Bio-based solvent mediated synthesis of dihydropyrimidinthiones via biginelli reaction

Article abstract of DOI:10.1080/10426507.2013.855767

(Equation present) The three-component Biginelli reaction using aldehyde, thiourea, and 1,3-dicarbonyl compounds was performed smoothly in ethyl lactate (EL) with the catalysis of trimethylsilyl chloride (TMSCl). A class of 3,4-dihydropyrimidinthiones (DH

Full text of DOI:10.1080/10426507.2013.855767

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Phosphorus, Sulfur, and Silicon and the
Related Elements
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Bio-Based Solvent Mediated Synthesis
of Dihydropyrimidinthiones Via Biginelli
Reaction
Zhen Xua, Yangyang Jianga, Shuang Zoua & Yunyun Liua
a College of Chemistry and Chemical Engineering, Jiangxi Normal
University, Nanchang, 330022, China
Accepted author version posted online: 23 Jan 2014.Published
online: 12 Jun 2014.
To cite this article: Zhen Xu, Yangyang Jiang, Shuang Zou & Yunyun Liu (2014) Bio-Based Solvent
Mediated Synthesis of Dihydropyrimidinthiones Via Biginelli Reaction, Phosphorus, Sulfur, and Silicon
and the Related Elements, 189:6, 791-795, DOI: 10.1080/10426507.2013.855767
To link to this article: http://dx.doi.org/10.1080/10426507.2013.855767
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Phosphorus, Sulfur, and Silicon, 189:791–795, 2014
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2013.855767
BIO-BASED SOLVENT MEDIATED SYNTHESIS
OF DIHYDROPYRIMIDINTHIONES VIA
BIGINELLI REACTION
Zhen Xu, Yangyang Jiang, Shuang Zou,
and Yunyun Liu
College of Chemistry and Chemical Engineering, Jiangxi Normal University,
Nanchang 330022, China
GRAPHICAL ABSTRACT
R1
O
O
R1
CHO
NH2
NH
TMSCl, 90oC
EtO
NH
S
ethyl lactate
N
S
EtO
O
R2
R2
R1 = H, alkyl, alkoxyl, halides, formyl etc.; R2 = H, alkyl
Abstract The three-component Biginelli reaction using aldehyde, thiourea, and 1,3-
dicarbonyl compounds was performed smoothly in ethyl lactate (EL) with the catalysis of
trimethylsilyl chloride (TMSCl). A class of 3,4-dihydropyrimidinthiones (DHPMs) were
synthesized in good to excellent yields via the bio-based solvent mediated catalytic protocol.
Keywords Biginelli reaction; 3,4-dihydropyrimidinthiones; bio-based solvent mediated syn-
thesis; ethyl lactate; heterocycle
INTRODUCTION
Dihydropyrimidinthiones (DHPMs) have been known as valuable heterocyclic scaf-
folds due to their versatile bioactivities found in both the synthesized form as well as related
marine natural products.1–3 Typically, the antitumor,4 antihypertension5 as well as selective
α1a adrenoceptor antagonism activity6 were promising properties that have attracted signif-
icant research interest. In organic synthesis, DHPMs have also been extensively employed
as starting materials for the synthesis of numerous other heterocyclic derivatives.7
Received 3 June 2013; accepted 11 October 2013.
Address correspondence to Yunyun Liu, College of Chemistry and Chemical Engineering, Jiangxi Normal
University, Nanchang 330022, China. E-mail: chemliuyunyun@gmail.com; chemliuyuyun@jxnu.edu.cn
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/gpss.
791

