Novel four-component reaction towards diastereoselective synthesis of tetrahydropyrimidinthiones

Article abstract of DOI:10.1016/j.tet.2010.12.011

The first multicomponent synthesis of tetrahydropyrimidinthiones has been realized via the four-component assembly of aromatic aldehyde, enaminone, aromatic amine, and thiourea. The reaction was performed at room temperature and the products were obtained

Full text of DOI:10.1016/j.tet.2010.12.011

Tetrahedron 67 (2011) 922e926
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Novel four-component reaction towards diastereoselective synthesis
of tetrahydropyrimidinthiones
,
,
Jie-Ping Wan a b, Chunping Wang a, Yuanjiang Pan b
*
a College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330022, China
b Department of Chemistry, Zhejiang University, Hangzhou 310027, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 October 2010
Received in revised form 30 November 2010
Accepted 7 December 2010
Available online 10 December 2010
The first multicomponent synthesis of tetrahydropyrimidinthiones has been realized via the four-com-
ponent assembly of aromatic aldehyde, enaminone, aromatic amine, and thiourea. The reaction was
performed at room temperature and the products were obtained in excellent diastereoselectivity.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Multicomponent
Heterocycle
Tetrahydropyrimidinthones
Multiple bond formation
Diastereoselective
1. Introduction
isocyanate was also reported to afford THPMs.8 However, in the
viewpoint of molecular diversity and complexity, multicomponent
Creating molecular diversity in organic reactions is one of the
main goals of organic synthesis due to the urgent requirement on
compound libraries in drug discovery process.1 The central issue to
achieve this goal is to develop fast and efficient synthetic technol-
ogies, which exclude the drawbacks embedded in traditional step-
by-step synthesis, such as tedious repeated work-up, long cyclic
period, low total yield, and continuous production of organic wastes.
Multicomponent reaction (MCR), known to construct complex
products in one-pot by the assembly of three or more substrates,
provided an ideal solution to the contradiction between low effi-
ciency of tradition linear synthesis and the high requirement of
candidate compounds for drug discovery.2
Tetrahydropyrimidinthiones (THPMs) could be regarded as the
reduced derivatives of dihydropyrimidinones (DHPMs) and represent
a class of highly valuable heterocylic identities in the study of
medicinal chemistry. Properly elaborated THPMs have been reported
to possess a broad range of bioactivities: HIV protease inhibiting ac-
tivity,3 antineoplastic activity,4 antiproleferative,5 and herbicidal
activity,6 to name but a few. Presently, THPMs are generally synthe-
sized by the annulation reaction of ureas and 1,3-dihalides.7 The Pd-
catalyzed ring expansion reaction of N-alkyl-2-vinylazetidine with
reaction is arguably the most ideal strategy for the synthesis of these
heterocyclic scaffolds. The presently known MCR protocols for the
synthesis of THPMs are using Biginelli-like transformation. Un-
fortunately, controlling the Biginelli-like process to provide THPMs is
ratherdifficult since the THPMs prone to dehydrate to give more stable
DHPMs (Biginelli reaction). It is possible to obtain THPMs as products
using this methodology only when substrates with particular func-
tional groups, such as fluorinated 1,3-dicarbonyl9 compounds or tri-
chloromethylated 1,3-dicarbonyl compounds10 were employed. Or
alternatively, using the two-step operation of Knoevenagel conden-
sation and (thio)urea annulation.11 To the best of our knowledge, not
a multicomponent protocol for the synthesis of THPMs tolerating
conventional and simple reactants is presentlyavailable. It istherefore
highly desirable to develop MCR methods for the generous synthesis
of THPMs. As our continuous efforts in developing novel MCRs for the
synthesis of useful heterocyclic scaffolds12 we wish to report herein
the first four-component synthesis of THPMs by using aromatic al-
dehyde, emaminone, aromatic amine, and thiourea.
2. Results and discussion
In the initial study, we tentatively employed enaminone 1a,
benzaldehyde 2a, aniline 3a, and thiourea for the synthesis of THPM
5a in the manner of four-component reaction at the presence of
trimethylsilyl chloride (TMSCl). To our delight, albeit in low yield,
* Corresponding author. Tel.: þ86 571 8795 1264; fax: þ86 571 8795 1629; e-mail
address: cheyjpan@zju.edu.cn (Y. Pan).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.12.011

J.-P. Wan et al. / Tetrahedron 67 (2011) 922e926
923
Table 2
THPM 5a was provided in the reaction as expected (entry 1, Table 1).
