Nano copper oxide mediated ligand-free C-S cross-coupling and concomitant oxidative aromatization of 4-aryl-3,4-dihydropyrimidin-2(1H)-thione with diaryliodonium salts

Article abstract of DOI:10.1016/j.tetlet.2012.10.131

A wide range of Biginelli 4-aryl-3,4-dihydropyrimidin-2(1H)-thiones undergo ligand-free C-S cross-coupling with diaryliodonium triflates in the presence of CuO nanoparticles with the concomitant oxidative aromatization to form highly substituted 2-(thioar

Full text of DOI:10.1016/j.tetlet.2012.10.131

Tetrahedron Letters xxx (2012) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Nano copper oxide mediated ligand-free C–S cross-coupling and concomitant
oxidative aromatization of 4-aryl-3,4-dihydropyrimidin-2(1H)-thione with
diaryliodonium salts
⇑
Bhagyashree Y. Bhong, Amol V. Shelke, Nandkishor N. Karade
Department of Chemistry, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, Maharashtra 440 033, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A wide range of Biginelli 4-aryl-3,4-dihydropyrimidin-2(1H)-thiones undergo ligand-free C–S cross-
coupling with diaryliodonium triflates in the presence of CuO nanoparticles with the concomitant
oxidative aromatization to form highly substituted 2-(thioaryl)pyrimidine. The nano CuO catalyst can
be recycled and reused three times without any significant loss of catalytic activity.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 13 September 2012
Revised 27 October 2012
Accepted 30 October 2012
Available online xxxx
Keywords:
Nanoparticles
Biginelli reaction
C–S cross-coupling
Diaryliodonium salts
Oxidative aromatization
Aryl sulfides are structural motifs found in many biological and
pharmaceutically active compounds and have been used as impor-
tant intermediates in several organic transformations.1 The transi-
tion metal (Pd, Cu, Ni, Co, and Fe) catalyzed cross-coupling
reactions of aryl halides with appropriate thiols are generally a
method of choice for the construction of a C(aryl)–S bond.2 Re-
cently, the advent of nanostructured transition metals has been
considered as a sustainable and competitive alternative to conven-
tional catalysis.3 This is due to the high surface areas and rich ex-
posed active sites of the nano-catalysts which enhance catalytic
efficiency, thereby requiring lower loading of catalyst. Addition-
ally, the insolubility of nano-catalysts in reaction solvents imparts
the advantages of heterogeneous catalysis such as simplified isola-
tion of the product along with easy recovery and recyclability of
the catalysts. As a result, intensive work has recently been reported
for the C(aryl)–S cross-coupling reactions of iodoarenes with thiols
to form diaryl sulfides using various nanoparticle size catalysts
such as CuI,4 CuFe2O4,5 and CuO6 and In2O3.7
considerable growth in the decoration of all the six positions of
DHPMs (N1, C2, N3, C4, C5, and C6) to produce low molecular
weight ‘drug like’ compounds.9 As the original Biginelli reaction
is carried out by a three-component condensation of ethyl acetoac-
etate, aldehyde, and urea or thiourea, the C2 position of DHPMs is
always either with carbonyl or thiocarbonyl functional groups. The
C2 position of DHPMs with thiocarbonyl functional group has been
synthetically manipulated (Fig. 1) by (i) reaction with alkyl halide
to produce 1,4-dihydropyrimidine10 followed by oxidative aroma-
tization using (diacetoxyiodo)benzene, CAN, Mn(OAc)3, and MnO2
to form pyrimidine,11 (ii) reaction of alkyne or doubly electrophilic
building block like
a
-halo ketone to furnish fused pyrimidines,12
(iii) oxidative aromatization to form disulfide,13 and (iv) desulfita-
tive Liebeskind–Srogl coupling of arylboronic acid or aryltributyl-
tin to form 2-arylation product.14 The C–S cross-coupling of
3,4-dihydropyrimidin-2(1H)-thione with aryl halide is a relatively
less investigated reaction in the literature.
Among the various cross-coupling reactions, there is a great
synthetic challenge for C–S bond formation due to the susceptibil-
ity of sulfur for oxidative dimerization and its tendency to bind
with metal which causes the modification or deactivation of the
catalyst.15 In contrast to aryl sulfides, the methods for the synthe-
sis of heterocyclic sulfides including pyrimidine moiety are very
limited. The 3,4-dihydropyrimidine-2(1H)-thione can be consid-
ered as the structural analog of cyclic thiourea and therefore, we
were intrigued with the possibility of C–S cross-coupling reaction
with a suitable arylating agent. Moreover, only a few reports have
Biginelli 3,4-dihydropyrimidine-2(1H)-one (DHPM) is a privi-
leged heterocyclic scaffold exhibiting a wide range of pharmaco-
logical properties such as calcium channel blockers, hepatitis B
virus replication inhibitors, mitotic kinesin inhibitors, and
a
1a-adrenergic receptor antagonists.8 Owing to this remarkable
pharmacological profile, the recent decade has witnessed
a
⇑
Corresponding author. Fax: +91 712 2532841.