792
Z. XU ET AL.
During the past century, tremendous efforts have been made to discover clean and
effective methodologies for the synthesis of DHPMs.8–11 Although many new methods have
been developed for the construction of DHPMs of different functionalities, the Biginelli
reaction still plays an important role in the field of DHPMs synthesis. As it is now possible
to perform Biginelli DHPMs synthesis with a broad array of elegant synthetic approaches,
establishing a method of environmental friendliness is of particularly high significance.
Among the reported catalyst systems for the Biginelli reaction, eco-friendly protocols,
especially protocols using biomass derived green media are rarely available at present
although other favorable media such water, ionic liquid and solventless synthesis have been
extensively investigated.12–17 Ethyl lactate (EL) is a solvent available from biomass with a
low-cost process; this bio-based solvent has been known to be very useful in the chemical
and food industries by serving as food additives, lubricants as well as wine condiment.18,19
The broad application of EL is attributed to its unique advantages of nontoxicity, excellent
solubility in both water and conventional organic solvents, high polarity, high boiling
point as well as complete biodegradability. On the other hand, these features of EL mean
that it can be a promising solvent for being used as a medium for sustainable organic
synthesis in despite the fact that this kind of research is still in its infancy. Currently, several
different types of reactions such imine condensation,20 Suzuki-Miyaura coupling,21 and
multicomponent Hantzsch reaction22 have been successfully performed in EL. In order to
expand the application scope of EL as a reaction medium in organic synthesis, we report
herein the effective EL-mediated three-component Biginelli reactions involving aldehydes,
ethyl acetate, and thiourea.
RESULTS AND DISCUSSION
Initially, the three-component reaction of benzaldehyde 1a, ethyl acetoacetate 2a,
and thiourea 3a as the model reaction has been performed in EL in the presence of 1 eq mol
of TMSCl, after heating the mixture at 60 ◦C for 12 h, the target product 4a was produced
in 19% yield (entry 1, Table 1). Although the product was obtained in a low yield, we
were encouraged to further investigate the reaction by optimizing conditions. Increasing
the reaction temperature showed that 90◦C was optimal for the Biginelli reaction (entries
1–5, Table 1). Later on, the variation on catalyst loading demonstrated that 1.5 eq mole of
TMSCl23–25 was able to further enhance yield of target product (entry 6, Table 1). Further
attempts to change the catalyst to other species such FeCl3, p-TSA, and CF3COOH didn’t
give satisfactory results (entries 9–12).
With the optimized results in hand, we then examined the application scope of the
Biginelli reaction by employing different aldehydes, and thioureas to react with ethyl ace-
toacetate. The results for the synthesis of different DHPMs 4 are shown in Table 2. Based
on these products, it has been found that aromatic aldehydes that containing different func-
tional groups such as alkyl, alkoxyl, halide, hydroxyl, and formyl tolerated well to present
approach. Thioureas with and without N-alkyl substitution have both been successfully
employed to yield corresponding DHPMs with and without N1-substitution. Generally, an
electron withdrawing group in aldehydes led to the formation of corresponding DHPMs
with good yields (entries 6–8 and 10–11, Table 2), while reactions using aldehydes sub-
stituted with an electron donating group gave the corresponding product in slightly lower
yields (entries 2–4, Table 1). N1-methyl DHPMs 4j and 4k have been synthesized under
standard reactions by utilizing N-methyl thiourea as starting material. Unfortunately, urea
has been found inapplicable for equivalent reactions in despite our efforts in employing
different aldehydes as reaction partners.

ETHYL LACTATE-MEDIATED BIGINELLI REACTION
793
Table 1 Optimization on conditions of EL mediated Biginelli reactiona
O
CHO
1a
O
EtO
NH
EL
NH2
conditions
N
H
S
H2N
S
EtO
O
3a
4a
2
Yield
(%)b
Entry
T (◦C)
Catalyst (eq)
1
2
3
4
5
6
7
8
9
60
70
80
90
100
90
90
90
90
90
90
90
TMSCl (1.0)
TMSCl (1.0)
TMSCl (1.0)
TMSCl (1.0)
TMSCl (1.0)
TMSCl (1.5)
TMSCl (2.0)
TMSCl (2.5)
FeCl3 (1.5)
19
23
27
42
25
73
41
37
18
25
28
nrc
10
11
12
p-TSA (1.5)
CF3COOH (1.5)
CAN (1.5)
aGeneral conditions: aldehyde 1a (0.3 mmol), ethyl acetoacetate 2 (0.3 mmol), and thiourea 3a (0.45 mmol) in
2 mL EL, stirred for 12 h. bIsolated yield. cNo reaction.
CONCLUSIONS
In conclusion, we have developed an environmentally benign protocol for three-
component synthesis of DHPMs. The three-component reactions of aldehydes, thioureas,
and ethyl acetoacetate were performed smoothly in EL, a typical bio-based, nontoxic
organic solvent. This method has been found applicable for reactions using both thiourea
and N-alkyl thiourea to give DHPMs with moderate to good yields. The advantage of
environmental friendliness means that the present catalytic method will be complementary
to known methods of Biginelli reaction in DHPMs synthesis.
Experimental Section
All reagents and solvents were obtained from commercial sources and used without
further purification, all reaction were performed at air atmosphere. 1H NMR and 13C were
recorded in 400 MHz frequency using DMSO-d6 as solvent. Chemical shifts were recorded
in ppm with TMS as internal standard. Melting points were recorded in X - 4A apparatus
without correcting the temperature. HRMS was tested in under ESI model. All products
1
were assigned by either comparing the H NMR spectra and melting point data with
literature results or characterizing with adequate spectra analysis (for 4i and 4j).
General Procedure for EL Mediated Biginelli Reaction. In a 25 mL round
bottom flask located with aldehyde (0.3 mmol), ethyl acetoacetate (0.3 mmol), and thiourea
(0.45 mmol) was added EL (2 mL) and TMSCl (0.45 mmol). The mixture was heated at

