Efficient one-pot synthesis of spiro[indoline-3,4′-pyrazolo[3,4-e][1, 4]thiazepine]dione via three-component reaction

Article abstract of DOI:10.1016/j.tet.2011.05.069

An efficient one-pot synthesis of spiro[indoline-3,4′-pyrazolo[3,4-e] [1,4]thiazepine] dione derivatives via three-component reaction of 5-amino-3-methylpyrazole, isatin, and thioacid is described. This new protocol produces novel heptacyclic spirooxindole derivatives in good yields in comparison to conventional pentacyclic compounds. This method proceeds through a 3-(5-aminopyrazol-3-yl)-3-hydroxy-2-oxindoline intermediate (Baylis-Hillman type adduct), unlike 3-indolylimine (the intermediate like Shiff-Bases) as in conventional methods. The structure of one representative compound has been confirmed by X-ray diffraction analysis.

Full text of DOI:10.1016/j.tet.2011.05.069

Tetrahedron 67 (2011) 5686e5692
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Tetrahedron
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Efficient one-pot synthesis of spiro[indoline-3,40-pyrazolo[3,4-e][1,4]thiazepine]
dione via three-component reaction
*
Hui Chen, Daqing Shi
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, PR China
a r t i c l e i n f o
a b s t r a c t
An efficient one-pot synthesis of spiro[indoline-3,40-pyrazolo[3,4-e][1,4]thiazepine] dione derivatives via
three-component reaction of 5-amino-3-methylpyrazole, isatin, and thioacid is described. This new
protocol produces novel heptacyclic spirooxindole derivatives in good yields in comparison to conven-
tional pentacyclic compounds. This method proceeds through a 3-(5-aminopyrazol-3-yl)-3-hydroxy-2-
oxindoline intermediate (BayliseHillman type adduct), unlike 3-indolylimine (the intermediate like
Shiff-Bases) as in conventional methods. The structure of one representative compound has been con-
firmed by X-ray diffraction analysis.
Article history:
Received 30 March 2011
Received in revised form 12 May 2011
Accepted 17 May 2011
Available online 1 June 2011
Keywords:
One-pot synthesis
Spirooxindole derivatives
Multi-component reactions
1,4-Thiazepine derivatives
Ó 2011 Published by Elsevier Ltd.
1. Introduction
5-HT1A and dopamine D2 receptors,6c and vasoconstrictor agents.6d
Numerous methods for the synthesis of fused 1,4-thiazepine de-
Multi-component reactions (MCRs) have been designed to
produce elaborate biologically active compounds and have become
an important area of research in organic, combinatorial, and me-
dicinal chemistry.1 Such reactions offer a wide range of possibilities
for the efficient construction of highly complex molecules in a sin-
gle procedure step, thus avoiding the complicated purification
operations and allowing savings of both solvents and reagents.
Thus, they are perfectly amenable to automation for combinatorial
synthesis.2 In the past decade there have been tremendous de-
velopment in three- and four-component reactions and great effort
continue to be made to develop new MCRs.3
rivatives in recent years have been reported with respect to their
different structures.7
The spirooxindole moiety is a core structure in many complex
natural products; such natural products often possess interesting
biological activities.8e10 This structure has also drawn the attention
of medicinal chemists because of its potential as an important
pharmacophore.11 Various spiro ring systems have been reported in
spirooxindole natural products, for example, communesin A and B,
which were isolated from a Penicillium fungus growing on the
marine alga Enteromorpha intestinalis.12 Communesins A and B
show cytotoxicity against P-388 lymphocytic leukemia cells with
Heterocycles containing the 1,4-thiazepine moietyare important
targets in synthetic and medicinal chemistry because this fragment
is a key moiety in a wide number of natural and synthetic bi-
ologically active agents.4 Among them, aryl- and heteroaryl-fused
derivatives of this heterocycle represent an important group of
compounds with interesting pharmaceutical properties.5,6 In par-
ticular, different alkyl derivatives of 3,4-dihydro-5-oxo-1,4-
benzothiazepine were described as calcium channel antagonists,5a
HIV-1 enzyme integrase5b and reverse transcriptase5c inhibitors,
and antitumor agents.5d Several heteroannelated bioisosteric ana-
logues of this core fragment were described as potent inhibitors of
Herpes simplex virus type 1 (HSV-1) replication,6a compounds
possessing H1 antihistamine activity,6b selective antagonists of
moderate to potent activity (ED50¼3.5
mg/mL and 0.45 mg/mL, re-
spectively). Citrinadins A and B are recently isolated marine derived
pentacyclic spiroindolinone alkaloids, they both exhibit important
cytotoxic activities against various cancer cell lines with IC50’s in
the low micromolar range (Fig. 1).13,14
Thia-azaheterocycles have attracted considerable attention be-
cause of their wide biological and pharmacological activities.15
Therefore, a number of methods have been reported for the prepa-
ration of spirooxindole derivatives involving the synthon thioacid.16
However, all the above multi-component reactions involving isatin,
2-mercaptoacetic acid and aniline or heteroaniline afford spiro
[indoline thiazolidines], which is obtained by reacting
2-mercaptoacetic acid with 3-indolylimines (the intermediate like
Shiff-Bases formed by condensation of isatin and aniline) (Scheme
1a). In our previous work, we found 5-amino-3-methylpyrazoles 1
react with isatins 2 giving 3-(5-aminopyrazol-3-yl)-3-hydroxy-
* Corresponding author. E-mail address: dqshi@263.net (D. Shi).
0040-4020/$ e see front matter Ó 2011 Published by Elsevier Ltd.
doi:10.1016/j.tet.2011.05.069

H. Chen, D. Shi / Tetrahedron 67 (2011) 5686e5692
5687
different Brønsted and Lewis acids (Table 1, entries 2e5). Lewis
acids, such as CAN and FeCl3 can catalyze this reaction with low
yields (Table 1, entries 2 and 3). The use of Brønsted acid HCl led to
moderate product formation (Table 1, entry 4). However, p-TSA was
identified as the optimal catalyst with 4a being isolated in 86% yield
(Table 1, entry 5). Performing the reaction in the presence of p-TSA
at room temperature led to low conversion of 4a even with pro-
longed time (Table 1, entry 6). Subsequently, we further turned to
testing the effect of solvents. AcOH, THF, DMF, EtOH or water
showed no superiority to CH3CN (Table 1, entries 7e11). Therefore,
CH3CN is the solvent of choice for this reaction.
The optimized reaction conditions were then tested for library
construction with two 5-amino-3-methylpyrazoles 1, seven isatins
2 and two thioacids 3. A series of spiro[indoline-3,40-pyrazolo[3,4-
e][1,4]thiazepine]dione derivatives 4 were obtained in good yields.
The results are summarized in Table 2. The protocol was effective
with isatins having either electron-withdrawing or electron-
donating groups, and also with different position substituted
isatins.
Me
Me
O
H
O
H
N
N
H
H
N
N
O
O
NH
NH
N
Me
H
N
H
Me
communesin A
communesin B
H3CO
O
O
OH H
R
H
H
O
HN
N
N
N
NHCH3
O
NO2
O
citrinadin A R = O2CCH(NMe2)iPr
Cyclopiamine B
citrinadin B R = H
Fig. 1. Naturally occurring and biologically active spirocyclic oxindoles.
O
O
Het/Ar
N
S
N
Het/Ar
HS
COOH
(a)
+
Ar/Het NH2
O
O
O
N
H
N
N
H
H
H2N
NH
S
Ph
OH
O
N
N
HS
COOH
O
(b)
N
+
O
NH2
N
N
O
N
H
N
H
N
Ph
Ph
N
H
O
1
4
2
7
Scheme 1. Synthesis of spirooxindole derivatives involving the synthon thioacid.
2-oxindolines 7,17 we planned to synthesize novel heptacyclic spiro
[indoline thiazepines] 4 by reacting 7 with thioacids 3 (Scheme 1b).
Hence, in continuation of our earlier interest on the developments of
new routes to spirooxindole derivatives,18 we report herein for the
first time a facile one-pot synthesis of spiro[indoline-3,40- pyrazolo
[3,4-e][1,4]thiazepine]dione derivatives catalyzed by p-TSA (p-tol-
uenesulfonic acid).
Table 1
Optimization of reaction conditions
Entry
Solvent
Temperature
Catalyst
Time (h)
Isolated
yield (%)
(ꢀC)
1
2
3
4
5
6
7
8
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
AcOH
THF
80
80
80
80
80
rt
95
65
95
80
80
d
24
12
12
12
12
24
12
12
12
12
12
Trace
54
39
63
86
<10
72
79
68
76
CAN (30%)
FeCl3 (30%)
HCl (30%)
p-TSA (30%)
p-TSA (30%)
p-TSA (30%)
p-TSA (30%)
p-TSA (30%)
p-TSA (30%)
p-TSA (30%)
2. Results and discussion
Initially, the three-component reaction of 5-amino-1-phenyl-3-
methylpyrazole 1a, isatin 2a, and 2-mercaptoacetic acid 3a as
a simple model substrate was investigated to establish the feasi-
bility of the strategy and to optimize the reaction conditions
(Scheme 2). The effects of solvents and catalysts were evaluated for
this model reaction, and the results are summarized in Table 1. It
was found that when the reaction was carried out without any
catalysts only trace product was detected even after 24 h (Table 1,
entry 1). To improve the yields, we examined this reaction using
9
10
11
DMF
EtOH
Water
65
To further explore the potential of this protocol for synthesis of
spiro-heterocyclic compounds, we investigated reaction involving
acenaphthylene-1,2-dione 5 and obtained spiro[acenaphthylene-
1,40-pyrazolo[3,4-e][1,4]thiazepine]dione derivatives 6 (Fig. 2).
The structures of all products 4 and 6 were characterized by IR,
1H NMR, 13C NMR spectral data as well as HRMS analysis. The
structure of 4p was further confirmed by X-ray diffraction analysis.
The molecular structure of 4p is shown in Fig. 3.