E-mail address: nnkarade@gmail.com (N.N. Karade).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.131
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2
B. Y. Bhong et al. / Tetrahedron Letters xxx (2012) xxx–xxx
reactions as a more reactive version of iodobenzene.17 It has been
explored in the C–S cross-coupling reactions of aromatic and ali-
phatic thiols using Pd(PPh3)4.18 Here, we report our studies on
the C–S cross-coupling reaction of 3,4-dihydropyrimidine-2(1H)-
thione with a diaryliodonium salt using CuO nano-catalyst under
ligand-free conditions. It was observed that 3,4-dihydropyrimi-
dine-2(1H)-thione undergoes C–S cross-coupling with a symmetri-
cal diaryliodonium salt with concomitant oxidative aromatization
to form highly functionalized 2-thioarylpyrimidine derivatives
(Scheme 1).
O
Ar
N
O
Ar
[O]
EtO
N
EtO
N
ref. 11
SR
N
H
SR
RX, base
R = alkyl
ref. 10
Ar
O
O
Ar
O
Ar
R
ref. 14
EtO
N
ref. 12
EtO
N
EtO
NH
N
H
Ar
N
S
N
H
S
The optimum conditions for the S-arylation of 4-phenyl-3,4-
dihydropyrimidine-2(1H)-thione (1a) were investigated by screen-
ing of appropriate arylating agents and copper catalysts in DMF
using K2CO3 as the base. The results are summarized in Table 1.
The initial attempts of utilizing iodobenzene for arylation of 1a
using various copper catalysts such as Cu(OAc)2, CuCl2, CuI, and
nano CuO (entries 1–6) resulted in poor yields (0–27%) of 2-phen-
ylthio-1,4-dihydropyrimidine 3a. Therefore, we used diphenyliod-
onium salts as arylating agents for the tentative C–S cross-coupling
using different copper catalysts (entries 7–15). In the absence of
copper catalyst, C(aryl)–S coupling of 1a with diphenyliodonium
salts did not take place (entries 7 and 12). When the same coupling
reaction was examined with diphenyliodonium chloride (entry 8)
using CuI (10 mol %), the formation of 3a and aromatized 2-(phen-
ylthio)pyrimidine 4a, respectively, took place in 17% and 46%
yields. Other catalysts such as Cu(OAc)2 and CuCl2 were found to
be inferior for the C–S cross-coupling of diphenyliodonium chlo-
ride with 1a (entries 9 and 10). Screening of nano CuO as a catalyst
revealed that the yield of aromatized pyrimidine 4a was much
higher than CuI with negligible formation of 3a (entry 11). Further
ref. 13
O
Ar
EtO
N
S
N
N
S
N
OEt
O
Ar
Figure 1. Decoration of 3,4-dihydropyrimidine-2(1H)-thione via functionalization
at the C-2 position.
appeared describing the coupling of thiocarbonyl functional groups
with aryl halides.16 To date, there is only one example in the liter-
ature for C–S cross-coupling of 3,4-dihydropyrimidine-2(1H)-thi-
one with phenylboronic acid using stoichiometric Cu(OAc)2
under microwave conditions (45 min) to form 2-thiophenyl-1,4-
dihydropyrimidine.14a Recently, a diaryliodonium salt has gained
a renewed interest in various C–C, C–N, C–O, and C–S coupling
R1
O
O
R1
nano CuO (10 mol %)
I
K2CO3 (2.5 equiv)
R2
NH
R2
N
OTf
R3
DMF, reflux, 12 h
R3
N
H
S
N
S
R3
Scheme 1. C–S cross-coupling and concomitant oxidative aromatization of 4-aryl-3,4-dihydropyrimidine-2(1H)-thione.
Table 1
Optimization of reaction conditions for C–S cross-coupling of 4-phenyl-3,4-dihydropyrimidine-2(1H)-thione with arylating agentsa
O
O
O
2
arylating agent
EtO
N
EtO
N
EtO
NH
copper cat.
K2CO3
DMF, reflux
N
H
S
N
S
N
H
1a
S
4a
3a
Entry
Arylating agent
Copper catalyst (mol %)
Yield 3a (%)
Yield 4a (%)
Time (h)
1
2
3
4
5
6
7
8
9
10
11
12
13
14b
15
PhI
PhI
PhI
PhI
PhI
PhI
Ph2ICl
Ph2ICl
Ph2ICl
Ph2ICl
Ph2ICl
Ph2IOTf
Ph2IOTf
Ph2IOTf
Ph2IBF4
Cu(OAc)2 (10 mol %)
CuCl2 (10 mol %)
CuI (10 mol %)
00
00
14
23
18
27
00
17
21
00
14
00
00
00
00
00
00
00
46
00
00
58
24
24
24
24
24
24
24
12
24
24
24
08
12
08
12
CuI (20 mol %)
CuO nano (10 mol %)
CuO nano (20 mol %)
—
CuI (10 mol %)
Cu(OAc)2 (10 mol %)
CuCl2 (10 mol %)
CuO nano (10 mol %)
—
CuO nano (10 mol %)
CuO nano (10 mol %)
CuO nano (10 mol %)
12
00
16
67
84
63
a
Reaction conditions unless otherwise stated: Arylating agent (1 equiv), K2CO3 (1.5 equiv), catalyst, DMF (10 mL).
