Microwave-assisted and iodine-catalyzed synthesis of dihydropyrimidin-2- thiones via Biginelli reaction under solvent-free conditions

Article abstract of DOI:10.1080/00397911.2011.593289

Microwave-assisted synthesis of 3,4-dihydropyrimidin-2-thiones via Biginelli reaction from aldehydes, acetoacetates, and thiourea in the presence of iodine under solvent-free conditions has been accomplished in good yields and purity without chromatograph

Full text of DOI:10.1080/00397911.2011.593289

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Microwave-Assisted and Iodine-Catalyzed
Synthesis of Dihydropyrimidin-2-thiones
via Biginelli Reaction Under Solvent-Free
Conditions
Qingjian Liu a , Ning Pan a , Jiehua Xu a , Wenwen Zhang a & Fanpeng
Kong a
a College of Chemistry, Chemical Engineering, and Materials Science,
Key Laboratory of Molecular and Nano Probes, Engineering Research
Center of Pesticide and Medicine Intermediate Clean Production,
Ministry of Education, Shandong Provincial Key Laboratory of Clean
Production of Fine Chemicals, Shandong Normal University, Jinan,
China
Accepted author version posted online: 01 Feb 2012. Version of
record first published: 05 Sep 2012
To cite this article: Qingjian Liu, Ning Pan, Jiehua Xu, Wenwen Zhang & Fanpeng Kong (2013):
Microwave-Assisted and Iodine-Catalyzed Synthesis of Dihydropyrimidin-2-thiones via Biginelli
Reaction Under Solvent-Free Conditions, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 43:1, 139-146
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Synthetic Communications1, 43: 139–146, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.593289
MICROWAVE-ASSISTED AND IODINE-CATALYZED
SYNTHESIS OF DIHYDROPYRIMIDIN-2-THIONES VIA
BIGINELLI REACTION UNDER SOLVENT-FREE
CONDITIONS
Qingjian Liu, Ning Pan, Jiehua Xu, Wenwen Zhang, and
Fanpeng Kong
College of Chemistry, Chemical Engineering, and Materials Science, Key
Laboratory of Molecular and Nano Probes, Engineering Research Center of
Pesticide and Medicine Intermediate Clean Production, Ministry of
Education, Shandong Provincial Key Laboratory of Clean Production of Fine
Chemicals, Shandong Normal University, Jinan, China
GRAPHICAL ABSTRACT
Abstract Microwave-assisted synthesis of 3,4-dihydropyrimidin-2-thiones via Biginelli reac-
tion from aldehydes, acetoacetates, and thiourea in the presence of iodine under solvent-free
conditions has been accomplished in good yields and purity without chromatographic
separation.
Keywords Biginelli reaction; 3,4-dihydropyrimidin-2-thiones; microwave-assisted
synthesis; solvent-free reaction
INTRODUCTION
Dihydropyrimidinones (DHPMs) have attracted considerable attention recently
in synthetic organic chemistry because of their wide range of biological activities,[1]
Received February 27, 2011.
Address correspondence to Qingjian Liu, College of Chemistry, Shandong Normal University,
Jinan 250014, P. R. China. E-mail: liuqj@sdnu.edu.cn
139

140
Q. LIU ET AL.
pharmaceutical and therapeutic properties, and antibacterial, antiviral, antitumor, and
anti-inflammatory activities.[2] Well-known examples are batzelladine alkaloids, which
are potent HIV group-120-CD4 inhibitors,[3] and monastrol, which is the only
cell-permeable molecule currently known to specifically inhibit mitotic kinesin Eg5
and can therefore be considered as a lead for the development of new anticancer drugs.[4]
The Biginelli reaction,[5] a one-pot condensation of aldehyde, acetoacetate, and
urea under strongly acidic conditions, is one of the most useful multicomponent reac-
tions (MCRs), gaining increasing importance in organic and medicinal chemistry
because of its the capacity to generate multifunctionalized products including
3,4-dihydropyrimidin-2-ones, their thiones analogs, and other related heterocyclic com-
pounds. Therefore, many improvements and modifications of the Biginelli reaction have
been made, especially inthe catalysisofthereaction.[6] A numberofnew catalystssuchas
FeCl3 ꢀ 6H2O, BF3 ꢀ OEt2, LaCl3, La(OTf)3, Yb(OTf)3, InX3, ZrCl4, Mn(OAc)3, LiClO4,
or a combination of Lewis acids with transition-metal salts have been reported.[7] Iodine
as a nontoxic and readily available catalyst has been used in the Biginelli reaction.[8]
Microwave irradiation (MWI), a nonconventional energy source, has become
an important method in organic synthesis.[9] Moreover, many reactions under micro-
wave irradiation can be performed without any solvent.[10]
As increasing environmental consciousness in chemical research and industry,
the challenge for a sustainable environment calls for clean processes that can avoid
using harmful organic solvents or, even better, do not need solvents at all.
In continuation of our interest in the use of cheap and commercially available
catalysts along with MWI for the green synthesis of heterocyclic compounds such as
3,4-dihydropyrimidin-2(1H)-thione derivatives, we report herein the microwave-
assisted and iodine-catalyzed synthesis of substituted 3,4-dihydropyrimidin-
2(1H)-thiones via the Biginelli reaction from aldehydes, methyl and ethyl acetoace-
tates, and thiourea under solvent-free conditions (Scheme 1).
EXPERIMENTAL
In a typical procedure, 2.5 mmol of an aldehyde, 5 mmol of acetoacetate, and
5 mmol of thiourea with a catalytic amount of iodine were mixed and irradiated in a
microwave synthesizer (XH-200A, 600 W) at 60 ꢁC for 15–30 min. After completion
of the reaction, monitored by thin-layer chromatography (TLC), the resulting mix-
ture was dissolved in ethyl acetate and cooled to precipitate out, then filtered to
obtain the crude products in good yield. Recrystallization from ethanol afforded

SYNTHESIS OF DIHYDROPYRIMIDIN-2-THIONES
141
Scheme 1. Synthesis of 3,4-dihydropyrimidin-2-thiones.
the pure products (Table 1). The best results were observed when the molar ratio of
aldehyde, acetoacetate, and thiourea was 1:2:2.
The present microwave-induced and iodine-catalyzed protocol is efficient, con-
venient, and practical. The prominent aspect is the short reaction time (15–30 min).
Iodine works well as an excellent catalyst for this one-pot, three-component syn-
thesis of dihydropyrimidinthiones. It is seen from Table 1 that a wide range of sub-
stituents can be incorporated in the 4-aryl ring, including the hydroxyl and the azido
groups. This facile procedure represents a valid alternative to the existing methods,
especially for aldehydes bearing acid-sensitive groups. Iodine may play a crucial role
in accelerating the dehydration step and enolization of the b-ketoester.
1
All the products prepared have been characterized by H NMR and infrared
(IR), and unknown compounds were characterized also by 13C NMR, mass spec-
trometry (MS), and elemental analysis. The structures of methyl 6-methyl-4-
(2-furyl)-1,2,3,4-tetrahydro-2-thioxo-5-pyrimidinecarboxylate
11
and
ethyl
6-methyl-4-phenyl-1,2,3,4-tetrahydro-2-thioxo-5-pyrimidinecarboxylate 22 have
been unambiguously confirmed by single-crystal x-ray crystallographic analysis
(Figs. 1 and 2). In the molecular structures of the crystals 11 and 12, the
3,4-dihydropyrimidine ring has a boat-type conformation, and the phenyl ring
is almost perpendicular to the tetrahydropyrimidin-2-thione, which is similar to
the structure of monastrol.[11]
Crystal Data for 11
Methyl 6-Methyl-4-(2-furyl)-1,2,3,4-tetrahydro-2-thioxo-5-pyrimidi-necarboxylate.
CCDC reference: 763044, mp 252.3–253.7 ꢁC. C11H12N2O3S, M ¼ 252.29, tri-
ꢁ
ꢁ
˚
˚
clinic, C2=c, a ¼ 7.2590(14) A, a ¼ 85.691(3) , b ¼ 7.8640(16) A, b ¼ 88.594(2) ,
c ¼ 10.552(2) A, c ¼ 80.156(3) , V ¼ 591.8(2) A , Z ¼ 2, Dcalcd ¼ 1.416 mg=mꢂ3
,
3
ꢁ
˚
˚
T ¼ 298(2) K, radiation ¼ 0.71073 A, final R indices [I > 2r(I)], R1 ¼ 0.0423,
wR2 ¼ 0.1159, R indices (all data), R1 ¼ 0.0457, wR2 ¼ 0.1191, for all data total reflec-
tions collected=unique 3107=2156 [R(int) ¼ 0.0143], GOF ¼ 1.035. Diffraction data
were measured on a Siemens 4 Circle single-crystal x-ray diffractometer.
Crystal Data for 22: Ethyl 6-Methyl-4-phenyl-1,2,3,4-tetrahydro-2-
thioxo-5-pyrimidine-carboxylate
CCDC reference: 763043, mp 187.5–188.2 ꢁC. C14H16N2O2S, M ¼ 276.35,
ꢁ
ꢁ
˚
˚
triclinic, C2=c, a ¼ 7.379(2) A, a ¼ 69.794(4) , b ¼ 9.505(3) A, b ¼ 89.860(4) ,

142
Q. LIU ET AL.
iodine-catalyzed, and
Table 1. Microwave-assisted,
3,4-dihydropyrimidin-2-thionesa,b,c
solvent-free
Biginelli
synthesis
of
Entry No.
Aldehydes
R
Reaction time (min) Yield (%)
Mp (lit.) (ꢁC)
1
2
1
2
3
4
5
6
7
8
9
C6H5
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
15
15
15
15
20
20
20
15
25
15
15
15
20
15
15
20
20
20
30
20
20
20
20
20
30
20
30
20
30
20
20
20
20
30
20
20
20
20
20
30
20
95
88
90
95
88
95
84
90
82
90
90
92
91
90
93
89
88
90
78
88
95
93
92
94
90
95
90
92
89
94
90
91
92
78
92
93
90
90
92
77
86
221.6–223.8 (220–222)[7h]
153.5–155.8
4-ClC6H4
3
4-BrC6H4
179.7–180.9
4
4-FC6H4
183.1–184.7
5
4-O2NC6H4
3-O2NC6H4
2-O2NC6H4
4-MeOC6H4
3-HOC6H4
204.7–207.1
6
249.6–251.7
7
215.2–217.1
8
178.3–179.6
9
217.8–220.2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
10 4-HO-3-MeOC6H3
11 2-Furyl
254.6–255.5
252.3–253.7
246–247 (243–245)[7i]
12 3-ClC6H4
13 3-N3C6H4
176.8–177.2
14 3,4-Cl2C6H3
15 4-HOC6H4
16 2-HOC6H4
17 4-HO-3,5-Br2C6H2
18 4-Me2NC6H4
19 4-C6H5C6H4
204.3–205.7
250.3–251.6
209.3–212.7
235.7–236.8
232.6–234.4
>306
20 2-Hydroxyl-1-naphthalyl Me
>326
206–208 (208–210)[7a]
21 C6H5
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
22 4-ClC6H4
188–190
23 4-BrC6H4
190.4–192.7
24 4-FC6H4
186.6–188.5
25 4-O2NC6H4
26 3-O2NC6H4
27 2-O2NC6H4
28 4-MeOC6H4
29 3-HOC6H4
30 4-HO-3-MeOC6H3
31 2-Furyl
111–112 (109–111)[7a]
206–207 (206–207)[10g]
215.4–216.4
147–149 (150–152)[7a]
182–184 (184–186)[12]
217.4–219.8
220–222 (188–190)[12]
203–205 (192–196)[12]
151.3–153.1
32 3-ClC6H4
33 3-N3C6H4
34 4-IC6H4
180.3–182.3
35 3,4-Cl2C6H3
36 4-HOC6H4
37 2-HOC6H4
38 4-HO-3,5-Br2C6H2
39 4-Me2NC6H4
40 4-C6H5C6H4
110.3–112.0
205–206 (198–200)[7b]
251.6–252.9
230.1–230.9
207–209 (209–210)[10h]
>310
41 2-Hydroxyl-1-naphthalyl Et
256.1–259.5
aThe reaction was conducted under solvent-free conditions.
bThe reaction was conducted under microwave irradiation in the presence of iodine.
c2.5 mmol of an aldehyde, 5 mmol of acetoacetate, and 5 mmol of thiourea with a catalytic amount of
iodine were mixed and irradiated in a microwave synthesizer (XH-200A, 600 W) at 60 ꢁC for 15–30 min.

SYNTHESIS OF DIHYDROPYRIMIDIN-2-THIONES
143
Figure 1. Crystal structure x-ray ORTEP diagram of compound 11. (Figure is provided in color online.)
3
c ¼ 11.068(3) A, c ¼ 69.931(4) , V ¼ 678.3(3) A , Z ¼ 2, Dcalcd ¼ 1.353 mg=mꢂ3
,
ꢁ
˚
˚
T ¼ 298(2) K, radiation ¼ 0.71073 A, final R indices [I > 2r(I)], R1 ¼ 0.0515,
wR2 ¼ 0.1286, R indices (all data), R1 ¼ 0.0615, wR2 ¼ 0.1355, for all data total
Figure 2. Crystal structure x-ray ORTE diagram of compound 22. (Figure is provided in color online.)

144
Q. LIU ET AL.
Table 2. Hydrogen bonds for 11 (A and deg)
D-H . . . A
d(D-H)
d(H . . . A)
d(D . . . A)
<(DHA)
N(2)-H(2A).. . . S(1)#1
N(1)-H(1A).. . . O(2)#2
0.86
0.86
2.62
2.13
3.3834 (18)
2.969 (2)
147.9
165.5
reflections collected=unique 3574=2483 [R(int) ¼ 0.0153], GOF ¼ 1.030. Diffraction
data were measured on a Siemens 4 Circle single-crystal x-ray diffractometer.
There are two molecules in the asymmetric unit linked by intermolecular
N-H...S and N-H...O hydrogen bonds (Table 2), forming a netted three-dimensional
structure along the b axis leading to a ladder pattern, which stabilized the crystal
packing.
In summary, we have developed a facile, simple, and general procedure for the
synthesis of 3,4-dihydropyrimidin-2-thiones from aldehydes, acetoacetates, and thio-
urea using iodine as catalyst under microwave irradiation and solvent-free con-
ditions. The present environmentally benign protocol has short reaction times,
good yields, and simple and easy workup and without chromatographic separation.
SUPPORTING INFORMATION
Structural characterization data and NMR spectra are available. Crystal data
(excluding structural factors) of compounds 11 and 22 have been deposited with the
Cambridge Crystallographic Data Centre, CCDC 763044 for 11 and 763043 for 22,
respectively. This material is available free of charge via the Internet at http://
www.ccde.cam.ac.uk.
ACKNOWLEDGMENTS
Support of this work by the College of Chemistry, Chemical Engineering, and
Materials Science, and Shandong Normal University is acknowledged.
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