Convenient one-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones using TMSCl as a catalyst with ultrasonic irradiation in DMF

Article abstract of DOI:10.1080/00397910802654666

3,4-Dihydropyrimidin-2(1H)-one and their derivatives were synthesized in good yields (90-99%) by a one-pot, three-component Biginelli cyclocondensation of dimedone, aldehydes, and urea in the presence of trimethylsilyl chloride (TMSCl) in dimethylformamid

Full text of DOI:10.1080/00397910802654666

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Convenient One-Pot Synthesis
of 3,4-Dihydropyrimidin-2(1H)-
ones Using TMSCl as a Catalyst
with Ultrasonic Irradiation in
DMF
Sheng-Rong Guo a & Yan-Qin Yuan a
a College of Chemistry and Biology , Lishui
University , Zhejiang, China
Published online: 13 May 2009.
To cite this article: Sheng-Rong Guo & Yan-Qin Yuan (2009) Convenient One-
Pot Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones Using TMSCl as a Catalyst with
Ultrasonic Irradiation in DMF, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 39:12, 2205-2220, DOI:
10.1080/00397910802654666
To link to this article: http://dx.doi.org/10.1080/00397910802654666
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Synthetic Communications1, 39: 2205–2220, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802654666
Convenient One-Pot Synthesis of
3,4-Dihydropyrimidin-2(1H)-ones Using TMSCl
as a Catalyst with Ultrasonic Irradiation in DMF
Sheng-rong Guo and Yan-qin Yuan
College of Chemistry and Biology, Lishui University, Zhejiang, China
Abstract: 3,4-Dihydropyrimidin-2(1H)-one and their derivatives were synthesized
in good yields (90–99%) by a one-pot, three-component Biginelli cyclocondensa-
tion of dimedone, aldehydes, and urea in the presence of trimethylsilyl chloride
(TMSCl) in dimethylformamide (DMF).
Keywords: Biginelli reaction, 3,4-Dihydropyrimidin-2(1H)-one, one-pot multi-
component synthesis, trimethylsilyl chloride
The Biginelli-type compounds 3,4-dihydropyrimidin-2(1H)-(thi)ones
(DHPMs) have been reported to possess diverse pharmacological activ-
ities such as antiviral, antibacterial, and antihypertensive activity, as well
as efficacy as calcium channel modulators and a1a-antagonists.[1–3] In
recent years, the reaction and DHPMs have attracted considerable
interest, and DHPMs are regarded as some of the most important groups
of druglike scaffolds.[4] The initial one-pot Biginelli procedure, catalyzed
by hydrochloric acid in ethanolic solution, suffers from major drawbacks
such as long reaction times and low yields, especially when aliphatic and
substituted aromatic aldehydes are used.[5–7]
Recently, growing interest in these multicomponent one-pot
reactions and the elucidation of the mechanism of the Biginelli reaction
have been combined to considerably improve the efficiency of the reaction.
Various strategies have been developed to overcome problems: catalysis
Received July 17, 2008.
Address correspondence to Sheng-rong Guo, College of Chemistry and
Biology, Lishui University, Zhejiang 323000, China. E-mail: guosr9609@163.com
2205

2206
S.-r. Guo and Y.-q. Yuan
using ZrCl4,[8] Mn(OAc)3,[9] FeCl3 ꢀ 6H2O,[10] NiCl2 ꢀ 6H2O,[10] RuCl3,[11]
LaCl3,[12,13] InCl3,[14] InBr3,[15] Bi(OTf)3,[16] LiClO4,[17] SmI2,[18] SSA,[19]
and KHSO4,[20] and improvement of the one-pot procedure using ionic
liquids,[21] solid phase,[22] polymersupport,[23] heterogeneous catalysts,[24]
or activation by ultrasound[25] and microwave[26] energies. Obviously,
many of these methods involve expensive reagents, stoichiometric amounts
of catalysts, long reaction times, unsatisfactory yields, and cumbersome
product isolation procedures. In recent decades, the scope of the original
Biginelli reaction has been extended by varying aldehydes, 1,3-
dicarbonyl, or N-substituted urea building blocks. However, to the best
of our knowledge, there is no report of the synthesis of DHPMs
using those aromatic aldehydes containing diphenyl sulfides such as
4-phenylsulfanyl benzaldehyde.
In this communication, we report a mediated, simple, efficient, envir-
onmentally benign synthesis of DHPMs using trimethylsilyl chloride
(TMSCl) as promoter and water scavenger. The reaction conditions were
studied by carrying out the condensation of phenylsulfanyl benzalde-
hydes, ethyl acetoacetate, and urea as the reactants. The desired dihydro-
pyrimidinine was obtained with good yield in the presence of TMSCl with
ultrasonic irradiation in dimethylformamide (DMF) solution at room
temperature. The model reaction with 4-phenylsulfanyl-benzaldehyde
(1a) gave the final product 4a in 87% yield and in 95% purity.
Initially, a pilot reaction was attempted using 4-phenylsulfanyl-
benzaldehyde (1), a,b-keto ester (2), and urea (3) in the presence of
H2NSO3H (0.5 equiv) as a catalyst refluxed in EtOH[25] for 12 h. The
product is a heavy-bodied oil and too hard to purify. We also investigated
the effect of different solvents such as CH3CN, CH3CO2C2H5, and
i-PrOH, but the products were still in a ropy state and could not be crys-
tallized in a solid state. The procedures of purification using the normal
metal Lewis acid such as ZnCl4, Mn(OAc)3, FeCl3 ꢀ 6H2O, and NiCl2 ꢀ
6H2O as catalyst to obtain the solid product are still difficult.
Among the various silicon-based acidic reagents, TMSCl has
received considerable attention as an inexpensive and readily available
reagent for various organic transformations.[27–30] It has been extensively
used as a promoter for cycloadddition and conjugate addition reactions
under mild and convenient conditions to offer the products in excellent
yield and high selectivity. According the results of the pilot reaction
and the excellent catalytic activity of TMSCl, we believe that using
TMSCl as catalyst to avoid the high reaction temperature or reflux may
be a better method to get the expected solid products in good yields.
Then we investigated the Biginelli condensation of ethyl acetoacetate,
4-phenylsulfanyl-benzaldehyde, and urea catalyzed by TMSCl. We
were pleased to find that this method provided good yields with simple

3,4-Dihydropyrimidin-2(1H)-ones
2207
Scheme 1. One-pot synthesis of DHPMs under TMSCl-catalyzed.
isolation procedures (Scheme 1). Accordingly, the optimal reaction con-
ditions were 4 eq. TMSCl as catalyst in DMF for 24 h at room tempera-
ture. Increasing the amount of TMSCl (>5 eq.) or decreasing the amount
of TMSCl (<4 eq.) did not improve the product yield by a considerable
amount. Iodotrimethylsilane was generated in situ from chlorotrimethyl-
silane and sodium iodide in DMF solution with comparable results.
In addition, we investigated the effect of different solvents on the
reaction rate and as well as yields of the products (Table 1). In protic sol-
vents such as dry MeOH or EtOH, the reaction was very slow and
resulted in less product yield. Similar results were obtained in coordinat-
ing solvents such as THF and diethyl ether. On the other hand, conduct-
ing the reactions in chlorinated solvents such as dichloromethane and
chloroform improved both the reaction rates and product yields. After
screening for different solvents, DMF was the solvent of choice, which
Table 1. Effect of solvents and temperature in the Biginelli reaction catalyst
by TMSCl
Entrya
Solvent
Time (h)
Temp. (ꢁC)
Yield (%)b
1
2
3
4
5
6
7
8
Neat
3
5
4
3
4
3
2
2
rt=60
rt=60
rt=60
rt=60
rt=60
rt=60
rt=60
rt=60
27=47
36=44
42=43
45=65
49=65
52=55
63=75
87=95
Methanol
Ethanol
THF
Et2O
CH2Cl2
CHCl3
DMF
aAll reactions were performed using 4-phenylsulfanyl-benzaldehyde (2 mmol),
urea (2 mmol), dimedone (2 mmol), and TMSCl (8 mmol).
bIsolated yields.

2208
S.-r. Guo and Y.-q. Yuan
not only afforded the products in good yield but also used simple
isolation procedures.
To evaluate the generality of the process, several diversified examples
illustrating the present method for the synthesis of 3,4-dihydropyrimidin-
2(1H)-(thi)ones 4 or 5 were studied (Scheme 1, Table 2). The reaction of
Table 2. TMSCl-mediated synthesis of various 3,4-dihydropyrimidin-2(1H)-
(thi)onesa
Time Temp.
(ꢁC)
Yield
(%)c
Productb
R1
R2
X
(h)
4a
4b
5a
5b
4c
4d
5c
5d
4e
4f
H
H
H
H
4-CH3
4-CH3
4-CH3
4-CH3
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-F
4-F
4-F
4-F
3-F
3-F
3-F
3-F
2-F
2-F
2-F
2-F
OEt
CH3
OEt
CH3
OEt
CH3
OEt
CH3
OEt
CH3
OEt
CH3
OEt
CH3
OEt
CH3
OEt
CH3
OEt
CH3
OEt
CH3
OEt
CH3
OEt
CH3
OEt
CH3
OEt
O
O
S
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
60
50
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
95.0
91.3
94.2
82.9
93.4
84.3
88.7
80.2
86.5
75.8
79.2
78.6
88.8
75.7
86.0
71.9
81.4
75.0
80.5
65.9
83.7
75.7
81.2
68.6
86.9
76.8
89.9
80.8
94.8[31]
S
O
O
S
S
O
O
S
5e
5f
S
4g
4h
5g
5h
4i
O
O
S
S
O
O
S
4j
5i
5j
S
4k
4l
O
O
S
5k
5l
S
4m
4n
4o
4p
4q
2-Me, 6-Cl
2-Me, 6-Cl
3-F,4-OMe
3-F,4-OMe
Thiophene-2-carbaldehyde
O
O
O
O
O
aAll reactions were performed using aldehyde (2 mmol), urea (2 mmol),
dimedone (2 mmol), and TMSCl (8 mmol).
bAll the products were characterized by 1H NMR, IR, and mass spectral data.
cIsolated yields.