Although the detailed mechanism of this reaction remains to be
fully clarified, a plausible mechanism of this three-component re-
action is presented in Scheme 3. The first step involves the for-
mation of a BayliseHillman type adduct 7 by the nucleophilic
addition of 5-amino-3-methylpyrazole 1 to isatin 2 as a key
NH
O
O
OH
S
N
O
+
+
HS
NH2
N
Ph
N
H
O
N
N
Ph
N
H
O
1a
2a
3a
Scheme 2. Model reaction.
4a

5688
H. Chen, D. Shi / Tetrahedron 67 (2011) 5686e5692
Table 2
Synthesis of spirooxindole derivatives 4
R3
R2
N
N
R4
O
CH3CN, 80
O
OH
S
N
N
NH2 R2
+
+
O
HS
R4
p-TSA, 12-24h
N
O
R1
R3
N
H
N
O
R1
1
2
3
4
Entry
R1
R2
R3
R4
H
CH3
H
CH3
H
CH3
H
CH3
CH3
H
H
CH3
H
CH3
CH3
H
CH3
CH3
H
Products
Time (h)
Isolated yield (%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
5-CH3
5-CH3
5-F
H
H
CH3
CH3
H
H
H
H
H
H
H
H
H
H
CH3
H
H
H
4a
4b
4c
4d
4e
4f
4g
4h
4i
12
12
18
12
12
12
12
12
24
24
24
24
12
12
12
12
12
18
24
24
24
86
83
80
85
83
81
85
89
74
75
78
76
83
83
85
87
82
80
71
79
75
5-F
9
5-Cl
5-Br
6-Br
6-Br
H
10
11
12
13
14
15
16
17
18
19
20
21
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
4t
H
H
5-CH3
5-CH3
5-F
5-Br
6-Br
6-Br
H
H
H
H
CH3
4u
carried out for 1 h, the intermediate 3-(5-amino-3-methyl-1-
phenyl-1H-pyrazol-4-yl)-3-hydroxyindolin-2-one 7 was isolated
and characterized by spectroscopic methods. We were pleased to
find that the reaction of intermediate 7 with 2-mercaptoacetic acid
3a in the presence of p-TSA under the same reaction conditions
proceeded smoothly giving the desired product 4a in a yield similar
to that obtained in the one-pot reaction (Scheme 4).
O
O
CH3CN, 80
p-TSA, 12h
O
S
N
+
NH2
+
HS
COOH
N
R1
N
N
N
H
O
R1
1
5
3
6a 87%
6b
84%
3. Conclusion
Fig. 2. Synthesis of spirocyclic acenaphthyleneones 6.
In summary, an efficient multi-component tandem reaction to
give spiro[indoline thiazepines] has been developed. Unlike con-
ventional pentacyclic spirooxindole products, this new procedure
described in this paper is a very facile and practical method for the
synthesis of novel heptacyclic spirooxindole derivatives. The one-
pot operational simplicity and the high efficiency nature make this
new heterocycle synthetic strategy highly attractive and promising
for the access of compounds of potential biological interest.
intermediate, which might occur to afford 8. Then, 8 is attacked via
Michael addition of thioacid 3 to give the intermediate 9 followed
by cycloaddition, dehydration to form the desired product 4.
In order to prove the mechanism, when the reaction of 5-amino-
1-phenyl-3-methylpyrazole 1a, isatin 2a, 2-mercaptoacetic acid 3a
4. Experimental section
4.1. General
Melting points were determined in open capillaries and un-
corrected. IR spectra were recorded on a Varian F-1000 spectrom-
eter in KBr pellet. 1H NMR and 13C NMR spectra were obtained from
a solution in DMSO-d6 with Me4Si as internal standard using Varian
Invoa-400 MHz or Invoa-300 MHz spectrometer. HRMS analyses
were carried out using TOF-MS or GCT-TOF instrument.
4.2. General procedure for the synthesis of 4 and 6
A mixture of 5-amino-3-methylpyrazole (1 mmol), isatin or
acenaphthylene-1,2-dione (1 mmol), thioacid (1 mmol), and p-TSA
(30 mol %) in CH3CN (5 mL) was stirred at 80 ꢀC for 12e24 h. After
Fig. 3. The crystal structure of compound 4p.

H. Chen, D. Shi / Tetrahedron 67 (2011) 5686e5692
5689
Ph
N
N
N
H2N
NH2
O
N
OH
O
H+
Ph
1
OH
O
N
H
O
N
H
N
H
2
Ph
N
Ph
N
N
N
NH2
NH2
-H+
H+
-H2O
OH2
O
OH
O
N
H
N
H
7
Ph
N
Ph
N
Ph
N
N
H
N
NH2
OH
OH
HO
NH2
N
N
O
OH
HS
S
O
S
O
O
3
N
H
N
H
N
H
O
-H+
8
9
10
Ph
N
H
N
N
O
-H2O
S
O
N
H
4
Scheme 3. Proposed mechanism for the synthesis of spirooxindole derivatives 4.
completion of the reaction confirmed by TLC (eluent acetone/pe-
troleum ether, 1:2), the reaction mixture was cooled to room
temperature. Then, the solvent was removed under vacuum. The
solid was recrystallizated from CH3CN and ethanol to afford the
pure 4 or 6 as a white or yellow powder.