Various THPMs synthesized by four-component reactionsa
This result encouraged us to further investigate proper reaction
conditions to enhance the reaction efficiency. Typical results on
condition optimization were summarized in Table 1. It is interesting
that significantly higher yield of 5a could be obtained when
employing a co-catalyst, such as FeCl3 or cerium (IV) ammonium
nitrate (CAN) to promote the reaction, and CAN is better favored by
this four-component reaction (entries 2 and 3, Table 1). The loading
of catalysts as well as reaction solvent has also been briefly exam-
ined. Finally, it was found that the co-catalyst of TMSCl/CAN in the
loading of 0.5/0.5 equiv in EtOH gave the best result among the
performed entries (entry 3, Table 1). The transformation gave sig-
nificantly better yield under co-catalyst system may be attributed to
the water scavenging effect of TMSCl as well as the Lewis acid
function of CAN or FeCl3.13
O
R2
O
N
R1
1
EtOH/rt
R1
NH
CHO
NH2
TMSCl/CAN
N
H
S
HN
H2N
NH2
R3
S
R3
R2
2
3
4
5
Entry
R1
R2
R3
Productb
Yieldc (%)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
5a
5b
5c
5d
5e
5f
63
57
72
66
48
42
50
37
40
53
57
73
75
47
64
55
70
69
47
4-Me
4-MeO
4-F
4-Cl
3-MeO
3-NO2
2-F
Table 1
Screening on the reaction conditions for the four-component THPM synthesisa
CHO
O
H
H
H
5g
5h
5i
O
N
NH
9
4-Me
4-MeO
H
H
H
H
H
1a
2a
10
11
12
13
14
15
16
17
18
19
H
5j
HN
N
H
S
H2N
NH2
4-Me
4-Cl
4-Br
H
H
H
4-Cl
4-Cl
4-Cl
5k
5l
NH2
H
H
S
H
5m
5n
5o
5p
5q
5r
5s
3a
4a
4-MeO
4-Cl
4-Me
4-Me
4-MeO
4-Me
4-Me
4-Br
4-MeO
H
5a
Entry
Solvent
Catalyst(s)
Cat. (%)
Yieldb (%)
1
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
TMSCl
50
28
40
63
Trace
29
35
19
Messy
30
H
2c
3d
4
TMSCl/FeCl3
TMSCl/CAN
CAN
TMSCl/CAN
TMSCl/CAN
TMSCl/CAN
TMSCl/CAN
TMSCl/CAN
50/50
50/50
50
100/50
50/70
50/30
50/50
50/50
4-MeO
a
Reactions conditions: 0.30 mmol 1, 2, and 3 as well 0.35 mmol 4 located in 2 mL
EtOH in the presence of 0.5 equiv mol of TMSCl and 0.5 equiv mol of CAN, stirred at
room temperature for 16 h.
5
6
7
8
b
The stereochemistry of the products were assigned by NOE NMR experiment
(see below).
ClCH2CH2Cl
Toluene
c
Isolated yield
9
a
All reactions were carried out at 0.30 mmol scale (thiourea was used in
0.35 mmol) in 2 mL solvent and stirred at room temperature for 16 h.
to react with benzaldehyde, aniline, and thiourea for one-pot reaction
under identical conditions as described above. However, the target
product wasnot formed eventhoughwerepeated the operation (Eq.1),
which further confirmed that the four-component protocol developed
in our study is uniquely applicable for the synthesis of THPMs.
b
Isolated yield.
c
Iron chloride was used in the form of commercial FeCl3$6H2O.
CAN: cerium (IV) ammonium nitrate.
d
Subsequently, we performed the experiments using various sub-
strates, including enaminones, aldehydes, and primary aromatic
amines with different functional groups. The results of different
THPMs synthesis are outlined in Table 2. It can be found in the results
that this reactions system tolerates a wide range of functional groups
of different properties. The products are generally furnished in
moderate to good yields, and the present data on product yields
implied that the factors affecting the reaction efficiency are complex.
Notably, all the entries in our THPMs synthesis provided single ra-
cemate products based on their 1H NMR results, which demonstrates
thatthisfour-componentassemblyproceedsinthemannerofspecific
diastereoselectivity. However, urea was found incompatible to this
kind of reaction when used as the alternative substrate of thiourea.
The stereochemistry of products 5 was assigned based on the
NOE NMR analysis on 5q. As exhibited in Fig. 1, the relative con-
figuration of the three chiral centers formed in 5q was identified via
the NOE signal interactions between protons Ha to Hf. First, clear
NOE signals of Ha/Hb and Hb/Hc were observed in the NMR spec-
trum; secondary, no NOE interaction signal between Ha/He, Hb/Hd,
Hb/Hf or Hc/He were observed. Therefore, the stereostructure of 5q
was established as shown in Fig. 1.
S
O
O
O
NH2
NH2
H2N
OEt
EtO
HN
NH
4a
(1)
N
H
S
CHO
2a
3a
Finally, to investigate the stability and potential transformation
property of the THPMs synthesized in our research, product 5m
(0.1 mmol) was selected and subjected to the acidic environment. In the
presence of 1 equiv mol of TMSCl in reflux CH3CN, 5m was completely
transformed to corresponding DHPM 6a by undergoing a deamination
process (Eq. 2).
O
O
NH
CH3CN/reflux
NH
N
H
S
HN
(2)
TMSCl, 1.0 equiv
Following the examination on the application scope of this new
four-component reaction, we sought to survey if this type of trans-
formation is applicable for classical Biginelli reaction to synthesize
corresponding THPMs. We then employed typical acetyl ethyl acetate
N
H
S
6a (92 %)
5m
Br

924
J.-P. Wan et al. / Tetrahedron 67 (2011) 922e926
177.8, 146.9, 138.4, 138.2, 136.1, 134.4, 130.1, 129.5, 129.3, 128.2,
118.8, 114.8, 65.5, 59.9, 51.5, 21.8; HRMS: calcd for C24H23N3OSNa
[MþNa]þ 424.1454; found: 424.1461.
He
O
Hd
Hd
Ha
Hb
Hc
4.1.3. 4-(p-Methoxylphenyl)-5-benzoyl-6-phenylamino-1,4,5,6-tetra-
hydropyrimidine-2-thione (5c). White solid; mp 221e222 ꢁC; 1H
NH
NMR (500 MHz, DMSO-d6):
d
¼8.46 (s, 1H), 8.05 (s, 1H), 7.65 (d, 2H,
He
HN
J¼7.7 Hz), 7.46 (t, 1H, J¼7.5 Hz), 7.29 (t, 2H, J¼7.6 Hz), 7.12 (d, 2H,
J¼8.5 Hz), 7.04 (t, 2H, J¼7.6 Hz), 6.75 (d, 2H, J¼8.5 Hz), 6.60e6054
(m, 3H), 6.06 (d, 1H, J¼10.5 Hz), 5.36 (t, 1H, J¼10.0 Hz), 4.68 (d, 1H,
J¼10.2 Hz), 4.18 (t, 1H, J¼9.7 Hz), 3.61 (s, 3H); 13C NMR (DMSO-d6,
H3C
N
H
Hf
S
Hf
125 MHz)
d
¼200.1, 177.3, 159.6, 146.4, 137.8, 133.9, 130.3, 129.6,
129.1, 129.0, 128.8, 118.4, 114.6, 114.4, 65.0, 59.1, 55.7, 51.1; HRMS:
calcd for C24H23N3O2SNa [MþNa]þ 440.1403; found: 440.1393.
Cl
4.1.4. 4-(p-Fluorophenyl)-5-benzoyl-6-phenylamino-1,4,5,6-tetrahy-
dropyrimidine-2-thione (5d). White solid; mp 249e251 ꢁC; 1H NMR
Fig. 1. NOE analysis of 5q.
(500 MHz, DMSO-d6):
d
¼8.62 (s, 1H); 8.16 (s, 1H), 7.64 (d, 2H,
J¼7.6 Hz), 7.47 (t, 1H, J¼7.3 Hz), 7.30 (t, 2H, J¼7.3 Hz), 7.25e7.22 (m,
2H), 7.06e6.99 (m, 4H), 6.60e6.55 (m, 3H), 6.09 (d, 1H, J¼10.5 Hz),
5.39 (t, 1H, J¼10.0 Hz), 4.74 (d, 1H, J¼10.2 Hz), 4.19 (t, 1H,
3. Conclusion
J¼10.0 Hz); 13C NMR (DMSO-d6, 125 MHz)
¼200.4, 177.9, 146.9,
d
138.2,135.2,134.5,130.5,130.1,129.5,129.2,118.8,116.4,116.3,114.8,
65.4, 59.5, 51.6; HRMS: calcd for C23H20FN3OSNa [MþNa]þ
428.1203; found: 428.1200.
Through the design of multicomponent reactions using simple
starting materials, the first four-component synthesis of THPMs
has been achieved. The reactions proceeded in mild reaction
conditions to give unprecedented THPMs in specific diaster-
eoslectivity. This approach is therefore potentially useful for the
synthesis of structurally diversified heterocyclic compounds with
the THPM backbone for the sake of medicinal or biological
research.