794
Z. XU ET AL.
Table 2 Synthesis of different DHPMs via Biginelli reactions in ethyl lactatea
R1
O
O
R1
CHO
NH2
NH
R2
TMSCl, 90oC
ethyl lactate
EtO
NH
S
EtO
O
N
S
1
3
R2
2a
4
Entry
R1
H
4-Me
4-MeO
4-OH
4-Cl
4-CF3
4-NO2
2-Cl
R2
Product
Yield (%)b
m.p. /L (◦C)
206-207/20526
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
4a
4b
4c
4d
4e
4f
4g
4h
4i
73
76
71
59
80
83
89
66
81
85
190-192/192-19427
151-153/150-15227
189-190/193-19428
195-196/192-19427
214-215/21829
105-107/109-11127
212-213/216-21830,31
106-108/–
4-Br
4-CF3
Me
Me
10
4j
105-106/–
aGeneral reaction conditions: aldehyde 1 (0.3 mmol), ethyl acetoacetate 2 (0.3 mmol), and thiourea 3
(0.45 mmol) and TMSCl (0.45 mmol) in 2 mL EL, and stirred at 90◦C for 12 h. bIsolated yield.
90 ◦C for 12 h (TLC). After being cooled down to room temperature, water (10 mL) was
added and the resulting mixture was extracted with (3 × 10 mL) ethyl acetate. The organic
phases were combined and dried over anhydrous Na2SO4. The solid was filtered out and
the solution was subjected to vacuum evaporation to remove solvent. Finally, the residue
was subjected to silica column chromatography (V3:1 of petroleum ether and ethyl acetate
as eluent) to give the pure product.
Ethyl 4-(4-bromophenyl)-1,6-dimethyl-2-thioxo-1,2,3,4-tetrahydropyri-
midine-5 –carboxylate (4i). Pale yellow solid; m.p. 106–108 ◦C; 1H NMR (400 MHz,
DMSO-d6) δ 9.81 (s, 1 H), 7.46 (d, 2 H, J = 8.0 Hz), 7.14 (d, 2 H, J = 8.0 Hz), 5.18 (s,
1 H), 4.13 (q, 2 H, J = 6.8 Hz), 3.45 (s, 3 H), 2.48 (s, 3 H), 1.15 (t, 3 H, J = 6.8 Hz);
13C NMR (100 MHz, DMSO-d6) δ 178.6, 165.6, 148.8, 142.0, 132.0, 128.8, 121.4, 105.4,
60.6, 52.2, 36.7, 16.7, 14.5; ESI-HRMS Calcd for C15H18BrN2O2S [M+H]+: 369.0272;
Found: 369.0278.
Ethyl 1,6-dimethyl-2-thioxo-4-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetra
hydro pyrimidine-5-carboxylate (4j). White solid; m.p. 105–106◦C; 1H NMR
(400 MHz, DMSO-d6) δ 9.98 (d, 1 H, J = 4.0 Hz), 7.74 (d, 2 H, J = 8.0 Hz), 7.45 (d, 2 H,
J = 8.0 Hz), 5.33 (d, 1 H, J = 4.0 Hz), 4.10 (q, 2 H, J = 6.8 Hz), 3.51 (s, 3 H), 2.56 (s,
3 H), 1.16 (t, 3 H, J = 6.8 Hz); 13C NMR (100 MHz, DMSO-d6) δ 179.1, 166.9, 165.8,
149.3, 147.3, 130.8, 1127.6, 126.3 (m), 105.6, 60.9, 52.6, 36.9, 16.9, 14.6; ESI-HRMS
Calcd for C16H18F3N2O2S [M+H]+: 359.1041; Found: 359.1037.
FUNDING
Financial support from NSFC (no. 21202064), a sponsored project from Jiangxi
Provincial Department of Education (no. GJJ12211) are gratefully acknowledged.

ETHYL LACTATE-MEDIATED BIGINELLI REACTION
795
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