Nickel Chloride Hexahydrate Catalyzed Multicomponent Biginelli's Synthesis of 3,4-Dihydropyrimidin-2(1H)-Ones and Thiones

Article abstract of DOI:10.1002/jhet.2700

An efficient protocol is reported for the one-pot three-component Bignelli synthesis of a series of 3,4-dihydropyrimidine-2(1H)-ones and thiones in good yields (66–90%) from the aldehydes (4-benzyloxybenzaldehyde, 5-bromovanilin, 4-formyl-1-cyclohexene, a

Full text of DOI:10.1002/jhet.2700

Month 2016
Nickel Chloride Hexahydrate Catalyzed Multicomponent Biginelli’s
Synthesis of 3,4-Dihydropyrimidin-2(1H)-Ones and Thiones
Şirin Gülten*
Department of Chemistry, Faculty of Arts and Sciences, Çanakkale Onsekiz Mart University, 17020 Çanakkale, Turkey
*
E-mail: siringulten@hotmail.com
Received February 16, 2016
DOI 10.1002/jhet.2700
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
An efficient protocol is reported for the one-pot three-component Bignelli synthesis of a series of
3,4-dihydropyrimidine-2(1H)-ones and thiones in good yields (66–90%) from the aldehydes (4-
benzyloxybenzaldehyde, 5-bromovanilin, 4-formyl-1-cyclohexene, and trans-cinnamaldehyde), β-keto
esters (ethyl acetoacetate, allyl acetoacetate, and t-butyl acetoacetate), and urea/thiourea in ethanol, using
nickel chloride hexahydrate as a catalyst.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
derivatives. In order to improve the efficiency and
synthetic procedure of the classical one-pot Biginelli
reaction, using different types of catalysts and
conditions have been reported by different research
groups. Most of these procedures are all similar, using
different acid catalyst such as BF3 · OEt2 [6],
FeCl3 · 6H2O [7], MgCl2 · 6H2O [8], MgBr2 [8b,9],
BiCl3 [10], InCl3 [11], ZnO nano particles [12],
zeolites [13], LaCl3 · 7H2O [14], LiClO4 [15], Mn
(OAc)3 · 2H2O [16], NiCl2 · 6H2O [7d], and so on, in
solvent such as CH3CN, CH2Cl2, THF, EtOH, or
H2O. In addition, procedures employing ultrasound
[17], microwave [18], solid, and fluorous [19] phase
syntheses have been reported.
A number of procedures under solvent free conditions
using different acid catalyst have also been reported [20].
However, despite their potential utility, some of these
procedures use expensive catalysts, strong acidic
conditions, higher temperatures, stoichometric amounts of
catalyst, toxic reagents, large amounts of solvents,
unsatisfactory yields, inconvenient purification techniques,
incompatibility with other functional groups, and require
longer reaction times are not all acceptable in the context
of green synthesis.
3,4-Dihydropyrimidin-2-(1H)-ones (DHPMs) and their
derivatives gained considerable interest from the first
reported in 1891 until today both in academia and industry
because of their important and promising therapeutic and
pharmacological properties [1]. For instance, they have
emerged as integral backbones of several channel blockers,
antihypertensive agents α-1-antagonists and neuropeptide
Y antagonists [2].
Biginelli products are promising heterocyclic compounds
for the treatment of cancers in which monastrol 1 is the most
studied with this consideration. Monastrol 1, a protype
anti-cancer drug, inhibits the mitotic kinesin Eg5 (kinesin
spindle protein, KSP) [2c,3]. Biginelli compounds bearing
cinnamoyl group 2a and 2b showed significant cytotoxic
effects against the MCF-7 breast cancer cells line [4].
Compound 3 was found to be almost 90-fold more potent
than monastrol
1
against NCI-ADR/RES multiple
drug-resistant ovarian cancer cells line [5]. Compounds 4a
and 4b were determined to be most promising scavenging
of reactive nitrogen species, and they showed scavenging
activity as potent as resveratrol [5]. The examples of
biologically active Biginelli compounds (1-4) are shown in
Figure 1.
The classical Biginelli reaction involves the strong
acid-catalyzed cyclocondensation reaction of ethyl
acetoacetate, benzaldehyde, and urea in ethanol at re-
flux temperature for long reaction time. Furthermore,
this one-pot three-component procedure often provides
with relatively low yields of the dihydropyrimidine
Herein, we wish to report an efficient synthesis of
3,4-dihydropyrimidine-2(1H)-ones (-thiones) from the
corresponding aldehydes (4-benzyloxybenzaldehyde,
5-bromovanilin, 4-formyl-1-cyclohexene and trans-
cinnamaldehyde), β-keto esters (ethyl acetoacetate, allyl
acetoacetate and t-butyl acetoacetate), and urea/thiourea
using NiCl2 · 6H2O as a mild catalyst in EtOH (Scheme 1).
© 2016 Wiley Periodicals, Inc.

Ş. Gülten
Vol 000
Figure 1. Examples of biologically active Biginelli compounds.
Scheme 1. Synthesis of 3,4-dihydropyrimidine-2(1H)-ones (-thiones) 8a-t.
RESULTS AND DISCUSSION
been used with similar success to provide the corresponding
3,4-dihydropyrimidine-2(1H)-thiones (Table 1, entries 13–
20), which are also of much interest with respect to their bio-
logical activities. The structure of Biginelli products (8a-t) are
shown in Figure 2.
The plausible mechanism similar to that of Kappe [21]
for the synthesis of DHPM. The first step involves the
acid-catalyzed formation of N-acyliminium ion intermedi-
ate from the aldehyde and urea/thiourea. Interception of
the iminium ion by β-ketoester produces an open chain
ureide, which subsequently cyclizes to DHPM (Scheme 2).
Prototropic tautomerism occurs in pyrimidines; they
are substituted by hydroxy, mercapto, or amino groups.
In a previous communication, we had reported that
MgBr2 and MgCl2 · 6H2O can catalyze the one-pot
three-component Biginelli reaction [8b]. Herein, we
continued to describe a simple and efficient procedure for
the synthesis of 3,4-dihydropyrimidine-2(1H)-ones
(-hiones). Furthermore, the use of NiCl2 · 6H2O as a
catalyst in the synthesis of 3,4-dihydropyrimidine-2(1H)-
ones via the one-pot three-component Biginelli reaction
has been reported [7d]. The report that includes only
synthesis of 3,4-dihydropyrimidine-2(1H)-ones using
NiCl2 · 6H2O (0.25 eq, 25% mmol) as a catalyst but our
work that includes synthesis of both 3,4-dihydropyrimidine-
2(1H)-ones and 3,4-dihydropyrimidine-2(1H)-thiones using
the same catalyst NiCl2 ·6H2O (0.1eq, 10% mmol).
