDCl3): 3.37 (s, 3H, CH3-3); 3.49 (s, 3H, CH3-1); 7.67 (q, 1H,
13
JH,F = 1.1, H-6). C NMR (125.7 MHz, CDCl3): 28.03 (CH3-3); 37.77 (CH3-1); 104.17 (q, JC,F = 33.3,
19
C-5); 121.95 (q, JC,F = 269.8, CF3); 143.45 (q, JC,F = 5.8, CH-6); 150.90 (C-2); 158.65 (C-4). F{1H}
NMR (470.3 MHz, CDCl3): -59.99. IR: 1727, 1665, 1648, 1501, 1462, 1391, 1360, 1329, 1215, 1119,
1074, 1021. MS (EI+), m/z (% relative intensity): 42 (43), 56 (10), 60 (8), 75 (10), 91 (7), 103 (5), 123
(31), 132 (13), 150 (33), 160 (10), 179 (4), 188 (34), 208 (M+, 100). HR MS (M+): 208.0462 (calcd for
C7H7N2O2F3 208.0460).
1,3-Dimethyl-6-(trifluoromethyl)pyrimidine-2,4(1H,3H)-dione (3)

HETEROCYCLES, Vol. 89, No. 5, 2014
1167
1.3-Dimethyluracil (1) (70.1 mg, 0.5 mmol), [Ir(cod)(OMe)]2 (1.7 mg, 0.5 mol%), dtbpy (1.4 mg, 1.0
mol%), and B2pin2 (101.6 mg, 0.4 mmol) were placed into an oven-dried sealed vial. The vial was
evacuated and refilled with argon three times. Under flow of argon, dry THF (1.0 mL) was added. The
reaction mixture was stirred at 80 °C for 24 h. After cooling to rt, the reaction mixture was diluted with
CHCl3 and the volatiles were removed under vacuum. To the residue was added CuTc (9.5 mg, 0.05 mmol),
1,10-phenanthroline (18.0 mg, 0.10 mmol), LiOH·H2O (42.0 mg, 1.0 mmol), Togni’s reagent (181.5 mg,
0.55 mmol) and 2.0 mL of CH2Cl2. The reaction mixture was refluxed under an air atmosphere at 50 °C for
22 h. After cooling to rt, the solvent was evaporated under reduced pressure and products were isolated by
column chromatography on silica gel (70 g) in eluent hexanes / EtOAc 8:2. It gave compound 2 (21.8 mg,
1
21%) and compound 3 (8.4 mg, 8%). Compound 3: white powder, mp 84-86 °C (lit16 mp 85-87 °C). H
13
NMR (499.8 MHz, CDCl3): 3.37 (s, 3H, CH3-3); 3.52 (q, 3H, JH,F = 1.3 CH3-1); 6.25 (s, 1H, H-5). C
NMR (125.7 MHz, CDCl3): 28.48 (CH3-3); 32.48 (q, JC,F = 3.6, CH3-1); 102.63 (q, JC,F = 5.6, CH-5);
19
119.45 (q, JC,F = 275.1, CF3); 140.51 (q, JC,F = 34.3, C-6); 151.66 (C-2); 161.05 (C-4). F{1H} NMR
(470.3 MHz, CDCl3): -62.05. IR: 1721, 1684, 1661, 1637, 1498, 1444, 1411, 1377, 1274, 1219, 1178,
1163, 1128, 1077, 1024. MS (EI+), m/z (% relative intensity): 44 (12), 82 (100), 115 (9), 141 (20), 151
(12), 208 (M+, 51). HR MS (M+): 208.0465 (calcd for C7H7N2O2F3 208.0460).