3,4-Dihydropyrimidin-2(1H)-ones
2209
dimedone 2 with urea or thiourea 3 and various aldehydes 1 bearing
electron-withdrawing groups or electron-releasing groups was carried
out in the presence of 4 eq. TMSCl. The yields obtained were good to
excellent without formation of any side products such as 1,8-dioxo-
octahydroxanthenes, which are normally observed under the influence
of strong acids. The results are illustrated in Table 2. All the products
obtained were fully characterized by spectroscopic methods such as infra-
red (IR), 1H NMR, and mass spectroscopy (MS) and also by comparison
with the reported spectral data. The overall yields ranged from 95% of 4a
to 68.6% of 5 l. Thiourea was also used with similar success along with
substituted aldehydes and ethylacetoacetate, although the yields of
DHPM thiones were slightly less than those of their corresponding
DHPMs.
The mechanism of the Biginelli reaction has recently been revised
by Varala et al.[16] Based on this work, we suggest the following mechan-
ism for the TMSCl-catalyzed Biginelli reaction (Scheme 2): The first step
is the TMSCl-catalyzed condensation of aldehyde and urea (or
thiourea). The formation of N-acyl imine intermediate A is the rate-
limiting step of the reaction. The intermediate A acts as an electrophile
for the nucleophilic addition of the ketoester enol. The resulting add-
uct B undergoes condensation with the urea NH2 to give the cyclized
product.
In summary, TMSCl showed remarkable reactivity as a ‘‘hard–soft’’
reagent and considerably accelerated the reactions. A novel method for
Biginelli condensation catalyzed by TMSCl at 60ꢁC was developed.
The advantages of this method were safety, ease of workup procedure,
and large-scale synthesis. The simplicity, together with the use of inexpen-
sive, nontoxic, and environmentally benign nature of TMSCl under
DMF solvent, is a remarkable feature of the procedure.
Scheme 2. Mechanism for the TMSCl-catalyzed one-pot synthesis of DHPMs.

2210
S.-r. Guo and Y.-q. Yuan
EXPERIMENTAL
1H NMR spectra were obtained on a Bruker Avance (300-MHz) spectro-
meter using tetramethylsilane (TMS) as internal standard and CDCl3 as
solvent. Infrared (IR) spectra were determined on a Vector-55 instru-
ment. Elemental analyses were conducted using a Yanaco MT-5CHN
elemental analyzer. Thin-layer chromatography (TLC) was GF254 with
petroleum ether=ethyl acetate as eluent. Aldehydes, ethyl acetoacetate,
urea, and thiourea were all commercial products and were used without
further purification. All liquid reagents were distilled before use. Melting
points were determined on a microscopy apparatus and are uncorrected.
Typical Experimental Procedure for the Preparation
of Compounds 4a–w
Method A
Ethyl acetoacetate 2 (2.1 mmol), the appropriate aldehyde 1 (2 mmol),
and the appropriate urea or thiourea 3 (2.1 mmol) were placed in a
15-mL Ace pressure tube and dissolved in DMF (5 mL). TMSCl (8 mmol)
was added dropwise to the solution. The tube was thoroughly sealed and
allowed to stand at 60ꢁC in an ultrasonic bath for 2 h and cooled to room
temperature. Then the mixture was poured into H2O (20ꢂ30 mL) was left
at rt in an ultrasonic bath for 1h. The precipitate that formed was filtered
and washed with a small amount of i-PrOH. The product was purified by
recrystallization from an appropriate solvent. A further 5–10% of the
product could be collected by extracting the mother liquor with chloro-
form and evaporating it under reduced pressure. The yellow residue
was recrystallization from ethanol to give pure products.
Method B
Ethyl acetoacetate 2 (2.1 mmol), the appropriate aldehyde 1 (2 mmol),
and the appropriate urea 3 or thiourea 3 (2.1 mmol) were placed in a
15-mL Ace pressure tube and dissolved in DMF (5 mL). TMSCl (8 mmol)
was added dropwise to the solution. The tube was thoroughly sealed,
allowed to stand at rt in an ultrasonic bath for 1h, and was then left
to stand at rt for 1ꢂ2 days. The mixture was poured into H2O (20ꢂ
30 mL) and was left at rt in an ultrasonic bath for 1h. The precipitate
that formed was filtered and washed with a small amount of i-PrOH.
The product was purified by recrystallization from an appropriate sol-
vent. A further 5–10% of the product could be collected by extracting