According to our work, the use of small amount of
NiCl2 ·6H2O (0.1eq) as a catalyst does not decrease the
product yields but the reaction completion time (5–7h) is
slightly higher then the reported reaction completion time
(4–5h) [7d]. A broad range of structurally diverse β-keto
esters, and aldehydes (aromatic and aliphatic) and
urea/thiourea were also well placed. Especially aromatic
aldehydes carrying either electron-withdrawing groups or
electron-donating substituents very well to give the
corresponding DHPMs in good yields (Scheme 1). Herein,
we used a 1:1:1.2 ratio of aldehyde, β-ketoester and
urea/thiourea, respectively. The results are reported in
Table 1.
3,4-Dihydropyrimidine-2(1H)-one
8g-i
and
3,4-
dihydropyrimidine-2(1H)-thione 8p, 8q, and 8s exist in
a dynamic equilibrium mixture of three tautomeric
forms, the lactim form III and the thiolactim form III
are the most thermodynamically stable forms because
of the presence of two conjugated double bonds
(Scheme 3). The tautomerism of 8g-i, 8p, 8q, and 8s
was detected by means of spectroscopic studies (1H
NMR and 13C NMR). The appearance of lactam-lactim
and thiolactam-thiolactim tautomeric forms in the same
time causes double peaks in the spectra of the DHPM
8g-i, 8p, 8q, and 8 s solutions.
The 1H NMR spectra of Biginelli compounds 8a-t
showed characteristic resonances for aromatic and aliphatic
protons and groups in addition a singlet, a doublet, a quar-
tet or multiplet observed for C(4) proton at 5.30 to
4.01 ppm with coupling constant (J) of 3.56 to 2.69 Hz,
which was split with the neighboring N(3) proton and/or
aliphatic protons. The N-H signal in the downfield (10.39
The efficiency of this reaction is substrate dependent with
the use of highly functionalized or sterically hindered β-keto
esters and aldehydes leading to reduced yield. Thiourea has
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Nickel Chloride Hexahydrate Catalyzed Multicomponent Biginelli’s Synthesis of
3,4-Dihydropyrimidin-2(1H)-Ones and Thiones
Table 1
Synthesis of NiCl2 · 6H2O catalyzed 3,4-dihydropyrimidine-2(1H)-ones and (-thiones) 8a-t.
Entry
Aldehyde
β-Ketoester
Urea/thiourea
Product
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
4-Benzyloxybenzaldehyde
4-Benzyloxybenzaldehyde
4-Benzyloxybenzaldehyde
5-Bromovanilin
Ethyl acetoacetate
t-Butyl acetoacetate
Allyl acetoacetate
Ethyl acetoacetate
t-Butyl acetoacetate
Allyl acetoacetate
Ethyl acetoacetate
t-Butyl acetoacetate
Allyl acetoacetate
Ethyl acetoacetate
t-Butyl acetoacetate
Allyl acetoacetate
Ethyl acetoacetate
Allyl acetoacetate
Ethyl acetoacetate
Allyl acetoacetate
Ethyl acetoacetate
Ethyl acetoacetate
t-Butyl acetoacetate
Allyl acetoacetate
Urea
Urea
Urea
Urea
Urea
Urea
Urea
Urea
Urea
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
8q
8r
8s
7
5
7
6
6
6
5
5
5
5
5
5
7
7
6
6
7
7
7
7
85
66
78
84
81
74
90
80
77
88
74
66
79
76
85
73
75
90
70
79
5-Bromovanilin
5-Bromovanilin
4-Formyl-1-cyclohexene
4-Formyl-1-cyclohexene
4-Formyl-1-cyclohexene
trans-Cinnamaldehyde
trans-Cinnamaldehyde
trans-Cinnamaldehyde
4-Benzyloxybenzaldehyde
4-Benzyloxybenzaldehyde
5-Bromovanilin
9
10
11
12
13
14
15
16
17
18
19
20
Urea
Urea
Urea
Thiourea
Thiourea
Thiourea
Thiourea
Thiourea
Thiourea
Thiourea
Thiourea
5-Bromovanilin
4-Formyl-1-cyclohexene
trans-Cinnamaldehyde
trans-Cinnamaldehyde
trans-Cinnamaldehyde
8t
to 8.92 ppm in DMSO and 8.25 to 5.91 ppm in CDCl3)
characteristic of NH proton in 1-position of the pyrimidine
ring and NH proton in the 3-position of the pyrimidine ring
(9.63 to 7.29 ppm in DMSO and 8.13 to 5.50ppm in
CDCl3) were recorded.
procedure), spectroscopic data and physical properties on
published literature [12,22,23]. 8c, 8g, 8i, 8l, 8m, 8n, and
8s only have Chemical Abstracts Service Registry number
but no published sources of literature. 8d, 8e, and 8o do
not have the detail of the experiments, spectroscopic data,
and physical properties on published literatures [24–26].
To the best of our knowledge, seven of the synthesized
Biginelli compounds 8a, 8j, and 8r have all the detail of
the experiments (with different methods except our
Figure 2. Biginelli compounds 8a-t.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Ş. Gülten
Vol 000
Scheme 2. The plausible mechanism for NiCl2 · 6H2O catalyzed Biginelli reaction.
3,4-dihydropyrimidine-2(1H)-ones (-thiones), 8b, 8f, 8h, 8k,
8p, 8q, and 8t are new compounds.
available catalyst; (b) the reactions are easy to carry
out without high temperature, and the workup is very
simple; (c) the required reaction times are relatively
shorter (5–7 h); (d) compatibility with various functional
groups; and (e) the products are isolated in good yields
(66–90%).
In summary, we report a simple the one-pot three-
component Biginelli reaction via NiCl2 · 6H2O (0.1 eq) as
a catalyst for the synthesis of 3,4-dihydropyrimidine-
2(1H)-ones (-thiones) in good yields. The use of
NiCl2 · 6H2O as a catalyst provides an efficient and
improved modification of Biginelli reaction.