1,1',3,3'-Tetramethyl-[5,5'-bipyrimidine]-2,2',4,4'(1H,1'H,3H,3'H)-tetraone (4) and 1,1',3,3'-
tetramethyl-[4,5'-bipyrimidine]-2,2',4',6(1H,1'H,3H,3'H)-tetraone (5)
In a 5 mL sealed tube, 1.3-dimethyluracil (1) (70.1 mg, 0.5 mmol, 1.0 equiv), Pd(OAc)2 (11.2 mg, 0.05
mmol, 0.1 equiv), Cu(OAc)2 (90.8 mg, 0.5 mmol, 1.0 equiv) and 5-(trifluoromethyl)-dibenzothiophenium
tetrafluoroborate (255.1 mg, 0.75 mmol, 1.5 equiv) were dissolved in 2.5 mL dry CH2Cl2 under air, and then
trifluoroacetic acid (371.5 μL, 5.0 mmol, 10 equiv) was added. The tube was sealed with a cap and the
reaction mixture was stirred at 100 °C for 48 h. After cooling to rt, the volatiles were removed under
vacuum and the residue was purified by column chromatography on 40 g of silica gel in gradient 10% of
hexanes in EtOAc to 100% of EtOAc to afford compound 4 (22.8 mg, 16%) and compound 5 (9.5 mg,
7%). Compound 4: yellowish powder, identical spectroscopic data to those previously described.17 1
H
NMR (499.8 MHz, CDCl3): 3.40 (s, 6H, CH3-3); 3.48 (s, 6H, CH3-1); 8.41 (s, 2H, H-6). 13C NMR (125.7
MHz, CDCl3): 28.33 (CH3-3); 37.58 (CH3-1); 104.03 (C-5); 142.96 (CH-6); 150.68 (C-2); 162.58 (C-4).
IR: 1696, 1647, 1442, 1380, 1344, 1314, 1220, 1192, 1130, 1112, 1006. MS (EI+), m/z (% relative
intensity): 43 (47), 55 (87), 69 (61), 83 (73), 97 (77), 111 (51), 125 (29), 139 (15), 149 (43), 167 (13), 180
(26), 193 (57), 221 (10), 252 (6), 278 (M+, 100). HR MS (M+): 278.1013 (calcd for
C12H14N4O4 278.1015). Compound 5: yellowish powder, identical spectroscopic data to those previously
described.17 1H NMR (499.8 MHz, CDCl3): 3.29 (s, 3H, CH3-1B); 3.37 (s, 3H, CH3-3B); 3.40 (s, 3H,
CH3-3A); 3.50 (s, 3H, CH3-1A); 5.65 (s,1H, H-5B); 7.40 (s, 2H, H-6A). 13C NMR (125.7 MHz, CDCl3):

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HETEROCYCLES, Vol. 89, No. 5, 2014
28.09 (CH3-3B); 28.40 (CH3-3A); 33.57 (CH3-1B); 37.60 (CH3-1A); 103.71 (CH-5B); 108.31 (C-5A);
143.08 (CH-6A); 147.56 (C-6B); 151.00 (C-2A); 152.14 (C-2B); 160.34 (C-4A); 162.33 (C-4B). IR:
1707, 1649, 1607, 1440, 1402, 1379, 1350, 1189, 1102, 1083, 1011. MS (ESI+), m/z (% relative intensity):
279 (M++H, 100), 579 (2M++Na, 11). HR MS (M++H): 279.10882 (calcd for C12H15O4N4 279.10878).
1,3-Dimethyl-6-(p-tolyl)-5-(trifluoromethyl)pyrimidine-2,4(1H,3H)-dione (8)
Dry DMF (2 mL) was added through a septum to an argon purged vial containing a
1,3-dimethyl-5-(trifluoromethyl)pyrimidine-2,4(1H,3H)-dione (2) (62.4 mg, 0.3 mmol), 4-iodotoluene
(130.8 mg, 0.6 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol, 5 mol %), CuI (171.4 mg, 0.9 mmol) and CsF
(113.9 mg, 0.75 mmol). Reaction mixture was stirred at 160 °C for 48 h. After cooling to rt, the mixture
was diluted with CHCl3 (20 mL) and solvents were evaporated under reduced pressure. Products were
isolated by column chromatography on 40 g of silica gel in eluent hexanes / EtOAc 8:2. Compound 8
(22.5 mg, 25%) was obtained as a white crystals by recrystallization from hexanes / EtOAc, mp
1
191-193 °C. H NMR (499.8 MHz, CDCl3): 2.24 (s, 3H, CH3-C6H4); 3.05 (s, 3H, CH3-1); 3.44 (s, 3H,
13
CH3-3); 7.11 (m, 2H, H-o-C6H4Me); 7.32 (m, 2H, H-m-C6H4Me). C NMR (125.7 MHz, CDCl3): 21.43
(CH3-C6H4); 28.39 (CH3-3); 34.47 (CH3-1); 103.94 (q, JC,F = 30.3, C-5); 122.42 (q, JC,F = 272.2, CF3);
126.77 (q, JC,F = 1.3, CH-o-C6H4Me); 128.33 (C-i-C6H4Me); 129.78 (CH-m-C6H4Me); 140.58
19
(C-p-C6H4Me); 151.12 (C-2); 155.95 (C-6); 158.82 (C-4). F{1H} NMR (470.3 MHz, CDCl3): -51.84.
