One-pot synthesis of difluoromethyl-containing dihydropyrimidinones catalyzed by Yb(PFO)3 under solvent and dehydrating agent free conditions

Article abstract of DOI:10.1016/j.jfluchem.2010.12.010

The difluoromethyl-containing Biginelli dihydropyrimidinone derivatives were synthesized by a one-pot cyclocondensation of ethyl 4,4- difluoroacetoacetate, urea, and a variety of aldehydes in the presence of 5 mol% ytterbium perfluorooctanoate [Yb(PFO)

Full text of DOI:10.1016/j.jfluchem.2010.12.010

Journal of Fluorine Chemistry 132 (2011) 155–159
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
One-pot synthesis of difluoromethyl-containing dihydropyrimidinones catalyzed
by Yb(PFO)3 under solvent and dehydrating agent free conditions
*
Mingxi Wu, Jinlong Yu, Wenwen Zhao, Jingjing Wu, Song Cao
Shanghai Key Laboratory of Chemical Biology, Center of Fluorine Chemical Technology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
A R T I C L E I N F O
A B S T R A C T
Article history:
The difluoromethyl-containing Biginelli dihydropyrimidinone derivatives were synthesized by a one-
pot cyclocondensation of ethyl 4,4-difluoroacetoacetate, urea, and a variety of aldehydes in the presence
of 5 mol% ytterbium perfluorooctanoate [Yb(PFO)3] under solvent and dehydrating agent free conditions.
The comparison of reaction conditions and products was made among the different 1,3-dicarbonyl
substrates (ethyl acetoacetate, ethyl 4,4-difluoroacetoacetate and ethyl 4,4,4-trifluoroacetoacetate) for
the Biginelli reaction.
Received 5 November 2010
Received in revised form 10 December 2010
Accepted 14 December 2010
Available online 21 December 2010
Keywords:
ß 2010 Elsevier B.V. All rights reserved.
Ethyl 4,4-difluoroacetoacetate
Biginelli reaction
3,4-Dihydropyrimidin-2(1H)-ones
Solvent-free
Yb(PFO)3
1. Introduction
been reported for the improvement of Biginelli reaction conditions
[7]. For example, the use of various Lewis acids such as BF3ÁOEt2,
Organofluorine compounds have received remarkable interest
due to their various important applications in many areas,
including medicinal, agricultural and materials chemistry [1].
Recently, introduction of a gem-difluoromethyl group to bioactive
compounds is increasingly used as a strategy to alter properties of
molecules for improvement of their biological activity [2].
However, only a limited number of methods are available for
the synthesis of gem-difluoromethyl-containing compounds com-
pared to their CF3 analogues. In addition, ethyl 4,4-difluoroace-
toacetate is a commercially available difluorinated building block,
which can be used to prepare a variety of difluoromethyl-
containing compounds [3]. But little is known about the reactivity,
properties and products of this difluoro-containing building block
when it is used as a component in the multicomponent reactions.
There are only a few reports on the three-component reactions
involving ethyl difluoroacetoacetate [4].
FeCl3, LaCl3, Yb(OTf)3 (OTf = trifluoromethanesulfonate, the same as
below), La(OTf)3, In(OTf)3, Cu(OTf)3, InCl3, ZrCl4, BiCl3, Mn(OAc)3,
LiClO4, VCl3 have been reported [8]. Other new methodologies of
organic synthesis, for instance, microwave-assisted synthesis,
ultrasound irradiation, the use of ionic liquids or water as new
reaction media, solvent-free method have been employed for the
synthesis of DHPMs [9]. However, most of the improvement and
modification are based on the use of ethyl acetoacetate as one of
substrates. According to the existing literature, the reaction
conditions and products of ethyl 4,4,4-trifluoroacetoacetate are
different from that of the ethyl acetoacetate when it undergoes
Biginelli reaction due to the existence of strong electron withdraw-
ing CF3 group [10]. Considering the difference in the number of
fluorine atoms in ethyl 4,4-difluoroacetoacetate, it is desirable to
investigate the reactivity of ethyl 4,4-difluoroacetoacetate in the
Biginelli reaction. Herein, we reported a simple and efficient
synthesis of the difluoromethyl-containing dihydropyrimidinones
via Biginelli reaction of ethyl difluoroacetoacetate, urea and
aldehydes catalyzed by Yb(PFO)3 under solvent-free conditions
without additional dehydrating agent (Table 4).
