Solvent-free synthesis of monastrol derivatives catalyzed by NaHSO 4

Article abstract of DOI:10.1002/jhet.368

(Chemical Equation Presented) Monastrol derivatives were synthesized by environment-friendly three component condensation reaction of salicylaldehyde analogues, b-ketoester, and urea or thiourea under solvent-free conditions with NaHSO4 as catalyst in hig

Full text of DOI:10.1002/jhet.368

624
Solvent-Free Synthesis of Monastrol Derivatives Catalyzed by
NaHSO4
Vol 47
Qingfang Cheng,a,b* Qifa Wang,b Xingyou Xu,b Mingjie Ruan,b Hailun Yao,b
and Xujie Yangb
aMaterials Chemistry Laboratory, Nanjing University of Science and Technology, Nanjing, Jiangsu
210094, China
bDepartment of Chemical Technology, Huaihai Institute of Technology, Lianyungang, Jiangsu
222005, China
*E-mail: cheng_qingfang@yahoo.com.cn
Received October 15, 2009
DOI 10.1002/jhet.368
Published online 3 May 2010 in Wiley InterScience (www.interscience.wiley.com).
Monastrol derivatives were synthesized by environment-friendly three component condensation reac-
tion of salicylaldehyde analogues, b-ketoester, and urea or thiourea under solvent-free conditions with
NaHSO4 as catalyst in high yields. The reactions formed two different monastrol products, 4-(2-hydrox-
yphenyl)pyrimidines 4 and 9- methyl- 11-oxo(or thioxo)-8-oxa-10,12-diazatricyclotrideca derivatives 5.
J. Heterocyclic Chem., 47, 624 (2010).
INTRODUCTION
1,2,3,4-tetrahydropyrimidine-5-carboxylate, is a recently
highlighted Biginelli compound [5,6], which showed
promise in a new strategic approach to cancer research
[7] and has been found to affect the function of mitotic
kinesin Eg5, a motor protein responsible for spindle
bipolarity [8]. Thus, kinesin spindle protein represents
an attractive target for biochemical studies because
human Eg5 inhibitors induce cell death via apoptosis
[9]. Owing to the versatile biological activity of Monas-
trol derivatives, development of an alternative synthetic
methodology is of paramount importance. This has led
to the development of several new synthetic strategies
involving combinations of Lewis acids and transition
metal salts, e.g. Sr(OTf)2 [10], p-TsOH [11,12], HPA
[13], NiCl2.6H2O [14], LaCl3 [15], InBr3 [16] and
Bakers’ yeast [17]. Obviously, most of these catalysts
It is well known that 3,4-dihydropyrimidin-2-(1H)-
ones (DHPMs) and their derivatives are an important
class of heterocyclic compounds having important bio-
logical activities, pharmaceutical and therapeutic proper-
ties, such as antiviral [1], antitumour [2], antibacterial,
anti-inflammatory, and antihypertensive [3]. Therefore,
the preparation of this heterocyclic nucleus has gained
great importance in organic synthesis. One of the simple
and direct method for the synthesis of this class of com-
pounds is known as Biginelli reaction involving one-pot
condensation of aldehyde, b-ketoester, and urea under
strong acidic conditions, which was first reported by
Biginelli in 1893 [4]. In this class of compounds, Mon-
astrol, ethyl 6-methyl-4-(3-hydroxyphenyl)-2-thioxo-
C
V
2010 HeteroCorporation

May 2010
Solvent-Free Synthesis of Monastrol Derivatives Catalyzed by NaHSO4
625
Table 1
NaHSO4 mediated synthesis of monastrol derivatives.
Productsa
R1
R2
R3
X
Time (h)
Yieldb (%)
Mp (ꢀC)
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
H
Et
Et
H
H
O
S
3
3
91
86
83
88
86
82
81
84
82
82
81
92
89
90
86
84
85
83
201–202
162–164
98–100
H
Et
Et
Ph
H
O
O
O
O
O
O
O
O
O
O
O
S
4
Cl
Br
Cl
Br
Cl
Br
Cl
Br
H
3.5
3.5
4.5
4.5
3.5
3.5
4.5
4.5
3
228–230
231–233
102–104
111–113
257–259
215–217
107–109
114–116
197–200
118–120
148–150
238–240
216–218
157–159
127–129
Et
Et
Et
H
Ph
Ph
H
Me
Me
Me
Me
Me
Me
Me
Me
Et
H
4j
Ph
Ph
H
4k
5a
5b
5c
5d
5e
5f
H
H
Ph
H
3.5
3
Cl
Cl
Br
Br
H
H
S
S
4
3.5
4
Me
Et
H
H
S
S
5g
3.5
a Products were characterized by 1H, 13C NMR, IR, MS, and elemental analyses.
b Isolated yield.
and solvents are not acceptable in the context of green
synthesis. Thus, as a part of our program towards green
synthesis [18], and continuing our studies on the Multi-
Component reactions (MCRs) [19], we report herein, a
simple, facile, and efficient MCRs for the preparation of
some new Monastrol analogues with NaHSO4 as a non-
toxic, inexpensive, and easily available reagent.
not only for urea or thiourea, but also for salicylalde-
hydes as well as 5-chloro and 5-bromo salicylaldehydes.
In most cases, the reactions proceeded smoothly to pro-
duce the corresponding Monastrol derivatives in high
yields.
In the course of our work, we have observed that
the product from reactions involving salicylaldehyde,
methyl acetoacetate with urea (or thiourea, phenylurea)
is in fact the 9-methyl-11-oxo(or thioxo)-8-oxa-10,
Herein we wish to report the utilization of NaHSO4
as a catalyst in Biginelli’s reaction of substitued salicy-
laldehydes, b-ketoester and urea or thiourea for the syn-
thesis of some new Monastrol derivatives under solvent-
free conditions.
12-diazatricyclo
rather than
[7.3.1.02,7]trideca-2,4,6-triene
5a-c
free hydroxyl compounds, 4-(2-
a
The three-component cyclocondensation reaction was
performed under relatively simple reaction conditions by
heating together the three components, salicylaldehyde,
b-ketoester, and urea or thiourea, in the ratio of 1:1:1.5
and NaHSO4 (20 mol %), to 90ꢀC with stirring. After the
completion of the reaction, as indicated by TLC, the reac-
tion mixture was poured onto crushed ice. From which
the Monastrol derivatives were isolated by filtration and
recrystallized from ethanol as indicated in Table 1.
Reactions of salicylaldehyde, methyl acetoacetate
with urea (or thiourea, phenylurea) as well as reactions
of 5-chloro or 5-bromo salicylaldehyde, methyl (or
ethyl) acetoacetate with thiourea did not give the
expected free hydroxyl compounds 4, however, the
product is the 9-methyl-11-oxo(or thioxo)-8-oxa-10,12-
Scheme 1
diazatricyclo
(Scheme 1).
[7.3.1.02,7]trideca-2,4,6-triene
5a-g
The results presented in the Table 1 indicate the
scope and generality of the method, which is efficient,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

626
Q. Cheng, Q. Wang, X. Xu, M. Ruan, H. Yao, and X. Yang
Vol 47
Scheme 2
Ethyl 6-methyl-2-oxo-4-(2-hydroxyphenyl)-1,2,3,4-tetrahy-
dropyrimidine-5-carboxylate (4a). Yellow powder, yield 91%,
mp 201–202ꢀC, IR(KBr), (mmax/cmꢁ1): 3355, 3267, 1683,
hydroxyphenyl)pyrimidines 4. However, this oxygen-
bridged pyrimidine structures were not discussed in sev-
eral recent reports [13–15,20,21], but were supported by
others [12,16,17]. The product from reactions involving
5-chloro or 5-bromosalicylaldehyde, methyl (or ethyl)
acetoacetate with thiourea is also an oxygen-bridged
compounds 5d-g rather than the corresponding 4-(2-
hydroxyphenyl)pyrimidines.
1
1597. H NMR (DMSO-d6) dH : 9.6 (s, 1H, NH), 9.10 (s, 1H,
NH), 6.68–7.16 (m, 5H, arom, OH), 5.45 (s, 1H, H-4), 3.93 (q,
J ¼ 6.8 Hz, 2H, CH2), 2.26 (s, 3H, CH3), 1.01 (t, J ¼ 6.8 Hz,
3H, CH3). 13C NMR (DMSO-d6) dC: 14.9, 18.6, 44.7, 59.8,
98.6, 116.1, 119.6, 121.3, 128.1, 129.5, 149.4, 151.5, 155.5,
169.3. MS(ESI) m/z: 277.0 (MþH). Anal. Calcd. for
C14H16N2O4: C, 60.86; H, 5.84; N, 10.14. Found : C, 60.89;
H, 5.88; N, 10.17.
Ethyl 6-methyl-2-thioxo-4-(2-hydroxyphenyl)-1,2,3,4-tetra-
hydropyrimidine-5-carboxylate (4b). Yellow powder, yield
86%, mp 162–164ꢀC, IR(KBr), (mmax/cmꢁ1): 3359, 3279,
1689. 1H NMR (DMSO-d6) dH : 9.72 (s, 1H, NH), 9.10 (s,
1H, NH), 6.83–7.31 (m, 5H, arom, OH), 5.51 (s, 1H, H-4),
4.14 (q, J ¼ 7.3 Hz, 2H, CH2), 2.21 (s, 3H, CH3), 1.13 (t, J ¼
7.3 Hz, 3H, CH3). 13C NMR (DMSO-d6) dC: 14.4, 18.9, 44.2,
58.6, 102.5, 118.7, 120.9, 127.2, 129.1, 130.1, 148.3, 150.5,
169.2, 177.5. MS(ESI) m/z: 293.1 (MþH). Anal. Calcd. for
C14H16N2O3S: C, 57.51; H, 5.52; N, 9.58. Found : C, 57.46;
H, 5.44; N, 9.65.
The production of compounds 5a-g can be explained
by the isomerization reaction of the 4-(2-hydroxyphenyl)
pyrimidines, 4 which were initially formed (Scheme 2).
In summary, we have described a convenient, envi-
ronment-friendly method for the preparation of some
new Monastrol derivatives by the Biginelli cycloconden-
sation reaction of salicylaldehyde analogues, b-ketoester
with urea or thiourea using nontoxic, cheap NaHSO4
catalyst. Additionally, when using salicylaldehyde as the
aldehyde reagent, methyl acetoacetate as the active
methylene compound, urea (or thiourea, phenylurea) as
the condensation reagent, as well as using 5-chloro or 5-
bromo salicylaldehyde as the aldehyde reagent, methyl
(or ethyl) acetoacetate as the active methylene com-
pound, thiourea as the condensation reagent, the Bigi-
nelli product will be an oxygen-bridged compound, 9-
Ethyl 1-phenyl-6-methyl-2-oxo-4-(2-hydroxyphenyl)-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (4c). Green powder, yield
83%, mp 98–100ꢀC, IR (KBr), (mmax/cmꢁ1): 3347, 3268, 1681,
1
1589. H NMR (DMSO-d6) dH : 7.50 (s, 1H, NH), 6.83–7.45
(m, 10H, arom, OH), 5.58 (s, 1H, H-4), 4.22 (q, J ¼ 6.9 Hz,
2H, CH2), 2.29 (s, 3H, CH3), 1.28 (t, J ¼ 6.9 Hz, 3H, CH3).
13C NMR (DMSO-d6) dC: 14.7, 18.9, 44.9, 59.2, 99.3, 113.1,
117.5, 119.3, 121.5, 127.6, 129.1, 129.8, 130.7, 149.6, 150.1,
152.2, 155.9, 169.7. MS(ESI) m/z: 353.1 (MþH). Anal. Calcd.
for C20H20N2O4: C, 68.17; H, 5.72; N, 7.95. Found : C, 68.22;
H, 5.75; N, 7.87.
methyl-11-oxo(or thioxo)-8-oxa-10,12-diazatricy-
clo[7.3.1.02,7]trideca-2,4,6-triene
5 rather than 4-(2-
hydroxyphenyl)pyrimidines 4.
EXPERIMENTAL
Ethyl 6-methyl-2-oxo-4-(2-hydroxy-5-chlorphenyl)-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (4d). Yellow powder,
yield 88%, mp 228–230ꢀC, IR(KBr), (mmax/cmꢁ1): 3344, 3249,
IR spectra were recorded on a Nicolet FTIR-500 spectrome-
1
ter. H NMR and 13C NMR spectra were recorded on a Bruker
1
AVANCE 400 MHz spectrometer at 400 MHz and 75 MHz.
Elemental analysis was performed on an Elementar Vario EL
III analyzer. Melting points were determined on a XT-5A digi-
tal melting-points apparatus and are uncorrected.
1679, 1605. H NMR (DMSO-d6) dH : 9.93 (s, 1H, NH), 9.17
(s, 1H, NH), 6.80 (t, J ¼ 6.8 Hz, 1H, ArH), 6.92 (s, 1H, ArH
), 7.19 (t, J ¼ 6.8 Hz, 1H, ArH), 7.28 (s, 1H, OH ), 5.41 (s,
1H, H-4), 3.92 (q, J ¼ 7.0 Hz, 2H, CH2), 2.27 (s, 3H, CH3),
1.04 (t, J ¼ 7.0 Hz, 3H, CH3). 13C NMR (DMSO-d6) dC:
14.4, 18.2, 51.2, 59.5, 97.7, 117.6, 122.5, 127.6, 128.4, 132.5,
149.4, 152.5, 154.2, 165.8. MS (ESI) m/z: 309.0 (M-H). Anal.
Calcd. for C14H15N2O4Cl: C, 54.11; H, 4.87; N, 9.02. Found :
C, 54.16; H, 4.92; N, 9.07.
General procedure for the synthesis of Monastrol deriva-
tives 4a-k and 5a-g. A mixture of the appropriate salicylalde-
hyde (2 mmol), b-ketoester (2 mmol), urea or thiourea (3
mmol), and NaHSO4 (0.4 mmol) was heated with stirring at
90ꢀC for the time period as indicated in Table 1. After com-
pletion of the reaction (TLC analysis), ice water was added to
the mixture, and the crude products collected by filtration were
recrystallized from EtOH, to give the products 4a-k or 5a-g
(Table 1). All products were characterized by 1H, 13C NMR,
IR, MS spectral, and by elemental analyses.
Ethyl 6-methyl-2-oxo-4-(2-hydroxy-5-bromophenyl)-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (4e). Gray powder, yield
86%, mp 231–233ꢀC, IR(KBr), (mmax/cmꢁ1): 3339, 3252,
1
1677, 1609. H NMR (DMSO-d6) dH : 9.91 (s, 1H, NH), 9.19
(s, 1H, NH), 6.77 (t, J ¼ 6.9 Hz, 1H, ArH), 6.95 (s, 1H, ArH),
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Solvent-Free Synthesis of Monastrol Derivatives Catalyzed by NaHSO4
627
7.23 (t, J ¼ 6.9 Hz, 1H, ArH), 7.31 (s, 1H, OH ), 5.42 (s, 1H,
H-4), 5.42 (s, 1H, H-4), 3.90 (q, J ¼ 7.1 Hz, 2H, CH2), 2.29
(s, 3H, CH3), 1.07 (t, J ¼ 7.1 Hz, 3H, CH3). 13C NMR
(DMSO-d6) dC: 14.5, 18.6, 51.1, 59.3, 97.5, 110.2, 118.2,
129.7, 132.0, 132.5, 149.7, 152.8, 154.5, 166.8. MS(ESI) m/z:
356.9 (MþH). Anal. Calcd. for C14H15N2O4Br: C, 47.34; H,
4.26; N,7.89. Found: C, 47.38; H, 4.22; N, 7.83.
Ethyl 6-methyl-1-phenyl-2-oxo-4-(2-hydroxy-5-chlorphenyl)-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (4f). Yellow pow-
der, yield 82%, mp 102–104ꢀC, IR(KBr), (mmax/cmꢁ1): 3355,
3269, 1688, 1611. 1H NMR (DMSO-d6) dH : 9.06 (s, 1H,
NH), 6.86–7.45 (m, 9H, arom, OH), 5.48 (s, 1H, H-4), 4.12 (q,
J ¼ 7.1 Hz, 2H, CH2), 2.27 (s, 3H, CH3), 1.25 (t, J ¼ 7.1 Hz,
3H, CH3). 13C NMR (DMSO-d6) dC: 14.9, 18.6, 50.3, 59.4,
99.8, 113.1, 117.3, 118.1, 122.1, 127.9, 129.1, 129.9, 132.4,
149.5, 150.3, 152.6, 154.9, 167.4. MS(ESI) m/z: 385.1 (M-H).
Anal. Calcd. for C20H19N2O4Cl: C, 62.11; H, 4.95; N, 7.24.
Found: C, 62.07; H, 4.88; N, 7.29.
Ethyl 6-methyl-1-phenyl-2-oxo-4-(2-hydroxy-5-bromophenyl)-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (4g). Yellow pow-
der, yield 81%, mp 111–113ꢀC, IR(KBr), (mmax/cmꢁ1): 3349,
3257, 1678, 1599. 1H NMR (DMSO-d6) dH : 9.09 (s, 1H,
NH), 6.73–7.32 (m, 9H, arom, OH), 5.49 (s, 1H, H-4), 4.12 (q,
J ¼ 6.9 Hz, 2H, CH2), 2.29 (s, 3H, CH3), 1.26 (t, J ¼ 6.9 Hz,
3H, CH3). 13C NMR (DMSO-d6) dC: 14.4, 18.2, 50.9, 58.9,
98.4, 110.5, 117.8, 118.4, 122.6, 129.4, 129.9, 132.8, 133.3,
149.6, 150.8, 152.7, 154.8, 168.1. MS(ESI) m/z: 432.9 (MþH).
Anal. Calcd. for C20H19N2O4Br: C, 55.70; H, 4.44; N, 6.50.
Found : C, 55.66; H, 4.41; N, 6.57.
Methyl 6-methyl-2-oxo-4-(2-hydroxy-5-chlorphenyl)-1,2,3,
4-tetrahydropyrimidine-5-carboxylate (4h). Yellow powder,
yield 84%, mp 257–259ꢀC, IR(KBr), (mmax/cmꢁ1): 3346, 3261,
1688, 1592. 1H NMR (DMSO-d6) dH : 9.96 (s, 1H, NH), 9.22 (s,
1H, NH), 6.78 (t, J ¼ 7.0 Hz, 1H, ArH), 7.05 (s, 1H, ArH ), 7.24
(t, J ¼ 7.0 Hz, 1H, ArH), 7.29 (s, 1H, OH ), 5.41 (s, 1H, H-4),
ꢁ7.24 (m, 4H, arom, OH), 5.37 (s, 1H, H-4), 3.41 (s, 3H, CH3),
2.19 (s, 3H, CH3). 13C NMR (DMSO-d6) dC: 18.4, 48.9, 50.8,
98.3, 110.1, 118.1, 129.1, 130.7, 132.2, 147.9, 151.2, 154.3,
164.9. MS(ESI) m/z: 297.1. Anal. Calcd. for C13H13N2O4Cl: C,
52.62; H, 4.42; N, 9.44. Found : C, 52.67; H, 4.38; N, 9.48.
Methyl 6-methyl-2-oxo-4-(2-hydroxy-5-bromophenyl)-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (4i). Yellow powder, yield
82%, mp 215–217ꢀC, IR(KBr), (mmax/cmꢁ1): 3339, 3254,
1676, 1599. 1H NMR (DMSO-d6) dH : 10.03 (s, 1H, NH),
9.21 (s, 1H, NH), 6.77 (t, J ¼ 7.2 Hz, 1H, ArH), 7.02 (s, 1H,
ArH ), 7.22 (t, J ¼ 7.2 Hz, 1H, ArH), 7.27 (s, 1H, OH ), 5.41
(s, 1H, H-4), 5.41 (s, 1H, H-4), 3.50 (s, 3H, CH3), 2.29 (s, 3H,
CH3). 13C NMR (DMSO-d6) dC: 18.3, 49.6, 51.2, 97.5, 110.3,
118.3, 130.0, 131.4, 132.8, 149.8, 152.6, 154.7, 166.2.
MS(ESI) m/z: 342.9 (MþH). Anal. Calcd. for C13H13N2O4Br:
C, 45.77; H, 3.84; N, 8.21. Found: C, 45.73; H, 3.89; N, 8.26.
Methyl 6-methyl-1-phenyl-2-oxo-4-(2-hydroxy-5-chlorphenyl)-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (4j). Brown powder,
yield 82%, mp 107–109ꢀC, IR(KBr), (mmax/cmꢁ1): 3341, 3269,
1682, 1603. 1H NMR (DMSO-d6) dH : 9.11 (s, 1H, NH),
6.71–7.39 (m, 9H, arom, OH), 5.44 (s, 1H, H-4), 3.45 (s, 3H,
CH3), 2.24 (s, 3H, CH3). 13C NMR (DMSO-d6) dC: 18.1,
48.4, 51.3, 99.6, 112.1, 117.4, 118.5, 122.3, 128.1, 129.5,
130.1, 132.6, 148.4, 150.2, 152.8, 154.2, 166.9. MS(ESI) m/z:
373.1. Anal. Calcd. for C19H17N2O4Cl: C, 61.21; H, 4.60; N,
7.53. Found : C, 61.16; H, 4.53; N, 7.56.
Methyl 6-methyl-1-phenyl-2-oxo-4-(2-hydroxy-5-bromophenyl)-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (4k). Yellow powder,
yield 81%, mp 114–116ꢀC, IR(KBr), (mmax/cmꢁ1): 3336, 3258,
1671, 1589. 1H NMR (DMSO-d6) dH : 9.15 (s, 1H, NH),
6.69–7.37 (m, 9H, arom, OH), 5.49 (s, 1H, H-4), 3.52 (s, 3H,
CH3), 2.26 (s, 3H, CH3). 13C NMR (DMSO-d6) dC: 18.2,
49.1, 51.7, 98.6, 111.3, 115.7, 118.3, 120.4, 128.3, 129.1,
130.6, 131.5, 149.1, 151.9, 153.7, 154.2, 167.1. MS(ESI) m/z:
418.9 (MþH). Anal. Calcd. for C19H17N2O4Br: C, 54.69; H,
4.11; N, 6.72. Found : C, 54.62; H, 4.06; N, 6.78.
13-Methoxycarbonyl-9-methyl-11-oxo-8-oxa-10,12-diazatri-
cyclo[7.3.1.02,7]trideca-2,4,6-triene (5a). Yellow powder,
yield 92%, mp 117–120ꢀC, IR(KBr), (mmax/cmꢁ1): 3308, 3075,
1683, 1643. 1H NMR (DMSO-d6) dH : 7.19 (s, 1H, NH),
6.78–7.18 (m, 5H, arom, NH), 4.61 (dd, J ¼ 2.8, 2.8 Hz, 1H,
H-1), 3.69 (s, 3H, CH3), 3.49–3.52 (m, 1H, H-13), 1.78 (s, 3H,
CH3). 13C NMR (DMSO-d6) dC: 24.7, 44.0, 48.9, 51.8, 82.1,
116.4, 121.7, 124.6, 128.5, 130.1, 151.3, 155.8, 169.1.
MS(ESI) m/z: 262.9 (MþH). Anal. Calcd. for C13H14N2O4: C,
59.53; H, 5.38; N, 10.68. Found : C, 59.58; H, 5.35; N, 10.62.
13-Methoxycarbonyl-9-methyl-10-phenyl-11-oxo-8-oxa-10,12-
diazatricyclo[7.3.1.02,7]trideca-2,4,6-triene (5b). Green powder,
yield 89%, mp 118–120ꢀC, IR(KBr), (mmax/cmꢁ1): 3316, 3089,
1675, 1653. 1H NMR (DMSO-d6) dH : 8.51 (s, 1H, NH),
6.78–7.68 (m, 9H, arom), 4.38 (dd, J ¼ 2.9, 2.9 Hz, 1H, H-1),
3.70 (s, 3H, CH3), 3.43–3.58 (m, 1H, H-13), 1.85 (s, 3H,
CH3). 13C NMR (DMSO-d6) dC: 25.1, 47.2, 49.1, 51.8, 83.1,
112.3, 116.5, 117.8, 120.9, 123.5, 128.3, 129.7, 130.4, 150.6,
151.7, 156.4, 167.3. MS(ESI) m/z: 339.1 (MþH). Anal. Calcd.
for C19H18N2O4: C, 67.44; H, 5.36; N, 8.28. Found : C, 67.48;
H, 5.31; N, 8.25.
13-Methoxycarbonyl-9-methyl-11-thioxo-8-oxa-10,12-diaza-
tricyclo[7.3.1.02,7]trideca-2,4,6-triene (5c). Yellow powder,
yield 90%, mp 148–150ꢀC, IR(KBr), (mmax/cmꢁ1): 3307, 3073,
1
1670. H NMR (DMSO-d6) dH : 9.17 (s, 1H, NH), 6.81–7.22
(m, 4H, ArH), 4.58 (dd, J ¼ 3.1, 2.4 Hz, 1H, H-1), 3.69 (s,
3H, CH3), 3.34–3.37 (m, 1H, H-13), 1.77 (s, 3H, CH3). 13C
NMR (DMSO-d6) dC: 24.2, 43.0, 48.8, 53.0, 82.2, 117.3,
121.7, 124.6, 129.6, 130.6, 151.3, 169.2, 177.2. MS(ESI) m/z:
279.0 (MþH). Anal. Calcd. for C13H14N2O3S: C, 56.09; H,
5.07; N, 10.07. Found : C, 56.13; H, 5.13; N, 10.02.
13-Methoxycarbonyl-9-methyl-4-chlor-11-thioxo-8-oxa-10,12-
diazatricyclo[7.3.1.02,7]trideca-2,4,6-triene (5d). Gray powder,
yield 86%, mp 238–240ꢀC, IR(KBr), (mmax/cmꢁ1): 3298, 3079,
1689. 1H NMR (DMSO-d6) dH : 10.01 (s, 1H, NH), 9.22 (s,
1H, NH), 6.80 (t, J ¼ 6.7 Hz, 1H, ArH), 6.90 (s, 1H, ArH ),
7.13 (t, J ¼ 6.7Hz, 1H, ArH), 5.41 (s, 1H, H-4), 4.55 (dd, J ¼
3.2, 2.4 Hz, 1H, H-1), 3.56 (s, 3H, CH3), 3.35–3.41 (m, 1H,
H-13), 1.82 (s, 3H, CH3). 13C NMR (DMSO-d6) dC: 24.5,
43.5, 47.2, 52.5, 82.1, 117.8, 122.7, 125.0, 129.4, 131.3, 150.2,
168.1, 177.2. MS(ESI) m/z: 313.0 (MþH). Anal. Calcd. for
C13H13N2O3SCl: C, 49.92; H, 4.19; N, 8.96. Found : C, 49.88;
H, 5.15; N, 8.93.
13-Ethoxycarbonyl-9-methyl-4-chlor-11-thioxo-8-oxa-10,12-
diazatricyclo[7.3.1.02,7]trideca-2,4,6-triene (5e). Yellow pow-
der, yield 84%, mp 216–218ꢀC, IR(KBr), (mmax/cmꢁ1): 3315,
3091, 1689. 1H NMR (DMSO-d6) dH : 10.06 (s, 1H, NH),
9.23 (s, 1H, NH), 6.82 (t, J ¼ 7.1 Hz, 1H, ArH), 6.94 (s, 1H,
ArH ), 7.18 (t, J ¼ 7.1 Hz, 1H, ArH), 5.41 (s, 1H, H-4), 4.58
(dd, J ¼ 3.0, 2.6 Hz, 1H, H-1), 4.03 (q, J ¼ 7.1 Hz, 2H,
CH2), 3.34–3.44 (m, 1H, H-13), 1.80 (s, 3H, CH3), 1.24 (t, J
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

628
Q. Cheng, Q. Wang, X. Xu, M. Ruan, H. Yao, and X. Yang
Vol 47
¼ 7.1 Hz, 3H, CH3). 13C NMR (DMSO-d6) dC: 14.9, 24.4,
43.1, 47.3, 57.5, 82.2, 117.9, 123.3, 125.6, 130.4, 133.5, 152.2,
167.1, 177.1. MS(ESI) m/z: 328.5 (MþH). Anal. Calcd. for
C14H15N2O3SCl: C, 51.45; H, 4.63; N, 8.57. Found : C, 51.48;
H, 4.67; N, 8.53.
[3] Grover, G. J.; Dzwonczyk, S.; Mc Multen, D. M.; Norman-
din, D. E.; Parham, C. S.; Sleph, P.G.; Moreland, S. J Cardiovasc
Pharmacol 1995, 26, 289.
[4] Kappe, C. O. Tetrahedron 1993, 49, 6937.
[5] Mayer, T. U.; Kapoor, T. M.; Haggarty, S. J.; King, R. W.;
Schreiber, S. J.; Mitchison, T. J. Science 1999, 286, 971.
[6] Kapoor, T. M.; Mayer, T. U.; Coughlin, M. L.; Mitchison,
T. J. J Cell Biol 2000, 150, 975.
13-Methoxycarbonyl-9-methyl-4-bromo-11-thioxo-8-oxa-10,12-
diazatricyclo[7.3.1.02,7]trideca-2,4,6-triene (5f). Gray powder,
yield 85%, mp 157–159ꢀC, IR(KBr), (mmax/cmꢁ1): 3295, 3077,
[7] Wood, K.W.; Bergnes, G. Annu Rep Med Chem 2004, 39,
173.
1
1681. H NMR (DMSO-d6) dH : 10.04 (s, 1H, NH), 9.25 (s, 1H,
NH), 6.77 (t, J ¼ 6.8 Hz, 1H, ArH), 6.95 (s, 1H, ArH ), 7.27 (t,
J ¼ 6.8 Hz, 1H, ArH), 5.41 (s, 1H, H-4), 4.57 (dd, J ¼ 3.0, 2.4
Hz, 1H, H-1), 3.61 (s, 3H, CH3), 3.41 (m, 1H, H-13), 1.75 (s,
3H, CH3). 13C NMR (DMSO-d6) dC: 24.3, 43.2, 47.6, 52.3,
82.3, 113.5, 120.4, 124.5, 130.8, 131.7, 149.9, 168.8, 177.5.
MS(ESI) m/z: 358.9 (MþH). Anal. Calcd. for C13H13N2O3SBr:
C, 43.71; H, 3.67; N, 7.84. Found : C, 43.78; H, 3.72; N, 7.81.
13-Ethoxycarbonyl-9-methyl-4-bromo-11-thioxo-8-oxa-10,12-
diazatricyclo[7.3.1.02,7]trideca-2,4,6-triene (5g). Gray powder,
yield 83%, mp 127–129ꢀC, IR(KBr), (mmax/cmꢁ1): 3309, 3091,
[8] (a) Sharp, D. J.; Rogers, G. C.; Scholey, J. M. Nature 2000,
407, 41; (b) Endow, S. A.; Baker, D. S. Annu Rev Physiol 2003, 65,
161.
[9] (a) Walczak, C. E.; Vernos, I.; Mitchison, T. J.; Karsenti,
E.; Heald, R. Curr Biol 1998, 8, 903; (b) Marcus, A. I.; Peters, U.;
Thomas, S. L.; Garrett, S.; Zelnak, A.; Kapoor, T. M.; Giannakakou,
P. J Biol Chem 2005, 280, 11569.
[10] Su, W.; Li, J.; Zheng, Z.; Shen, Y. Tetrahedron Lett 2005,
46, 6037.
[11] Azizian, J.; Mohammadi, A. A.; Kohshari, M.; Karimi, A.
R.; Mohammadizadeh, M. R. J Heterocycl Chem 2007, 44, 455.
˘ ´ ´
[12] Svetlık, J.; Veizerova, L.; Kettmann, V. Tetrahedron Lett
1
1673. H NMR (DMSO-d6) dH : 10.04 (s, 1H, NH), 9.21 (s, 1H,
NH), 6.75 (t, J ¼ 7.0 Hz, 1H, ArH), 7.04 (s, 1H, ArH ), 7.24 (t,
J ¼ 7.0 Hz, 1H, ArH), 5.41 (s, 1H, H-4), 4.54 (dd, J ¼ 3.2, 2.2
Hz, 1H, H-1), 3.92 (q, J ¼ 7.1 Hz, 2H, CH2), 3.35ꢂ3.42 (m,
1H, H-13), 1.78 (s, 3H, CH3), 1.23 (t, J ¼ 7.1 Hz, 3H, CH3).
13C NMR (DMSO-d6) dC: 14.3, 24.5, 43.4, 47.2, 61.2, 82.1,
112.6, 119.2, 125.6, 131.8, 132.2, 150.7, 167.5, 177.2. MS(ESI)
m/z: 372.9 (MþH). Anal. Calcd. for C14H15N2O3SBr: C, 45.29;
H, 4.07; N, 7.55. Found : C, 45.23; H, 4.04; N, 7.52.
2008, 49, 3520.
[13] Rafiee, E.; Jafari, H. Bioorg Med Chem Lett 2006, 16,
2463.
[14] Lu, J.; Bai, Y. Synthesis, 2002, 4, 466.
[15] Lu, J.; Bai, Y.; Wang, Z.; Yang, B.; Ma, H. Tetrahedron
Lett 2000, 41, 9075.
[16] Fu, N. Y.; Yuan, Y. F.; Cao, Z.; Wang, S. W.; Wang, J. T.;
Peppe, C. Tetrahedron 2002, 58, 4801.
[17] Kumar, A.; Maurya, R. A. Tetrahedron Lett 2007, 48,
4569.
Acknowledgments. We gratefully acknowledge the financial
support from the Foundation of Technology Research of Lia-
nyungang (grant No. CG0713).
[18] Cheng, Q. F.; Xu, X. Y.; Ma, W. X.; Zhang, H.; Liu, L. S.;
Liu, F.; Yang, X. J. Chin J Org Chem 2008, 28, 1767.
[19] Cheng, Q. F.; Xu, X. Y.; Ruan, M. J.; Wen, Y. L.; He, X.
J.; Yang, X. J. Chin J Org Chem 2009, 29, 1138.
[20] Tu, S.; Fang, F.; Zhu, S.; Li, T.; Zhang, X.; Zhuang, Q.
Synlett 2004, 3, 537.
REFERENCES AND NOTES
[1] Kappe, C. O. Eur J Med Chem 2000, 35, 1043.
[2] Kappe, C. O.; Kumar, D.; Varma, R.S. Synthesis 1999, 10,
1799.
[21] Folkers, K.; Harwood, H. J.; Johnson, T. B. J Am Chem
Soc 1932, 54, 3751.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet