Ionic liquid/HCl catalyzed synthesis of 4-(trifluoromethyl)-2(1H)- pyrimidinones

Article abstract of DOI:10.1007/s00706-013-1126-0

4-(Trifluoromethyl)-2(1H)-pyrimidinones were synthesized from the reaction between 1,1,1-trifluoro-4-methoxy-3-buten-2-ones [CF₃C(O)C(R ²)C(R¹)(OCH₃) where R¹ = Ph, 4-F-C₆H₄, 4-C

Full text of DOI:10.1007/s00706-013-1126-0

Monatsh Chem
DOI 10.1007/s00706-013-1126-0
ORIGINAL PAPER
Ionic liquid/HCl catalyzed synthesis of 4-(trifluoromethyl)-2(1H)-
pyrimidinones
•
Clarissa P. Frizzo Mara R. B. Marzari Caroline R. Bender
•
•
•
Izabelle M. Gindri Jefferson Trindade Lilian Buriol Guilherme S. Caleffi
•
•
•
•
Helio G. Bonacorso Nilo Zanata Marcos A. P. Martins
•
Received: 12 July 2013 / Accepted: 2 December 2013
Ó Springer-Verlag Wien 2014
Abstract 4-(Trifluoromethyl)-2(1H)-pyrimidinones were
synthesized from the reaction between 1,1,1-trifluoro-4-
development of new synthetic strategies for the introduc-
tion of a trifluoromethyl group into an aromatic or
heteroaromatic ring is an interesting challenge in current
organic and medicinal chemistry, as evidenced by recent
advances in these areas and by the increasing number of
trifluoromethyl-containing drugs and drug candidates [6–
11]. One of the best methods for introducing this group into
heterocycles is based on the trifluoromethylated building
block approach, which relies on the trifluoroacetylation of
enol ethers or acetals to give, in one step, the 1,1,1-tri-
fluoro-4-methoxy-3-buten-2-ones in good yields [12]. Our
research group has developed a general procedure for
preparing 1,1,1-trifluoro-4-alkoxy-3-alken-2-ones and we
have extensively studied their versatility in five- [13], six-
[14–16], and seven-membered [17] heterocyclic synthesis.
These reagents are remarkable because the trifluorome-
thylated pyrimidine nucleus can be constructed by a simple
and efficient cyclocondensation reaction. Pyrimidines
occupy an important position in organic and medicinal
chemistry owing to their high biological activity. The
pyrimidine core is a structural constituent of vital bio-
molecules like DNA and also of critically important drugs
such as bactericides, fungicides, analgesics, antipyretics,
and anti-inflammatories [18].
methoxy-3-buten-2-ones
[CF3C(O)C(R2)C(R1)(OCH3)
where R1 = Ph, 4-F-C6H4, 4-Cl-C6H4, 4-Br-C6H4, 4-I-
C6H4, 4-CH3-C6H4, naphth-2-yl, 4-OCH3-C6H4, thien-2-yl
and R2 = H, CH3] and urea in the presence of ionic liquid
[BMIM][BF4] combined with HCl. The results demonstrate
that [BMIM][BF4]/HCl catalyzed the reaction in the
absence of molecular solvents. Use of ionic liquid com-
bined with HCl allowed the reaction temperatures to be
increased to 100 °C and decreased the reaction times from
48–72 to 3–6 h. The products were obtained in good yields
(70–97 %).
Keywords 4-(Trifluoromethyl)-2(1H)-pyrimidinones Á
Ionic liquid Á 1,1,1-Trifluoro-4-methoxy-3-buten-2-ones Á
Cyclocondensation reaction Á Homogeneous catalysis
Introduction
It is well known that the introduction of a trifluoromethyl
substituent into a heterocycle frequently results in com-
pounds which display more potent activity than the parent,
probably owing to the high electronegativity and hence
strong electron density localization, steric hindrance, and
lipophilicity of the perfluoroalkyl substituents [1–5]. The
A literature overview has shown that there is a lack of
reports dealing with trifluoromethylated pyrimidinone
synthesis with shorter reaction times [19], because the
actual methods for obtaining the trifluoromethylated
pyrimidines and analogous pyrimidinones require long
reaction times (48–72 h) and the yields are unsatisfactory
(48–52 %) [15, 16]. Ionic liquids (IL) have shown the
capability of accelerating many organic reactions relative
to those conducted in molecular solvents [19] and this is
associated with strong dipolar and dispersion forces.
Besides, hydrogen bond acidity and hydrogen bond
C. P. Frizzo (&) Á M. R. B. Marzari Á C. R. Bender Á
I. M. Gindri Á J. Trindade Á L. Buriol Á G. S. Caleffi Á
H. G. Bonacorso Á N. Zanata Á M. A. P. Martins
´
´
Nucleo de Quımica de Heterociclos (NUQUIMHE), Chemistry
Department, Federal University of Santa Maria (UFSM),
Santa Maria, RS 97105-900, Brazil
e-mail: clarissa.frizzo@yahoo.com.br
123

C. P. Frizzo et al.
basicity account for the complex solvent interactions
exhibited by IL [19]. In this context, our objective in this
paper was to explore the potential of ionic liquids as a
catalyst/solvent in cyclocondensation reactions to develop
an efficient method for the synthesis of 4-(trifluoromethyl)-
2(1H)-pyrimidinones with short reaction times and with
good yields.
Table 1 Conditions of reaction between 1,1,1-trifluoro-4-methoxy-3-
buten-2-ones 1 and urea
CF3
O
OCH3
N
O
F3C
N
O
+
H
H2N
NH2
1a
2
3a
Entry
Ionic liquid/HCla
Temp./°C
Time/h
Yield/%b
Results and discussion
1
2
3
4
5
6
a
[BMIM][BF4]/HCl
[BMIM][BF4]/HCl
80
100
100
100
100
100
2
2
2
3
3
3
44
70
33
74
78
66
The 1,1,1-trifluoro-4-methoxy-3-buten-2-ones 1a–1j were
synthesized from the reaction of trifluoroacetic anhydride
with acetal according to the methodology developed in our
laboratory [15, 16, 20, 21] and urea (2) was obtained
commercially. In order to synthesize a series of 4-(tri-
fluoromethyl)-2(1H)-pyrimidinones, we started the studies
with the reaction of 1,1,1-trifluoro-4-methoxy-3-buten-2-
one (1a) with urea in a molar ratio of 1:1.2, in the presence
[HMIM][HSO4]/HCl
[BMIM][BF4]/HCl
[BMIM][BF4]/HClc
[HMIM][TsO]/HClc
Reactants ratio of 1/2/IL/HCl in mmol was 1:1.2:1:0.2
Isolated yield
b
c
HCl was used in a ratio of 0.1 equiv.
¨
of ionic liquids combined with Bronsted acids. The reac-
tions were performed using different combinations of ionic
liquids and acid, amount of acid, temperature and time of
the reactions. In the first set of experiments, the ionic liq-
uids [BMIM][BF4], [HMIM][HSO4], and [HMIM][TsO]
were evaluated in the presence of each catalyst: BF3ÁOEt2,
TsOH, and HCl. Reactions performed using BF3ÁOEt2 and
TsOH were not successful in converting reactants to pro-
ducts, because the product was obtained as a mixture of
4-(trifluoromethyl)-2(1H)-pyrimidinones and 1,1,1-tri-
fluoro-4-methoxy-3-buten-2-ones. The only catalyst that
promoted the total conversion of reactants and afforded
moderate yields was HCl. Therefore, the reaction was
performed using HCl for each ionic liquid and the yields
are described in Table 1. It can be seen that the ionic liquid
had an effective influence on the yield of the 4-(trifluoro-
methyl)-2(1H)-pyrimidinone, because the yields in
[HMIM][HSO4] and [HMIM][TsO] were unsatisfactory
(Table 1, entries 3 and 6) whereas in [BMIM][BF4] the
product was obtained in good yield (Table 1, entry 5).
The effects of temperature (Table 1, entries 1 and 2) and
the reaction time (Table 1, entries 2 and 4) were also
evaluated. An increase of 20 °C (Table 1, entries 1 and 2)
led to an increase of 26 % in the yield. An increase in the
reaction time by 1 h resulted in a higher yield (Table 1,
entries 2 and 4). Finally, the amount of acid was fixed at
10 mol %, because the yield increases slightly when the
acid amount is reduced (Table 1, entries 4 and 5). There-
fore, the best conditions were achieved when using
[BMIM][BF4] in the presence of 10 mol % of HCl at
100 °C for 3 h (Table 1, entry 5).
using the established reaction conditions. Thus, other pro-
ducts were prepared by varying the substituent at the R1
and R2 positions of the 1,1,1-trifluoro-4-methoxy-3-buten-
2-ones (1a–1f, 1h, 1j), resulting in pyrimidin-2(1H)-ones
substituted at the 5 and 6 positions (3a–3f, 3h, 3j). In
general, all reactions resulted in the expected product with
good yields (78–97 %); the yields were significantly higher
when compared with those of reactions using MeOH as
solvent and HCl as catalyst (28–52 %), as can be seen in
Table 2.
Since we obtained good yields for the 1,1,1-trifluoro-4-
methoxy-3-buten-2-ones substituted with a phenyl group,
we decided to test substrates with different electronic
effects on this group. In order to evaluate other groups
besides phenyl at the R1 position, the reaction was per-
formed with 1,1,1-trifluoro-4-methoxy-3-buten-2-ones
substituted with thien-2-yl and naphth-2-yl groups
(Table 2). When the naphth-2-yl group was utilized the
yield was 94 % (3i) and the thien-2-yl group (3g) had the
lowest yield (70 %) among all groups evaluated.
Products were characterized by 1H, 13C NMR, and mass
spectrometry. The 4-(trifluoromethyl)-2(1H)-pyrimidinon-
es 3a–3j showed a set of 1H and 13C NMR data that
corresponds to the proposed structures (see ‘‘Experimental’’
section). The structure of compound 3j was also confirmed
by crystal X-ray diffraction (Fig. 1).
A mechanism for the formation of the 4-(trifluoro-
methyl)-2(1H)-pyrimidinones in MeOH/HCl was proposed
by Zanatta et al. [22]. The reaction starts with the Michael
addition of the amino groups of the urea at the b-carbon
atom of the 4-methoxy-1,1,1-trifluoro-3-buten-2-ones,
which furnishes the ether function. Since the ether formed
To gain insight into the generality of this reaction, a
catalytic cyclocondensation reaction was performed on
several other 1,1,1-trifluoro-4-methoxy-3-buten-2-ones
123

Ionic liquid/HCl catalyzed synthesis
furnishes the 4-(trifluoromethyl)-2(1H)-pyrimidinones by
elimination of a water molecule. When ionic liquid is
present in the reaction medium, the steps of the mechanism
are probably the same as those proposed by Zanatta et al.
[22]; however, it is reasonable to suggest that the interac-
tions (intermolecular interactions, polarity, and solvent
strength) of an ionic liquid with an activated complex will
lead to a decrease in activation energy [19] and an increase
in the rate of the reactions. Besides, the used of ionic liquid
allows the use of higher temperatures which imply a
greater supply of energy for the reaction. A representative
schematic energy diagram of the activated complex with
and without the presence of ionic liquid is proposed in
Fig. 2.
Table 2 Reaction conditions and yields of pyrimidin-2(1H)-one series
Compound R1
R2
Time/h [BMIM][BF4] Refs. [15, 16]b
Yield/%a
Yield/%a
3a
3b
3c
3d
3e
3f
Ph
H
H
H
H
H
H
3
3
3
6
6
3
78
81
87
91
97
85
50
50
48
50
–
4-F-C6H4
4-Cl-C6H4
4-Br-C6H4
4-I-C6H4
Conclusion
4-CH3-
C6H4
51
We developed a fast and efficient method to obtain 4-(tri-
fluoromethyl)-2(1H)-pyrimidinones using an ionic liquid
and acid catalyst in the absence of molecular solvents. The
results of this study demonstrated that the condensation
process was substantially affected by the ionic liquid,
because the yield of the reaction was increased by up to
55 % and the reaction time was reduced from 24–72 to
3–6 h when compared with reactions performed in
molecular solvents [15, 16]. Furthermore, the novel com-
pounds 3e and 3g obtained by the protocol described in this
work were achieved with excellent yields.
3g
3h
Naphth-
2-yl
H
H
3
3
94
94
–
4-OCH3-
C6H4
52
3i
3j
a
Thien-2-yl
Ph
H
6
6
70
83
52
28
CH3
Yield of isolated product
b
MeOH/HClconc., reflux, 24–72 h
Experimental
Unless otherwise indicated, all common reagents and sol-
vents were used as obtained from commercial supplies
without further purifications. 1H and 13C NMR spectra
were recorded on a Bruker DPX 400 (1H at 400.13 MHz
and 13C at 100.62 MHz) in 5-mm sample tubes and at
298 K (digital resolution 0.01 ppm) in DMSO-d6/TMS
solutions. Mass spectra were registered in an HP-5973
MSD connected to an HP-6890 GC and interfaced to a
Pentium PC. The GC was equipped with a split–splitless
injector, autosampler, cross-linked to an HP-5 capillary
column (30 m length, 0.32 mm internal diameter), and He
was used as the carrier gas. X-ray diffraction measurements
were performed with graphite monochromatized Mo Ka
˚
radiation with k = 0.71073 A on a Bruker SMART CCD
diffractometer [23]. Structures were solved with direct
methods using the SHELXS-97 program and refined on F2
by full-matrix least-squares using SHELXL-97 [24]. The
absorption correction was performed by Gaussian methods
[25]. Figure 1 depicts the ORTEP view [26] of the mole-
cule indicating the atom numbering scheme with thermal
Fig. 1 ORTEP of 3j with thermal ellipsoids drawn at 50 %
probability level
is unstable in the presence of hydrochloric acid, the
methoxy group is eliminated as methanol to give the
enaminone intermediate. The enaminone then cyclizes and
123

C. P. Frizzo et al.
Fig. 2 Representative
schematic energy diagram of
activated complex with and
without the presence of ionic
liquid
ellipsoids at 50 % probability. The melting points of
compounds 3e and 3g were determined using an MDSC
Q2000 (T-zero DSC- technology, TA Instruments Inc.,
USA). A mechanical cooling system was used for the
experimental measurement. Dry high purity (99.999 %)
nitrogen gas was applied as the purge gas (50 cm3 min-1).
The instrument was initially calibrated in the standard
MDSC mode, using the extrapolated onset temperatures of
solid product was dried under vacuum (4 mbar, 25 °C,
24 h).
The spectroscopic data found for compounds 3a–3d, 3f,
and 3h–3j are in accordance with those in Refs. [15, 16].
Crystallographic data for structure 3j, reported in this
paper, have been deposited with the Cambridge Crystal-
lographic Data Center (CCDC 921487). Copies of the data
can be obtained, free of charge, on application to CCDC 12
Union Road, Cambridge CB2 1EZ, UK (Fax: ?44-1223-
336033 or e-mail: deposit@ccdc.cam.ac.uk).
melting indium (156.60 °C) at
a heating rate of
10 °C min-1 and the heat from the fusion of indium
(28.71 J g-1). The heat capacity calibration was done by
running a standard sapphire (a-Al2O3) measurement at the
experimental temperature. The heating rate used for the
samples was 10 °C min-1 from 25 to 300 °C and the
sample amount used was between 1 and 5 mg. The sample
mass was weighed on a Sartorius M 500 P microbalance
with an accuracy of 0.001 mg. Samples were crimped in
hermetic aluminum pans with lids.
4-(Trifluoromethyl)-6-(4-iodophenyl)-pyrimidin-2(1H)-one
(3e, C11H6F3IN2O)
Yield 97 %; yellow solid; m.p.: 291.20 °C; 1H NMR
(400 MHz, DMSO-d6): d = 6.92 (1H, s, H5), 6.96 (2H, d,
Ar), 7.03 (2H, d, Ar) ppm; 13C NMR (100 MHz, DMSO-
d6): d = 166.8 (C6), 164.1 (C2), 157.8 (q, 2J = 36 Hz,
C3), 137.9, 137.4, 130.5, 129.4 (6C, Ar), 120.4 (q,
1J = 276 Hz, CF3), 103.8 (C-5) ppm; GC–MS (EI,
70 eV): m/z = 366 (M?, 100), 297 (2), 239 (9), 127 (10);
HRMS (ESI): m/z calcd for C11H6F3IN2O [M?H]?
290.0667, found 291.0734.
General procedure for the synthesis
of 4-(trifluoromethyl)-2(1H)-pyrimidinones
1,1,1-Trifluoro-4-methoxy-3-buten-2-ones 1a–1j (1 mmol),
0.060 g urea (1.2 mmol), 0.226 g ionic liquid (1 mmol),
and 0.0365 g HCl (0.1 mmol) were placed in a round-
bottomed flask. The reaction mixtures were stirred at
100 °C for 3 h (for 3a–3c and 3f–3h) or 6 h (for 3d, 3e, 3i,
4-(Trifluoromethyl)-6-(naphth-2-yl)-pyrimidin-2(1H)-one
(3g, C15H9F3N2O)
Yield 94 %; yellow solid; m.p.: 223.74 °C; 1H NMR
(DMSO-d6): d = 7.60–7.68 (2H, m, Ar), 7.95 (1H, s, Ar),
8.00 (1H, d, Ar), 8.09 (1H, s, H5), 8.09 (1H, t, Ar), 8.27
(1H, d, Ar), 8.86 (1H, s, Ar), 12.86 (1H, s, NH) ppm; 13C
NMR (100 MHz, DMSO-d6): d = 167.3 (C6), 163.6 (C2),
157.9 (q, 2J = 34 Hz, C3), 134.6, 132.6, 129.2, 128.6,
128.5, 128.2, 127.7, 127.0, 123.9, (10C, Ar), 120.6 (q,
1J = 276 Hz, CF3), 103.9 (C5) ppm; GC–MS (EI, 70 eV):
1
3j). The conversion of the reaction was monitored by H
NMR. When the reaction was complete, the product was
precipitated by cold water addition and isolated by filtra-
tion. The filtration furnishes the products with sufficient
purity without the need for additional purification. The
123

Ionic liquid/HCl catalyzed synthesis
m/z = 290 (M?, 100), 269 (30), 127 (10), 89 (20); HRMS
(ESI): m/z calcd for C15H9F3N2O [M?H]? 365.9477,
found 366.9545.
12. Martins MAP, Cunico W, Pereira CMP, Flores AFC, Bonacorso
HG, Zanatta N (2004) Curr Org Synth 1:391
13. Vovk MV, Lebed’ PS, Polovinko VV, Manoilenko OV (2008)
Russ J Org Chem 44:1836
14. Kushnir OV, Melnichenko NV, Vovk MV (2011) Russ J Org
Chem 47:1727
15. Bonacorso HG, Lopes IS, Wastowski AD, Zanatta N, Martins
MAP (2003) J Fluor Chem 120:29
16. Flores AFC, Pizzuti L, Brondani S, Rossato M, Zanatta N,
Martins MAP (2007) J Braz Chem Soc 18:1316
17. Vovk MV, Dorokhov VI, Samarai LI (2004) Chem Heterocycl
Compd 40:241
18. Olivier-Bourbigou H, Magna L, Morvan D (2010) Appl Catal A
Gen 373:1
Acknowledgments The authors are thankful for the financial sup-
port from the Coordination for Improvement of Higher Education
Personnel (CAPES); the National Council for Scientific and Tech-
nological Development (CNPq), Universal/Proc. 471519/2009-0; and
the Foundation for Research Support of the State of Rio Grande do
Sul (FAPERGS). Fellowships from CNPq (M. A. P. M., N. Z., H.
G. B., C.R.B., M.R.B.M.), CAPES (L.B., I.M.G., G.S.C., J.T.), and
FAPERGS (C.P.F., L.B.) are also acknowledged.
19. Martins MAP, Frizzo CP, Moreira DN, Bonacorso HG, Zanatta N
(2008) Chem Rev 108:2015
20. Martins MAP, Guarda EA, Frizzo CP, Moreira DN, Marzari
MRB, Zanatta N, Bonacorso HG (2009) Catal Lett 130:93
21. Flores AFC, Brondani S, Zanatta N, Rosa A, Martins MAP
(2002) Tetrahedron Lett 43:8701
22. Zanatta N, Faoro D, Fernandes LS, Brondani PB, Flores DC,
Flores AFC, Bonacorso HG, Martins MAP (2008) Eur J Org
Chem 34:5832
23. Bruker (2006) APEX2 (Version 2.1), COSMO (Version 1.56),
BIS (Version 2.0.1.9), SAINT (Version 7.3A), and SADABS
(Version 2004/1) & XPREP (Version 2005/4). Bruker AXS Inc,
Madison, Wisconsin
References
1. Filler R, Banks RE (1979) Organofluorine chemicals and their
industrial applications. Ellis Horwood, London
2. Inouye Y, Tezuka K, Takeda W, Sugai S (1987) J Fluor Chem
35:275
3. Kirk KLJ (2006) J Fluor Chem 127:1013
4. Filler R, Saha R (2009) Future Med Chem 1:777
5. Ismail FMD (2002) J Fluor Chem 118:27
6. Zanardi A, Novikov MA, Martin E, Benet-Buchholz J, Grushin
VV (2011) J Am Chem Soc 133:20901
7. Cho EJ, Senecal TD, Kinzel T, Zhang Y, Watson DA, Buchwald
SL (2010) Science 328:1679
8. Zhang CP, Wang ZL, Chen QY, Zhang CT, Gu YC, Xiao JC
(2011) Angew Chem Int Ed 50:1896
9. Furuya T, Kamlet AS, Ritter T (2011) Nature 473:470
10. Yi H, Song L, Wang W, Liu J, Zhu S, Deng H, Shao M (2010)
Chem Commun 46:6941
24. Sheldrick GM (1997) SHELXS-97: program for crystal structure
¨
solution. University of Gottingen, Germany
25. Coppens P, Leiserowitz L, Rabinovich D (1965) Acta Cryst
18:1035
26. Farrugia LJ (1997) J Appl Crystallogr 30:565
11. Liu J, Li J, Zhanga L, Song L, Zhanga M, Caoa W, Zhub S, Deng
H, Shao M (2012) Tetrahedron Lett 53:2469
123