CH), 6.98e7.03 (m, 2H, ArH), 7.11 (d, J¼7.6 Hz, 1H, ArH), 7.33 (t,
J¼7.6 Hz, 1H, ArH), 7.41 (t, J¼7.2 Hz, 1H, ArH), 7.51 (t, J¼7.6 Hz, 2H,
ArH), 7.58 (d, J¼7.6 Hz, 2H, ArH), 9.98 (s, 1H, NH), 10.89 (s, 1H, NH).
13C NMR (75 MHz, DMSO-d6): dC 12.6, 15.9, 35.8, 49.9, 107.0, 110.9,
123.4, 125.4, 125.6, 128.1, 128.5, 129.7, 130.7, 137.6, 139.0, 142.0,
147.0, 173.4, 178.7. HRMS (ESI): m/z calcd for C21H18N4O2S: 391.1223
[MþH]þ, found: 391.1205.
4.2.1. 30-Methyl-10-phenyl-60,80-dihydrospiro[indoline-3,40-pyrazolo
[3,4-e][1,4]thiazepine]-2,70 (10H)-dione (4a). Mp: 256e257 ꢀC. IR
(KBr)
n
: 3364, 3150, 1707, 1584, 1523, 1476, 1400, 1319, 1206, 1134,
4.2.3. 1,30-Dimethyl-10-phenyl-60,80-dihydrospiro[indoline-3,40-pyr-
azolo[3,4-e][1,4]thiazepine]-2,70(10H)-dione (4c). Mp: 243e244 ꢀC.
IR (KBr) n: 3222, 3123, 2989, 2920,1710,1607,1533,1491,1367,1126,
757, 696 cmꢁ1. 1H NMR (300 MHz, DMSO-d6): dH 1.46 (s, 3H, CH3),
3.11 (d, J¼15.0 Hz, 1H, CH2), 4.54 (d, J¼15.0 Hz, 1H, CH2), 6.96e7.04
(m, 2H, ArH), 7.15 (d, J¼7.2 Hz, 1H, ArH), 7.32 (t, J¼7.8 Hz, 1H, ArH),
7.40 (t, J¼6.9 Hz, 1H, ArH), 7.47e7.56 (m, 4H, ArH), 9.94 (s, 1H, NH),
10.89 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6): dC 12.7, 30.8, 49.2,
106.5, 110.9, 123.4, 125.5, 125.6, 128.2, 129.0, 129.8, 130.7, 137.6,
139.0, 142.0, 147.2, 171.6, 178.5. HRMS [found: m/z 376.0993 (Mþ),
calcd for C20H16N4O2S: M, 376.0994].
1086, 932, 751, 694 cmꢁ1. 1H NMR (400 MHz, DMSO-d6): dH 1.38 (s,
3H, CH3), 3.15 (d, J¼15.2 Hz, 1H, CH2), 3.29 (s, 3H, CH3), 4.58 (d,
J¼14.8 Hz, 1H, CH2), 7.12 (t, J¼7.2 Hz, 1H, ArH), 7.19e7.24 (m, 2H,
ArH), 7.40e7.47 (m, 2H, ArH), 7.50e7.58 (m, 4H, ArH), 9.94 (s, 1H,
NH). 13C NMR (75 MHz, DMSO-d6): dC 12.7, 27.1, 31.0, 48.9, 106.4,
110.0, 124.1, 125.2, 125.6, 128.2, 128.3, 129.8, 130.8, 137.6, 139.0,
143.4, 147.1, 171.5, 176.8. HRMS (ESI): m/z calcd for C21H18N4O2S:
413.1043 [MþNa]þ, found: 413.1073.
4.2.2. 30,60-Dimethyl-10-phenyl-60,80-dihydrospiro[indoline-3,40-pyr-
azolo[3,4-e][1,4]thiazepine]-2,70(10H)-dione (4b). Mp: 270e271 ꢀC.
IR (KBr)
n
: 3232, 2975, 2926, 2884, 1712, 1617, 1522, 1473, 1378,
4.2.4. 1,30,60-Trimethyl-10-phenyl-60,80-dihydrospiro[indoline-3,40-pyr-
azolo[3,4-e][1,4]thiazepine]-2,70(10H)-dione (4d). Mp: 280e281 ꢀC. IR
(KBr) n: 3308, 1707, 1606, 1524, 1497, 1368, 1259, 1129, 1080, 934,
1264, 1209, 1077, 917, 756, 692 cmꢁ1. 1H NMR (400 MHz, DMSO-d6):
dH 1.27 (d, J¼7.2 Hz, 3H, CH3), 1.49 (s, 3H, CH3), 4.73 (q, J¼7.2 Hz, 1H,
H2N
OH
NH
S
HS
Ph
OH
O
CH3CN, 80
N
N
3a
O
O
+
N
NH2
N
p-TSA, 12h
p-TSA, 1h
N
H
O
N
H
O
N
Ph
N
Ph
N
H
O
1a
2a
7
4a
Scheme 4. Two-step synthesis of spirooxindole 4a.

5690
H. Chen, D. Shi / Tetrahedron 67 (2011) 5686e5692
758, 693 cmꢁ1. 1H NMR (400 MHz, DMSO-d6): dH 1.28 (d, J¼7.2 Hz,
3H, CH3), 1.40 (s, 3H, CH3), 3.29 (s, 3H, CH3), 4.75 (q, J¼7.2 Hz, 1H,
CH), 7.10 (t, J¼7.2 Hz, 1H, ArH), 7.18 (t, J¼8.0 Hz, 2H, ArH), 7.39e7.45
(m, 2H, ArH), 7.51 (t, J¼7.6 Hz, 2H, ArH), 7.58 (d, J¼8.0 Hz, 2H, ArH),
9.93 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6): dC 12.7, 15.9, 27.2,
36.0, 49.6, 107.0, 110.0, 124.1, 125.2, 125.6, 127.9, 128.1, 129.7, 130.8,
137.6, 139.0, 143.4, 146.8, 173.3, 177.1. HRMS (ESI): m/z calcd for
C22H20N4O2S: 427.1208 [MþNa]þ, found: 427.1199.
J¼7.2 Hz, 1H, CH), 7.02 (d, J¼8.4 Hz, 1H, ArH), 7.10 (s, 1H, ArH), 7.20
(d, J¼7.6 Hz, 1H, ArH), 7.38e7.44 (m, 2H, ArH), 7.52 (t, J¼7.6 Hz, 2H,
ArH), 7.58 (d, J¼8.0 Hz, 2H, ArH), 9.91 (s, 1H, NH), 10.99 (s, 1H, NH).
13C NMR (75 MHz, DMSO-d6): dC 12.7, 15.9, 35.9, 50.0, 106.4, 112.6,
125.2, 125.6, 127.2, 128.2, 129.7, 130.6, 130.7, 137.8, 139.0, 140.9,
146.9, 173.2, 178.3. HRMS (ESI): m/z calcd for C21H17ClN4O2S:
411.0677 [MþH]þ, found: 411.0663.
4.2.10. 5-Bromo-30-methyl-10-phenyl-60,80-dihydrospiro[indoline-
4.2.5. 30,5-Dimethyl-10-phenyl-60,80-dihydrospiro[indoline-3,40-pyr-
azolo[3,4-e][1,4]thiazepine]-2,70(10H)-dione (4e). Mp: 268e270 ꢀC.
3,40-pyrazolo[3,4-e][1,4]
thiazepine]-2,70(10H)-dione
(4j). Mp:
274e276 ꢀC. IR (KBr)
n: 3129, 2926, 1722, 1681, 1610, 1532, 1468,
IR (KBr)
n
: 3219, 2916, 1715, 1621, 1490, 1398, 1345, 1196, 1107, 921,
1401, 1206, 1162, 814, 766, 690 cmꢁ1. 1H NMR (400 MHz, DMSO-d6):
dH 1.51 (s, 3H, CH3), 3.22 (d, J¼14.8 Hz, 1H, CH2), 4.46 (d, J¼14.8 Hz,
1H, CH2), 6.98 (d, J¼8.4 Hz, 1H, ArH), 7.31 (s, 1H, ArH), 7.43 (t,
J¼7.2 Hz, 1H, ArH), 7.50e7.58 (m, 5H, ArH), 9.98 (s, 1H, NH), 11.09 (s,
1H, NH). 13C NMR (75 MHz, DMSO-d6): dC 12.7, 30.9, 49.5, 105.9,
113.1, 114.8, 125.7, 127.8, 128.3, 129.8, 131.8, 133.5, 137.7, 138.9, 141.2,
147.1, 171.4, 178.0. HRMS [found: m/z 456.0059 (Mþ), calcd for
C20H1581BrN4O2S: M, 456.0079].
811, 766, 692 cmꢁ1. 1H NMR (400 MHz, DMSO-d6): dH 1.49 (s, 3H,
CH3), 2.24 (s, 3H, CH3), 3.12 (d, J¼14.8 Hz, 1H, CH2), 4.55 (d,
J¼14.8 Hz, 1H, CH2), 6.88 (d, J¼8.0 Hz, 1H, ArH), 7.00 (s, 1H, ArH),
7.13 (d, J¼8.0 Hz, 1H, ArH), 7.42 (t, J¼6.8 Hz, 1H, ArH), 7.50e7.57 (m,
4H, ArH), 9.92 (s, 1H, NH), 10.77 (s, 1H, NH). 13C NMR (75 MHz,
DMSO-d6): dC 12.7, 21.2, 30.9, 49.3, 106.6, 110.7, 125.6, 125.8, 128.2,
129.0, 129.8, 131.0, 132.5, 137.5, 139.0, 139.5, 147.3, 171.7, 178.5.
HRMS (ESI): m/z calcd for C21H18N4O2S: 413.1043 [MþNa]þ, found:
413.1036.
4.2.11. 6-Bromo-30-methyl-10-phenyl-60,80-dihydrospiro[indoline-
3,40-pyrazolo[3,4-e][1,4]
thiazepine]-2,70(10H)-dione
(4k). Mp:
4.2.6. 30,5,60-Trimethyl-10-phenyl-60,80-dihydrospiro[indoline-3,40-
pyrazolo[3,4-e][1,4]thiazepine]-2,70(10H)-dione (4f). Mp: 193e194 ꢀC.
IR (KBr) n: 3383, 3220, 2979, 2925, 1706, 1593, 1495, 1373, 1255,
260e263 ꢀC. IR (KBr)
n: 3165, 3124, 3040, 2923, 1709, 1601, 1448,
1405, 1314, 1210, 1133, 1056, 953, 764, 687 cmꢁ1. 1H NMR (400 MHz,
DMSO-d6): dH 1.51 (s, 3H, CH3), 3.16 (d, J¼14.8 Hz, 1H, CH2), 4.50 (d,
J¼14.8 Hz,1H, CH2), 7.13 (d, J¼8.0 Hz,1H, ArH), 7.16 (s, 1H, ArH), 7.22
(d, J¼8.0 Hz, 1H, ArH), 7.42 (t, J¼7.2 Hz, 1H, ArH), 7.50e7.57 (m, 4H,
ArH), 9.93 (s, 1H, NH), 11.03 (s, 1H, NH). 13C NMR (100 MHz, DMSO-
d6): dC 12.7, 30.8, 49.0, 105.9, 113.8, 123.3, 125.6, 125.7, 126.1, 127.2,
128.4, 129.7, 137.7, 138.9, 143.5, 147.1, 171.4, 178.2. HRMS (ESI): m/z
calcd for C20H15BrN4O2S: 476.9991 [MþNa]þ, found: 377.0011.
1194, 1073, 912, 814, 765, 693 cmꢁ1. 1H NMR (400 MHz, DMSO-d6):
dH 1.26 (d, J¼6.0 Hz, 3H, CH3), 1.50 (s, 3H, CH3), 2.22 (s, 3H, CH3),
4.71e4.74 (m, 1H, CH), 6.87 (d, J¼7.6 Hz, 1H, ArH), 6.93 (s, 1H, ArH),
7.11 (d, J¼7.2 Hz, 1H, ArH), 7.41 (d, J¼6.8 Hz, 1H, ArH), 7.49e7.58 (m,
4H, ArH), 9.96 (s, 1H, NH), 10.75 (s, 1H, NH). 13C NMR (75 MHz,
DMSO-d6): dC 12.7, 15.9, 21.1, 35.8, 50.0, 107.1, 110.7, 125.5, 125.7,
128.1, 128.6, 129.7, 131.0, 132.5, 137.6, 139.1, 139.6, 147.1, 173.4, 178.6.
HRMS [found: m/z 404.1037 (Mþ), calcd for C22H20N4O2S: M,
404.1037].
4.2.12. 6-Bromo-30,60-dimethyl-10-phenyl-60,80-dihydrospiro[indo-
line-3,40-pyrazolo[3,4-e][1,4] thiazepine]-2,70(10H)-dione (4l). Mp:
280e282 ꢀC. IR (KBr)
n: 3385, 3230, 3058, 2928, 1726, 1679, 1606,
4.2.7. 5-Fluoro-30-methyl-10-phenyl-60,80-dihydrospiro[indoline-3,40-
pyrazolo[3,4-e][1,4]thiazepine]-2,70(10H)-dione (4g). Mp: 251e253 ꢀC.
IR (KBr) n: 3381, 3155, 2921, 1708, 1587, 1486, 1402, 1289, 1178, 1126,
1479, 1445, 1373, 1258, 1195, 1060, 946, 910, 767, 684 cmꢁ1. 1H NMR
(400 MHz, DMSO-d6): dH 1.28 (d, J¼7.2 Hz, 3H, CH3), 1.53 (s, 3H,
CH3), 4.70 (q, J¼7.2 Hz, 1H, CH), 7.06 (d, J¼8.0 Hz, 1H, ArH), 7.15 (s,
1H, ArH), 7.20 (d, J¼7.6 Hz, 1H, ArH), 7.41 (t, J¼7.2 Hz, 1H, ArH), 7.51
(t, J¼7.6 Hz, 2H, ArH), 7.58 (d, J¼7.6 Hz, 2H, ArH), 9.94 (s, 1H, NH),
10.99 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6): dC 12.7, 15.9, 35.9,
49.7, 106.4, 113.8, 123.3, 125.6, 126.2, 127.3, 127.9, 128.7, 129.7, 137.7,
139.0, 143.6, 146.9, 173.3, 178.4. HRMS (ESI): m/z calcd for
C21H17BrN4O2S: 491.0148 [MþNa]þ, found: 491.0141.
927, 859, 693 cmꢁ1. H NMR (400 MHz, DMSO-d6): dH 1.50 (s, 3H,
CH3), 3.20 (d, J¼14.8 Hz, 1H, CH2), 4.51 (d, J¼14.8 Hz, 1H, CH2),
6.98e7.02 (m, 1H, ArH), 7.07e7.09 (m, 1H, ArH), 7.16e7.27 (m, 1H,
ArH), 7.42 (t, J¼6.8 Hz, 1H, ArH), 7.50e7.56 (m, 4H, ArH), 10.02 (s, 1H,
NH), 10.97 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6): dC 12.7, 30.8,
49.7, 106.0, 112.0, 112.1, 112.7, 113.1, 117.1, 117.4, 125.7, 128.2, 129.8,
130.8, 131.0, 137.7, 138.2, 139.0, 147.1, 157.4, 160.6, 171.4, 178.4.