4.1.5. 4-(p-Chlorophenyl)-5-benzoyl-6-phenylamino-1,4,5,6-tetrahy-
dropyrimidine-2-thione (5e). White solid; mp 238e241 ꢁC; 1H NMR
(500 MHz, DMSO-d6):
d
¼8.64 (s, 1H), 8.18 (s, 1H), 7.66 (d, 2H,
J¼7.7 Hz), 7.48 (t, 1H, J¼7.6 Hz), 7.30 (t, 2H, J¼7.6 Hz), 7.26e7.21 (m,
4H), 7.04 (t, 2H, J¼7.7 Hz), 6.60e6.55 (m, 3H), 6.07 (d, 1H, J¼10.2 Hz),
5.39 (t, 3H, J¼9.6 Hz), 4.75 (d,1H, J¼10.1 Hz), 4.20 (t,1H, J¼9.7 Hz); 13C
4. Experimental section
NMR (DMSO-d6, 125 MHz)
d¼200.3, 177.9, 146.9, 138.1, 138.0, 134.6,
133.6, 130.3, 130.0, 129.5, 129.2, 118.8, 114.8, 65.4, 59.5, 51.4; HRMS:
4.1. Four-component synthesis of THMPs (5aes)
calcd for C23H20ClN3OSNa [MþNa]þ 444.0908; found: 444.0902.
Aldehyde (0.30 mmol), 0.30 mmol enaminone, 0.30 mmol ar-
omatic amine, and 0.35 mmol thiourea were located in
a 25 mmol round bottom flask. Then, 2 mL EtOH and 0.15 mmol
CAN were added. Finally, 0.15 mmol TMSCl was injected into the
flask, and the reaction was stirred at room temperature for 16 h
to complete (TLC). The THPMs products directly precipitated
from the reaction and were filtrated. Generally, analytically pure
products were obtained by simply washing the residue with
EtOH (3ꢀ3 mL) and drying in vacuum. Further purification of
recrystallization in EtOH/DMF/H2O was employed when
necessary.
4.1.6. 4-(m-Methoxylphenyl)-5-benzoyl-6-phenylamino-1,4,5,6-tet-
rahydropyrimidine-2-thione (5f). White solid; mp 205e207 ꢁC; 1H
NMR (500 MHz, DMSO-d6):
d
¼8.55 (s, 1H), 8.11 (s, 1H), 7.65 (d, 2H,
J¼7.8 Hz), 7.46 (t, 1H, J¼7.6 Hz), 7.30 (t, 2H, J¼7.6 Hz), 7.10 (t, 1H,
J¼7.8 Hz), 7.03 (t, 2H, J¼7.5 Hz), 6.77 (d, 1H, J¼7.6 Hz), 6.73 (s, 1H),
6.67 (d, 1H, J¼7.6 Hz), 6.61e6.54 (m, 3H), 6.00 (d, 1H, J¼10.3 Hz),
5.37 (t, 1H, J¼9.6 Hz), 4.70 (d, 1H, J¼9.9 Hz), 4.21 (t, 1H, J¼10.3 Hz),
3.64 (s, 3H); 13C NMR (DMSO-d6, 125 MHz)
d
¼200.4, 177.8, 160.2,
146.8, 140.6, 138.2, 134.4, 130.7, 130.1, 129.4, 129.2, 120.5, 118.9,
114.8, 113.9, 65.3, 60.0, 56.2, 51.5; HRMS: calcd for C24H23N3O2SNa
[MþNa]þ 440.1403; found: 440.1394.
4.1.1. 4-Phenyl-5-benzoyl-6-phenylamino-1,4,5,6-tetrahydropyr-
4.1.7. 4-(m-Nitrophenyl)-5-benzoyl-6-phenylamino-1,4,5,6-tetrahy-
imidine-2-thione (5a). Pale yellow solid; mp 228e230 ꢁC; 1H NMR
dropyrimidine-2-thione (5g). Pale yellow solid; mp 268e270 ꢁC; 1H
(500 MHz, DMSO-d6):
d
¼8.60 (s, 1H), 8.14 (s, 1H), 7.61 (d, 2H,
NMR (500 MHz, DMSO-d6):
d
¼8.83 (s, 1H), 8.35 (s, 1H), 8.08 (s, 1H),
J¼7.6 Hz), 7.43 (t, 2H, J¼7.0 Hz), 7.27 (t, 2H, J¼7.7 Hz), 7.20e7.11 (m,
5H), 7.04 (t, 2H, J¼7.8 Hz), 6.60e6.54 (m, 3H), 6.07 (d, 1H,
J¼10.6 Hz), 5.39 (t, 1H, J¼10.0 Hz), 4.72 (d, 1H, J¼10.2 Hz), 4.19 (t,
7.97 (d, 1H, J¼7.9 Hz), 7.66 (t, 3H, J¼8.2 Hz), 7.48e7.43 (m, 2H), 7.28
(t, 2H, J¼7.7 Hz), 7.04 (t, 2H, J¼7.8 Hz), 6.61e6.55 (m, 3H), 6.01 (d,
1H, J¼10.1 Hz), 5.41 (t, 1H, J¼10.1 Hz), 4.93 (d, 1H, J¼9.8 Hz), 4.31 (t,
1H, J¼9.7 Hz); 13C NMR (DMSO-d6, 125 MHz)
d
¼200.4, 177.9, 146.9,
1H, J¼9.6 Hz); 13C NMR (DMSO-d6, 125 MHz)
¼200.0, 178.0, 148.6,
d
139.1, 138.2, 134.4, 130.1, 129.6, 129.4, 129.3, 129.2, 128.3, 118.8,
114.8, 65.4, 60.2, 51.7; HRMS: calcd for C23H21N3OSNa [MþNa]þ
410.1298; found: 410.1293.
146.8, 141.4, 138.0, 135.3, 134.7, 131.2, 130.6, 129.6, 129.2, 124.1,
123.2, 118.8, 114.8, 65.2, 59.0, 51.3; HRMS: calcd for C23H20N4O3SNa
[MþNa]þ 455.1148; found: 455.1143.
4.1.2. 4-p-Tolyl-5-benzoyl-6-phenylamino-1,4,5,6-tetrahydropyr-
4.1.8. 4-(o-Fluorophenyl)-5-benzoyl-6-phenylamino-1,4,5,6-tetrahy-
imidine-2-thione (5b). White solid; mp 287e289 ꢁC; 1H NMR
dropyrimidine-2-thione (5h). White solid; mp 242e244 ꢁC; 1H NMR
(500 MHz, DMSO-d6):
d
¼8.50 (s, 1H), 8.09 (s, 1H), 7.65 (d, 2H,
(500 MHz, DMSO-d6):
d
¼8.67 (s, 1H), 8.12 (s, 1H), 7.70 (d, 2H,
J¼7.5 Hz), 7.45 (t, 1H, J¼7.7 Hz), 7.29 (t, 2H, J¼7.7 Hz), 7.09 (d, 2H,
J¼8.0 Hz), 7.05e6.95 (m, 4H), 6.60e6.54 (m, 3H), 6.07 (d, 1H,
J¼10.6 Hz), 5.36 (t, 1H, J¼9.9 Hz), 4.71 (d, 1H, J¼10.0 Hz), 4.19 (t, 1H,
J¼7.8 Hz), 7.47 (t, 1H, J¼7.3 Hz), 7.31 (t, 3H, J¼7.3 Hz), 7.19e7.14 (m,
1H), 7.08e6.97 (m, 3H), 6.95 (t, 1H, J¼9.5 Hz), 6.58 (t, 3H, J¼8.3 Hz),
6.16 (d, 1H, J¼10.5 Hz), 5.41 (t, 1H, J¼9.7 Hz), 4.94 (d, 1H, J¼10.2 Hz),
J¼9.7 Hz), 2.14 (s, 3H); 13C NMR (DMSO-d6, 125 MHz)
d
¼200.5,
4.39 (t, 1H, J¼10.0 Hz); 13C NMR (DMSO-d6, 125 MHz)
¼199.9,
d

J.-P. Wan et al. / Tetrahedron 67 (2011) 922e926
925
177.7,162.1, 160.2, 146.9,138.0, 134.6, 131.4, 130.8, 130.6, 129.5, 129.1,
125.7, 118.8, 116.8, 116.6, 114.8, 65.4, 54.6, 49.4; HRMS: calcd for
C23H20FN3OSNa [MþNa]þ 428.1203; found: 428.1206.
273e275 ꢁC; 1H NMR (500 MHz, DMSO-d6):
d
¼8.64 (s, 1H), 8.22 (s,
1H), 7.67 (d, 2H, J¼8.5 Hz), 7.39 (t, 4H, J¼8.7 Hz), 7.16 (d, 2H,
J¼8.3 Hz), 7.03 (t, 2H, J¼7.7 Hz), 6.60e6.54 (m, 3H), 6.06 (br s, 1H),
5.38 (br s, 1H), 4.74 (d, 1H, J¼10.2 Hz), 4.16 (t, 1H, J¼9.9 Hz); 13C
4.1.9. 4-Phenyl-5-(p-methylbenzoyl)-6-phenylamino-1,4,5,6-tetrahy-
NMR (DMSO-d6, 125 MHz)
d
¼199.3, 177.9, 146.8, 139.7, 138.4, 136.8,
dropyrimidine-2-thione (5i). Pale yellow solid; mp 250e253 ꢁC; 1H
132.5, 131.1, 130.6, 130.0, 129.7, 122.3, 118.9, 114.8, 65.4, 59.4, 51.6;
HRMS: calcd for C23H19BrClN3OSNa [MþNa]þ 522.0013; found:
522.0037.
NMR (500 MHz, DMSO-d6):
d
¼8.56 (s, 1H), 8.08 (s, 1H), 7.54 (d, 2H,
J¼8.5 Hz), 7.20 (s, 4H), 7.14e7.12 (m, 1H), 7.09e7.02 (m, 4H),
6.60e6.54 (m, 3H), 6.03 (d, 1H, J¼10.5 Hz), 5.35 (t, 1H, J¼8.6 Hz), 4.73
(d, 1H, J¼10.2 Hz), 4.15 (t, 1H, J¼9.7 Hz), 2.24 (s, 3H); 13C NMR
4.1.16. 4-(p-Methoxylphenyl)-5-(p-methylbenzoyl)-6-phenylamino-
(DMSO-d6, 125 MHz)
d
¼199.8, 177.8, 146.9, 145.0, 139.2, 135.8, 130.1,
1,4,5,6-tetrahydropyrimidine-2-thione (5p). White solid; mp 228e
130.0, 129.6, 129.4, 129.3, 128.3, 118.8, 114.8, 65.4, 60.2, 51.4, 22.2;
230 ꢁC; 1H NMR (500 MHz, DMSO-d6):
d
¼8. 43 (s, 1H), 8.01 (s, 1H),
HRMS: calcd for C24H23N3OSNa [MþNa]þ 424.1454; found: 424.1449.
7.58 (d, 2H, J¼8.0 Hz), 7.14e7.09 (m, 4H), 7.03 (t, 2H, J¼7.3 Hz), 6.76
(d, 2H, J¼8.4 Hz), 6.60e6.54 (m, 3H), 6.04 (d, 1H, J¼10.2 Hz), 5.33 (t,
1H, J¼9.8 Hz), 4.69 (d, 1H, J¼10.2 Hz), 4.15 (t, 1H, J¼9.8 Hz), 3.62 (s,
4.1.10. 4-Phenyl-5-(p-methoxylbenzoyl)-6-phenylamino-1,4,5,6-tet-
rahydropyrimidine-2-thione (5j). Pale yellow solid; mp 213e215 ꢁC;
3H), 2.37 (s, 3H); 13C NMR (DMSO-d6, 125 MHz)
d¼199.9, 177.7,
1H NMR (500 MHz, DMSO-d6):
d
¼8.54 (s, 1H), 8.05 (s, 1H), 7.64 (d,
160.0, 146.9, 145.0, 135.8, 130.9, 130.1, 129.6, 129.5, 118.8, 114.9,
114.8, 65.6, 59.6, 56.2, 51.3, 22.2; HRMS: calcd for C25H25N3O2SNa
[MþNa]þ 454.1560; found: 454.1571.
2H, J¼7.7 Hz), 7.20 (s, 4H), 7.15e7.12 (m, 1H), 7.04 (t, 2H, J¼7.7 Hz),
6.79 (d, 2H, J¼7.4 Hz), 6.60e6.54 (m, 3H), 6.03 (d, 1H, J¼10.5 Hz),
5.35 (t, 1H, J¼9.8 Hz), 4.71 (d, 1H, J¼10.2 Hz), 4.13 (t, 1H, J¼10.2 Hz),
3.75 (s, 3H); 13C NMR (DMSO-d6, 125 MHz)
d¼198.3, 177.8, 164.3,
4.1.17. 4-Phenyl-5-(p-methylbenzoyl)-6-(p-chlorophenyl)amino-
1,4,5,6-tetrahydropyrimidine-2-thione (5q). White solid; mp 257e
146.9, 139.2, 131.7, 131.3, 130.1, 129.5, 129.2, 128.3, 118.8, 114.8, 114.7,
65.4, 60.2, 56.6, 51.1; HRMS: calcd for C24H23N3O2SNa [MþNa]þ
440.1403; found: 440.1409.