Significant benefits of this improved modification of
Biginelli reaction include the following: (a) application
of inexpensive and the use of small amount of
NiCl2 · 6H2O cheap, easy to handle, and commercially
EXPERIMENTAL
All chemicals and solvents were purchased from Acros
Organics, Aldrich and Merck and used without further
Scheme 3. Possible tautomeric structures for 8g-i, 8p, 8q, and 8s.
lactim form
lll
lactim form
lactam form
l
ll
OAllyl
thiolactim form
lll
thiolactim form
l
thiolactam form
ll
OAllyl
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Nickel Chloride Hexahydrate Catalyzed Multicomponent Biginelli’s Synthesis of
3,4-Dihydropyrimidin-2(1H)-Ones and Thiones
purification. The melting points were measured on an Stuart
SMP10 melting point apparatus and are uncorrected. The IR
spectra were recorded on a One FT-IR ATR Perkin Elmer.
The 1H and 13 C NMR spectra were taken with a 300MHz
and 400MHz Bruker Ultra Shield and Jeol NMR 400MHz
spectrometers and chemical shifts were recorded as ppm
downfield from internal tetramethylsilane. The LC/MS were
taken on a Waters Micromass ZQ connected with Waters Al-
liance HPLC and a Schimadzu 8040 spectrometers by using
the ESI (+) and ESI (-) methods. Elemental analyses were
performed with a Leco 932 CHNS instrument. Reaction
progress was monitored by TLC on precoated aluminum-
backed plates (Merck SIL G/UV254) and chromophoric com-
pounds were visualized by UV light and subsequent staining
with alkaline potassium permanganate solution or iodine.
General procedure for the synthesis of 3,4-dihydropyrimidine-2
J=8.57Hz, CHAr), 5.30 (s, 1H, CHNH), 5.05 (s, 2H,
CH2), 2.31 (s, 3H, CH3), 1.33 (s, 9H, (CH3)3C). 13C-NMR
(100MHz, CDCl3) δ: 165.0 (Cq), 158.3 (Cq), 153.5 (Cq),
145.1 (Cq), 136.9 (Cq), 136.5 (Cq), 128.6 (CHAr), 127.9
(CHAr), 127.8 (CHAr), 127.5 (CHAr), 114.9 (CHAr), 102.7
(Cq), 80.4 (Cq), 70.0 (CH2), 55.4 (CH), 28.2 (CH3), 18.4
(CH3). MS (ES+): m/z (%)=396 (M++2, 27), 395 (M++1,
100). Anal. Calcd. for C23H26N2O4 ·0.20H2O: C, 69.34; H,
6.63; N, 7.03. Found: C, 69,39; H, 6.54; N, 7.28.
Allyl
4-(4-(benzyloxy)phenyl)-6-methyl-2-oxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (8c).
White solid
(78%), Rf =0.16 (50% ethyl acetate/hexane), mp 183–185°
C. IR (ATR diamond) cm–1: 3242, 3112, 2919, 1703, 1687,
1650, 1608, 1584, 1509, 1456. 1H-NMR (400MHz,
CDCl3) δ: 8.25 (s, 1H, NH), 7.41–7.29 (m, 5H, CHAr), 7.23
(d, 2H, J=8.57Hz, CHAr), 6.91 (d, 2H, J=8.57Hz, CHAr),
5.85–5.76 (m, 1H, CH=CH2), 5.75 (br s, 1H, NH), 5.36 (d,
1H, J=2.38Hz, CH=CH2), 5.16–5.14 (m, 1H, CH=CH2),
5.12 (s, 1H, CHNH), 5.03 (s, 2H, CH2), 4.53 (d, 2H,
J=5.46Hz, CH2), 2.34 (s, 3H, CH3). 13C-NMR (100MHz,
CDCl3) δ: 165.4 (Cq), 158.5 (Cq), 153.7 (Cq), 146.8 (Cq),
136.9 (Cq), 136.3 (Cq), 132.3 (CH), 128.6 (CH), 127.9
(CH), 127.8 (CH), 127.5 (CH), 117.8 (CH2), 114.9 (CH),
101.2 (Cq), 70.0 (CH2), 64.7 (CH2), 55.0 (CH), 18.7 (CH3).
MS (ES+): m/z (%) =380 (M++2, 22), 379 (M++1, 17), 378
(M+, 21). Anal. Calcd. for C22H22N2O4: C, 69.83; H, 5.86;
N, 7.40. Found: C, 69,65; H, 6.04; N, 7.43.
(1H)-ones (-thiones) (8a–t).
The mixture of appropriate
aldehyde (2.5mmol), β-ketoester (2.5 mmol), urea/thiourea
(3mmol), and NiCl2 ·6H2O (0.25mmol, 10% mmol) and
conc. HCl (2–3 drops) in EtOH (3mL) was heated under
reflux for 5–7 h. The reaction mixture was cooled to room
temperature and poured onto crushed ice (20g) and stirred
for 10min. The crude product was filtered and washed with
cold water (3×10mL) to remove the unreacted urea or
thiourea. The product was further purified by
recrystallization with ethanol, ethyl acetate, or a mixture of
ethanol and ethyl acetate.
Ethyl
4-(4-(benzyloxy)phenyl)-6-methyl-2-oxo-1,2,3,4-
Ethyl 4-(3-bromo-4-hydroxy-5-methoxyphenyl)-6-methyl-2-
oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (8d). White
crystal (84%), Rf = 0.13 (50% ethyl acetate/hexane), mp
237–239°C. IR (ATR diamond) cm–1: 3572, 3278, 3220,
3102, 2935, 1703, 1677, 1642, 1575, 1496, 1463, 1450.
1H-NMR (300MHz, DMSO-d6) δ: 9.41 (s, 1H, NH),
9.19 (s, 1H, NH), 7.70 (s, 1H, OH), 6.86 (d, 1H,
J = 1.69Hz, CHAr), 6.82 (d, 1H, J = 1.66Hz, CHAr), 5.08
(d, 1H, J= 3.14 Hz, CHNH), 4.03–3.99 (m, 2H,
CH2CH3), 3.77 (s, 3H, OCH3), 2.25 (s, 3H, CH3), 1.14
(t, 3H, J = 7.02Hz, OCH2CH3). 13C-NMR (75.45MHz,
DMSO-d6) δ: 165.7 (Cq), 152.5 (Cq), 148.9 (Cq), 148.7
(Cq), 143.4 (Cq), 137.2 (Cq), 122.0 (CH), 109.9 (Cq),
109.4 (CH), 99.4 (Cq), 59.7 (CH2), 56.5 (CH2), 53.7
(CH), 18.2 (CH3), 14.6 (CH3). MS (ES+): m/z (%)= 388
(M++3, 15), 387 (M++2, 72), 385 (M+, 100). Anal. Calcd.
for C15H17BrN2O5 · 1.1H2O: C, 44.44; H, 4.74; N, 6.91.
Found: C, 44.37; H, 4.54; N, 7.00.
tetrahydropyrimidine-5-carboxylate (8a).
White solid
(85%), Rf = 0.12 (50% ethyl acetate/hexane). mp 183–185°C,
(lit. [22] mp 188–189°C). IR (ATR diamond) cm–1:
3241, 3111, 2973, 1701, 1675, 1641, 1610, 1584, 1509,
1456. 1H-NMR (300MHz, DMSO-d6) δ: 9.14 (s, 1H, NH),
7.66 (m, 1H, NH), 7.44–7.43 (m, 2H, CHAr), 7.41–7.37
(m, 2H, CHAr), 7.34–7.31 (m, 1H, CHAr), 7.15 (d, 2H,
J=8.7Hz, CHAr), 6.97 (d, 2H, J=8.7Hz, CHAr), 5.09–5.08
(m, 3H, PhCH2 and CHNH), 3.99 (q, 2H, J=7.09Hz,
CH3CH2O), 2.24 (s, 3H, CH3), 1.12 (t, 3H, J=7.09Hz,
CH3CH2O). 13C-NMR (75.45 MHz, DMSO-d6) δ: 165.8
(Cq), 157.9 (Cq), 152.6 (Cq), 148.5 (Cq), 137.8 (Cq), 137.9
(Cq), 128.9 (CHAr), 128.2 (CHAr), 128.1 (CHAr), 127.9
(CHAr), 115.1 (CHAr), 100 (Cq), 69.6 (CH2), 59.6 (CH2),
53.8 (CH), 18.2 (CH3), 14.6 (CH3). MS (ES+): m/z (%)
=409 (M++1+CH3CN, 41), 389 (M++Na, 100), 367
(M++1, 38). Anal. Calcd. for C21H22N2O4: C, 68.84; H,
6.05; N, 7.65. Found: C, 68.92; H, 6.22; N, 7.79.
tert-Butyl
4-(3-bromo-4-hydroxy-5-methoxyphenyl)-6-
methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(8e). Pale brown solid (81%), Rf =0.31 (ethyl acetate), mp
195–197°C. IR (ATR diamond) cm–1: 3335, 3225, 2973,
tert-Butyl 4-(4-(benzyloxy)phenyl)-6-methyl-2-oxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (8b). Pale yellow solid
(66%), Rf =0.20 (50% ethyl acetate/hexane), mp 174–176°
C. IR (ATR diamond) cm–1: 3242, 3113, 2973, 1716,
1
2937, 1693, 1642, 1620, 1500, 1456. H-NMR (300MHz,
1
DMSO-d6) δ: 9.39 (br s, 1H, OH), 9.05 (s, 1H, NH), 7.63
(s, 1H, NH), 6.85 (d, 1H, J=1.78Hz, CHAr), 6.79 (d, 1H,
J=1.78Hz, CHAr), 5.01 (d, 1H, J=2.69Hz, CHNH), 3.75
(s, 3H, OCH3), 2.19 (s, 3H, CH3), 1.31 (s, 9H, (CH3)3C).
1698, 1644, 1609, 1585, 1509, 1454. H-NMR (400MHz,
CDCl3) δ: 7.43–7.39 (m, 3H, 2xCHAr, and NH), 7.38–7.36
(m, 2H, CHAr), 7.33–7.30 (m, 1H, CHAr), 7.23 (d, 2H,
J=8.57Hz, CHAr), 6.95 (s, 1H, NH), 6.92 (d, 2H,
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13C-NMR (75.45MHz, DMSO-d6) δ: 165.2 (Cq), 148.6
(Cq), 147.9 (Cq), 143.3 (Cq), 137.3 (Cq), 122.0 (CH), 110.1
(Cq), 110.1 (Cq), 109.8 (Cq), 109.3 (CH), 100.7 (Cq), 79.7
(Cq), 56.5 (OCH3), 53.9 (CH), 28.3 (CH3), 18.2 (CH3). MS
(ES+): m/z (%)=415 (M++2, 17), 414 (M++1, 38), 413
(M+, 100). Anal. Calcd. for C17H21BrN2O5: C, 49.41; H,
5.12; N, 6.78. Found: C, 49.51; H, 5.50; N, 6.42.
J = 2.89Hz and 2.87Hz, 2xCH3), 2.00–1.64 (m, 7H,
3xCH2 and CH cyclohexene), 1.16 (s, 9H, (CH3)3C).
13C-NMR (75.45 MHz, DMSO-d6) δ: (tautomeric
mixture): 165.7 (Cq), 165.7 (Cq), 153.7 (Cq), 153.6 (Cq),
148.2 (Cq), 148.1 (Cq), 127.1 (CH), 126.9 (CH), 126.6
(CH), 99.8 (Cq), 99.7 (Cq), 79.4 (Cq), 59,6 (CH), 55.4
(CH), 54.6 (CH), 54.4 (CH), 42.6 (CH), 41.4 (CH), 41,1
(CH), 28.4 (CH3), 27.4 (CH2), 25.9 (CH2), 25.8 (CH2),
25.6 (CH2), 25.4 (CH2), 25.3 (CH2), 22.8 (CH2), 22.7
(CH2), 18.2 (CH2), 18.1 (CH2), 14.7 (CH3). MS (ES+):
m/z (%) =295 (M++3, 11), 293 (M++1, 5), 292 (M+, 8),
285 (100), 263 (49), 261 (5). Anal. Calcd. for
C16H24N2O3 · 0.21H2O: C, 64.83; H, 8.24; N, 9.45.
Found: C, 64.84; H, 7.98; N, 9.75.
Allyl 4-(3-bromo-4-hydroxy-5-methoxyphenyl)-6-methyl-2-
oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (8f).
White
solid (74%), Rf =0.46 (ethyl acetate), mp 212–214°C. IR
(ATR diamond) cm–1: 3570, 3221, 3102, 2965, 2939,
1681, 1631, 1578, 1498, 1449. 1H-NMR (400MHz,
CDCl3) δ: 7.04 (d, 1H, J=1.69Hz, CHAr), 6.76 (d, 1H,
J=1.66Hz, CHAr), 5.91 (br s, 1H, NH), 5.87–5.80 (m, 1H,
CH=CH2), 5.50 br s, 1H, NH), 5.46 (br s, 1H, OH), 5.34
(d, 1H, J=2.55Hz, CH=CH2), 5.23 (d, 1H, J=7.55Hz,
CH=CH2), 5.18 (s, 1H, CHNH), 4.55 (t, 2H, J=5.73Hz
CH2O), 3.86 (s, 3H, CH3O), 2.37 (s, 3H, CH3). 13C-NMR
(100MHz, CDCl3) δ: 165.1 (Cq), 152.6 (Cq), 147.3 (Cq),
146.6 (Cq), 142.9 (Cq), 136.3 (Cq), 132.2 (CH), 122.8
(CH), 118.3 (CH2), 108.5 (Cq), 108.3 (CH), 100.9 (Cq),
64.9 (CH2O), 56.4 (CH3O), 55.3 (CH), 19.0 (CH3). MS
(ES-): m/z (%)=395 (M+-2, 91), 397 (M+, 100). Anal.
