Oxidation of 3,4-dihydropyrimidin-2(1H)-thione using (diacetoxyiodo) benzene: Unprecedented formation of substituted 2-(1,4-dihydropyrimidin-2- ylthio)pyrimidine

Article abstract of DOI:10.1016/j.tetlet.2013.01.099

4-Aryl-6-methyl-3,4-dihydropyrimidin-2(1H)-thione scaffolds of Biginelli type were oxidized using (diacetoxyiodo)benzene and the reaction afforded 2-(1,4-dihydropyrimidin-2-ylthio)pyrimidine derivatives through an unprecedented oxidation-desulfurization p

Full text of DOI:10.1016/j.tetlet.2013.01.099

Tetrahedron Letters 54 (2013) 1862–1865
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Oxidation of 3,4-dihydropyrimidin-2(1H)-thione using (diacetoxyiodo)
benzene: unprecedented formation of substituted
2-(1,4-dihydropyrimidin-2-ylthio)pyrimidine
⇑
Bhagyashree Y. Bhong, Prerana B. Thorat, 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:
4-Aryl-6-methyl-3,4-dihydropyrimidin-2(1H)-thione scaffolds of Biginelli type were oxidized using
(diacetoxyiodo)benzene and the reaction afforded 2-(1,4-dihydropyrimidin-2-ylthio)pyrimidine deriva-
tives through an unprecedented oxidation–desulfurization process.
Received 29 November 2012
Revised 22 January 2013
Accepted 24 January 2013
Available online 30 January 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Biginelli reaction
3,4-Dihydropyrimidin-2(1H)-thione
Oxidation
Hypervalent iodine
Desulfurization
Recent decades have witnessed an exponential growth in the
applications of hypervalent iodine reagents for carrying out a num-
ber of oxidative transformations.1 These reagents are commercially
available, mild, highly selective and resemble in reactivity with
heavy metal reagents without the toxicity and environmental
issues.2 Currently, both iodine(III) and iodine(V) reagents are
widely used in organic synthesis.3 (Diacetoxyiodo)benzene (DIB)
is one of the most extensively used parent hypervalent iodine(III)
reagent and its reactions with various nitrogen, sulfur and oxygen
nucleophilic compounds are known.4 In particular, the reactions of
DIB with nucleophilic sulfur compounds such as thiols,5 thioam-
ides,6 thioureas,7 sulfides,8 and ammonium thiocyanate9 have re-
sulted in useful functional group interconversions as well as in
the formation of heterocycles.
Recently, it has been revealed by Singh et al. that the acyclic
1,3-disubstituted thiourea undergoes desulfurization reaction with
DIB leading to the formation of N-acylated ureas via carbodiimide
intermediate.7a The 3,4-dihydropyrimidin-2(1H)-thione, which can
be easily obtained by Biginelli reaction,10 is a structural analog of
cyclic thiourea and therefore, we were interested to find out the
fate of this compound in the oxidation reaction using hypervalent
iodine reagents. Owing to the simplicity of an original three-
component Biginelli reaction, the direct oxidative dehydrogenation
of 3,4-dihydropyrimidin-2(1H)-one or 3,4-dihydropyrimidin-
2(1H)-thione has been long desired for the formation of aroma-
tized pyrimidine which is a common structural motif found in
many biologically active compounds.11 However, there are a few
literature reports mainly constrained to the oxidative aromatiza-
tion of 3,4-dihydropyrimidin-2(1H)-one to form pyrimidine under
different reaction conditions.12 In contrast to 3,4-dihydropyrimi-
din-2(1H)-one, there is a great synthetic challenge for oxidative
dehydrogenation of 3,4-dihydropyrimidine-2(1H)-thione to form
pyrimidine because the sulfur functional unit is susceptible for
oxidative dimerization and may act as a poison for metal-based
catalysts.13 The reaction of 3,4-dihydropyrimidine-2(1H)-thione
with alkyl halide followed by oxidative aromatization is one of
the most common two-step strategy for the synthesis of highly
substituted pyrimidine derivatives (Scheme 1).14 In another litera-
ture report, an attempt has been made to oxidize 3,4-dihydropy-
rimidine-2(1H)-thione using oxone on wet alumina or hydrogen
peroxide in the presence of catalytic amount of vanadyl sulfate
to provide desulfurated 1,4-dihydropyrimidine, which was further
oxidized to 2-unsubstituted pyrimidines by treatment with excess
KMnO4.15 Recently, a successful oxidative transformation of 3,4-
dihydropyrimidine-2(1H)-thione to symmetrical bis(2-pyrimidyl)
disulfides have been achieved by using 100 wt % of activated
carbon.16 Thus, there are very few reports available on the oxida-
tion reactions of 3,4-dihydropyrimidine-2(1H)-thione. Herein, we
wish to investigate the oxidation reactions of 3,4-dihydropyrimi-
dine-2(1H)-thione using hypervalent iodine(III) reagent. We
envisaged that the strong electrophilic nature of the hypervalent
iodine in combination with the super leaving group ability of
⇑
Corresponding author.