Dihydropyrimidinone (DHPM) derivatives are widely used as
core unit of some biologically active compounds such as calcium
channel blockers, anti-tumor agents, and anti-inflammatory drugs
[5]. They are generally synthesized by the Biginelli reaction which
involves the one-pot condensation of aldehyde,
b-ketoester and
urea in presence of acidic catalysts [6]. Since the first report on the
synthesis of DHPMs by Biginelli in 1893, numerous methods have
2. Results and discussion
The only example of using ethyl 4,4-difluoroacetoacetate as
an alternative substrate for Biginelli cyclocondensation was
reported by Saloutin et al. in 2000 [4]. According to their study,
4-difluoromethyl-4-hydroxy-2-oxo-6-phenyl-hexahydropyrimi-
* Corresponding author. Tel.: +86 21 64252945; fax: +86 21 64252603.
E-mail address: scao@ecust.edu.cn (S. Cao).
0022-1139/$ – see front matter ß 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2010.12.010

156
M. Wu et al. / Journal of Fluorine Chemistry 132 (2011) 155–159
Scheme 1. Two methods for the synthesis of 2a.
dine-5-carboxylate
3
was obtained via Biginelli reaction
expected product in 87% yield. However, the yield of 2a decreased
with decreasing temperature (Table 2).
coupling of ethyl 4,4-difluoroacetoacetate, benzaldehyde and
urea under acidic conditions. Dehydration of 3 in the presence of
p-toluenesulfonic acid afforded 6-difluoromethyl-5-(ethoxycar-
bonyl)-4-phenyl-3,4- dihydropyrimidin-2(1H)-one 2a (Scheme
1).
The effect of amount of catalyst on the reaction was also studied
by varying the amount of Yb(PFO)3 under solvent-free conditions
(Table 3). It was found that 5 mol% of Yb(PFO)3 was sufficient to
carry out this reaction successfully. An increase in the amount of
Yb(PFO)3 to more than 5 mol% showed no significant improvement
in yield, whereas the yield was reduced by decreasing the amount
of Yb(PFO)3 to 2.5 mol%.
Organic synthesis involving multi-component reactions (MCRs)
under solvent-free conditions has been receiving much attention
[11]. As a continuation of our research to develop more efficient
and practical methods in MCRs [12], we examined the Biginelli
solvent-free reactions of ethyl 4,4-difluoroacetoacetate with
several aldehydes and urea in the presence of metal catalysts.
For our initial studies, ethyl 4,4-difluoroacetoacetate, benzalde-
hyde and urea were selected as representative substrates to
investigate the reaction conditions. To our delight, the reaction
proceeded smoothly using 5 mol% metal catalysts under solvent-
free conditions at relatively high temperatures to afford the
dehydrated compound 2a, the normal product of the Biginelli
reaction (Scheme 1).
The effect of different catalysts on the yields of 2a under
solvent-free conditions at 120 8C was shown in Table 1. When the
model reaction was performed in the absence of catalyst, 3 was
obtained as the main product, whereas the yield of the dehydrated
product 2a was only 15%. Among the various catalysts tested,
Yb(PFO)3 gave high yield of 2a.
In order to determine the limitations of the method, we tested it
on several additional aldehydes. Generally, the solvent-free three-
component reaction proceeded smoothly to give the expected
difluoromethyl-containing dihydropyrimidinones in good to high
yields (Table 4). Aromatic aldehydes afforded the higher yields of
the desired products than aliphatic aldehydes. In addition, the
target compounds (2a–i) were easily purified by recrystallization
from ethanol without the use of column chromatography.
For comparison, the reaction conditions and products of
different types of 1,3-dicarbonyl substrates (ethyl acetoacetate,
ethyl 4,4-difluoroacetoacetate and ethyl 4,4,4-trifluoroacetoace-
tate) for the Biginelli reaction were summarized in Scheme 2.
When ethyl acetoacetate used as substrate, the reaction takes place
with good yield at 80 8C under solvent-free or reflux conditions and
gives the normal 3,4-dihydropyrimidin-2(1H)-one products (I)
[13]. In the case of ethyl 4,4,4-trifluoroacetoacetate, the corre-
sponding trifluoromethyl-containing Biginelli product (II) is
obtained in the presence of TaBr5 [14], however, an undehydrated
product, ethyl 4-(trifluoromethyl) -4-hydroxy-2-oxo-6-phenyl-
hexahydropyrimidine-5-carboxylate (III) is formed in the presence
of other Lewis acid such as ZrCl4 [15]. The intermediate (III) can be
further dehydrated to (II) by using dehydration agents such as
p-toluenesulfonicacid [8b]. As toour workin this paper, the reaction
of ethyl 4,4-difluoroacetoacetate, ethyl acetoacetate, and ethyl
4,4,4-trifluoroacetoacetate with benzaldehyde and urea, respec-
tively, yielded the corresponding normal Biginelli product in good
yield in the presence of Yb(PFO)3 under solvent-free conditions,
whereas the undesired undehydrated product was not isolated.
In summary, we reported an efficient and practical approach to
the synthesis of difluoromethyl-containing dihydropyrimidinones
through a solvent-free one-pot three-component condensation of
ethyl 4,4-difluoroacetoacetate, aldehydes and urea in the presence
of Yb(PFO)3 without additional dehydrating agent.
The effect of temperature on the reaction was examined under
solvent-free conditions in the presence of Yb(PFO)3. As can be seen
from Table 2, the reaction proceeded smoothly at 120 8C giving the
Table 1
Effect of catalyst on the yields under solvent-free conditions at 120 8C.
Catalysta
Reaction time (h)
2a Yield (%)b
None
>12
8
15c
34
55
73
72
68
87
HCl
ZnCl2
4
InCl3
4
BiCl5
4
(NH4)2Ce(NO3)6
Yb(PFO)3
4
4
a
Amount of catalysts 5 mol%.
b
Yields were based on GC analysis.
c
Compound 3 was a major product.
Table 2
Effect of temperature on the one-pot reaction under solvent-free conditionsa.
3. Experimental
2a Yield (%)b
3.1. Materials and instruments
Temperature (8C)
Reaction time (h)
60
80
>12
4
30
55
81
87
All reagents were of analytic grade and obtained from
commercial suppliers and used without further purification.
Melting points were measured in an open capillary using Bu¨chi
melting point B-540 apparatus and are uncorrected. 1H and 13C
NMR spectra were recorded on a Bruker AM-400 spectrometer
100
120
4
4
a
Catalyst: 5 mol% of Yb(PFO)3.
b
Yields were based on GC analysis.

M. Wu et al. / Journal of Fluorine Chemistry 132 (2011) 155–159
157
152.0, 163.6 ppm. 19F NMR (CDCl3):
d
= À122.85 (d, J = 54.0 Hz, 1F),
Table 3
Optimization of amount of catalyst.
À123.07 (d, J = 54.0 Hz, 1F) ppm. HRMS (EI) for C14H14F2N2O3,
Amount of Yb(PFO)3 (mol%)
Reaction time (h)
2a Yield (%)a
Calcd: 296.0972, Found: 296.0971.
2.5
5
6
4
4
4
77
88
91
93
3.2.2. 6-Difluoromethyl-5-(ethoxycarbonyl)-4-(4-methylphenyl)-
7.5
10
3,4-dihydropyrimidin-2(1H)-one (2b)
White solid, mp 193.5–194.4 8C. 1H NMR (CDCl3):
d = 1.19 (t,
a
Yields were based on GC analysis.
J = 7.1 Hz, 3H), 2.33 (s, 3H), 4.13 (q, J = 7.1 Hz, 2H), 5.40 (s, 1H),
6.07 (s, 1H), 7.12–7.21 (m, 4H), 7.39 (t, JHF = 53.7 Hz, 1H), 7.70 (s,
1H) ppm. 13C NMR (CDCl3):
d = 13.9, 21.1, 55.5, 61.3, 106.2 (t,
(400 MHz and 100 MHz, respectively) using TMS as the internal
standard. The 19F NMR spectra were recorded Bruker AM-400
spectrometer (376 MHz) using CF3CO2H as external standard. Gas
chromatography–mass spectra (GC–MS) were recorded on HP
5973 MSD with 6890 GC. High resolution mass spectra (HRMS)
were recorded under electron impact conditions using a Micro-
Mass GCT CA 055 instrument and recorded on a MicroMass LCTTM
spectrometer.
3JCF = 6.0 Hz), 108.2 (t, 1JCF = 241.4 Hz), 126.5, 129.6, 138.5, 138.8
2
(t, JCF = 23.0 Hz), 139.1, 151.6, 163.6 ppm. 19F NMR (CDCl3):
d
= À122.80 (d, J = 53.7 Hz, 1F), À123.08 (d, J = 53.7 Hz,
1F) ppm. HRMS (EI) for C15H16F2N2O3, Calcd: 310.1129, Found:
310.1128.
3.2.3. 6-Difluoromethyl-5-(ethoxycarbonyl)-4-(2-methylphenyl)-
3,4-dihydropyrimidin-2(1H)-one (2c)
White solid, mp 229.9–231.4 8C. 1H NMR (DMSO-d6):
d = 0.99 (t,
3.2. General procedure for compounds 2a–i
J = 7.0 Hz, 3H), 2.41 (s, 3H), 3.93–3.96 (m, 2H), 5.48 (s, 1H), 7.16–
7.17 (m, 4H), 7.44 (t, JHF = 53.3 Hz, 1H), 7.82 (s, 1H), 9.68 (s,
Aldehyde 1 (2 mmol) and urea (3 mmol) were added to a flask
and stirred at room temperature for 30 min before the addition of
Yb(PFO)3 (0.1 mmol) and ethyl 4,4-difluoroacetoacetate (2 mmol).
The mixture was heated to 120 8C and stirred for another 3–4 h.
After the reaction was completed (monitored by TLC), the mixture
was cooled to room temperature. Then water (20 mL) was added
and the solid precipitate was filtered, washed with cold water. The
crude product was recrystallized from ethanol to give the pure
product 2.
1H) ppm. 13C NMR (DMSO-d6):
d
= 14.0, 19.1, 51.0, 61.0, 105.3 (t,
1
3JCF = 6.1 Hz), 109.0 (t, JCF = 239.2 Hz), 126.8, 127.2, 128.2, 130.9,
135.4, 140.9 (t, JCF = 23.0 Hz), 142.0, 151.5, 164.1 ppm. 19F NMR
2
(DMSO-d6):
d
= À121.3 (d, J = 53.3 Hz, 1F), À121.6 (d, J = 53.3 Hz,
1F) ppm. HRMS (EI) for C15H16F2N2O3, Calcd: 310.1129, Found:
310.1130.
3.2.4. 4-(3-Bromophenyl)-6-difluoromethyl-5-(ethoxycarbonyl)-3,4-
dihydropyrimidin-2(1H)-one (2d)
White solid, mp 235.9–237.2 8C. 1H NMR (DMSO-d6):
d
= 1.12 (t,
3.2.1. 6-Difluoromethyl-5-(ethoxycarbonyl)-4-phenyl-3,4-
J = 7.1 Hz, 3H), 4.01–4.13 (m, 2H), 5.24 (s, 1H), 7.25–7.55 (m, 5H),
dihydropyrimidin-2(1H)-one (2a)
7.99 (s, 1H), 9.83 (s, 1H) ppm. 13C NMR (DMSO-d6):
d = 14.2, 53.9,
White solid, mp 190.2–190.7 8C. 1H NMR (CDCl3):
d
= 1.18 (t,
61.2, 104.6 (t, 3JCF = 6.1 Hz), 109.0 (t, 1JCF = 239.6 Hz), 122.2, 125.7,
2
J = 7.0 Hz, 3H), 4.13 (q, J = 6.5 Hz, 2H), 5.43 (s, 1H), 6.11 (s, 1H), 7.32
129.7, 131.2, 131.5, 141.2 (t, JCF = 23.2 Hz), 146.2, 151.9,
(s, 5H), 7.39 (t, JHF = 54.0 Hz, 1H), 7.71 (s, 1H) ppm. 13C NMR
164.0 ppm. 19F NMR (DMSO-d6):
1F) ppm. HRMS (EI) for C14H13BrF2N2O3, Calcd: 374.0078, Found:
374.0079.
d
= À121.3 (s, 1F), À121.4 (s,
3
(CDCl3):
d
= 13.9, 55.7, 61.3, 106.0 (t, JCF = 6.1 Hz), 108.2 (t,
1JCF = 241.2 Hz), 126.6, 128.5, 128.9, 139.1 (t, 2JCF = 23.8 Hz), 142.0,
Table 4
Yields of difluoromethyl dihydropyrimidinones 2a–i.
.
Compd.
R
Isolated
yield (%)
Compd.
R
Isolated
yield (%)
Compd.
R
Isolated
yield (%)
2a
86
2d
81
2g
(CH3)2CHCH2–
77
2b
2c
82
83
2e
2f
88
82
2h
2i
CH3CH2CH2–
81
78
(CH3)2CH–

158
M. Wu et al. / Journal of Fluorine Chemistry 132 (2011) 155–159
Scheme 2. The comparison of reaction conditions and products among the different 1,3-carbonyl substrates for the Biginelli reaction.
3.2.5. 6-Difluoromethyl-5-(ethoxycarbonyl)-4-(2-fluoro-5-
(m, 2H), 4.36–4.39 (m, 1H), 6.06 (s, 1H), 7.33 (t, JHF = 54.1 Hz, 1H),
methylphenyl)-3,4-dihydropyrimidin-2(1H)-one (2e)
7.42 (s, 1H) ppm. 13C NMR (CDCl3):
d
= 13.5, 14.0, 17.4, 38.5, 51.4,
White solid, mp 224.2–225.0 8C. 1H NMR (CDCl3):
d
= 1.14 (t,
61.1, 106.7 (t, JCF = 6.0 Hz), 108.1 (t, JCF = 239.7 Hz), 139.5 (t,
3
1
J = 7.1 Hz, 3H), 2.29 (s, 3H), 4.11 (q, J = 7.1 Hz, 2H), 5.74 (s, 1H), 5.95
(s, 1H), 6.91–7.07 (m, 3H), 7.48 (t, JHF = 53.9 Hz, 1H), 7.83 (s,
2JCF = 22.8 Hz), 153.0, 163.7 ppm. 19F NMR (CDCl3):
J = 54.1 Hz, 1F), À124.1 (d, J = 54.1 Hz, 1F) ppm. HRMS (EI) for
11H16F2N2O3, Calcd: 262.1129, Found: 262.1133.
d
= À122.9 (d,
1H) ppm. 13C NMR (CDCl3):
d
= 13.7, 20.7, 49.7, 61.3, 103.8 (t,
C
1
3JCF = 5.7 Hz), 108.0 (t, JCF = 241.4 Hz), 115.6 (d, JCF = 21.8 Hz),
127.9 (d, JCF = 13.2 Hz), 128.5 (d, JCF = 3.4 Hz), 130.8 (d,
3.2.9. 6-Difluoromethyl-5-(ethoxycarbonyl)-4-isopropyl-3,4-
2
JCF = 8.1 Hz), 134.3 (d, JCF = 3.30 Hz), 140.4 (t, JCF = 23.11 Hz),
151.5, 158.2 (d, JCF = 245.1 Hz), 163.4 ppm. 19F NMR (CDCl3):
dihydropyrimidin-2(1H)-one (2i)
White solid, mp 172.4–173.6 8C. 1H NMR (CDCl3):
d = 0.90 (d,
d
= À123.07 (d, J = 53.9 Hz, 1F), À123.21 (d, J = 53.9 Hz, 1F),
J = 6.8 Hz, 3H), 0.95 (d, J = 6.9 Hz, 3H), 1.30 (t, J = 7.1 Hz, 3H), 1.87–
1.95 (m, 1H), 4.20–4.26 (m, 2H), 4.28 (s, 1H), 6.24 (s, 1H), 7.35 (t,
À124.86 (s, 1F) ppm. HRMS (EI) for
C
15H15F3N2O3, Calcd:
328.1035, Found: 328.1038.
JHF = 52.3 Hz, 1H), 7.49 (s, 1H) ppm. 13C NMR (CDCl3):
d
= 14.1,
3
15.5, 18.4, 34.2, 56.9, 61.2, 105.4 (t, JCF = 5.9 Hz), 108.2 (t,
2
3.2.6. 6-Difluoromethyl-5-(ethoxycarbonyl)-4-(2-fluoro-4-
1JCF = 240.7 Hz), 140.1 (t, JCF = 22.8 Hz), 153.8, 164.1 ppm. 19F
methylphenyl)-3,4-dihydropyrimidin-2(1H)-one (2f)
NMR (CDCl3):
d
= À122.70 (t, J = 52.3 Hz, 2F) ppm. HRMS (EI) for
White solid, mp 210.9–211.8 8C. 1H NMR (DMSO-d6):
d
= 1.08 (t,
C11H16F2N2O3, Calcd: 262.1129, Found: 262.1137.
J = 7.0 Hz, 3H), 2.29 (s, 3H), 4.01 (q, J = 7.0 Hz, 2H), 5.48 (s, 1H),
7.00–7.17 (m, 3H), 7.42 (t, JHF = 53.3 Hz, 1H), 7.84 (s, 1H), 9.75 (s,
Acknowledgements
1H) ppm. 13C NMR (DMSO-d6):
d = 14.1, 21.0, 49.3, 61.0, 103.6 (t,
1
3JCF = 6.1 Hz), 108.9 (t, JCF = 239.4 Hz), 116.5 (d, JCF = 21.7 Hz),
We are grateful for financial supports from the National Natural
Science Foundation of China (Grant No. 21072057), the National
Basic Research Program of China (973 Program, 2010CB126101),
Shanghai Foundation of Science of Technology (09391911800), and
the Shanghai Leading Academic Discipline Project (B507).
125.7 (d, JCF = 2.7 Hz), 127.5 (d, JCF = 13.8 Hz), 129.0 (d,
JCF = 4.6 Hz), 140.7 (d, JCF = 8.2 Hz), 141.1 (t, JCF = 23.0 Hz),
151.6, 159.8 (d, JCF = 246.8 Hz), 164.0 ppm. 19F NMR (CDCl3):
2
d
= À119.54 to À119.49 (m, 1F), À121.47 (d, J = 53.3 Hz, 1F),
À121.61 (d, J = 53.3 Hz, 1F) ppm. HRMS (EI) for C15H15F3N2O3,
Calcd: 328.1035, Found: 328.1033.
Appendix A. Supplementary data
3.2.7. 6-Difluoromethyl-5-(ethoxycarbonyl)-4-isobutyl-3,4-
dihydropyrimidin-2(1H)-one (2g)
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.jfluchem.2010.12.010.
White solid, mp 168.2–169.7 8C. 1H NMR (DMSO-d6):
d = 0.88
(d, J = 6.4 Hz, 6H), 1.13–1.25 (m, 4H), 1.41–1.48 (m, 1H), 1.73–1.76
(m, 1H), 4.13–4.18 (m, 3H), 7.36 (t, JHF = 53.4 Hz, 1H), 7.68 (s, 1H),
References
9.54 (s, 1H) ppm. 13C NMR (DMSO-d6):
d = 14.3, 21.7, 23.2, 24.0,
3
1
45.4, 48.7, 61.0, 106.7 (t, JCF = 6.1 Hz), 108.9 (t, JCF = 238.7 Hz),
[1] (a) P. Jeschke, Chem. Biol. Chem. 5 (2004) 570–589;
2
140.6 (t, JCF = 22.9 Hz), 152.9, 164.2 ppm. 19F NMR (DMSO-d6):
(b) W.K. Hagmann, J. Med. Chem. 51 (2008) 4359–4369;
(c) S. Purser, P.R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev. 37 (2008)
320–330.
[2] (a) M.S. Costa, N. Boechat, E.A. Rangel, F. de, C. da Silva, A.M.T. de Souza, C.R.
Rodrigues, H.C. Castro, I.N. Junior, M.C.S. Lourenco, S.M.S.V. Wardell, V.F. Ferreira,
Bioorg. Med. Chem. 14 (2006) 8644–8653;
d
= À121.36 (d, J = 53.4 Hz, 1F), À121.54 (d, J = 53.4 Hz, 1F) ppm.
HRMS (EI) for C12H18F2N2O3, Calcd: 276.1285, Found: 276.1287.
3.2.8. 6-Difluoromethyl-5-(ethoxycarbonyl)-4-propyl-3,4-
(b) S.B. Ferreira, M.S. Cost, N. Boechat, R.J.S. Bezerra, M.S. Genestra, M.M. Canto-
Cavalheiro, W.B. Kover, V.F. Ferreira, Eur. J. Med. Chem. 42 (2007) 1388–1395;
(c) J.L. David, J.D. Robert, S. Dean, A. Alexander, D.D. David, J.G. Ronald, J.W. Xu, P.
Li, L. Brian, F. Luc, S.B. Randy, J. Dylan, M. Kira, W. O. Pat. 111,904 (2007).
dihydropyrimidin-2(1H)-one (2h)
White solid, mp 174.6–174.8 8C. 1H NMR (CDCl3):
d
= 0.94 (t,
J = 7.2 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H), 1.47–1.66 (m, 4H), 4.22–4.29

M. Wu et al. / Journal of Fluorine Chemistry 132 (2011) 155–159
159
[3] (a) B. Gallenkamp, L. Mulder, U.S. Pat. 7,585,998 (2009).
(b) M. Jagodzinska, F. Huguenot, M. Zanda, Tetrahedron 63 (2007) 2042–2046;
(c) A. Shavnya, S.M. Sakya, M.L. Minich, B. Rast, K.L. DeMello, B.H. Jaynes,
Tetrahedron Lett. 46 (2005) 6887–6891;
(d) M.V. Pryadeina, Y.V. Burgart, M.I. Kodess, V.I. Saloutin, O.N. Chupakhin, Russ.
Chem. Bull., Int. Ed. 53 (2004) 1261–1266.
[4] V.I. Saloutin, Y.V. Burgart, O.G. Kuzueva, C.O. Kappe, O.N. Chupakhin, J. Fluorine
Chem. 103 (2000) 17–23.
[5] (a) D. Russowsky, R.F.S. Canto, S.A.A. Sanches, M.G.M. DvOca, A. de Fatima, R.A.
Pilli, L.K. Kohn, M.A. Antonio, J.E. de Carvalho, Bioorg. Chem. 34 (2006) 173–182;
(b) C.O. Kappe, Eur. J. Med. Chem. 35 (2000) 1043–1052;
(c) C.O. Kappe, QSAR Comb. Sci. 22 (2003) 630–645;
(f) K.A. Kumar, M. Kasturaiah, C.S. Reddy, C.D. Reddy, Tetrahedron Lett. 42 (2001)
7873–7875;
(g) A. Shaabani, A. Bazgir, F. Teimouri, Tetrahedron Lett. 44 (2003) 857–859.
[9] (a) V.R. Choudhary, V.H. Tillu, V.S. Narkhede, H.B. Borate, R.D. Wakharkar, Catal.
Commun. 4 (2003) 449–453;
(b) J.J. Peng, Y.Q. Deng, Tetrahedron Lett. 42 (2001) 5917–5919;
(c) W.K. Su, J.J. Li, Z.G. Zheng, Y.C. Shen, Tetrahedron Lett. 46 (2005) 6037–6040;
(d) H.A. Stefani, C.B. Oliveira, R.B. Almeida, C.M.P. Pereira, R.C. Braga, R. Cella, V.C.