Ar2IOTf (1.5 equiv), K2CO3 (2.5 equiv), catalyst, DMF (10 mL).
b
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B. Y. Bhong et al. / Tetrahedron Letters xxx (2012) xxx–xxx
3
Table 2
Cross-coupling of 3,4-dihydropyrimidine-2(1H)-thione with diphenyl iodonium triflatesa
O
R1
nano CuO (10 mol%)
K2CO3 (1.5 equiv)
O
R1
N
I
R2
NH
R2
N
OTf
DMF, reflux, 12 h
N
H
S
R3
S
R3
R3
2
4
1
OMe
OMe
S
O
O
O
O
O
O
O
EtO
N
EtO
N
EtO
N
EtO
EtO
N
N
S
N
4a, 84%
S
N
4d, 69%
N
S
4b, 79%
4c, 76%
Cl
Br
Br
NO2
O
N
EtO
N
N
EtO
N
EtO
O
N
N
S
S
4g, 79%
4h, 64%
N
S
N
S
4f, 88%
4e, 83%
OMe
Cl
O
O
Cl
O
N
N
Cl
N
N
N
S
N
S
4l, 66%
N
S
N
4j, 63%
N
S
4i, 74%
4k, 70%
Cl
NO2
O
O
Cl
O
O
EtO
EtO
N
Br
Br
EtO
N
EtO
N
N
S
S
N
4m
, 80%
N
S
4p
, 75%
N
S
4n
, 83%
4o
, 69%
a
Reaction conditions: 3,4-Dihydropyrimidine-2(1H)-thione (1 mmol), diaryliodonium triflate (1.5 mmol), CuO nanoparticle (0.025 mmol), and K2CO3 (2.5 mmol) in 10 mL
DMF under reflux for 12 h.
studies were also carried out about the influence of different coun-
ter anions of diphenyliodonium salts (entries 12–15), which
showed that satisfactory results could be obtained with diphenyli-
odonium triflates, resulting in the formation of aromatized pyrim-
idine 4a in good yields. However, 1.5 equiv of diphenyliodonium
triflates with respect to 1a were required for the exclusive forma-
tion of aromatized 4a in 84% excellent yield (entry 14). Therefore,
the optimized conditions for C–S cross-coupling of 1a employed
nano CuO (10 mol %), diphenyliodonium triflate (1.5 equiv), and
K2CO3 (2.5 equiv) in DMF for the exclusive formation of aromatized
4a.19
With the successful optimization results in hand, we moved on
to investigate the scope of the process in terms of the reaction of
various 4-aryl-3,4-dihydropyrimidine-2(1H)-thiones with diphe-
nyliodonium triflates (Table 2). A wide variety of 4-aryl-3,4-dihy-
dropyrimidine-2(1H)-thiones derived from ethyl acetoacetate
(entries 4a–h and 4m–p) and acetyl acetone (entries 4i–l) with dif-
ferently substituted aromatic ring at the C4 position were em-
ployed for C–S cross-coupling reaction with diphenyliodonium
triflates. As can be seen, in all the cases excellent yields of highly
functionalized 2-(thioaryl)pyrimidine were obtained and all the
products were characterized by IR, NMR and mass spectrometry.20
To the best of our knowledge, this is the first kind of report on the
one-pot synthesis of biologically and synthetically important 2-
(thioaryl)pyrimidine from readily accessible 4-aryl-3,4-dihydropy-
rimidine-2(1H)-thione.
Various symmetrical diaryliodonium salts were also examined
in C–S cross-coupling with 4-aryl-3,4-dihydropyrimidine-2(1H)-
thione (entries 4k–p). The protocol is tolerant to the presence of
electron-donating and withdrawing functional groups of symmet-
rical diaryliodonium salts. The reaction of unsymmetrical iodoni-
um salts with 1 resulted in a mixture of 2-(thioaryl)pyrimidines
due to the transfer of both the aryl groups on sulfur (Supplemen-
tary data).
As nano CuO is a heterogeneous catalyst, the recyclability of the
catalyst in this coupling reaction was examined. To facilitate the
catalyst recovery, the model C–S cross-coupling reaction of diphe-
nyliodonium triflate with 4-phenyl-3,4-dihydropyrimidine-2(1H)-
thione was carried out on 5 mmol scale. After each cycle, the
catalyst was recovered by simple centrifugation, washing with
deionized water and ethanol, and then drying in vacuo. The
separated catalyst was again reused for C–S cross-coupling and this
was repeated three times. In these cases, the yield of 4a was found
to be 87%, 79%, and 73% in successive three times use.
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4
B. Y. Bhong et al. / Tetrahedron Letters xxx (2012) xxx–xxx
12. (a) Singh, S.; Schober, A.; Gebinoga, M.; Groß, G. A. Tetrahedron Lett. 2011, 52,
In summary, we have developed a facile one-pot CuO nanopar-
3814; (b) Xiao, D.; Han, L.; Sun, Q.; Chen, Q.; Gong, N.; Lv, Y.; Suzenet, F.;
Guillaumet, G.; Cheng, T.; Li, R. RSC Adv. 2012, 2, 5054.
13. Hayashi, M.; Okunaga, K.; Nishida, S.; Kawamura, K.; Eda, K. Tetrahedron Lett.
2010, 51, 6734.
14. (a) Lengar, A.; Kappe, C. O. Org. Lett. 2004, 5, 771; (b) Sun, Q.; Suzenet, F.;
Guillaumet, G. Tetrahedron Lett. 2012, 53, 2694.
15. Kondo, T.; Mitsudo, T. A. Chem. Rev. 2000, 100, 3205.
16. Niu, L.-F.; Cai, Y.; Liang, C.; Hui, X.-P.; Xu, P.-F. Tetrahedron 2011, 67, 2878.
17. (a) Merritt, E. A.; Olofsson, B. Angew. Chem., Int. Ed. 2009, 48, 9052; (b) Yusubov,
M. S.; Maskaev, A. V.; Zhdankin, V. V. Arkivoc 2011, 1, 370.
ticle catalyzed ligand-free C–S cross-coupling of diaryliodonium
salts with 4-aryl-3,4-dihydropyrimidine-2(1H)-thione to furnish
highly functionalized 2-(phenylthio)pyrimidine which are biologi-
cally and synthetically important scaffolds. It is a unique example
of CuO nanoparticle catalysis for a C–S cross-coupling reaction of
thiocarbonyl functional groups of DHPMs with concomitant oxida-
tive aromatization to produce pyrimidine. This method also offers
significant advantages such as operational simplicity with a recy-
clable catalytic system. This is also a first report of a C–S cross-
coupling reaction of diaryliodonium salts using a copper based
catalytic system.
18. Wang, L.; Chen, Z. C. Synth. Commun. 2001, 1227.
19. General procedure for C–S cross-coupling of 4-aryl-3,4-dihydropyrimidin-2(1H)-
thione with symmetrical diaryliodonium triflates: CuO nano particles (mean
particle size, 33 nm, surface area, 29 m2/g, and purity, 99.99%) were purchased
from Sigma Aldrich. A mixture of 4-aryl-3,4-dihydropyrimidin-2(1H)-thione
(1.5 mmol), diaryliodonium triflates (2.25 mmol), K2CO3 (2.5 mmol), nano CuO
(10 mol %) was refluxed in DMF (10 mL) for the appropriate time (8–12 h) till
the consumption of starting material took place. The progress of the reaction
was monitored by TLC using ethyl acetate and hexane as eluent. After
completion of reaction, water (10 mL) and EtOAc (10 mL) were added and the
organic layers were separated. The combined organic layers were dried on
anhydrous Na2SO4 followed by the evaporation of the solvent to obtain the
crude product, which was purified by column chromatography on silica gel
using petroleum ether/EtOAc 9:1 as eluent to give desired products in excellent
purity.
Acknowledgments
The authors are thankful to the Department of Science and
Technology, New Delhi, India (No. SR/S1/OC-72/2009) for the
financial support. The authors are also grateful to SAIF, Punjab Uni-
versity, Chandigarh, India, for recording the NMR spectra.
20. Spectral data for all the compounds: Ethyl 4-methyl-6-phenyl-2-
(phenylthio)pyrimidine-5-carboxylate (4a): Yellow solid, mp 87–88 °C. 1H
NMR 400 MHz (CDCl3): d 1.06 (3H, t, J = 6.8 Hz, CH3), 2.51 (3H, s, CH3), 4.16
(2H, q, J = 7.2 Hz, CH2), 7.38–7.43 (4H, m, ArH), 7.51 (2H, d, J = 8 Hz, ArH), 7.65
(2H, d, J = 7.2 Hz, ArH). 13C NMR 100 MHz (CDCl3): d 13.63, 22.62, 61.80,
121.49, 128.39, 128.42, 128.95, 129.10, 129.46, 130.21, 135.22, 137.34, 163.57,
165.95, 168.12, 172.10. IR (cmÀ1): 3059, 2980, 1718, 1524, 1215, 686. HRMS
(ESI) Calcd for C20H18N2O2S (M+H) 351.10890. Found: 351.19550.
Ethyl 4-methyl-2-(phenylthio)-6-p-tolylpyrimidine-5-carboxylate (4b): White
solid, mp 62–63 °C. 1H NMR 400 MHz (CDCl3): d 1.10 (3H, t, J = 7.12 Hz, CH3),
2.35 (3H, s, CH3), 2.49 (3H, s, CH3), 4.20 (2H, q, J = 7.12 Hz, CH2), 7.16 (2H, d,
J = 8 Hz), 7.38–7.43 (5H, m, ArH), 7.63–7.65 (2H, m, ArH). 13C NMR 100 MHz
(CDCl3): d 13.74, 21.41, 22.61, 61.80, 121.26, 128.42, 128.92, 129.05, 129.14,
129.54, 134.40, 135.26, 140.63, 163.30, 165.75, 168.36, 171.94. IR (cmÀ1):
3058, 2922, 1715, 1609, 1524, 1222, 832, 687. HRMS (ESI) Calcd for
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
10.131.
References and notes
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C
21H20N2O2S (M+H) 365.12455. Found: 365.24188.
Ethyl 4-(4-methoxyphenyl)-6-methyl-2-(phenylthio)pyrimidine-5-carboxylate
(4c): White solid, mp 78–80 °C. 1H NMR 400 MHz (CDCl3): d 1.05 (3H, t,
J = 7.16 Hz, CH3), 2.40 (3H, s, CH3), 3.73 (3H, s, CH3), 4.14 (2H, q,
J = 7.16 Hz,CH2), 6.78 (2H, d, J = 8 Hz, ArH), 7.32–7.34 (3H, m, ArH), 7.41 (2H,
d, J = 8 Hz, ArH), 7.55–7.57 (2H, m, ArH). 13C NMR 100 MHz (CDCl3): d 13.83,
22.58, 29.72, 61.82, 113.84, 120.84, 128.93, 129.06, 129.52, 129.59, 130.17,
135.28, 161.49, 162.58, 165.66, 168.55, 171.80. IR (cmÀ1): 3063, 2918, 1714,
1605, 1526, 1224, 841, 687. HRMS (ESI) Calcd for
381.11946. Found: 381.17743.
C21H20N2O3S (M+H)
Ethyl
4-(3-methoxyphenyl)-6-methyl-2-(phenylthio)pyrimidine-5-carboxylate
(4d): White solid, mp 69–70 °C. 1H NMR 400 MHz (CDCl3): d 1.08 (3H, t,
J = 7.2 Hz, CH3), 2.51 (3H. s, CH3), 3.72 (3H, s, OCH3), 4.19 (2H, q, J = 7.2 Hz,
CH2), 6.93 (1H, d, J = 7.6 Hz, ArH), 7.07 (2H, d, J = 7.2 Hz, ArH), 7.23 (1H, s, ArH),
7.40 (3H, d, J = 6 Hz, ArH), 7.64 (2H, d, J = 7.6 Hz, ArH). 13C NMR 100 MHz
(CDCl3): d 13.70, 22.59, 55.28, 61.86, 113.07, 117.02, 120.72, 121.49, 128.96,
129.09, 129.34, 129,53, 135.37, 138.52, 159.64, 163.10, 165.90, 168.13, 172.11.
IR (cmÀ1): 3074, 2922, 1714, 1597, 1524, 1223, 778, 686. HRMS (ESI) Calcd for
C
20H17N3O4S (M+H) 381.11946. Found: 381.22009.
Ethyl 4-(4-chlolophenyl)-6-methyl-2-(phenylthio)pyrimidine-5-carboxylate (4e):
White Solid, mp 87–89 °C. 1H NMR 400 MHz (CDCl3): d 1.04 (3H, t, J = 7.2 Hz,
CH3), 2.43 (3H, s, CH3), 4.13 (2H, q, J = 7.48 Hz, CH2), 7.21 (2H, d, J = 6.6 Hz),
7.33–7.38 (5H, m, ArH), 7.56 (2H, d, J = 6.84 Hz, ArH). 13C NMR 100 MHz
(CDCl3): d 13.74, 22.67, 61.96, 99.99, 121.25, 128.67, 128.99, 129.22, 129.26,
129.79, 135.30, 135.72, 136.59, 162.17, 166.16, 167.94, 172.32. IR (cmÀ1):
3072, 2922, 1719, 1605, 1523, 1219, 841, 687. HRMS (ESI) Calcd for
6. (a) Rout, L.; Sen, T. K.; Punniyamurthy, T. Angew. Chem., Int. Ed. 2007, 46, 5583;
(b) Zhang, J.; Zhang, Z.; Wang, Y.; Zheng, X.; Wang, Z. Eur. J. Org. Chem. 2008,
5112; (c) Jammi, S.; Sakthivel, S.; Rout, L.; Mukherjee, T.; Mandal, S.; Mitra, R.;
Saha, P.; Punniamurthy, T. J. Org. Chem. 2009, 74, 1971; (d) Reddy, V. P.;
Swapna, K.; Kumar, A. V.; Rao, K. R. Synlett 2009, 17, 2783; (e) Schwab, R. S.;
Singh, D.; Alberto, E. E.; Piquini, P.; Rodrigues, O. E. D.; Braga, A. L. Catal. Sci.
Technol. 2011, 1, 569; (f) Harsha Vardhan, Reddy K.; Prakash, Reddy V.; Ashwan,
Kumar A.; Kranthi, G.; Nageswar, Y. V. D. Beilstein J. Org. Chem. 2011, 7, 886; (g)
Harsha Vardhan, Reddy K.; Satish, G.; Ramesh, K.; Karnakar, K.; Nageswar, Y. V.
D. Tetrahedron Lett. 2012, 53, 3061.
C
20H17ClN2O2S (M+H) 384.06993. Found: 384.17688.
Ethyl 4-(4-bromophenyl)-6-methyl-2-(phenylthio)pyrimidine-5-carboxylate (4f):
White solid, mp 82–84 °C. 1H NMR 400 MHz (CDCl3): d 1.11 (3H, t, J = 7.16 Hz,
CH3), 2.50 (3H, s, CH3), 4.20 (2H, q, J = 7.12 Hz, CH2), 7.36–7.42 (5H, m, ArH),
7.50 (2H, d, J = 8.48 Hz), 7.60 (2H, d, J = 8.68 Hz). 13C NMR 100 MHz (CDCl3): d
13.75, 22.68, 61.98, 121.23, 125, 129, 129.23, 130.01, 130.06, 131.64, 135.30,
136.19, 137.59, 162.24, 166.19, 167.91, 172.36. IR (cmÀ1): 3071, 2920, 1718,
7. Reddy, V. P.; Kumar, A. V.; Swapna, K.; Rao, K. R. Org. Lett. 2009, 11, 1697.
8. (a) Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043; (b) Kaan, H. Y. K.;
Ulaganathan, V.; Rath, O.; Prokopcova, H.; Dallinger, D.; Kappe, C. O.; Kozielski,
F. J. Med. Chem. 2010, 53, 5676.
1588, 1523, 1224, 839, 698. HRMS (ESI) Calcd for
430.01941. Found: 431.16266.
C20H17BrN2O2S (M+H)
9. Dallinger, D.; Kappe, C. O. Pure Appl. Chem. 2005, 77, 155.
Ethyl 4-(3-bromophenyl)-6-methyl-2-(phenylthio)pyrimidine-5-carboxylate (4g):
White solid, mp 88–90 °C. 1H NMR 400 MHz (CDCl3): d 1.04 (3H, t, CH3,
J = 7.16 Hz), 2.47 (3H, s, CH3), 4.14 (2H, q, CH2, J = 7.2 Hz), 7.33–7.37 (5H, m,
ArH), 7.45 (1H, d, ArH, J = 7 Hz), 7.54–7.59 (3H, m, ArH). 13C NMR 100 MHz
(CDCl3): d 13.80, 22.68, 62.00, 121.29, 122.50, 129.02, 129.25, 129.27, 129.85,
129.92, 131.59, 133.12, 135.30, 139.03, 139.18, 161.57, 161.73, 166.31, 172.42.
IR (cmÀ1): 3061, 2980, 1712, 1604, 1519, 1225, 780, 687. HRMS (ESI) Calcd for
10. (a) Atwal, K.; Rovnyak, G. C.; Schwartz, J.; Moreland, S.; Hedberg, A.;
Gougoutas, J. Z.; Malley, M. F.; Floyd, D. M. J. Med. Chem 1990, 33, 1510; (b)
Pathak, P.; Kaur, R.; Kaur, B. Arkivoc 2006, xvi, 160; (c) Singh, S.; Schober, A.;
Gebinoga, M.; Grob, G. A. Tetrahedron Lett. 2009, 50, 1838; (d) Kappe, C. O.;
Roschger, P. J. Heterocycl. Chem. 1989, 26, 55.
11. Mn(OAc)3: (a) Akhtar, M. S.; Seth, M.; Bhaduri, A. P. Indian J. Chem. 1987, 26B,
556; PhI(OAc)2: (b) Karade, N. N.; Gampawar, S. V.; Tale, N. P.; Kedar, S. B. J.
Heterocycl. Chem. 2010, 47, 740; (c) Matloobi, M.; Kappe, C. O. J. Comb. Chem.
2007, 9, 275.
C
20H17BrN2O2S (M+H) 428.01941. Found: 429.11279.
Ethyl 4-methyl-6-(3-nitrophenyl)-2-(phenylthio)pyrimidine-5-carboxylate (4h):
White Solid, mp 98–99 °C. 1H NMR 400 MHz (CDCl3): d 1.17 (3H, t, J = 7.2 Hz,
Please cite this article in press as: Bhong, B. Y.; et al. Tetrahedron Lett. (2012), http://dx.doi.org/10.1016/j.tetlet.2012.10.131

B. Y. Bhong et al. / Tetrahedron Letters xxx (2012) xxx–xxx
5
CH3), 2.55 (3H, s, CH3), 4.26 (2H, q, J = 7.6 Hz, CH2), 7.44 (3H, d, J = 6.4 Hz, ArH),
1578, 1519, 1225, 842, 688. HRMS (ESI) Calcd for
355.05936. Found: 355.28076.
C
19H15ClN2OS (M+H)
7.54 (1H, t, J = 8 Hz, ArH), 7.65 (2H, d, J = 7.2 Hz, ArH), 7.84 (1H, d, J = 7.6 Hz,
ArH), 8.27 (1H, d, J = 7.6 Hz, ArH), 8.41 (1H, s, ArH). 13C NMR 100 MHz (CDCl3):
d 13.77, 22.81, 62.24, 121.35, 123.73, 124.81, 128.91, 129.15, 129.44, 129.49,
134.21, 135.32, 138.82, 148.23, 160.66, 166.71, 167.43, 172.89. IR (cmÀ1):3080,
2923, 1724, 1598, 1519, 1218, 772, 688. HRMS (ESI) Calcd for C20H17N3O4S
(M+H) 396.0933. Found: 396.10890.
1-(4-methyl-2-(phenylthio)-6-p-tolylpyrimidin-5-yl)ethanone (4i): White solid,
mp 114–116 °C. 1H NMR 400 MHz (CDCl3): d 2.03 (3H, s, CH3), 2.36 (3H, s, CH3),
2.41 (3H, s, CH3), 7.19 (2H, d, J = 7.6 Hz, ArH), 7.38–7.42 (5H, m, ArH), 7.64–7.66
(2H, m, ArH). 13C NMR 100 MHz (CDCl3): d 21.44, 22.49, 32.06, 128.72, 128.93,
129.06, 129.50, 129.59, 134.20, 135.26, 141.22, 162.21, 164.59, 171.51, 204.55.
IR (cmÀ1): 3032, 2919, 1696, 1607, 1518, 1206, 833, 689. HRMS (ESI) Calcd for
Ethyl 2-(4-chlorophenylthio)-4-methyl-6-phenylpyrimidine-5-carboxylate (4m):
Yellow solid, mp 42–44 °C. 1H NMR 400 MHz (CDCl3): d 1.04 (3H, t, J = 7.2 Hz,
CH3), 2.50 (3H, s, CH3), 4.17 (2H, q, J = 7.2 Hz, CH2), 7.35–7.44 (5H, m, ArH), 7.52
(2H, d, J = 6.8 Hz, ArH), 7.57 (2H, d, J = 8 Hz, ArH). 13C NMR 100 MHz (CDCl3): d
13.64, 22.63, 61.85, 121.76, 127.98, 128.36, 128.48, 129.16, 130.30, 135.38,
136.48, 137.24, 163.70, 166.08, 167.98, 171.46. IR (cmÀ1): 3062, 2923, 1719,
1601, 1524, 1215, 817, 694. HRMS (ESI) Calcd for C20H17ClN2O2S (M+H)
385.06993. Found: 385.17963.
Ethyl 2-(4-bromophenylthio)-4-methyl-6-p-tolylpyrimidin-5-carboxylate (4n):
Yellow solid, mp 74–76 °C. 1H NMR 400 MHz (CDCl3):
d 1.09 (3H, t,
J = 7.2 Hz, CH3), 2.36 (3H, s, CH3), 2.49 (3H, s, CH3), 4.20 (2H, q, J = 7.2 Hz,
CH2), 7.19 (2H, d, J = 7.6 Hz, ArH), 7.43 (2H, d, J = 8.4 Hz, ArH), 7.51 (4H, d,
J = 7.2 Hz, ArH). 13C NMR 100 MHz (CDCl3): d 13.75, 21.43, 22.60, 61.85, 121.55,
123.57, 128.38, 128.75, 129.23, 132.07, 134.29, 136.69, 138.02, 140.75, 163.46,
165.88, 168.19, 171.15. IR (cmÀ1): 3011, 2921, 1713, 1609, 1507, 1218, 813,
688. HRMS (ESI) Calcd for C21H19BrN2O2S (M+H) 443.03506. Found: 443.13110.
Ethyl 2-(4-bromophenyl)-4-(4-chlorophenyl)-6-methylpyrimidine-5-carboxylate
(4o): White solid, mp 102–104 °C. 1H NMR 400 MHz (CDCl3): d 1.11 (3H, t,
J = 7.12 Hz, CH3), 2.50 (3H, s, CH3), 4.20 (2H, q, J = 7.08 Hz, CH2), 7.34–7.37 (2H,
m, ArH), 7.44–7.50 (4H, m, ArH), 7.52–7.55 (2H, m, ArH). 13C NMR 100 MHz
(CDCl3): d 13.73, 22.64, 61.99, 121.59, 123.76, 128.47, 128.76, 129.74, 132.15,
135.61, 136.71, 138.11, 162.34, 166.28, 167.76, 171.52. IR (cmÀ1): 3074, 2984,
2925, 1730, 1593, 1524,1214, 816, 659, 840. HRMS (ESI) Calcd for
C20H18N2OS (M+H) 335.11398. Found: 335.26208.
1-(4-(3-methoxyphenyl)-6-methyl-2-(phenylthio)pyrimidin-5-yl) ethanone (4j):
White solid, mp 62–63 °C. 1H NMR 400 MHz (CDCl3): d 2.05 (3H, s, CH3),
2.42 (3H, s. CH3), 3.74 (3H, s, CH3), 6.97–7.07 (3H, m, ArH), 7.21–7.29 (2H, m,
ArH), 7.42 (2H, d, J = 6 Hz, ArH), 7.53 (1H, d, J = 6.8 Hz, ArH), 7.67 (1H, d,
J = 7.6 Hz, ArH). 13C NMR 100 MHz (CDCl3): d 21.36, 29.72, 55.3, 117.60, 121.56,
121.58, 125.91, 128.75, 128.86, 128.96, 129.11, 129.46, 135.36, 135.39, 161.90,
164.68, 164.75, 171.68, 204.35. IR (cmÀ1): 3056, 2924, 1693, 1598, 1518, 1202,
774, 688. HRMS (ESI) Calcd for
351.21466.
C20H18N2O2S (M+H) 351.10890. Found:
1-(4-(4-chlorophenyl)-6-methyl-2-(phenylthio)pyrimidin-5-yl) ethanone (4k):
White solid, mp 95–96 °C. 1H NMR 400 MHz (CDCl3): d 1.13 (3H, s, CH3),
2.50 (3H, s, CH3), 7.34 (2H, d, J = 8.5 Hz, ArH), 7.41–7.46 (5H, m, ArH), 7.63 (2H,
d, J = 6.52 Hz, ArH). 13C NMR 100 MHz (CDCl3): d 22.66, 29.72, 121.26, 128.67,
128.98, 129.21, 129.79, 135.29, 135.73, 136.59, 162.16, 166.15, 167.93, 172.32,
199.87. IR (cmÀ1): 3059, 2922, 1708, 1579, 1475, 1237, 830, 685. HRMS (ESI)
Calcd for C19H15ClN2OS (M+H) 355.05936. Found: 355.26031.
C
20H16BrClN2O2S (M+H) 464.77524. Found: 465.12543.
Ethyl 4-methyl-6-(3-nitrophenyl)-2-(p-tolylthio)pyrimidine-5-carboxylate (4p):
Yellow solid, mp 82–84 °C. 1H NMR 400 MHz (CDCl3):
1.08 (3H, t,
d
J = 7.2 Hz), 2.33 (3H, s, CH3), 2.47 (3H, s, CH3), 4.18 (2H, q, J = 7.2 Hz, CH3),
7.18 (2H, d, J = 7.16 Hz, ArH), 7.43–7.52 (3H, m, ArH), 7.75 (2H, d, J = 6.28 Hz,
ArH), 8.21 (2H, d, J = 6 Hz, ArH), 8.33 (1H, s, ArH). 13C NMR 100 MHz (CDCl3): d
12.72, 20.36, 21.77, 61.16, 120.17, 122.78, 123.75, 124.31, 128.34, 128.93,
133.14, 134.21, 137.87, 138.76, 140.44, 147.24, 159.55, 165.60, 172.23. IR
(cmÀ1): 3057, 2922,2852, 1703, 1565, 1515, 1217, 690, 805. HRMS (ESI) CalCd
for C21H19N3O4S (M+H) 410.10963. Found: 410.19470.
1-(2-(4-chlorophenylthio)-4-methyl-6-phenylpyrimidin-5-yl)ethanone
(4l):
White solid, mp 92–94 °C. 1H NMR 400 MHz (CDCl3): d 2.02 (3H, s, CH3),
2.42 (3H, s, CH3), 7.38–7.51 (7H, m, ArH), 7.58 (2H, d, J = 6.8 Hz, ArH). 13C NMR
100 MHz (CDCl3):
d 22.51, 32.04, 127.92, 128.94, 129.01, 129.17, 130.83,
135.41, 136.92, 162.39, 164.87, 171.04, 204.23. IR (cmÀ1): 3057, 2923, 1696,
Please cite this article in press as: Bhong, B. Y.; et al. Tetrahedron Lett. (2012), http://dx.doi.org/10.1016/j.tetlet.2012.10.131