3,4-Dihydropyrimidin-2(1H)-ones
2211
the mother liquor with chloroform and evaporating it under reduced
pressure. The yellow residue was recrystallization from ethanol to give
pure products.
Data
6-Methyl-2-oxo-4-(4-phenylsulfanyl-phenyl)-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylic Acid Ethyl Ester (4a)
White solid, mp 225–228ꢁC. 1H NMR (CDC13): d ¼ 1.19 (t, 3H), 2.36 (s,
3H), 4.15 (q, 2H), 5.35 (d, J ¼ 3.65, 1H), 5.55 (s, 1H), 7.34 (m, 9H), 7.45
(s, 1H); IR (KBr): n ¼ 3600–3200 (br, NH), 3107, 2983, 2929, 1711, 1687,
1630, 1490, 1404, 1342, 1215, 1086, 1016, 833, 760, 698, 669 cmꢂ1; MS
(EI, 70 eV) m=z (%): 370 (M þ 2, 18.03), 368 (Mþ, 55.25), 343 (10.59),
341 (30.22), 297 (20.04), 295 (39.06), 294 (22.76), 293 (100.00), 127
(25.32), 111 (25.85), 77 (14.46), 45 (16.43), 44 (15.85), 43 (25.06). Anal.
calcd. for C20H20N2O3S: C, 65.20; H, 5.47; N, 7.60. Found: C, 65.36;
H, 5.68; N, 7.57.
5-Acetyl-6-methyl-4-(4-phenylsulfanyl-phenyl)-3,4-dihydro-1H-
pyrimidin-2-one (4b)
1
Red solid, mp 218–220ꢁC. H NMR (CDC13): d ¼ 2.17 (s, 3H), 2.36 (s,
3H), 5.35 (d, J ¼ 3.65, 1H), 5.41 (s, 1H), 7.24 (m, 4H), 7.28 (m, 5H),
7.35 (s, 1H); IR (KBr): n ¼ 3530–3350 (br, NH), 3186, 2984, 2929,
1708, 1657, 1630 cmꢂ1; MS (EI, 70 eV) m=z (%): 340 (M þ 2, 11.46),
338 (Mþ, 35.54), 274 (33.13), 244 (24.17), 169 (55.51). Anal. calcd. for
C19H18N2O2S: C, 67.43; H, 5.36; N, 8.28. Found: C, 67.36; H, 5.21; N,
8.39.
6-Methyl-4-(4-phenylsulfanyl-phenyl)-2-thioxo-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylic Acid Ethyl Ester (5a)
1
Red solid, mp 207–209ꢁC. H NMR (CDC13): d ¼ 1.17 (t, 3H), 2.37 (s,
3H), 5.38 (q, 2H), 5.38 (d, J ¼ 3.87, 1H), 5.76 (s, 1H), 7.20 (m, 9H),
7.96 (s, 1H); IR (KBr): n ¼ 3312, 3233, 2965, 2835, 1620, 1567 cmꢂ1
;
MS (EI, 70 eV) m=z (%): 386 (M þ 2, 18.95), 384 (Mþ, 100.00), 275
(35.83), 244 (24.17), 188 (45.71), 169 (55.51), 114 (72.15), 91 (68.21), 75
(35.80), 45 (42.56), 15 (26.80). Anal. calcd. for C20H20N2O2S2: C,
62.47; H, 5.24; N, 7.29. Found: C, 62.32; H, 5.29; N, 7.09.

2212
S.-r. Guo and Y.-q. Yuan
1-[6-Methyl-4-(4-phenylsulfanyl-phenyl)-2-thioxo-1,2,3,4-tetrahydro-
pyrimidin-5-yl]-ethanone (5b)
Red solid, mp 230–233. 1H NMR (CDC13): d ¼ 2.19 (s, 3H), 2.36 (s, 3H),
5.46 (d, J ¼ 3.87, 1H), 5.78 (s, 1H), 7.28 (m, 9H), 7.58 (s, 1H); IR (KBr):
n ¼ 3358, 3208, 2955, 2880, 1620, 1560, 920, 865, 638 cmꢂ1; MS (EI,
70 eV) m=z (%): 356 (M þ 2, 8.65), 354 (Mþ, 100.00), 199 (32.08), 158
(58.92), 109 (68.12), 84 (21.45), 74 (52.15), 58 (52.88), 42 (35.16). Anal.
calcd. for C19H18N2OS2: C, 64.38; H, 5.12; N, 7.90. Found: C, 64.30;
H, 5.21; N, 7.82.
6-Methyl-2-oxo-4-(4-p-tolylsulfanyl-phenyl)-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylic Acid Ethyl Ester (4c)
1
White solid, mp 170–173. H NMR (CDC13): d ¼ 1.17 (t, 3H), 2.34 (s,
3H), 2.75 (s, 3H), 4.15 (q, 2H), 5.38 (d, J ¼ 3.66, 1H), 5.55 (s, 1H), 7.34
(m, 8H), 7.45 (s, 1H); IR (KBr): n ¼ 3468, 3245, 2988, 1716, 1680,
1615, 1408, 1215, 839, 766, 668 cmꢂ1; MS (EI, 70 eV) m=z (%): 384
(M þ 2, 9.09), 382 (Mþ, 51.56), 213 (100.00), 198 (56.12), 124 (35.90),
91 (54.24), 77 (73.08), 60 (45.80), 45 (21.32), 41 (15.08), 15 (25.08). Anal.
calcd. for C21H22N2O3S: C, 65.95; H, 5.80; N, 7.32. Found: C, 65.86; H,
5.78; N, 7.37.
5-Acetyl-6-methyl-4-(4-p-tolylsulfanyl-phenyl)-3,4-dihydro-1H-
pyrimidin-2-one (4d)
Red solid, mp 218–220. 1H NMR (CDC13): d ¼ 2.18 (s, 3H), 2.38 (s, 3H),
2.58 (s, 3H), 5.46 (d, J ¼ 3.78, 1H), 7.28 (m, 8H), 7.68 (s, 1H), 8.78 (s,
1H); IR (KBr): n ¼ 3328, 3258, 2908, 2686, 1650, 1580, 1550, 910, 855,
618 cmꢂ1; MS (EI, 70 eV) m=z (%): 354 (M þ 2, 5.86), 352 (Mþ,
100.00), 213 (46.75), 199 (34.02), 158 (56.12), 109 (60.18), 82 (51.48), 74
(58.56), 58 (45.16), 42 (68.26). Anal. calcd. for C20H20N2O2S: C, 68.16;
H, 5.72; N, 7.95. Found: C, 68.20; H, 5.66; N, 7.92.
6-Methyl-2-thioxo-4-(4-p-tolylsulfanyl-phenyl)-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylic Acid Ethyl Ester (5c)
1
White solid, mp 238–241. H NMR (CDC13): d ¼ 1.18 (t, 3H), 2.36 (s,
3H), 2.78 (s, 3H), 4.25 (q, 2H), 5.39 (d, J ¼ 3.66, 1H), 7.34 (m, 8H),
7.45 (s, 1H), 8.55 (s, 1H); IR (KBr): n ¼ 3368, 3248, 2968, 1718, 1688,
1616, 1488, 1218, 838, 760, 658 cmꢂ1; MS (EI, 70 eV) m=z (%): 394
(Mþ, 45.09), 213 (100.00), 198 (56.12), 184 (75.08), 124 (35.90), 91

3,4-Dihydropyrimidin-2(1H)-ones
2213
(54.24), 76 (45.65), 77 (73.08), 45 (21.32), 41 (15.08), 15 (25.08). Anal.
calcd. for C22H22N2OS2: C, 66.97; H, 5.62; N, 7.10. Found: C, 66.90;
H, 5.68; N, 7.17.
1-[6-Methyl-2-thioxo-4-(4-p-tolylsulfanyl-phenyl)-1,2,3,4-tetrahydro-
pyrimidin-5-yl]-ethanone (5d)
Red solid, mp 218–220. 1H NMR (CDC13): d ¼ 2.20 (s, 3H), 2.35 (s, 3H),
2.60 (s, 3H), 5.36 (d, J ¼ 3.68, 1H), 7.30 (m, 8H), 7.48 (s, 1H), 8.58 (s,
1H); IR (KBr): n ¼ 3308, 3168, 2858, 2306, 1670, 1615, 1585, 1500, 817,
619 cmꢂ1; MS (EI, 70 eV) m=z (%): 370 (M þ 2, 17.05), 368 (Mþ,
45.05), 213 (46.75), 199 (34.02), 158 (56.12), 109 (60.18), 82 (51.48), 74
(58.56), 58 ( 45.16), 42 (68.26). Anal. calcd. for C20H20N2OS2: C, 65.18;
H, 5.47; N, 7.60. Found: C, 65.25; H, 5.46; N, 7.70.
4-[4-(4-Methoxy-phenylsulfanyl)-phenyl]-6-methyl-2-oxo-1,2,3,4-
tetrahydro-pyrimidine-5-carboxylic Acid Ethyl Ester (4e)
1
White solid, mp 183–185. H NMR (CDC13): d ¼ 1.21 (t, 3H), 2.34 (s,
3H), 3.35 (s, 3H), 4.15 (q, 2H), 5.33 (d, J ¼ 3.68, 1H), 5.65 (s, 1H), 7.18
(m, 2H), 7.34 (m, 6H), 7.45 (s, 1H); IR (KBr): n ¼ 3360, 3215, 2088,
1719, 1660, 1460, 806, 726, 638 cmꢂ1; MS (EI, 70 eV) m=z (%): 398 (Mþ,
71.05), 229 (100.00), 170 (75.08), 138 (42.45), 94 (42.61), 92 (56.14), 61
(63.14), 60 (35.64), 29 (18.15), 14 (35.67). Anal. calcd. for C21H22N2O4S:
C, 63.30; H, 5.56; N, 7.03. Found: C, 63.36; H, 5.61; N, 7.17.
5-Acetyl-4-[4-(4-methoxy-phenylsulfanyl)-phenyl]-6-methyl-3,4-
dihydro-1H-pyrimidin-2–one (4f)
Red solid, mp 221–223. 1H NMR (CDC13): d ¼ 2.08 (s, 3H), 2.36 (s, 3H),
3.18 (s, 3H), 5.58 (d, J ¼ 3.68, 1H), 7.28 (m, 8H), 7.68 (s, 1H), 8.78 (s,
1H); IR (KBr): n ¼ 3358, 3138, 2958, 1710, 1680, 1580, 930, 875,
716 cmꢂ1; MS (EI, 70 eV) m=z (%): 368 (Mþ, 15.86), 229 (100.00), 140
(77.45), 138 (42.45), 94 (49.74), 92 (46.15), 61 (63.14), 60 (25.34). Anal.
calcd. for C20H20N2O3S: C, 65.20; H, 5.47; N, 7.60. Found: C, 65.31;
H, 5.56; N, 7.62.
4-[4-(4-Methoxy-phenylsulfanyl)-phenyl]-6-methyl-2-thioxo-1,2,3,4-
tetrahydro-pyrimidine-5-carboxylic Acid Ethyl Ester (5e)
1
White solid, mp 268–270 H NMR (CDC13): d ¼ 1.13 (t, 3H), 2.41 (s,
3H), 3.37 (s, 3H), 5.38 (q, 2H), 5.52 (d, J ¼ 3.87, 1H), 5.78 (s, 1H), 7.15

2214
S.-r. Guo and Y.-q. Yuan
(m, 8H), 7.96 (s, 1H); IR (KBr): n ¼ 3359, 3212, 2885, 1712, 1660,
1580 cmꢂ1; MS (EI, 70 eV) m=z (%): 414 (Mþ, 23.09), 229 (100.00), 139
(78.45), 139 (54.45), 114 (72.14), 91 (78.18), 76 (55.75), 45 (35.16), 15
(26.80). Anal. calcd. for C21H22N2O3S2: C, 60.84; H, 5.35; N, 6.76.
Found: C, 60.90; H, 5.39; N, 6.79.
1-{4-[4-(4-Methoxy-phenylsulfanyl)-phenyl]-6-methyl-2-thioxo-
1,2,3,4-tetrahydro-pyrimidin-5-yl}-ethanone (5f)
Red solid, mp 278–280. 1H NMR (CDC13): d ¼ 2.21 (s, 3H), 2.33 (s, 3H),
3.45 (s, 3H), 5.43 (d, J ¼ 3.68, 1H), 5.68 (s, 1H), 7.28 (m, 8H), 7.88 (s,
1H); IR (KBr): n ¼ 3258, 2935, 1708, 1670, 1572, 980, 815 cmꢂ1; MS
(EI, 70 eV) m=z (%): 384 (Mþ, 100.00), 229 (58.58), 158 (48.06), 124
(71.08), 108 (78.26), 94 (64.61), 72 (56.25), 44 (25.07). Anal. calcd. for
C20H20N2O2S2: C, 62.47; H, 5.24; N, 7.29. Found: C, 62.36; H, 5.29;
N, 7.22.
4-[4-(4-Fluoro-phenylsulfanyl)-phenyl]-6-methyl-2-oxo-1,2,3,4-
tetrahydro-pyrimidine-5-carboxylic Acid Ethyl Ester (4g)
1
White solid, mp 248–250. H NMR (CDC13): d ¼ 1.08 (t, 3H), 2.23 (s,
3H), 3.93 (q, 2H), 5.10 (d, J ¼ 3.68, 1H), 7.19 (m, 6H), 7.27 (d,
J ¼ 9.68, 2H), 7.77 (s, 1H), 9.25 (s, 1H); IR (KBr): n ¼ 3218, 2958,
2886, 1660, 1560, 960, 865, 739 cmꢂ1; MS (EI, 70 eV) m=z (%): 386
(Mþ, 18.55), 217 (100.00), 172 (76.03), 127 (58.45), 109 (42.12), 95
(67.24), 91 (71.12), 76 (67.45), 60 (53.24), 45 (35.48), 42 (46.28), 29
(25.60). Anal. calcd. for C20H19FN2O3S: C, 62.16; H, 4.96; N, 7.25.
Found: C, 62.31; H, 4.88; N, 7.36.
5-Acetyl-4-[4-(4-fluoro-phenylsulfanyl)-phenyl]-6-methyl-3,4-
dihydro-1H-pyrimidin-2-one (4h)
1
Red solid, mp 220–223. H NMR (CDC13): d ¼ 2.11 (s, 3H), 2.27 (s,
3H), 5.23 (d, J ¼ 3.68, 1H), 7.19 (m, 6H), 7.39 (m, 2H), 7.86 (s, 1H),
9.23 (s, 1H); IR (KBr): n ¼ 3208, 2878, 1726, 1680, 1590, 980, 885,
789, 645 cmꢂ1; MS (EI, 70 eV) m=z (%): 356 (Mþ, 68.85), 218
(100.00), 142 (78.08), 128 ( 52.25), 124 (65.34), 94 (67.24), 91 (74.28),
77 (66.45), 60 (51.28), 45 (25.15), 15 (25.15). Anal. calcd. for
C19H17FN2O2S: C, 64.03; H, 4.81; N, 7.86. Found: C, 64.10; H, 4.85;
N, 7.79.

3,4-Dihydropyrimidin-2(1H)-ones
2215
4-[4-(4-Fluoro-phenylsulfanyl)-phenyl]-6-methyl-2-thioxo-1,2,3,4-
tetrahydro-pyrimidine-5-carboxylic Acid Ethyl Ester (5g)
1
White solid, mp 268–271. H NMR (CDC13): d ¼ 1.18 (t, 3H), 2.29 (s,
3H), 3.93 (q, 2H), 5.10 (d, J ¼ 3.68, 1H), 7.19 (m, 6H), 7.27 (d,
J ¼ 9.88, 2H), 7.85 (s, 1H), 8.65 (s, 1H); IR (KBr): n ¼ 3318, 3156,
2886, 1730, 1660, 860, 765, 652 cmꢂ1; MS (EI, 70 eV) m=z (%): 402
(Mþ, 18.55), 217 (100.00), 172 (66.02), 109 (52.12), 91 (51.12), 76
(45.45), 60 (63.24), 45 (45.46), 29 (15.18). Anal. calcd. for
C20H19FN2O2S2: C, 59.68; H, 4.76; N, 6.96. Found: C, 59.61; H, 4.85;
N, 6.86.
1-{4-[4-(4-Fluoro-phenylsulfanyl)-phenyl]-6-methyl-2-thioxo-1,2,3,4-
tetrahydro-pyrimidin-5-yl}-ethanone (5h)
Red solid, mp 245–247. 1H NMR (CDC13): d ¼ 2.13 (s, 3H), 2.35 (s, 3H),
5.36 (d, J ¼ 3.68, 1H), 7.29 (m, 6H), 7.39 (m, 2H), 7.76 (s, 1H), 8.63 (s,
1H); IR (KBr): n ¼ 3228, 2978, 1716, 1690, 1580, 950, 865, 695 cmꢂ1
;
MS (EI, 70 eV) m=z (%): 372 (Mþ, 68.85), 218 (100.00), 142 (78.12), 94
(47.34), 91 (75.68), 77 (36.44), 45 (65.75), 15 (15.10). Anal. calcd. for
C19H17FN2OS2: C, 61.27; H, 4.60; N, 7.52. Found: C, 61.15; H, 4.65;
N, 7.49.
4-[4-(3-Fluoro-phenylsulfanyl)-phenyl]-6-methyl-2-oxo-1,2,3,4-
tetrahydro-pyrimidine-5-carboxylic Acid Ethyl Ester (4i)
1
White solid, mp 232–234. H NMR (CDC13): d ¼ 1.18 (t, 3H), 2.36 (s,
3H), 4.18 (q, 2H), 5.35 (d, J ¼ 3.68, 1H), 5.56 (s, 1H), 6.85 (m, 2H),
7.29 (m, 3H), 7.27 (d, 3H), 7.78 (s, 1H); IR (KBr): n ¼ 3328, 2928,
1720, 1660, 980, 835 cmꢂ1; MS (EI, 70 eV) m=z (%): 386 (Mþ, 81.35),
217 (56.90), 172 (100.00), 127 (51.45), 109 (48.68), 95 (68.02), 91
(75.72), 76 (66.40), 60 (43.26), 45 (38.48), 29 (25.60). Anal. calcd. for
C20H19FN2O3S: C, 62.16; H, 4.96; N, 7.25. Found: C, 62.18; H, 5.04;
N, 7.28.
5-Acetyl-4-[4-(3-fluoro-phenylsulfanyl)-phenyl]-6-methyl-3,4-dihydro-
1H-pyrimidin-2-one (4j)
Red solid, mp 233–235. 1H NMR (CDC13): d ¼ 2.19 (s, 3H), 2.37 (s, 3H),
5.48 (d, J ¼ 3.68, 1H), 5.62 (s, 1H), 6.85 (m, 3H), 7.05 (d, J ¼ 9.85, 2H),
7.39 (m, 3H), 7.86 (s, 1H); IR (KBr): n ¼ 3358, 3125, 1704, 1685, 960,

2216
S.-r. Guo and Y.-q. Yuan
875, 665 cmꢂ1; MS (EI, 70 eV) m=z (%): 356 (Mþ, 28.02), 218 (100.00),
141 (58.24), 128 (58.55), 124 (45.35), 91 (75.02), 77 (61.15), 60 (42.25),
15 (25.15). Anal. calcd. for C19H17FN2O2S: C, 64.03; H, 4.81; N, 7.86.
Found: C, 64.11; H, 4.73; N, 7.89.
4-[4-(3-Fluoro-phenylsulfanyl)-phenyl]-6-methyl-2-thioxo-1,2,3,4-
tetrahydro-pyrimidine-5-carboxylic Acid Ethyl Ester (5i)
1
White solid, mp 221–224. H NMR (CDC13): d ¼ 1.24 (t, 3H), 2.33 (s,
3H), 3.73 (q, 2H), 5.21 (d, J ¼ 3.68, 1H), 7.09 (m, 6H), 7.17 (d,
J ¼ 9.88, 2H), 7.55 (s, 1H), 8.14 (s, 1H); IR (KBr): n ¼ 3316, 2856,
1701, 1690, 960, 760 cmꢂ1. Anal. calcd. for C20H19FN2O2S2: C, 59.68;
H, 4.76; N, 6.96. Found: C, 59.73; H, 4.75; N, 6.88.
1-{4-[4-(3-Fluoro-phenylsulfanyl)-phenyl]-6-methyl-2-thioxo-1,2,3,4-
tetrahydropyrimidin-5-yl}-ethanone (5j)
Red solid, mp 212–215. 1H NMR (CDC13): d ¼ 2.16 (s, 3H), 2.45 (s, 3H),
5.46 (d, J ¼ 3.68, 1H), 5.62 (s, 1H), 7.29 (m, 6H), 7.39 (m, 2H), 7.76 (s,
1H); IR (KBr): n ¼ 3318, 1716, 1693, 1560, 980, 875 cmꢂ1. Anal. calcd.
for C19H17FN2OS2: C, 61.27; H, 4.60; N, 7.52. Found: C, 61.30; H,
4.57; N, 7.57.
4-[4-(2-Fluoro-phenylsulfanyl)-phenyl]-6-methyl-2-oxo-1,2,3,4-
tetrahydro-pyrimidine-5-carboxylic Acid Ethyl Ester (4k)
1
White solid, mp 239–242. H NMR (CDC13): d ¼ 1.17 (t, 3H), 2.34 (s,
3H), 4.12 (q, 2H), 5.35 (s, 1H), 5.56 (d, J ¼ 3.68, 1H), 7.15 (m, 2H),
7.29 (m, 6H), 7.78 (s, 1H); IR (KBr): n ¼ 3288, 3028, 1770, 1690, 1580,
990, 835, 684 cmꢂ1. Anal. calcd. for C20H19FN2O3S: C, 62.16; H, 4.96;
N, 7.25. Found: C, 62.23; H, 5.07; N, 7.18.
5-Acetyl-4-[4-(2-fluoro-phenylsulfanyl)-phenyl]-6-methyl-3,4-dihydro-
1H-pyrimidin-2-one (4l)
Red solid, mp 254–257. 1H NMR (CDC13): d ¼ 1.19 (s, 3H), 2.31 (s, 3H),
5.58 (d, J ¼ 3.68, 1H), 5.72 (s, 1H), 6.85 (m, 2H), 7.15 (d, J ¼ 9.85, 2H),
7.29 (m, 4H), 7.86 (s, 1H); IR (KBr): n ¼ 3185, 1734, 1680, 950,
855 cmꢂ1. Anal. calcd. for C19H17FN2O2S: C, 64.03; H, 4.81; N, 7.86.
Found: C, 63.91; H, 4.91; N, 7.79.

3,4-Dihydropyrimidin-2(1H)-ones
2217
4-[4-(2-Fluoro-phenylsulfanyl)-phenyl]-6-methyl-2-thioxo-1,2,3,4-
tetrahydro-pyrimidine-5-carboxylic Acid Ethyl Ester (5k)
1
White solid, mp 235–237. H NMR (CDC13): d ¼ 1.15 (t, 3H), 2.31 (s,
3H), 4.06 (q, 2H), 5.58 (d, J ¼ 3.38, 1H), 7.09 (m, 4H), 7.17 (d,
J ¼ 9.68, 2H), 7.55 (m, 2H), 7.85 (s, 1H); IR (KBr): n ¼ 3366, 2855,
1701, 1680, 950, 760, 630 cmꢂ1. Anal. calcd. for C20H19FN2O2S2: C,
59.68; H, 4.76; N, 6.96. Found: C, 59.63; H, 4.81; N, 6.98.
1-{4-[4-(2-Fluoro-phenylsulfanyl)-phenyl]-6-methyl-2-thioxo-1,2,3,4-
tetrahydro-pyrimidin-5-yl}-ethanone (5l)
Red solid, mp 212–215. 1H NMR (CDC13): d ¼ 2.16 (s, 3H), 2.45 (s, 3H),
5.46 (d, J ¼ 3.68, 1H), 5.62 (s, 1H), 7.29 (m, 6H), 7.39 (m, 2H), 7.76 (s,
1H); IR (KBr): n ¼ 3318, 1716, 1693, 1560, 980, 875 cmꢂ1. Anal. calcd.
for C19H17FN2OS2: C, 61.27; H, 4.60; N, 7.52. Found: C, 61.30; H,
4.57; N, 7.57.
4-[4-(2-Chloro-6-methyl-phenylsulfanyl)-phenyl]-6-methyl-2-oxo-
1,2,3,4-tetrahydro-pyrimidine-5-carboxylic Acid Ethyl Ester (4m)
White solid, mp 187–190. 1H NMR (DMSO-d6): d ¼ 1.26 (t, 3H), 2.15 (s,
3H), 2.51 (s, 3H), 3.92 (q, 2H), 5.42 (s, 1H), 7.30 (m, 7H), 7.95 (s, 1H),
9.25 (s, 1H); IR (KBr): n ¼ 3358, 3226, 1710, 1660, 1590, 960 cmꢂ1. Anal.
calcd. for C21H21ClN2O3S: C, 60.50; H, 5.08; N, 6.72. Found: C, 61.03;
H, 5.17; N, 6.68.
5-Acetyl-4-[4-(2-chloro-6-methyl-phenylsulfanyl)-phenyl]-6-methyl-
3,4-dihydro-1H-pyrimidin-2-one (4n)
White solid, mp 157–159. 1H NMR (DMSO-d6): d ¼ 2.13 (s, 3H), 2.15 (s,
3H), 2.29 (s, 3H), 5.26 (d, J ¼ 3.82, 1H), 6.99 (t, 1H), 7.25 (m, 6H), 7.83 (s,
1H), 9.25 (s, 1H); IR (KBr): n ¼ 3358, 3226, 1710, 1660, 1590, 960 cmꢂ1
.
Anal. calcd. for C20H19ClN2O2S: C, 62.09; H, 4.95; N, 7.24. Found: C,
61.94; H, 5.04; N, 7.28.
4-[4-(3-Fluoro-4-methoxy-phenylsulfanyl)-phenyl]-6-methyl-2-oxo-
1,2,3,4-tetrahydro-pyrimidine-5-carboxylic Acid Ethyl Ester (4o)
White solid, mp 270–273. 1H NMR (DMSO-d6): d ¼ 0.97 (t, 3H), 2.17 (s,
3H), 3.78 (s, 3H), 3.96 (q, 2H), 5.12 (d, J ¼ 3.82, 1H, 1H), 7.13 (m, 7H),

2218
S.-r. Guo and Y.-q. Yuan
7.69 (s, 1H), 9.17 (s, 1H); IR (KBr): n ¼ 3358, 3226, 1710, 1660, 1590,
960 cmꢂ1. Anal. calcd. for C21H21FN2O4S: C, 60.56; H, 5.08; N, 6.73.
Found: C, 60.43; H, 5.12; N, 7.08.
5-Acetyl-4-[4-(3-fluoro-4-methoxy-phenylsulfanyl)-phenyl]-6-methyl-
3,4-dihydro-1H-pyrimidin-2-one (4p)
White solid, mp 210–213. 1H NMR (DMSO-d6): d ¼ 2.25 (s, 3H), 2.32 (s,
3H), 3.19 (s, 3H), 5.36 (d, J ¼ 3.62, 1H), 6.56 (t, 1H), 7.15 (m, 6H), 7.85 (s,
1H), 9.05 (s, 1H); IR (KBr): n ¼ 3358, 3256, 1715, 1680, 1556, 785 cmꢂ1
.
Anal. calcd. for C20H19FN2O3S: C, 62.16; H, 4.96; N, 7.25. Found: C,
62.44; H, 5.02; N, 7.18.
6-Methyl-2-oxo-4-thiophen-2-yl-1,2,3,4-tetrahydro-pyrimidine-5-
carboxylic Acid Ethyl Ester[31] (4q)
White solid, mp 220–221. 1H NMR (DMSO-d6): d ¼ 1.09 (t, 3H), 2.27 (s,
3H), 4.00 (q, 2H), 5.15 (d, J ¼ 3.3 Hz, 1H), 7.20 (d, 2H), 7.85 (s, 1H), 8.50
(d, 2H), 9.38 (s, 1H).
ACKNOWLEDGMENTS
This work was funded by the Natural Science Foundation of Zhejiang
Province, China (Project Y407240).
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