Borges, L. Savegnago, C.W. Nogueira, Eur. J. Med. Chem. 41 (2006) 513–518;
(e) I. Suzuki, Y. Suzumura, K. Takeda, Tetrahedron Lett. 47 (2006) 7861–7864.
[10] (a) J. Azizian, B. Mirza, M.M. Mojtahedi, M.S. Abaee, M. Sargordan, J. Fluorine
Chem. 129 (2008) 1083–1089;
(d) C.O. Kappe, Acc. Chem. Res. 33 (2000) 879–888.
[6] P. Biginelli, Gazz. Chim. Ital. 23 (1893) 360–416.
(b) A. Manjula, B. Vittal Rao, P. Neelakantan, Synth. Commun. 14 (2004) 2665–
2671.
[7] (a) Z.L. Shen, X.P. Xu, S.J. Ji, J. Org. Chem. 75 (2010) 1162–1167;
(b) C. Ranjith, G.V. Srinivasan, K.K. Vijayan, Bull. Chem. Soc. Jpn. 83 (2010) 288–
290;
[11] (a) S. Bhagat, A.K. Chakraborti, J. Org. Chem. 72 (2007) 1263–1270;
(b) T. Re´gnier, F. Berre´e, O. Lavastre, B. Carboni, Green Chem. 9 (2007) 125–126.
[12] (a) L. Shen, S. Cao, J.J. Wu, J. Zhang, H. Li, N.J. Liu, X.H. Qian, Green Chem. 11 (2009)
1414–1420;
(c) M. Lei, L. Ma, L.H. Hu, Monatsh. Chem. 141 (2010) 1005–1008;
(d) H. Murata, H. Ishitani, M. Iwamoto, Org. Biomol. Chem. 8 (2010) 1202–1211;
(e) S. Fustero, S. Catalan, J.L. Acena, C. del Pozo, J. Fluorine Chem. 130 (2009)
1145–1150;
(b) L. Shen, S. Cao, N.J. Liu, J.J. Wu, L.J. Zhu, X.H. Qian, Synlett (2008) 1341–1344;
(c) L. Shen, J. Zhang, S. Cao, J.L. Yu, N.J. Liu, J.J. Wu, X.H. Qian, Synlett (2008) 3058–
3062;
(f) J.V. Kharchenko, O.S. Detistov, V.D. Orlov, J. Comb. Chem. 11 (2009) 216–219;
(g) I. Suzuki, Y. Iwata, K. Takeda, Tetrahedron Lett. 49 (2008) 3238–3241.
[8] (a) B.C. Ranu, A. Hajra, U. Jana, J. Org. Chem. 65 (2000) 6270–6272;
(b) Y. Ma, C.T. Qian, L.M. Wang, M. Yang, J. Org. Chem. 65 (2000) 3864–3868;
(c) G. Sabitha, G.S.K.K. Reddy, K.B. Reddy, J.S. Yadav, Tetrahedron Lett. 44 (2003)
6497–6499;
(d) H. Li, J.L. Yu, S. Cao, L. Shen, M.X. Wu, J.H. Cheng, X.H. Qian, Sci. China Chem. 53
(2010) 1509–1513;
(e) L. Shen, S. Cao, J.J. Wu, H. Li, J. Zhang, M.X. Wu, X.H. Qian, Tetrahedron Lett. 51
(2010) 4866–4869.
[13] D.S. Bose, L. Fatima, H.B. Mereyala, J. Org. Chem. 68 (2003) 587–590.
[14] N. Ahmed, J.E. van Lier, Tetrahedron Lett. 48 (2007) 5407–5409.
[15] C.V. Reddy, M. Mahesh, P.V.K. Raju, T.R. Babu, V.V.N. Reddy, Tetrahedron Lett. 43
(2002) 2657–2659.
(d) R. Ghosh, S. Maiti, A. Chakraborty, J. Mol. Catal. A: Chem. 217 (2004) 47–50;
(e) A.S. Paraskar, G.K. Dewkar, A. Sudalai, Tetrahedron Lett. 44 (2003) 3305–3308;