HRMS [found: m/z 394.0898 (Mþ), calcd for C20H15FN4O2S: M,
394.0900].
1
4.2.13. 10,30-Dimethyl-60,80-dihydrospiro[indoline-3,40-pyrazolo[3,4-
e][1,4]thiazepine]-2,70(10H)-dione (4m). Mp: 252e254 ꢀC. IR (KBr)
n:
3338, 3164, 3063, 2974, 2889, 2825, 1683, 1578, 1473, 1369, 1319,
4.2.8. 5-Fluoro-30,60-dimethyl-10-phenyl-60,80-dihydrospiro[indoline-
1226, 1173, 1092, 1048, 889, 741, 673 cmꢁ1 1H NMR (400 MHz,
.
3,40-pyrazolo[3,4-e][1,4]
thiazepine]-2,70(10H)-dione
(4h). Mp:
: 3382, 3222, 3065, 2928, 2980, 1710, 1592,
1486, 1373, 1259, 1178, 1073, 913, 860, 765, 693 cmꢁ1 1H NMR
DMSO-d6): dH 1.35 (s, 3H, CH3), 3.08 (d, J¼14.8 Hz, 1H, CH2), 3.66 (s,
3H, CH3), 4.37 (d, J¼14.8 Hz, 1H, CH2), 6.95e7.01 (m, 2H, ArH), 7.11
(d, J¼7.2 Hz, 1H, ArH), 7.30 (t, J¼7.6 Hz, 1H, ArH), 10.18 (s, 1H, NH),
10.85 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6): dC 12.4, 30.4, 36.3,
49.1, 104.9, 110.8, 123.2, 125.3, 129.1, 130.5, 137.7, 142.0, 144.7, 171.8,
178.6. HRMS [found: m/z 314.0835 (Mþ), calcd for C15H14N4O2S: M,
314.0837].
281e282 ꢀC. IR (KBr)
n
.
(400 MHz, DMSO-d6): dH 1.28 (d, J¼7.2 Hz, 3H, CH3), 1.53 (s, 3H,
CH3), 4.74 (q, J¼6.8 Hz, 1H, CH), 6.97e7.02 (m, 2H, ArH), 7.19 (t,
J¼8.8 Hz, 1H, ArH), 7.42 (t, J¼7.2 Hz, 1H, ArH), 7.51 (t, J¼7.6 Hz, 2H,
ArH), 7.57 (d, J¼7.6 Hz, 2H, ArH), 9.97 (s, 1H, NH), 10.91 (s, 1H, NH).
13C NMR (75 MHz, DMSO-d6): dC 12.7, 15.9, 35.8, 50.2, 106.4, 112.0,
112.1, 112.7, 113.0, 117.2, 117.5, 125.6, 128.1, 129.7, 130.1, 130.2, 137.7,
138.2, 139.0, 146.9, 157.3, 160.5, 171.6, 178.4. HRMS [found: m/z
408.1056 (Mþ), calcd for C21H17FN4O2S: M, 408.1056].
4.2.14. 10,30,60-Trimethyl-60,80-dihydrospiro[indoline-3,40-pyrazolo
[3,4-e][1,4]thiazepine]-2,70(10H)-dione (4n). Mp: 181e183 ꢀC. IR
(KBr) n: 3217, 3160, 2937, 2817, 1704, 1536, 1472, 1377, 1225, 1174,
1070, 998, 747, 672 cmꢁ1. 1H NMR (400 MHz, DMSO-d6): dH 1.24 (d,
J¼6.8 Hz, 3H, CH3), 1.38 (s, 3H, CH3), 3.66 (s, 3H, CH3), 4.53 (q,
J¼7.2 Hz, 1H, CH), 6.94e7.00 (m, 2H, ArH), 7.05 (d, J¼7.2 Hz, 1H,
ArH), 7.29 (t, J¼7.6 Hz, 1H, ArH), 10.11 (s, 1H, NH), 10.75 (s, 1H, NH).
13C NMR (75 MHz, DMSO-d6): dC 12.4, 15.9, 35.4, 36.2, 49.8, 105.4,
110.8, 123.3, 125.3, 128.7, 130.5, 137.7, 142.0, 144.5, 173.6, 178.7.
4.2.9. 5-Chloro-30,60-dimethyl-10-phenyl-60,80-dihydrospiro[indoline-
3,40-pyrazolo[3,4-e][1,4]
thiazepine]-2,70(10H)-dione
(4i). Mp:
270e272 ꢀC. IR (KBr)
n: 3288, 3148, 2930, 1722, 1699, 1596, 1524,
1472, 1362, 1253, 1211, 1072, 912, 825, 767 cmꢁ1. 1H NMR (400 MHz,
DMSO-d6): dH 1.29 (d, J¼7.2 Hz, 3H, CH3), 1.54 (s, 3H, CH3), 4.71 (q,

H. Chen, D. Shi / Tetrahedron 67 (2011) 5686e5692
5691
HRMS (ESI): m/z calcd for C16H16N4O2S: 329.1067 [MþH]þ, found:
CH2), 3.67 (s, 3H, CH3), 4.33 (d, J¼14.8 Hz,1H, CH2), 7.07 (d, J¼8.0 Hz,
1H, ArH), 7.13 (s, 1H, ArH), 7.18 (d, J¼7.6 Hz, 1H, ArH), 10.15 (s, 1H,
NH), 10.97 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6): dC 12.5, 30.4,
36.4, 48.9, 104.3, 113.7, 123.1, 126.0, 127.1, 128.5, 137.8, 143.5, 144.6,
171.6, 178.4. HRMS [found: m/z 391.9945 (Mþ), calcd for
C15H13N4O2S79Br: M, 391.9943].