IR: 1721, 1663, 1623, 1609, 1520, 1455, 1433, 1405, 1370, 1334, 1152, 1114, 1058, 1017. MS (ESI+),
m/z (% relative intensity): 299 (M++H, 10), 321 (M++Na, 100). HR MS (M++Na): 321.08211 (calcd for
C14H13O2N2F3Na 321.08213).
1,3-Dimethyluracil
(1),
1,3-dimethyl-6-p-tolylpyrimidine-2,4(1H,3H)-dione
(9)
and
1,3,7,10-tetramethyldibenzo[f,h]quinazoline-2,4(1H,3H)-dione (10)
Dry DMF (2 mL) was added through a septum to an argon purged vial containing a
1,3-dimethyl-5-(trifluoromethyl)pyrimidine-2,4(1H,3H)-dione (2) (62.4 mg, 0.3 mmol), 4-iodotoluene
(130.8 mg, 0.6 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol, 5 mol %), P(C6F5)3 (16.0 mg, 0.03 mmol, 10
mol %) and Cs2CO3 (244.4 mg, 0.75 mmol). Reaction mixture was stirred at 160 °C for 24 h. After
cooling to rt, the mixture was diluted with CHCl3 (20 mL) and solvents were evaporated under reduced
pressure. Products were isolated by column chromatography on 40 g of silica gel in gradient 10% of
hexanes in EtOAc to 100% EtOAc. It gave compound 1 (12.4 mg, 30%), compound 9 (17.3 mg, 25%)
and compound 10 (10.2 mg, 11%). Compound 1: white crystals from EtOAc, identical spectroscopic data
to authentic commercial sample. Compound 9: white crystals from hexanes / EtOAc, identical
spectroscopic data to those previously described.12a Compound 10: white powder, 1H NMR (600.1 MHz,

HETEROCYCLES, Vol. 89, No. 5, 2014
1169
CDCl3): 2.61 (s, 3H, CH3-7); 2.64 (s, 3H, CH3-10); 3.55 (s, 3H, CH3-3); 3.80 (s, 3H, CH3-1); 7.42 (ddq,
1H, J11,12 = 8.5, J11,9 = 1.7, J11,CH3 = 0.5, H-11); 7.53 (ddq, 1H, J6,5 = 8.5, J6,8 = 1.7, J6,CH3 = 0.5, H-6); 8.05
(d, 1H, J12,11 = 8.5, H-12); 8.38 (dq, 1H, J8,6 = 1.7, J8,CH3 = 0.7, H-8); 8.45 (dq, 1H, J9,11 = 1.7, J9,CH3 = 0.7,
H-9); 9.68 (d, 1H, J5,6 = 8.5, H-5). 13C NMR (150.9 MHz, CDCl3): 21.74 (CH3-7); 22.05 (CH3-10); 28.48
(CH3-3); 41.73 (CH3-1); 108.76 (C-4a); 121.05 (C-12a); 122.10 (CH-8); 123.72 (CH-9); 126.38 (CH-5);
126.43 (CH-12); 126.46 (C-4b); 127.37 (CH-11); 127.94 (C-8a); 130.26 (CH-6); 134.33 (C-8b); 135.98
(C-7); 140.05 (C-10); 14.31 (C-12b); 153.31 (C-2); 162.48 (C-4). IR: 1724, 1692, 1653, 1621, 1587, 1514,
1443, 1369, 1317, 1295, 1264, 1233, 1192, 1168, 1111, 1011. MS (ESI+), m/z (% relative intensity): 319
(M++H, 8), 341 (M++Na, 100), 359 (2M++Na, 17). HR MS (M++Na): 341.12606 (calcd for
C20H18O2N2Na 341.12605).
1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (11)
Dry DMF (1 mL) was added through a septum to an argon purged vial containing a
1,3-dimethyl-5-(trifluoromethyl)pyrimidine-2,4(1H,3H)-dione (2) (25 mg, 0.12 mmol, 1.0 equiv) and
Cs2CO3 (98 mg, 0.30 mmol, 2.5 equiv). The reaction mixture was heated at 160 °C until the reaction was
complete (3 h). After cooling to rt, DMF was evaporated under reduced pressure. The residue was
dissolved in H2O and acidified by HCl forming precipitate. The product was isolated by filtration as a
1
white powder, mp 185-187 °C (lit15 mp 188-189 °C). H NMR (499.8 MHz, D2O): 3.34 (s, 3H, CH3-3);
3.54 (s, 3H, CH3-1); 8.65 (s, 1H, H-6). 13C NMR (125.7 MHz, D2O): 30.84 (CH3-3); 40.84 (CH3-1);
103.49 (C-5); 154.65 (C-2); 155.88 (CH-6); 167.68 (C-4); 169.22 (COOH). IR: 1745, 1720, 1634, 1529,
1495, 1459, 1425, 1404, 1367, 1339, 1208, 1156, 1077, 1033, 1004. MS (ESI+), m/z (% relative
intensity): 185 (M++H, 100), 207 (M++Na, 27), 391 (2M++Na, 14). HR MS (M++Na): 207.03768 (calcd
for C7H8O4N2Na 207.03763).
Single crystal X-ray structure analysis
The diffraction data of single crystals of 2 (colorless, 0.27 x 0.32 x 0.78 mm) and 8 (0.07x 0.61x 0.79
mm) were collected on Xcalibur X-ray diffractometr with CuKα (λ=1.54180 Å) at 190 K. The structures
were solved by direct methods with SIR9218 and by charge flipping with SUPERFLIP19 and refined by
full-matrix least-squares on F with CRYSTALS.20 All hydrogen atoms were located in a difference map
but later were repositioned geometrically and then refined with riding constraints, while all other atoms
were refined anisotropically in both cases.
Crystal data for 2: C7H7F3N2O2, orthorhombic, space group P212121, a = 6.19806(12) Å, b =
10.53566(18) Å, c = 13.2460(2) Å, V = 864.97(3) Å3, Z = 4, M = 208.14, 3031 reflections measured, 1759

1170
HETEROCYCLES, Vol. 89, No. 5, 2014
independent reflections. Final R = 0.046, wR = 0.051, GoF = 1.110 for 1730 reflections with I > 2σ(I) and
129 parameters, Flack parameter x = 0.0(2). CCDC 945178.
Crystal data for 8: C14H13F3N2O2, monoclinic, space group P21/n, a = 8.2089(5) Å, b = 12.4775(6) Å, c
= 13.4481(7) Å, β = 97.690(5)°, V = 1365.05(12) Å3, Z = 4, M = 298.26, 8971 reflections measured, 2770
independent reflections. Final R = 0.131, wR = 0.141, GoF = 0.876 for 2590 reflections with I > 2σ(I) and
191 parameters. CCDC 945179. Unfortunately, the crystals of 8 were of rather poor quality and did not
diffract strongly, which led to higher R factor value. The precision of the structure determination is
therefore not excellent, but it still describes reasonably well all the main structural features of 8.
ACKNOWLEDGEMENTS
This work was supported by the institutional support of the Charles University and Academy of Sciences
of the Czech Republic (RVO: 61388963), by the Czech Science Foundation (P207/12/0205) and by
Gilead Sciences, Inc.
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