259 ꢁC; 1H NMR (500 MHz, DMSO-d6):
d
¼8. 53 (s, 1H), 8.32 (s, 1H),
7.51 (d, 2H, J¼7.9 Hz), 7.20 (s, 4H), 7.14e7.11 (m, 1H), 7.08e7.03 (m,
4H), 6.54 (d, 2H, J¼8.5 Hz), 6.24 (d, 1H, J¼10.4 Hz), 5.33 (t, 1H,
J¼9.8 Hz), 4.71 (d, 1H, J¼10.2 Hz), 4.12 (t, 1H, J¼9.7 Hz), 2.24 (s, 3H);
4.1.11. 4-Phenyl-5-benzoyl-6-(p-methylphenyl)amino-1,4,5,6-tetra-
hydropyrimidine-2-thione (5k). Pale yellow solid; mp 238e239 ꢁC;
13C NMR (DMSO-d6, 125 MHz)
135.8, 130.0, 129.6, 129.5, 129.3, 129.2, 128.2, 121.9, 116.2, 65.5, 60.1,
51.5, 22.2; HRMS: calcd for C24H22ClN3OSNa [MþNa]þ 458.1064;
found: 458.1061.
d
¼199.7, 177.9, 146.6, 145.0, 139.1,
1H NMR (500 MHz, DMSO-d6):
d
¼8.59 (s, 1H), 7.94 (s, 1H), 7.62 (d,
2H, J¼7.8 Hz), 7.44 (t, 1H, J¼7.5 Hz), 7.28 (t, 2H, J¼7.7 Hz), 7.20 (s,
4H), 7.12 (br s, 1H), 6.86 (d, 2H, J¼8.0 Hz), 5.84 (d, 2H, J¼8.1 Hz),
5.84 (d, 1H, J¼10.1 Hz), 5.34 (t, 1H, J¼9.8 Hz), 4.72 (d, 1H, J¼10.1 Hz),
4.18 (t, 1H, J¼10.0 Hz), 2.12 (s, 3H); 13C NMR (DMSO-d6, 125 MHz)
4.1.18. 4-Phenyl-5-(p-methoxylbenzoyl)-6-(p-chlorophenyl)amino-
1,4,5,6-tetrahydropyrimidine-2-thione (5r). Pale yellow solid; mp
259e262 ꢁC; 1H NMR (500 MHz, DMSO-d6, minor diastereoisomers
d
¼200.4, 177.8, 144.4, 139.1, 138.2, 134.4, 130.5, 129.6, 129.4, 129.3,
129.2, 128.3, 127.5, 115.1, 65.9, 60.2, 51.7, 21.2; HRMS: calcd for
C24H23N3OSNa [MþNa]þ 424.1454; found: 424.1455.
included):
d
¼8. 51 (s, 1H), 8.30 (s, 1H), 7.61 (d, 2H, J¼7.8 Hz),
7.20e7.12 (m, 5H), 7.03 (t, 3H, J¼8.3 Hz), 6.78 (d, 1H, J¼7.8 Hz), 6.54
(d, 2H, J¼8.7 Hz), 6.24 (d, 1H, J¼10.5 Hz), 5.32 (t, 1H, J¼9.9 Hz), 4.69
(d, 1H, J¼10.2 Hz), 4.09 (t, 1H, J¼9.7 Hz), 3.73 (s, 3H); 13C NMR
4.1.12. 4-Phenyl-5-benzoyl-6-(p-chlorophenyl)amino-1,4,5,6-tetrahy-
dropyrimidine-2-thione (5l). White solid; mp 251e252 ꢁC; 1H NMR
(500 MHz, DMSO-d6):
12H), 2.56 (2H), 6.27 (1H), 5.37 (1H), 4.72 (1H), 4.16 (1H); 13C NMR
(DMSO-d6, 125 MHz)
d¼8.56 (s, 1H), 8.36 (s, 1H), 7.59e7.04 (m,
(DMSO-d6, 125 MHz)
d
¼198.3, 177.8, 164.4, 146.1, 139.2, 131.7, 130.6,
129.6, 129.4, 128.2, 121.9, 118.9, 116.2, 114.6, 65.3, 60.2, 56.6, 51.2;
HRMS: calcd for C24H22ClN3O2SNa [MþNa]þ 474.0991; found:
474.1013.
d
¼200.4, 177.9, 146.0, 139.0, 138.2, 134.4, 129.6,
129.5, 129.4, 129.3, 129.1, 128.3, 122.0, 116.2, 65.4, 60.2, 51.7; HRMS:
calcd for C23H20ClN3OSNa [MþNa]þ 444.0908; found: 444.0901.
4.1.19. 4-(p-Methoxylphenyl)-5-(p-methylbenzoyl)-6-(p-chloro-
4.1.13. 4-Phenyl-5-benzoyl-6-(p-bromophenyl)amino-1,4,5,6-tetrahy-
phenyl) amino-1,4,5,6-tetrahydropyrimidine-2-thione (9s). Pale yel-
dropyrimidine-2-thione (5m). White solid; mp 240e241 ꢁC; 1H NMR
low solid; mp 249e251 ꢁC; 1H NMR (500 MHz, DMSO-d6):
d¼8. 42
(500 MHz, DMSO-d6):
d
¼8.55 (s, 1H), 8.38 (s, 1H), 7.59 (d, 2H,
(s, 1H), 8.28 (s, 1H), 7.55 (d, 2H, J¼8.0 Hz), 7.11 (t, 4H, J¼8.7 Hz), 7.04
(d, 2H, J¼8.5 Hz), 6.75 (d, 2H, J¼8.4 Hz), 6.54 (d, 2H, J¼8.6 Hz), 6.26
(d, 1H, J¼10.4 Hz), 5.31 (t, 1H, J¼9.8 Hz), 4.66 (d, 1H, J¼10.3 Hz), 4.11
(t, 1H, J¼9.7 Hz), 3.62 (s, 3H), 2.25 (s, 3H); 13C NMR (DMSO-d6,
J¼7.6 Hz), 7.44 (t, 1H, J¼7.8 Hz), 7.27 (t, 2H, J¼7.7 Hz), 7.20e7.10 (m,
7H), 6.51 (d, 2H, J¼8.8 Hz), 6.29 (d, 1H, J¼10.5 Hz), 5.37 (t, 1H,
J¼9.9 Hz), 4.73 (d, 1H, J¼10.2 Hz), 4.16 (t, 1H, J¼9.9 Hz); 13C NMR
(DMSO-d6, 125 MHz)
129.5, 129.4, 129.3, 129.1, 128.3, 116.7, 109.4, 65.3, 60.2, 51.7; HRMS:
d
¼200.4, 177.9, 146.5, 139.0, 138.2, 134.4, 132.5,
125 MHz)
d
¼199.9, 177.7, 160.1, 146.1, 145.0, 135.8, 130.8, 130.1, 129.7,
129.6, 129.4, 121.9, 116.2, 114.9, 65.6, 59.6, 56.2, 51.4, 22.2; HRMS:
calcd for C23H20BrN3OSNa [MþNa]þ 488.0403; found: 488.0411.
calcd for C25H24ClN3O2SNa [MþNa]þ 488.1170; found: 488.1176.
4.1.14. 4-p-Tolyl-5-(p-methoxylbenzoyl)-6-phenylamino-1,4,5,6-tetra-
Acknowledgements
hydropyrimidine-2-thione(5n). Pale yellow solid; mp 207e209 ꢁC; 1H
NMR (500 MHz, DMSO-d6):
d
¼8.44 (s, 1H), 8.01 (s, 1H), 7.09 (d, 2H,
The authors gratefully acknowledge the financial support from
NSFC of china (No. 21025207 and 20975092).
J¼8.7 Hz), 7.06e7.00 (m, 4H), 6.80 (d, 2H, J¼8.3 Hz), 6.61e6.54 (m,
3H), 6.03 (d, 1H, J¼10.3 Hz), 5.32 (t, 1H, J¼9.4 Hz), 4.69 (d, 1H,
J¼10.2 Hz), 4.13 (t, 1H, J¼10.3 Hz), 3.74 (s, 3H), 2.16 (s, 3H); 13C NMR
Supplementary data
(DMSO-d6, 125 MHz)
d
¼198.3, 177.7, 164.4, 146.9, 138.3, 136.2, 131.8,
131.3,130.1,128.2, 118.8, 114.8, 114.7, 65.5, 59.8, 56.6, 51.0, 21.8; HRMS:
General experiment details, copies of the 1H, 13C NMR spectra
for products 5aes. Supplementary data associated with this article
can be found in online version at doi:10.1016/j.tet.2010.12.011.
These data include MOL files and InChIKeys of the most important
compounds described in this article.
calcd for C25H25N3O2SNa [MþNa]þ 454.1560; found: 454.1560.
4.1.15. 4-(p-Bromophenyl)-5-(p-chlorobenzoyl)-6-phenylamino-
1,4,5,6-tetrahydropyrimidine-2-thione (5o). Pale yellow solid; mp

926
J.-P. Wan et al. / Tetrahedron 67 (2011) 922e926
7. (a) Cram, D. J.; Katz, H. E.; Dicker, I. B. J. Am. Chem. Soc. 1984, 106, 4987e5000;
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