E-mail addresses: nnkarade@gmail.com, nandkishorkarade@gmail.com (N.N.
Karade).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.099

B. Y. Bhong et al. / Tetrahedron Letters 54 (2013) 1862–1865
1863
R
N
O
N
R1
R
O
N
S
S
R1
N
air
100 wt% activated carbon
xylene, 140 °C
40-67 h, reflux
ref. 16
ref. 15
30% H2O2 (3.7 equiv),
VOSO4 xH2O (0.002 equiv),
H2O-EtOH, 50 °C, 8-12 h
O
R
O
R
O
R
N
R
O
.
Present work
PhI(OAc)2
R1
NH
R1
N
R1
N
N
R1
or
AcOH, rt
N
H
S
N
H
S
N
H
Oxone (3.2-3.7 equiv),
wet Al2O3
CHCl3, r. t., 5-8 h
KMnO4
acetone
r. t., 2 h
RX, base
R = alkyl
CAN or
O
Ar
N
O
Ar
Mn(OAc)3 or
PhI(OAc)2
O
R
N
EtO
N
EtO
N
R1
N
[O]
ref. 14
SR
N
SR
H
Scheme 1. Literature methods for the oxidation reactions of 3,4-dihydropyrimidine-2(1H)-thione.
phenyliodonium group can induce either oxidative dehydrogena-
tion or the oxidative dimerization of 3,4-dihydropyrimidine-
2(1H)-thione. However, the reaction of DIB with 3,4-dihydropy-
rimidine-2(1H)-thione resulted in the unusual formation of
substituted 2-(1,4-dihydropyrimidin-2-ylthio)pyrimidine through
oxidation–desulfurization process (Scheme 1). The product of
these reactions are derivatives of 2-(1,4-dihydropyrimidin-2-
ylthio)pyrimidine which can be regarded as the highly decorated
1,4-dihydropyrimidine type scaffolds at 2-position. It is important
to note that these 1,4-dihydropyrimidine and Hantzsch’s 1,4-dihy-
dropyridine are considered as the potent mimics of calcium
channel modulators of the nifedipine type drugs with a similar
pharmacological profile.17
The 4-phenyl-6-methyl-3,4-dihydropyrimidine-2(1H)-thione
1a (Table 1) was chosen as a model substrate for the oxidation
reaction using (diacetoxyiodo)benzene as the oxidant. The reaction
of 1a with DIB (1.2 equiv) in various solvents such as methanol,
acetone, acetonitrile, and dichloromethane was carried out. The
progress of the reactions, as monitored by the TLC, indicated that
the reaction did not proceed in these solvents and the starting
material was found to be almost unreacted. This may be partly
attributed to the insolubility of 1a in methanol, acetone, acetoni-
trile, and dichloromethane. The complete solubility of 1a in acetic
acid encouraged us to carry out its reaction with DIB (1.2 equiv)
and indeed, the formation of unusual product 2a through oxida-
tion–desulfuration process was observed in 84% yield in 6 h.18
The 1H NMR analysis of 2a indicated the presence of two distinct
ethyl ester groups giving triplets and quartets at d 3.99, 4.06, and
1.08, 1.15 ppm, respectively which is reminiscent of unsymmetri-
cal structure of the product 2a.19 Further, two singlets were ob-
served at d 5.34 and 6.20 due to the presence of C-4 and NH
protons. The LCMS of 2a corresponds to the m/z = 517 (M+H)+
which clearly confirms the unexpected removal of one sulfur atom.
The plausible mechanism for the formation of unusual oxida-
tion–desulfurization product 2 is shown in Scheme 2. DIB 3 may
undergo ligand association–dissociation process with nucleophilic
sulfur of 3,4-dihydropyrimidine-2(1H)-thione 1 to form 4. The ten-
dency of hypervalent iodine for reductive elimination of iodoben-
zene from 4 results in the formation of 5 which tautomerizes to
form 6. Again, the reaction of DIB 3 with 6 leads to form the key
intermediate 7. The susceptibility of pyrimidine 7 for nucleophilic
substitution at 2-position in combination with its tendency for
facile reductive elimination of iodobenzene may promote the
removal of elemental sulfur with the concomitant nucleophilic at-
tack of another molecule of 1 to form 2. There is a literature refer-
ence for the removal of sulfur from acyclic thiourea type substrate
to form either a carbodiimide or guanidine derivatives.7
The generality and scope of this oxidation–desulfurization pro-
cess was investigated by using diverse 4-aryl substituted 3,4-dihy-
dropyrimidine-2(1H)-thiones. As shown in Table 1, the presence of
electron-donating and withdrawing substituents at C-4 aryl group
of 3,4-dihydropyrimidin-2(1H)-thiones has little influence on the
yields of oxidation–desulfurization products. In all the cases, good
to excellent yields of the products were observed.
In conclusion, we have investigated the transition metal-free
oxidation reaction of 4-aryl-6-methyl-3,4-dihydropyrimidin-
2(1H)-thione scaffolds of Biginelli type using (diacetoxyiodo)
benzene under mild conditions to form structurally diverse
2-(1,4-dihydropyrimidin-2-ylthio)pyrimidine derivatives. The
product of this reaction is unusual due to the removal of one sulfur
Table 1
Oxidation of 3,4-dihydropyrimidine-2(1H)-thione with (diacetoxyiodo)benzene
O
Ar
O
Ar
Ar
O
PhI(OAc)2 (1.2 equiv)
AcOH, rt, 6 h
S
EtO
NH
EtO
N
N
OEt
N
H
N
S
N
H
2 (a-j)
1 (a-j)
Entry
Substrate 1
Ar
Product 2
Yielda (%)
a
b
c
d
e
f
h
i
k
l
1a
1b
1c
1d
1e
1f
1g
1h
1i
C6H5
2a
2b
2c
2d
2e
2f
2g
2h
2i
86
83
65
74
76
73
77
82
71
79
4-MeC6H4
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
3,4-(MeO)2C6H3
2-ClC6H4
4-ClC6H4
3-BrC6H4
4-BrC6H4
1j
2j
a
Isolated yields after silica gel column chromatography.

1864
B. Y. Bhong et al. / Tetrahedron Letters 54 (2013) 1862–1865
O
R
O
R
O
R
O
H
R
-AcOH
-PhI
H
S
R1
N
R1
N
R1
N
Ph
I
-AcOH
R1
N
OAc
OAc
Ph
O
I
N
6
SH
N
H
N
H
5
S
N
S
4
OAc
H
3
1
R
O
R
N
N
O
R
N
R
O
-AcOH
-PhI
-S
H
S
N
R1
R1
R1
N
N
R1
PhI(OAc)2
-AcOH
OAc
Ph
N
H
1
S
I
S
N
H
7
2
Scheme 2. Plausible mechanism for oxidation–desulfurization process.