Calcd. for C16H17BrN2O5 ·1.14H2O: C, 45.96; H, 4.61; N,
6.70. Found: C, 46.00; H, 4.45; N, 6.81.
Allyl-4-(cylohex-3-enyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine
-5-carboxylate (8i).
Pale yellow solid (77%), Rf =0.63
(80% ethyl acetate/hexane), mp 168–170°C . IR (ATR
diamond) cm–1: 3240, 3112, 3025, 2917, 2837, 1699,
1
1646, 1463. H-NMR (300MHz, DMSO-d6) δ: (tautomeric
mixture): 8.99 and 8.93 (2 s, 1H, 2xNH), 7.40 and 7.37 (2
br s, 1H, NH and OH), 6.00–5.88 (m, 1H, H2C=CH),
5.61–5.57 (m, 2H, CH=CH), 5.29–5.18 (m, 2H,
H2C= CH), 4.56 (d, 2H, J=5.04Hz, OCH2), 4.06 (m, 1H,
CHNH), 2.20 (d, 3H, J=3.28Hz, CH3), 2.08–1.90 (m, 3H,
CH2 and CH cyclohexene), 1.74–1.20 (m, 4H, 2xCH2
cyclohexene), 1.18 (t, 3H, J=7.05Hz, OCH2CH3). 13C-
NMR (75.45 MHz, DMSO-d6) δ: (tautomeric mixture):
166.2 (Cq), 166.1 (Cq), 165.8 (Cq), 165.7 (Cq), 153.6 (Cq),
153.6 (Cq), 149.9 (Cq), 149.7 (Cq), 149.2 (Cq), 149.1 (Cq),
133.6 (CH), 127.0 (CH), 126.8 (CH), 126,6 (CH), 117.5
(CH2), 98.4 (Cq), 98.3 (Cq), 97.9 (Cq), 97.9 (Cq), 64.2
(CH2), 59,6 (CH), 55.3 (CH), 54.4 (CH), 41.3 (CH), 41.0
(CH), 27.3 (CH2), 25.6 (CH2), 25.4 (CH2), 22.6 (CH2),
22.5 (CH2), 18.3 (CH2), 18.3 (CH2), 18.2 (CH3), 14.6
(CH3). MS (ES+): m/z (%) = 279 (M++3, 14), 277 (M++1,
9). Anal. Calcd. for C15H20N2O3 · 0.20H2O: C, 64.30; H,
7.28; N, 10.00. Found: C, 64.33; H, 7.28; N, 9.99.
Ethyl
4-(cylohex-3-enyl)-6-methyl-2-oxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (8g).
White crystal
(90%), Rf = 0.54 (80% ethyl acetate/hexane), mp 216–
218°C. IR (ATR diamond) cm–1: 3234, 3106, 2969,
1
2917, 1698, 1645, 1454. H-NMR (300 MHz, DMSO-d6)
δ: (tautomeric mixture): 8.92 (s, 1H, NH), 7.37 and 7.34
(2 br s, 1H, NH and OH), 5.66–5.57 (m, 2H, HC = CH
cyclohexene), 4.11–4.01 (m, 3H, CH2O and CHNH),
2.18 (d, 3H, J= 2.93Hz, CH3), 2.06–1.26 (m, 7H, 3xCH2
and CH cyclohexene), 1.21 (t, 3H, J= 7.08Hz,
CH3CH2O). 13C-NMR (75.45 MHz, DMSO-d6) δ:
(tautomeric mixture): 166.2 (Cq), 166.1 (Cq), 153.7 (Cq),
153.6 (Cq), 149.2 (Cq), 149.1 (Cq), 127.0 (CH), 126.8
(CH), 126.6 (CH), 98.4 (Cq), 98.3 (Cq), 59.6 (CH2), 55.2
(CH), 54.4 (CH), 41.3 (CH), 41.1 (CH), 27.3 (CH2), 25.8
(CH2), 25.6 (CH2), 25.3 (CH2), 25.2 (CH2), 22.7 (CH2),
18.2 (CH3), 18.1 (CH3), 14.6 (CH3). MS (ES-): m/z (%)
= 264 (M+, 5), 263 (M+-1, 9), 261 (M+-3, 23). Anal.
Calcd. for C14H20N2O3: C, 63.62; H, 7.63; N, 10.60.
Found: C, 63.55; H, 7.62; N, 10.47.
(E)-Ethyl 6-methyl-2-oxo-4-styryl-1,2,3,4-tetrahydropyrimidine
-5-carboxylate (8j).
White solid (88%), Rf =0.57 (80%
ethyl acetate/hexane), mp 228–230°C (lit. [23(b)] mp 230–
232°C). IR (ATR diamond) cm–1: 3239, 3111, 2977, 2935,
1
1720, 1699, 1650, 1463. H-NMR (300MHz, DMSO-d6)
δ: 9.13 (s, 1H, NH), 7.54 (s, 1H, NH), 7.41–7.29 (m, 5H,
CHAr), 6.38 (d, 1H, J=15.8Hz, CH=CHPh), 6.22 (dd,
1H, J=15.76, 5.93 Hz, CH=CHPh), 4.73–4.71 (m, 1H,
CHNH), 4.17–4.04 (m, 2H, OCH2), 2.19 (s, 3H, CH3),
1.22 (t, 3H, J=6.99Hz, CH3CH2O). 13C-NMR
(75.45MHz, DMSO-d6) δ: 165.7 (Cq), 153.0 (Cq), 149.0
(Cq), 136.7 (Cq), 130.4 (CH), 129.1 (CHAr), 128.6 (CH),
128.0 (CHAr), 126.8 (CHAr), 98.5 (Cq), 59.7 (CH2), 52.3
(CH), 18.2 (CH3), 14.7 (CH3). MS (ES+): m/z (%) =288
(M++2, 19), 287 (M++1, 100), 243 (16), 221 (26). Anal.
Calcd. for C16H18N2O3: C, 67.12; H, 6.34; N, 9.78. Found:
C, 67.30; H, 6.42; N, 9.89.
tert-Butyl
4-(cylohex-3-enyl)-6-methyl-2-oxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (8h).
White crystal
(80%), Rf = 0.57 (80% ethyl acetate/hexane), mp 250–
252°C. IR (ATR diamond) cm–1: 3225, 3099, 2982,
2925, 2839, 1701, 1650, 1470, 1450. 1H-NMR
(300 MHz, DMSO-d6) δ: (tautomeric mixture): 8.93 and
8.81 (2 s, 1H, 2xNH), 7.32 and 7.29 (2 br s, 1H, NH, and
OH), 5.60–5.70 (m, 2H, HC = CH cyclohexene), 4.07 and
4.02 (2m, 1H, 2xCHNH), 2.18 and 2.15 (2 d, 3H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Nickel Chloride Hexahydrate Catalyzed Multicomponent Biginelli’s Synthesis of
3,4-Dihydropyrimidin-2(1H)-Ones and Thiones
(E)-tert-butyl 6-methyl-2-oxo-4-styryl-1,2,3,4-tetrahydropyrimidine-
5-carboxylate (8k). Pale yellow solid (74%), Rf = 0.72 (80%
ethyl acetate/hexane), mp 188–189°C . IR (ATR diamond)
cm–1: 3237, 3108, 2966, 2922, 2851, 1721, 1698, 1647,
1453. 1H-NMR (400 MHz, CDCl3) δ: 7.66 (s, 1H, NH),
7.32–7.23 (m, 5H, CHAr), 6.48 (d, 1H, J= 15.6 Hz,
CH=CHPh), 6.19 (dd, 1H, J= 15.6, 6.5 Hz, CH=CHPh),
5.60 (s, 1H, NH), 4.92–4.91 (m, 1H, CHNH), 2.3 (s, 3H,
CH3), 1.46 (s, 9H, (CH3)3C). 13C-NMR (100MHz, CDCl3)
δ: 164.9 (Cq), 154.6 (Cq), 145.8 (Cq), 136.4 (Cq), 129.6 (CH),
128.9 (CH), 128.7 (CH), 128.4 (CH), 127.8 (CH), 101.4 (Cq),
80.6 (Cq), 53.5 (CH), 28.5 (CH3), 18.6 (CH3). MS (ES+):
m/z (%)= 316 (M++2, 10), 315 (M++1, 8), 314 (M+, 5). Anal.
Calcd. for C18H22N2O3 ·0.50H2O: C, 66.79; H, 7.11; N, 8.66.
Found: C, 66.99; H, 7.19; N, 8.79.
crystal (76%), Rf = 0.60 (50% ethyl acetate/hexane), mp
161–163°C. IR (ATR diamond) cm–1: 3325, 3179, 3115,
3024, 1660, 1648, 1611. H-NMR (400 MHz, CDCl3) δ:
1
7.74 (s, 1H, NH), 7.42–7.30 (m, 5H, CHAr), 7.21 (d, 2H,
J = 8.59Hz, CHAr), 7.13 (br s, 1H, NH), 6.92 (d, 2H,
J = 8.59Hz, CHAr), 5.84–5.74 (m, 1H, CH = CH2), 5.36
(dd, 1H, CH = CH2), 5.17 (s, 1H, CHNH), 5.14 (d, 1H,
J = 4.43Hz, CH =CH2), 5.04 (s, 2H, CH2), 4.55–4.52 (m,
2H, CH2), 2.36 (s, 3H, CH3). 13C-NMR (100MHz,
CDCl3) δ: 174.5 (Cq), 164.9 (Cq), 158.8 (Cq), 143.0 (Cq),
136.7 (Cq), 134.9 (Cq), 131.9 (CH), 128.6 (CH), 128.1
(CH), 128.0 (CH), 127.4 (CH), 118.2 (CH2), 115.1 (CH),
102.8 (Cq), 70.0 (CH2), 65.0 (CH2), 55.58 (CH), 18.3
(CH3). MS (ES-): m/z (%) = 394 (M+, 9), 393 (M+-1, 13),
392 (M+-2, 17), 311 (100), 295 (61), 290 (99). Anal.
Calcd. for C22H22N2O3S · 0.24H2O: C, 66.20; H, 5.64; N,
7.02; S, 8.02. Found: C, 66.19; H, 5.92; N, 7.15; S, 8.03.
Ethyl 4-(3-bromo-4-hydroxy-5-methoxyphenyl)-6-methyl-2-
thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (8o). Pale
(E)-Allyl 6-methyl-2-oxo-4-styryl-1,2,3,4-tetrahydropyrimidine
-5-carboxylate (8l).
White solid (66%), Rf =0.60 (80%
ethyl acetate/hexane), mp 198–200°C. IR (ATR diamond)
1
cm–1: 3242, 3112, 2942, 1701, 1648. H-NMR (300MHz,
DMSO-d6) δ: 9.20 (s, 1H, NH), 7.57 (s, 1H, NH), 7.40–
7.20 (m, 5H, CHAr), 6.39 (d, 1H, J=15.85Hz,
CH=CHPh), 6.24 (dd, 1H, J= 15.83, 5.87 Hz,
CH=CHPh), 6.01–5.88 (m, 1H, CH=CH2), 5.31 (dd, 1H,
J=1.54, 17,22Hz, CH=CH2), 5.20 (dd, 1H, J=1.28,
10.42Hz, CH=CH2), 4.76–4.73 (m, 1H, CHNH), 4.60–
4.57 (2H, m, OCH2), 2.21 (s, 3H, CH3). 13C-NMR
(75.45MHz, DMSO-d6) δ: 165.3 (Cq), 153.0 (Cq), 149.6
(Cq), 136.7 (Cq), 133.6 (CH), 130.4 (CH), 129.1 (CH),
128.6 (CH), 128.1 (CH), 126.8 (CH), 117.7 (CH2), 97.9
(Cq), 64.3 (CH2), 52.2 (CH), 18.3 (CH3). MS (ES+): m/z
(%)=300 (M++2, 20), 299 (M++1, 100), 256 (15), 241
(18), 198 (13). Anal. Calcd. for C17H18N2O3 ·0.33H2O: C,
67.04; H, 6.13; N, 9.20. Found: C, 67.16; H, 6.21; N, 9.58.
yellow
crystal
(85%),
Rf = 0.54
(50%
ethyl
acetate/hexane), mp 218–220°C. IR (ATR diamond) cm–
1: 3330, 3173, 2979, 2931, 1676, 1634, 1599. H-NMR
1
(300 MHz, DMSO-d6) δ: 10.34 (s, 1H, NH), 9.60 (m, 1H,
NH), 9.51 (s, 1H, OH), 6.83 (d, 1H, J = 1.88Hz, CHAr),
6.81 (d, 1H, J= 1.92 Hz, CHAr), 5.11 (d, 1H, J= 3.56 Hz,
CHNH), 4.12–3.99 (m, 2H, OCH2CH3), 3.78 (s, 3H,
OCH3), 2.29 (s, 3H, CH3), 1.05 (t, 3H, J= 7.08 Hz,
OCH2CH3). 13C-NMR (75.45MHz, DMSO-d6) δ: 174.7
(Cq), 165.5 (Cq), 148.7 (Cq), 145.6 (Cq), 143.8 (Cq),
135.9 (Cq), 122.2 (CH), 110.0 (Cq), 109.6 (CH), 100.9
(Cq), 60.1 (CH2), 56.5 (CH3), 53.7 (CH), 17.6 (CH3),
14.5 (CH3). MS (ES+): m/z (%) = 404 (M++3, 20), 403
(M++2, 89), 401 (M+, 100), 199 (15). Anal. Calcd. for
C15H17BrN2O4S: C, 44.90; H, 4.27; N, 6.98, S, 7.99.
Found: C, 44.58; H, 4.31; N, 7.06, S, 7.89.
Ethyl
4-(4-(benzyloxy)phenyl)-6-methyl-2-thioxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (8m).
White crystal
(79%), Rf = 0.61 (50% ethyl acetate/hexane), mp 184–
Allyl 4-(3-bromo-4-hydroxy-5-methoxyphenyl)-6-methyl-2-
thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (8p). Pale
185°C. IR (ATR diamond) cm–1: 3320, 3175, 2988,
1
1660, 1612. H-NMR (400 MHz, DMSO-d6) δ: 10.29 (s,
yellow
crystal
(73%),
Rf = 0.46
(50%
ethyl
1H, NH), 9.59 (s, 1H, NH), 7.44–7.41 (m, 2H, CHAr),
7.39–7.37 (m, 2H, CHAr), 7.34–7.33 (m, 1H, CHAr), 7.14
(d, 2H, J= 8.66 Hz, CHAr), 6.99 (d, 2H, J = 8.66Hz,
CHAr), 5.12 (d, 1H, J =3.55 Hz, CHNH), 5.08 (s, 2H,
PhCH2O), 4.02 (q, 2H, J =7.08 Hz, CH3CH2O), 2.29 (s,
3H, CH3), 1.11 (t, 3H, J= 7.09 Hz, CH3CH2O). 13C-
NMR (100 MHz, DMSO-d6) δ: 174.5 (Cq), 165.6 (Cq),
158.3 (Cq), 145.2 (Cq), 137.5 (Cq), 136.4 (Cq), 128.9
(CHAr), 128.3 (CHAr), 128.1 (CHAr), 128.0 (CHAr), 115.2
(CHAr), 100.4 (Cq), 69.7 (CH2), 60.0 (CH2), 53.9 (CH),
17.6 (CH3), 14.5 (CH3). MS (ES+): m/z (%) = 405
(M++Na, 33), 383 (M++1, 100%). Anal. Calcd. for
C21H22N2O3S: C, 65.95; H, 5.80; N, 7.32; S, 8.38.
Found: C, 65,69; H, 5.80; N, 7.38; S, 8.27.
acetate/hexane), mp 206–208°C. IR (ATR diamond) cm–
1
1: 3314, 3179, 2932, 1676, 1636, 1571, 1491, 1468. H-
NMR (300MHz, DMSO-d6) δ: (tautomeric mixture):
10.39 and 10.34 (2 s, 1H, 2xNH), 9.63 and 9.52 (br s and
s, 2H, OH, NH and SH), 6.84 (d, 2H, J =7.98 Hz, CHAr),
5.93–5.80 (m, 1H, CH =CH2), 5.16 (m, 2H, CH2 = CH),
4.54 (m, 2H, CH2O), 4.05 (m, 1H, CHNH), 3.77 (s, 3H,
CH3O), 2.31 and 2.29 (2s, 3H, 2xCH3). 13C-NMR
(75.45 MHz, DMSO-d6) δ: (tautomeric mixture): 174.6
(Cq), 165.6 (Cq), 165.1 (Cq), 148.8 (Cq), 146.2 (Cq),
145.6 (Cq), 143.8 (Cq), 135.9 (Cq), 135.7 (Cq), 133.2
(CH), 122.2 (CH), 117.7 (CH2), 110.4 (Cq), 109.6 (CH),
109.5 (CH), 100.9 (Cq), 100.5 (Cq), 64.6 (CH2), 60.1
(CH), 56.56 (CH), 53.8 (CH3), 53.7 (CH3), 17.7 (CH3),
14.5 (CH3). MS (ES+): m/z (%) = 416 (M++3, 16), 415
(M++2, 79), 413 (M+, 100). Anal. Calcd. for
Allyl
4-(4-(benzyloxy)phenyl)-6-methyl-2-thioxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (8n).
Pale yellow
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Ş. Gülten
Vol 000
C16H17BrN2O4S · 0.38H2O: C, 45.70; H, 4.23; N, 6.66; S,
7.60. Found: C, 45.70; H, 4.18; N, 6.89; S, 7.68.
(Cq), 81.3 (Cq), 54.2 (CH), 53.8 (CH), 28.4 (CH3), 18.4 (CH3).
18.3 (CH3). MS (ES+): m/z (%) =334 (M++4, 61), 333
(M++3, 20), 332 (M++2, 28), 331 (M++1, 39), 330 (M+, 20),
327 (100), 315 (32), 300 (30), 285 (74). Anal. Calcd. for
C18H22N2O2S·0.15H2O: C, 64.84; H, 6.69; N, 8.40; S, 9.60.
Found: C, 64.64; H, 6.48; N, 8.78; S, 9.68.
Ethyl
4-(cylohex-3-enyl)-6-methyl-2-thioxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (8q).
White solid
(75%), Rf = 0.65 (50% ethyl acetate/hexane), mp 206–
208°C. IR (ATR diamond) cm–1: 3163, 3020, 2988,
2975, 2905, 1705, 1640, 1593, 1569, 1479. 1H-NMR
(400 MHz, DMSO-d6) δ: (tautomeric mixture): 10.14 and
10.11 (2 br s, 1H, 2xNH), 9.29 and 9.28 (2 br s, 1H, NH
and SH), 5.59–5.53 (m, 2H, HC = CH cyclohexene),
4.10–3.97 (m, 3H, CHNH and OCH2CH3), 2.18 and 2.17
(2 s, 3H, 2xCH3), 2.01–1.41 (m, 7H, 3xCH2 and CH
cyclohexene), 1.14 (t, 3H, J = 6.9 Hz, CH3CH2O). 13C-
NMR (100 MHz, DMSO-d6) δ: (tautomeric mixture):
175.9 (Cq), 175.8 (Cq), 166.1 (Cq), 166.0 (Cq), 146.2
(Cq), 146.1 (Cq), 127.2 (CH), 127.1 (CH), 126.6 (CH),
126.3 (CH), 99.9 (Cq), 99.7 (Cq), 60.2 (CH2), 55.5 (CH),
54.8 (CH), 41.4 (CH), 41.1 (CH), 26.9 (CH2), 26.1
(CH2), 25.5 (CH2), 25.2 (CH2), 24.9 (CH2), 22.7 (CH2),
17.7 (CH3), 17.6 (CH3), 14.6 (CH3). MS (ES-): m/z (%)
= 280 (M+, 18), 279 (M+-1, 38), 277 (M+-3, 35), 273
(51), 260 (51), 258 (100). Anal. Calcd. for
C14H20N2O2S ·0.51H2O: C, 58.02; H, 7.26; N, 9.67; S,
11.05. Found: C, 58.19; H, 7.36; N, 9.87; S, 11.25.
(E)-Allyl 6-methyl-4-styryl-2-thioxo-1,2,3,4-tetrahydropyrimidine
-5-carboxylate (8t). White solid (79%), Rf = 0.74 (50% ethyl
acetate/hexane), mp 171–173°C. IR (ATR diamond) cm–1:
3151, 3003, 2938, 2907, 1706, 1676, 1651, 1597, 1470. 1H-
NMR (400MHz, CDCl3) δ: 8.24 (s, 1H, NH), 7.51 (s, 1H,
NH), 7.34–7.21 (m, 5H, CHAr), 6.50 (d, 1H, J= 16.1Hz,
CH =CHPh), 6.16 (dd, 1H, J= 15.5, 6.4Hz, CH=CHPh),
5.95–5.86 (m, 1H, CH=CH2), 5.32 (dd, 1H, J=1.4, 17Hz,
CH =CH2), 5.24 (dd, 1H, J=1.0, 10.6Hz, CH=CH2), 5.02
(q, 1H, J=3.2Hz CHNH), 4.62–4.66 (m, 2H, OCH2), 2.31
(s, 3H, CH3). 13C-NMR (100 MHz, CDCl3) δ: 175.6 (Cq),
164.9 (Cq), 143.9 (Cq), 135.9 (Cq), 132.1 (CH), 131.3 (CH),
128.7 (CHAr), 128.5 (CHAr), 127.2 (CH), 126.8 (CHAr),
118.6 (CH2), 101.5 (Cq), 65.3 (CH2), 53.8 (CH), 18.5
(CH3). MS (ES+): m/z (%) = 316 (M++2, 23), 315 (M++1,
100%). Anal. Calcd. for C17H18N2O2S·0.53H2O: C, 62.97;
H, 5.88; N, 8.64; S, 9.88. Found: C, 63.01; H,5.91; N, 8.68;
S, 10.00.
(E)-Ethyl 6-methyl-4-styryl-2-thioxo-1,2,3,4-tetrahydropyrimidine
-5-carboxylate (8r). White solid (90%), Rf =0.88 (80% ethyl
acetate/hexane), mp 187–188°C (lit. [23(c)] mp 205–207°C).
IR (ATR diamond) cm–1: 3129, 2980, 2903, 1705, 1678,
Acknowledgments. The author thanks Çanakkale Onsekiz Mart
University Scientific Research Projects Coordination Department
(BAP 2008/28) for financial support. The author also thank
Çanakkale Onsekiz Mart University, the Science and Technology
Research and Application Center for recording NMR spectra and
mass spectra, the NMR Analysis Laboratory of Hacettepe
University and Gazi University for recording NMR spectra and
Central Laboratory of Pharmacy, and Ankara University for the
measurement of the mass spectra and elemental analysis.
1
1651, 1593, 1471, 1446. H-NMR (400MHz, CDCl3) δ:
8.52 (s, 1H, NH), 7.81 (s, 1H, NH), 7.33–7.19 (m, 5H,
CHAr), 6.49 (d, 1H, J=16Hz, CH=CHPh), 6.13 (dd, 1H,
J=16.00, 6.91Hz, CH=CHPh), 4.98 (q, 1H, J=3.2Hz
CHNH), 4.18 (q, 2H, J=6.9Hz, OCH2CH3), 2.30 (s, 3H,
CH3), 1.26 (t, 3H, J=7.3Hz, OCH2CH3). 13C-NMR
(100MHz, CDCl3) δ: 175.7 (Cq), 165.2 (Cq), 143.3 (Cq),
135.9 (Cq), 131.3 (CH), 128.7 (CHAr), 128.2 (CHAr), 127.2
(CH), 126.8 (CHAr), 101.8 (Cq), 60.6 (CH2), 54.0 (CH),
53.8 (CH), 18.5 (CH3), 14.4 (CH3). MS (ES-): m/z (%)
=301 (M+-1, 29), 299 (M+-3, 15), 297 (M+-5, 30), 255
(100). Anal. Calcd. for C16H18N2O2S: C, 63.55; H, 6.00; N,
9.26, S, 10.60. Found: C, 63.66; H, 6.18; N, 9.40, S, 10.79.
(E)-tert-butyl 6-methyl-4-styryl-2-thioxo-1,2,3,4-tetrahydropyrimidine
-5-carboxylate (8s). White crystal (70%), Rf=0.42 (30% ethyl
acetate/hexane), mp 213–214°C. IR (ATR diamond) cm–1:
REFERENCES AND NOTES
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P. T.; Muralidharan, D.; Rajendran, M. Bioorg Med Chem Lett 2006, 16,
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1
3127, 2977, 2935, 1699, 1651, 1589, 1474, 1449. H-NMR
(400 MHz, CDCl3) δ: (tautomeric mixture): 7.8 and 7.4 (2 s,
1H, 2xNH), 7.34–7.25 (m, 5H, CHAr), 7.15 and 7.10 (2s, 1H,
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet