Cyclocondensation reaction of 4-aryl-4-methoxy-1,1,1-trifluoro-3-buten-2-ones with urea Synthesis of novel 6-aryl(5-methyl)-4-trifluoromethyl-2(1H)-pyrimidinones

Article abstract of DOI:10.1016/S0022-1139(02)00287-7

The synthesis of a novel series of eleven 6-aryl(5-methyl)-4-trifluoromethyl-2(1H)-pyrimidinones, where aryl = Ph, 4-CH3Ph, 4-FPh, 4-ClPh, 4-BrPh, 4-OCH3Ph and alkyl = H, CH3, from the reaction of 4-aryl-4-methoxy-1,1,1-trifluoro-3-buten-2-ones with urea

Full text of DOI:10.1016/S0022-1139(02)00287-7

Journal of Fluorine Chemistry 120 (2003) 29–32
Cyclocondensation reaction of
4-aryl-4-methoxy-1,1,1-trifluoro-3-buten-2-ones with urea
Synthesis of novel
6-aryl(5-methyl)-4-trifluoromethyl-2(1H)-pyrimidinones
H.G. Bonacorso*, I.S. Lopes, A.D. Wastowski, N. Zanatta, M.A.P. Martins
´ ´ ´
Departamento de Quımica, Nucleo de Quımica de Heterociclos (NUQUIMHE), Universidade Federal de Santa Maria,
Santa Maria, RS 97105-900, Brazil
Received 23 September 2002; received in revised form 14 October 2002; accepted 25 October 2002
Abstract
The synthesis of a novel series of eleven 6-aryl(5-methyl)-4-trifluoromethyl-2(1H)-pyrimidinones, where aryl ¼ Ph, 4-CH3Ph, 4-FPh, 4-
ClPh, 4-BrPh, 4-OCH3Ph and alkyl ¼ H, CH3, from the reaction of 4-aryl-4-methoxy-1,1,1-trifluoro-3-buten-2-ones with urea in the presence
of hydrochloric acid, is reported. Trifluoroacetylation of acetophenone- and propiophenone-dimethylacetals derived from phenones, was
employed to obtain the precursors.
# 2002 Elsevier Science B.V. All rights reserved.
Keywords: 2(1H)-pyrimidinones; Pyrimidines; Enones; Cyclization
1. Introduction
Only a few literature reference’s report the synthesis of
non-fluorinated phenyl- and alkyl-substituted 2(1H)-pyrimi-
dinones, via direct cyclization of 1,3-dicarbonyl derivatives
with urea [10,11]. Usually the synthesis of uracils involves a
multi-step strategy. One of these methods, involves the
condensation of b-ketoesters with thiourea or alkylisothiour-
eas [12–14] and subsequent removal of the S atom [15,16].
Another indirect method to obtain 2(1H)-pyrimidinones is
the condensation of b-ketoesters with O-methylisourea
bisulfate, followed by the hydrolysis of the 2-methoxy-
pyrimidin-4-one to the corresponding uracils [17].
A direct and convenient one-pot synthesis of a series of 4-
trifluoro[trichloro]methyl-2(1H)-pyrimidinones which relies
on the cyclocondensation of trifluoroacetylated enol ethers
(vinyl-, propenyl- and isopropenyl-alkyl ethers) or isobutyl
methyl dimethylacetals and urea was developed in our
research group [18,19]. This approach allowed only the
synthesis of 5-methyl-, 6-methyl- or 6-isobutyl-4-trifluoro-
methyl-2(1H)-pyrimidinones [18,19]. However, the introduc-
tion of a p-substituted phenyl as well as a phenyl and a methyl
substituent in the 6- and 5-position of the 4-trifluoro-2(1H)-
pyrimidinone ring, has not yet been reported. In 1996, C-M.
Hu et al. reported the synthesis of 2-substituted 6-fluoroalkyl-
4-(3H)-pyrimidinones, in excellent yields, by treatment of
a-fluoroalkylacetates or ethyl 3-fluoroalkyl-2-iodoacrylates
Introduction of a trifluoromethyl group and higher homo-
logue CnF2nþ1 substituents into a heterocycle frequently
results in compounds, which display more potent activity
than the parent, a fact which is probably due to the lipo-
phylicity of the perfluoroalkyl substituents [1,2]. One of the
better methods to introduce a trifluoromethyl group into
heterocycles is based on the trifluoromethylated building
block approach. This approach relies on the trifluoroacety-
lation of enolethers or acetals to give, in one step and good
yield, b-alkoxyvinyl trifluoromethyl ketones which proved
to be useful building blocks for the synthesis of five- [3–5],
six- [6,7], and seven-membered [8] heterocyclic com-
pounds. Recently, b-ethoxyvinyltrifluoromethyl ketone
and cycloanalogues, as building block to construct fluorine
containing heterocycles, have been widely studied and
reviewed [9].
As an extension of these works we are now investigating
the possibility to obtain 6-aryl substituted and 6-aryl-5-
methyl substituted 2(1H)-pyrimidinones using the trifluor-
omethylated building block approach.
* Corresponding author. Fax: þ55-55-220-8031.
E-mail address: heliogb@base.ufsm.br (H.G. Bonacorso).
0022-1139/02/$ – see front matter # 2002 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 0 2 ) 0 0 2 8 7 - 7

30
H.G. Bonacorso et al. / Journal of Fluorine Chemistry 120 (2003) 29–32
Scheme 1. Preparation of 2(1H)-pyrimidinones via trifluoroacetylation of phenones dimethylacetals.
with benzamidine and acetamidine [20]. However, attempts
to extend this reaction with thiourea and urea as reagent in
place of amidines failed even when potassium hydroxide or
sodium hydride was used as base [20]. This situation
prompted us to investigate and report the synthesis of 6-
aryl and 5-methyl-6-aryl-substituted trifluoromethylated
2(1H)-pyrimidinones 3 from the reaction between b-meth-
oxyvinyl trifluoromethyl ketones 2 obtained from the tri-
fluoroacetylation of phenones dimethylacetals 1 and urea
(Scheme 1).
hydrochloric acid. The reactions were monitored by TLC
and the optimal reaction time and temperature were 24 h at
60–65 8C (reflux) for 3a–f and 72 h at same temperature for
3g–k. The yields of the cyclization reactions depended on
1
the structure of the precursor 2a–k. The H NMR spectra
showed compounds 2g–k as a mixture of Z and E config-
uration in 2:1 ratio while compounds 2a–f exhibited almost
only E configuration [22]. These observations suggest that
the conformation of 2a–k is the main factor to explain the
yields of these reactions. Considering the similar reaction
conditions for the synthesis of 2(1H)-pyrimidinones 3a–k,
the difference of the observed yields could be related with
the activation energy required to achieve planarity of the
enone functionality in 2a–k. There is a significant difference
in energy among the molecules of the series 2a–f and 2g–k
for the fundamental state and the transition state (planar
structure). We performed MO calculation carried out by the
Austin Model 1 (AM1) semiempirical method [23,24] in
order to have a better understanding of the initial conforma-
tion and activation energy and consequently the reactivity of
2. Results and discussion
The best reaction conditions, selected physical and spec-
tral data are presented in the experimental part and in
Tables 1–3, respectively. The b-methoxyvinyl trifluoro-
methyl ketones 2a–k were prepared according to [21,22].
The cyclocondensation reactions of compounds 2a–k
with urea were carried out in methanol in the presence of
Table 1
Selected physical and mass spectral data of trifluoromethylated 2(1H)-pyrimidinones 3a–k
Compounds
Z
R
Yield (%)a
mp (8C)b
MS [m/z (%)]
3a
3b
3c
3d
3e
3f
H
H
50
51
50
48
50
52
24
28
23
24
25
233–235
253–255
>300
240 (Mþ, 100), 212 (33), 171 (9), 69 (8)
254 (Mþ, 100), 226 (11), 185 (7), 69 (4)
258 (Mþ, 100), 230 (20), 189 (7), 69 (10)
274 (Mþ, 100), 246 (16), 205 (7), 69 (9)
318 (Mþ, 56), 299 (15), 249 (5), 69 (12)
270 (Mþ,100), 249 (13), 201 (4), 69 (10)
253 (Mþ, 100), 235 (7), 184 (4), 69 (3)
267 (Mþ, 89), 198 (4) 69 (4)
CH3
F
H
H
Cl
H
207–209
200–202
244–246
250–252
221–223
218–220
206–207
210–211
Br
H
OCH3
H
H
3g
3h
3i
CH3
CH3
CH3
CH3
CH3
CH3
Cl
287 (Mþ, 100), 253 (20), 217 (1), 69 (5)
333 (Mþ, 100), 283 (43), 265 (4), 69 (8)
283 (Mþ, 100), 253 (16), 214 (2), 69 (3)
3j
3k
Br
OCH3
a Yield of isolated compounds.
b Melting points determined with a Reichert Thermovar apparatus and are uncorrected.

H.G. Bonacorso et al. / Journal of Fluorine Chemistry 120 (2003) 29–32
31
Table 2
Elemental analyses data of trifluoromethylated 2(1H)-pyrimidinones 3a–k
Compounds
Molecular formula weight (g/mol)
Elemental analysis (%)
Calculated
Found
C
C
H
N
H
N
3a
3b
3c
3d
3e
3f
C
11H7ON2F3 (240.18)
55.01
56.70
51.17
48.11
41.14
53.34
56.70
58.21
49.93
43.27
54.93
2.94
3.57
2.34
2.20
1.90
3.36
3.57
4.13
2.79
2.42
3.90
11.66
11.02
10.85
10.20
8.78
55.15
56.79
51.16
48.08
41.57
52.97
56.80
58.31
49.70
43.12
54.58
3.19
3.76
2.67
2.47
2.17
3.17
3.70
4.21
2.51
2.54
3.99
11.55
10.92
10.34
9.88
C12H9ON2F3 (254.21)
C11H6ON2F4 (258.17)
C11H6ON2F3Cl (274.62)
C
11H6ON2F3Br (319.08)
C12H9O2N2F3 (270.21)
12H9ON2F3 (254.21)
C13H11ON2F3 (268.23)
12H8ON2F3Cl (288.65)
8.56
10.37
11.02
10.44
9.70
10.05
10.81
10.26
9.43
3g
3h
3I
3j
C
C
C12H8ON2F3Br (333.10)
C13H11O2N2F3 (284.23)
8.41
8.17
3k
9.86
9.78
these compounds. From the MO calculation was observed
that the methyl substituent at the 3-position of 2g–k does not
favor the formation of the 2(1H)-pyrimidinones 3g–k. The
steric hindrance of the substituents attached to C-3 and C-4
of 2g–k takes the carbonyl and the olefinic double bond out
of the planarity. For example, the AM1 calculations showed
that 2g (propiophenone derivative) requires an activation
energy of 3.88 kcal/mol (Z isomer) and 9.09 kcal/mol (E
isomer) to establish a planar conformation while for 2a
(acetophenone derivative) only 0.1 kcal/mol is sufficient.
This indicate, that the attack of the urea nitrogen to C-4
might be more difficult, resulting in a low yield for com-
pounds 3g–k. On the other hand, the compounds derived
from acetophenones 2a–f allow the isolation of 2(1H)-
pyrimidinones 3a–f in satisfactory yield (48–52%).
We consider the presented one-pot reaction to be a useful
and convenient alternative to obtain 6-aryl- and 6-aryl-5-
methyl-4-trifluoromethyl-2(1H)-pyrimidinones 3. In summary,
Table 3
NMR spectral data of trifluoromethylated 2(1H)-pyrimidinones (3a–k) in DMSO-d6 and TMS as internal reference
Compounds
1H NMR, d/13C NMR, d, JC–F (Hz)
3a
12.9 (s, 1H, NH), 8.2–7.6 (m, 5H, H-Ar), 7.8 (s, 1H, H-5)
167.1 (C-6), 163.6 (C-2), 158.1 (q, J ¼ 31, C-4), 134.0, 132.2, 129.0, 128.0, (6C, Ar), 120.5 (q, J ¼ 274, CF3), 103.2 (C-5)
12.8 (s, 1H, NH), 8.1–7.3 (m, 4H, H-Ar), 7.7 (s, 1H, H-5), 2.4 (s, 3H, CH3)
3b
3c
3d
3e
3f
166.7 (C-6), 163.2 (C-2), 158.2 (q, J ¼ 29, C-4), 142.5, 130.9, 129.5, 127.5 (6C, Ar), 120.4 (q, J ¼ 274, CF3), 102.5 (C-5), 20.9 (p-CH3 )
12.9 (s, 1H, NH), 8.3–7.3 (4H, H-Ar), 7.8 (s, 1H, H-5)
166.4 (C-6), 164.0 (C-2), 157.9 (q, J ¼ 33, C-4), 164.9, 130.7, 130.3, 116.0, (6C, Ar), 120.5 (q, J ¼ 274, CF3), 103.7 (C-5)
12.9 (s, 1H, NH), 8.2–7.5 (m, 4H, H-Ar), 7.8 (s, 1H, H-5)
166.5 (C-6), 164.3 (C-2), 157.9 (q, J ¼ 34, C-4), 137.4, 133.1, 129.7, 129.0 (6C, Ar), 120.5 (q, J ¼ 274, CF3), 104.0 (C-5)
12.9 (s, 1H, NH), 8.1–7.7 (m, 4H, H-Ar), 7.9 (s, 1H, H-5)
166.6 (C-6), 164.3 (C-2), 157.8 (q, J ¼ 34, C-4), 133.5, 131.9, 129.5, 126.0 (6C, Ar), 123.1 (q, J ¼ 274, CF3), 104.0 (C-5)
12.7 (s, 1H, NH), 8.1–7.0 (m, 4H, H-Ar), 7.6 (s, 1H, H-5), 3.8 (s, 3H, p-OCH3)
166.6 (C-6), 163.0 (C-2), 158.0 (q, J ¼ 34, C-4), 166.6, 131.9, 129.5, 126.0 (6C-Ar), 120.5 (q, J ¼ 275, CF3), 101.7 (C-5)
12.6 (s, 1H, NH), 7.5 (s, 5H, H-Ar), 2.1 (s, 3H, CH3)
3g
3h
3i
167.0 (C-6), 159.5 (C-2), 157.0 (q, J ¼ 33, C-4), 134.6, 130.0, 128.7, 128.5 (6C, Ar), 121.0 (q, J ¼ 276, CF3), 112.7 (C-5), 12.6 (CH3)
12.5 (s, 1H, NH), 7.4–7.3 (m, 4H, H-Ar), 2.4 (s, 3H, p-CH3), 2.1 (s, 3H, CH3)
166.7 (C-6), 159.1 (C-2), 157.0 (q, J ¼ 32, C-4), 139.8, 131.5, 128.8 (6C, Ar), 120.9 (q, J ¼ 276, CF3), 112.2 (C-5), 20.7 (p-CH3), 12.5 (CH3)
12.5 (s, 1H, NH), 7.4–7.0 (m, 4H, H-Ar), 3.4 (s, 3H, CH3)
168.6 (C-6), 166.2 (C-2), 154.5 (q, J ¼ 30, C-4), 138.3, 133.0, 130.6, 127.9, (6C-Ar), 122.0 (q, J ¼ 276, CF3), 105.2 (C-5), 12.9 (CH3)
12.6 (s, 1H, NH), 7.8–7.5 (m, 4H, H-Ar), 2.1 (s, 3H, CH3)
3j
166.8 (C-6), 160.2 (C-2), 156.6 (q, J ¼ 34, C-4), 134.2, 131.4, 131.1, 123.7 (6C, Ar), 121.0 (q, J ¼ 276, CF3), 113.8 (C-5), 12.8 (CH3)
12.5 (s, 1H, NH), 7.5-7.0 (m, 4H, H-Ar), 3.8 (s, 3H, p-OCH3), 2.0 (s, 3H, CH3)
3k
166.1 (C-6), 159.0 (C-2), 157.1 (q, J ¼ 32, C-4), 160.6, 130.7, 126.3, 113.7 (6C, Ar), 120.9 (q, J ¼ 276, CF3), 111.9 (C-5), 55.2 (p-OCH3),
12.6 (CH3)

32
H.G. Bonacorso et al. / Journal of Fluorine Chemistry 120 (2003) 29–32
´
Tecnologico (CNPq/PADCT III- Project no. 62.0228/97-0-
QEQ).
the use of this methodology allowed the isolation of a
new series of 4-trifluoromethylated 2(1H)-pyrimidinones
3 which have been prepared in analytically pure form and
in relative satisfactory yield.
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3. Experimental
Unless otherwise indicated all common reagents and sol-
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3.1.1. General procedure
To a magnetically stirred solution of 4-alkoxy-1,1,1-tri-
fluoro-3-alken-2-ones 2a–k (5 mmol) and urea (0.6 g,
10 mmol) in 10 ml of methanol at 20–25 8C was added
1 ml of concentrated HCl. The mixture was refluxed at
60–65 8C for 24 h (2a–f) or for 72 h (2g–k). Distilled water
(15 ml) was added to the reaction mixture’s at room tem-
perature and the products (3a–k) were allowed to crystallize
by cooling the solutions to 5–8 8C for 12 h. The solids were
filtered off, washed with cold water and dried overnight in a
dessicator under phosphorus pentoxide at room temperature.
The products were recrystallized from dichloromethane:
ethanol 1:1 (3a–f) or from ethanol 96% (3g–k).
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Acknowledgements
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The authors are thankful for the financial support
´
from Conselho Nacional de Desenvolvimento Cientıfico e
[24] Hypercube, Inc., HyperChem 6.03 Package, Gainesville, FL, USA,
1999.