14. Mn(OAc)3: (a) Akhtar, M. S.; Seth, M.; Bhaduri, A. P. Ind. 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; MnO2 and then oxone: (c) Matloobi, M.; Kappe,
C. O. J. Comb. Chem. 2007, 9, 285.
atom in the oxidative dimerization process of 3,4-dihydropyrimi-
dine-2(1H)-thione.
15. Kim, S. S.; Choi, B. S.; Lee, J. H.; Lee, K. K.; Lee, T. H.; Kim, Y. H.; Shin, H. Synlett
2009, 599.
Acknowledgments
16. Hayashi, M.; Okunaga, K.-I.; Nishida, S.; Kawamura, K.; Eda, K. Tetrahedron Lett.
2010, 51, 6734.
17. Atwal, K. S.; Rovnyak, G. C.; Schwartz, J.; Moreland, S.; Hedberg, A.; Gougoutas,
J. Z.; Malley, M. F.; Floyd, D. M. J. Med. Chem. 1990, 33, 1510.
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
University, Chandigarh, India, for recording the NMR spectra.
18. Representative procedure for the preparation of 2-(1,4-dihydropyrimidin-2-
ylthio)pyrimidine derivatives: DIB (0.386 g, 1.2 mmol) was added to a solution
of 1a (0.276 g, 1 mmol) in acetic acid (10 mL) and the reaction mixture was
stirred at rt for 6 h. The progress of the reaction was monitored by TLC. After
completion of reaction, water (10 mL) was added and the mixture was
extracted with ethyl acetate (3 Â 10 mL). Organic layers were combined, dried
over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was
purified by column chromatography on silica gel using petroleum ether/EtOAc
9:1 as eluent to give the desired product 2a (0.887 g, 86%) as yellow solid in
excellent purity.
Supplementary data
Supplementary data (copies of NMR (1H and 13C) NMR spectra
and LCMS are provided for all the compounds synthesized) associ-
ated with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2013.01.099.
19. Characterization data new compounds:
Compound 2a: Yellow solid, mp 162–163 °C. 1H NMR 400 MHz (CDCl3): d 1.08
(3H, t, J = 7.1 Hz, CH3), 1.15 (3H, t, J = 7.1 Hz, CH3), 2.39 (3H, s, CH3), 2.42 (3H, s,
CH3), 3.99 (2H, q, J = 7.1 Hz, CH2), 4.06 (2H, q, J = 7.1 Hz, CH2), 5.46 (1H, s, CH),
6.20 (1H, s, NH), 7.29–7.33 (8H, m, ArH), 7.45–7.48 (2H, m, ArH). 13C NMR
100 MHz (CDCl3): d 14.07, 14.09, 22.85, 23.25, 56.11, 59.68, 60.30, 102.71,
106.43, 127.10, 127.43, 128.09, 128.28, 128.44, 128.67, 128.92, 129.15, 139.61,
140.06, 148, 97, 153.37, 156.32, 158.52, 165.49, 165.79. IR (cmÀ1): 2976, 1707,
1606, 1504, 1230, 810, 686. MS (ESI) m/z (M+H)+ Calculated for C28H28N4O4S:
516.18. Found: 517.10.
References and notes
1. For selected reviews, see: (a) Stang, P. J.; Zhdankin, V. V. Chem. Rev. 1996, 96,
1123; (b) Grushin, V. V. Chem. Soc. Rev. 2000, 29, 315; (c) Zhdankin, V. V.; Stang,
P. J. Chem. Rev. 2002, 102, 2523; (d) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008,
108, 5299.
2. (a) Wirth, T. Angew. Chem., Int. Ed. 2005, 44, 3656; (b) Moriarty, R. M. J. Org.
Chem. 2005, 70, 2893.
3. (a) Zhdankin, V. V. J. Org. Chem. 2011, 76, 1185; (b) Stang, P. J. J. Org. Chem. 2003,
68, 2997.
4. Varvoglis, A. Hypervalent Iodine in Organic Synthesis; Academic Press: London,
1997. Chapter 3.
5. Kita, Y.; Okuno, T.; Tohma, H.; Akai, S.; Matsumoto, K. Tetrahedron Lett. 1994,
35, 2717.
6. (a) Patil, P. C.; Bhalerao, D. S.; Dangate, P. S.; Akamanchi, K. G. Tetrahedron Lett.
2009, 50, 5820; (b) Yan, M.; Chen, Z.-C.; Zheng, Q.-G. J. Chem. Res. (S) 2003, 618;
(c) Cheng, D.-P.; Chen, Z.-C. Synth. Commun. 2002, 32, 2155.
7. (a) Singh, C. B.; Ghosh, H.; Murru, S.; Patel, B. K. J. Org. Chem. 2008, 73, 2924; (b)
Chaudhari, P. S.; Dangate, P. S.; Akamanchi, K. G. Synlett 2010, 3065; (c)
Dangate, P. S.; Akamanchi, K. G. Tetrahedron Lett. 2012, 53, 6765; (d) Chaudhari,
P. S.; Pathare, S. P.; Akamanchi, K. G. J. Org. Chem. 2012, 77, 3716.
8. (a) Tohma, H.; Takizawa, S.; Watanabe, H.; Kita, Y. Tetrahedron Lett. 1998, 39,
4547; (b) Ozanne-Beaudenon, A.; Quideau, S. Tetrahedron Lett. 2006, 47, 5869.
9. (a) Kita, Y.; Takeda, Y.; Okuno, T.; Egi, M.; Iio, K.; Kawaguchi, K.-I.; Akai, S. Chem.
Pharm. Bull. 1887, 1997, 45; (b) Prakash, O.; Kaur, H.; Pundeer, R.; Dhillon, R. S.;
Singh, S. P. Synth. Commun. 2003, 33, 4037; (d) Mico, A. D.; Margarita, R.;
Mariani, A.; Piancatelli, G. Tetrahedron Lett. 1889, 1996, 37.
Compound 2b: Yellow solid, mp 130–132 °C. 1H NMR 400 MHz (CDCl3): d 1.14
(3H, t, J = 7.1 Hz, CH3), 1.22 (3H, t, J = 7.1 Hz, CH3), 2.25 (3H, s, CH3), 2.38 (6H, s,
CH3), 2.42 (3H, s, CH3), 4.03 (2H, q, J = 7.1 Hz, CH2), 4.12 (2H, q, J = 7.1 Hz, CH2),
5.34(1H, s, CH), 6.20(1H, s, NH), 6.68 (2H, d, J = 8.1 Hz, ArH), 6.82 (2H, d,
J = 7.8 Hz, ArH), 7.12 (2H, d, J = 7.9 Hz, ArH), 7.30 (2H, d, J = 8.1 Hz, ArH). 13C
NMR 100 MHz (CDCl3): d 14.16, 21.22, 21.28, 22.84, 23.14, 55.58, 59.90, 59.97,
60.36, 104.18, 106.50, 127.07, 129.28, 136.24, 137.67, 138.27, 138.64, 150.91,
153.70, 155.56, 158.45, 165.70, 165.96. IR (cmÀ1): 2977, 1699, 1615, 1507,
1237, 820, 698. MS (ESI) m/z (M+H)+ Calcd C30H32N4O4S: 544.21. Found:
545.10.
Compound 2c: Yellow solid, mp 149–150 °C. 1H NMR 400 MHz (CDCl3): d 1.04
(3H, t, J = 7 Hz, CH3), 1.20 (3H, t, J = 7.1 Hz, CH3), 2.32 (6H, s, CH3), 3.34 (2H, s),
3.65 (2H, s), 3.82 (1H, s), 3.89 (1H, s), 3.96 (2H, q, J = 7.1 Hz, CH2), 4.03 (2H, q,
J = 7.1 Hz, CH2), 5.89 (1H, s, CH), 6.30 (1H, s, NH), 6.64 (1H, d, J = 8.1 Hz, ArH),
6.79 (1H, d, J = 8.2 Hz, ArH), 6.84 (1H, d, J = 6.7 Hz, ArH), 6.85–6.94 (2H, m,
ArH), 7.17–7.25 (2H, m, ArH), 7.27 (1H, d, J = 7.6 Hz, ArH). 13C NMR 100 MHz
(CDCl3): d 14.12, 14.18, 22.92, 23.07, 55.35, 59.99, 60.05, 101.94, 110.86,
110.95, 119.47, 119.68, 121.11, 121.33, 126.79, 129.28, 130.36, 157.63, 158.01,
159.22, 159.58, 165.97, 166.02, 166.10, 166.18. IR (cmÀ1): 2982, 1694, 1610,
1504, 1230, 743, 691. MS (ESI) m/z (M+H)+ Calcd C30H32N4O6S: 576.20. Found:
577.00
Compound 2d: Yellow solid, mp 104–105 °C. 1H NMR 400 MHz (CDCl3): d 1.15
(3H, t, J = 7.2 Hz, CH3), 1.21 (3H, t, J = 7.1 Hz, CH3), 2.40 (6H, s, CH3), 3.55 (3H, s,
CH3), 3.75 (3H, s, CH3), 4.06 (2H, q, J = 7 Hz, CH2), 4.14 (2H, q, J = 7.2 Hz, CH2),
5.39 (1H, s, CH), 6.24 (1H, s, NH), 6.39 (1H, d, J = 6.7 Hz, ArH), 6.51 (1H, t,
J = 6.7 Hz, ArH), 6.73 (1H, d, J = 8.1 Hz, ArH), 6.85 (1H, d, J = 8.2 Hz, ArH), 6.94–
6.98 (2H, m, ArH), 7.01(1H, t, J = 6.7 Hz), 7.20 (1H, t, J = 7.9 Hz, ArH). 13C NMR
100 MHz (CDCl3): d 14.16, 14.17, 22.92, 23.24, 54.98, 55.13, 55.67, 60.37,
103.67, 106.14, 112.54, 113.36, 114.39, 114.51, 119.23, 120.10, 129.40, 129.84,
140.65, 141.95, 150.48, 158.07, 159.40, 159.69, 165.63, 165.85. IR (cmÀ1):
2980, 1703, 1600, 1511, 1226, 779, 698. MS (ESI) m/z (M+H)+ Calcd
10. Reviews: (a) Kappe, C. O. Tetrahedron 1993, 49, 6937; (b) Kappe, C. O. Acc. Chem.
Res. 2000, 33, 879; (c) Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043.
11. (a) Brown, D. J. The Pyrimidines. In Chemistry of Heterocyclic Compdounds;
Wiley: New York, NY, 1994; (b) Majumdar, K. C.; Das, U.; Jana, N. K. J. Org.
Chem. 1998, 63, 3550. and more references therein; (c) Rizzo, R. C.; Tirado-
Rives, J.; Jorgensen, W. L. J. Med. Chem. 2001, 44, 145; (d) Chen, C.; Wilcoxen, K.
M.; Huang, C. Q.; Xie, Y.-F.; McCarthy, J. R.; Webb, T. R.; Zhu, Y.-F.; Saunders, J.;
Liu, X.-J.; Chen, T.-K.; Bozigian, H.; Grigoriadis, D. E. J. Med. Chem. 2004, 47,
4787.
12. The oxidative aromatization of 3,4-dihydropyrimidine-2(1H)-one is reported
by using HNO3, DDQ, Pd/C, TBHP/CuCl2, CAN/NaHCO3, Co(NO3)2/K2S2O8,
K2S2O8/ultrasound, TBHP/PhI(OAc)2, PCC, NaNO2, Ca(OCl)2, rhenium(I)
complexes/photochemical conditions and N-hydroxyphthalimide (NHPI)/
Co(OAc)2/O2. Review: Suresh; Sandhu, J. S. ARKIVOC 2012, i, 66–133 and the
references cited therein.
C
30H32N4O6S: 576.2; Found: 577
Compound 2e: Yellow solid, mp 154–156 °C. 1H NMR 400 MHz (CDCl3): d 1.14
(3H, t, J = 7.1 Hz, CH3), 1.21(3H, t, J = 7.1 Hz, CH3), 2.39 (1H, s, CH3), 2.43 (1H, s,
CH3), 3.73 (1H, s, CH3), 3.83 (1H, s, OCH3), 4.04 (2H, q, J = 7.1 Hz, CH2), 4.11 (2H,
q, J = 7 Hz, CH2), 5.31 (1H, s, CH), 6.18 (1H, s, NH), 6.54 (2H, d, J = 6.7 Hz, ArH),
6.71 (2H, d, J = 6.7 Hz, ArH), 6.84 (2H, d, J = 6.8 Hz, ArH), 7.34 (2H, d, J = 6.8,
13. Kondo, T.; Mitsudo, T.-A. Chem. Rev. 2000, 100, 3205.

B. Y. Bhong et al. / Tetrahedron Letters 54 (2013) 1862–1865
1865
ArH). 13C NMR 100 MHz (CDCl3): d 14 .17, 22.83, 23.10, 55.09, 55.25, 55.29,
59.67, 59.97, 60.34, 104.40, 106.52, 113.54, 113.89, 128.47, 129.51, 131.35,
132.92, 150.99, 153.74, 155.38, 158.37, 159.71, 159.77, 165.70, 165.97. IR
(cmÀ1): 2977, 1704, 1605, 1504, 1240, 830, 700. MS (ESI) m/z (M+H)+ Calcd
CH3), 4.02 (2H, q, J = 7 Hz, CH2), 4.08 (2H, q, J = 7.2 Hz, CH2), 5.45 (1H, s, CH),
6.16 (1H, s, NH), 7.23–7.33 (6H, m, ArH), 7.38–7.41 (2H, m, ArH). 13C NMR
100 MHz (CDCl3): d 14.13, 14.09, 22.85, 23.25, 56.11, 59.68, 59.92, 60.01, 60.30,
102.71, 106.43, 127.10, 127.43, 128.09, 128.44, 128.75, 128.92, 129.15, 139.61,
140.06, 153.37, 156.32, 158.52, 165.49, 165.79. IR (cmÀ1): 2980, 1707, 1606,
1504, 1230, 810, 686. MS (ESI) m/z (M+H)+ Calcd C28H26Cl2N4O4S: 584.11.
Found: 584.95.
C
30H32N4O6S: 576.20. Found: 577.05
Compound 2f: Yellow solid, mp 135–136 °C. 1H NMR 400 MHz (CDCl3): d 1.16
(3H, t, J = 7.1 Hz, CH3), 1.20 (3H, t, J = 7.1 Hz, CH3), 2.43 (3H, s, CH3), 2.45 (3H, s,
CH3), 3.46 (3H, s, OCH3), 3.81 (6H, s, OCH3), 3.87 (3H, s, CH3), 4.09 (4H, q,
J = 7.2 Hz, CH2), 5.37 (1H, s, CH), 6.21 (1H, s, NH), 6.40–6.45 (2H, d, J = 7.2 Hz,
ArH), 6.54 (1H, d, J = 8.1 Hz, ArH), 6.77 (1H, d, J = 8.3 Hz), 6.91 (2H, m, ArH),
7.12 (1H, t, J = 8.2 Hz, ArH). 13C NMR 100 MHz (CDCl3): d 14.21, 22.90, 23.19,
55.38, 55.49, 55.73, 55.78, 59.91, 60.03, 60.38, 103.89, 106.14, 109.83, 110.61,
110.64, 111.80, 119.70, 120.41, 131.76, 133.22, 148.35, 149.07, 149.10, 149.39,
150.44, 155.37, 165.71, 165.97. IR (cmÀ1): 2915, 1698, 1620, 1510, 1229, 853,
766, 686. MS (ESI) m/z (M+H)+ Calcd C32H36N4O8S: 636.23. Found: 637.10
Compound 2g: Yellow solid, mp 138–140 °C. 1H NMR 400 MHz (CDCl3): d 1.05
(3H, t, J = 7.1 Hz, CH3), 1.20 (3H, t, J = 7 Hz, CH3), 2.38 (3H, s, CH3), 3.96 (2H, q,
J = 7.2 Hz, CH2), 4.09 (2H, q, J = 6.9 Hz, CH2), 5.98 (1H, s, CH), 6.55 (1H, s, NH),
6.83 (1H, q, J = 7.5 Hz, ArH), 7.19 (1H,d, J = 8.2 Hz, ArH), 7.20–7.33 (5H, m, ArH),
7.33–7.46 (1H, m, ArH). 13C NMR 100 MHz (CDCl3): d 14.00, 14.22, 22.56, 22.99,
53.73, 60.01, 60.42, 102.03, 127.17, 127.98, 128.25, 129.39, 129.71, 130.45,
130.62, 132.78, 136.68, 150.49, 153.30, 157.05, 158.62, 165.35, 165.50. IR
(cmÀ1): 2978, 1702, 1608, 1511, 1206, 780, 689.MS (ESI) m/z (M+H)+ Calcd
Compound 2i: Yellow solid, mp 133–134 °C. 1H NMR 400 MHz (CDCl3): d 1.12
(3H, t, J = 7.1 Hz, CH3), 1.18 (3H, t, J = 7.1 Hz, ArH), 2.40 (3H, s, CH3), 2.44 (3H, s,
CH3), 4.04 (2H, q, J = 7 Hz, CH2), 4.11 (2H, q, J = 7.4 Hz, CH2), 5.45 (1H, s, CH),
6.17 (1H, s, NH), 7.17–7.26 (3H, m, ArH), 7.37–7.47 (4H, m, ArH), 7.65 (1H, t,
J = 7.4 Hz, ArH). 13C NMR 100 MHz (CDCl3): d 14.11, 14.15, 22.96, 23.28, 55.70,
60.16, 60.50, 102.37, 105.87, 122.28, 123.19, 126.14, 127.01, 129.97, 130.51,
131.90, 131.92, 132.38, 141.70, 141.90, 148.64, 153.85, 156.63, 158.00, 165.19,
165.52. IR (cmÀ1): 2974, 1701, 1605, 1493, 1232, 785, 665. MS (ESI) m/z (M+H)+
Calcd C28H26Br2N4O4S: 672.00. Found: 673.75.
Compound 2j: Yellow solid, mp 152–153 °C. 1H NMR 400 MHz (CDCl3): d 1.11
(3H, t, J = 7.1 Hz, CH3), 1.18 (3H, t, J = 7.1 Hz, CH3), 2.36 (3H, s, CH3), 2.42 (3H, s,
CH3), 4.02 (2H, q, J = 7.1 Hz, CH2), 4.09 (2H, q, J = 7.1 Hz, CH2), 5.44 (1H, s, CH),
6.15 (1H, s, NH), 7.19 (2H, d, J = 6.6 Hz, ArH), 7.34 (2H, d, J = 6.7 Hz, ArH), 7.43–
7.49 (4H, m, ArH). 13C NMR 100 MHz (CDCl3): d 14.11, 14.15, 22.91, 23.29,
55.57, 59.09, 60.12, 60.48, 102.60, 106.09, 122.99, 123.32, 129.09, 130.16,
131.49, 132.14, 138.44, 138.90, 148.78, 153.58, 156.26, 158, 03, 165.25, 165.56.
IR (cmÀ1): 2983, 1704, 1603, 1505, 1228, 816, 687. MS (ESI) m/z (M+H)+ Calcd
C
28H26Cl2N4O4S: 584.11. Found: 584.95.
Compound 2h: Yellow solid, mp 128–130 °C. 1H NMR 400 MHz (CDCl3): d 1.11
(3H, t, J = 7.1 Hz, CH3), 1.17 (3H, t, J = 7.1 Hz, CH3), 2.37 (3H, s, CH3), 2.42 (3H, s,
C28H26Br2N4O4S: 672.00. Found: 673.80.