329.1081.
4.2.15. 1,10,30,60-Tetramethyl-60,80-dihydrospiro[indoline-3,40-pyr-
azolo[3,4-e][1,4]thiazepine]-2,70 (10H)-dione (4o). Mp: 276e278 ꢀC.
IR (KBr)
n
: 3237, 3175, 3067, 2980, 2943, 1698, 1611, 1570, 1471, 1367,
1347, 1273, 1127, 1085, 924, 754, 690 cmꢁ1
.
1H NMR (400 MHz,
DMSO-d6): dH 1.25 (d, J¼7.2 Hz, 3H, CH3), 1.28 (s, 3H, CH3), 3.26 (s,
3H, CH3), 3.66 (s, 3H, CH3), 4.55 (q, J¼7.2 Hz, 1H, CH), 7.04e7.12 (m,
2H, ArH), 7.15 (d, J¼7.6 Hz, 1H, ArH), 7.40 (t, J¼7.6 Hz, 1H, ArH), 10.13
(s, 1H, NH). 13C NMR (75 MHz, DMSO-d6): dC 12.4, 15.9, 27.1, 35.6,
36.2, 49.5, 105.4, 109.9, 124.0, 125.1, 128.0, 130.7, 137.7, 143.4, 144.4,
173.5, 177.2. HRMS (ESI): m/z calcd for C17H18N4O2S: 343.1223
[MþH]þ, found: 343.1231.
4.2.21. 6-Bromo-10,30,60-trimethyl-60,80-dihydrospiro[indoline-3,40-
pyrazolo[3,4-e][1,4]thiazepine]-2,70(10H)-dione (4u). Mp: 208e210 ꢀC.
IR (KBr) n: 3236, 2933, 2813, 1712, 1610, 1577, 1480, 1450, 1374, 1314,
1273, 1237, 1173, 1059, 991, 929, 805, 682 cmꢁ1. 1H NMR (400 MHz,
DMSO-d6): dH 1.24 (d, J¼7.2 Hz, 3H, CH3), 1.41 (s, 3H, CH3), 3.66 (s, 3H,
CH3), 4.49 (q, J¼6.8 Hz, 1H, CH), 7.00 (d, J¼7.6 Hz, 1H, ArH), 7.12 (s, 1H,
ArH), 7.17 (d, J¼8.0 Hz, 1H, ArH), 10.14 (s, 1H, NH), 10.94 (s, 1H, NH). 13C
NMR (75 MHz, DMSO-d6): dC 12.5, 15.9, 35.4, 36.3, 49.6, 104.8, 113.7,
123.1,126.0,127.1,128.0,137.8,143.6,144.4,173.5,178.5. HRMS (ESI): m/z
calcd for C16H15BrN4O2S: 428.9991 [MþNa]þ, found: 428.9988.
4.2.16. 10,30,5-Trimethyl-60,80-dihydrospiro[indoline-3,40-pyrazolo
[3,4-e][1,4]thiazepine]-2,70(10H)-dione (4p). Mp: 260e262 ꢀC. IR
(KBr) n: 3296, 2989, 2939, 1710, 1572, 1528, 1491, 1378, 1300, 1233,
1127, 996,870, 813,676cmꢁ1.1HNMR(400MHz,DMSO-d6):dH 1.36(s,
3H, CH3), 2.21 (s, 3H, CH3), 3.06 (d, J¼14.8 Hz, 1H, CH2), 3.66 (s, 3H,
CH3), 4.37 (d, J¼15.2 Hz, 1H, CH2), 6.84 (d, J¼8.0 Hz, 1H, ArH), 6.92 (s,
1H, ArH), 7.09 (d, J¼8.0 Hz,1H, ArH),10.12 (s,1H, NH),10.68(s,1H, NH).
13C NMR (75 MHz, DMSO-d6): dC 12.5, 21.1, 30.5, 36.3, 49.1,105.1,110.6,
125.7,129.1,130.8,132.4,137.7,139.5,144.8,171.9,178.7. HRMS(ESI):m/
z calcd for C16H16N4O2S: 351.0886 [MþNa]þ, found: 351.0892.
4.2.22. 30-Methyl-10-phenyl-60,80-dihydro-2H-spiro[acenaphthylene-
1,40-pyrazolo[3,4-e][1,4]
thiazepine]-2,70(10H)-dione
(6a). Mp:
: 3229, 3110, 2990, 2915, 1683, 1582, 1410,
1252, 1144, 997, 932, 862, 778, 696 cmꢁ1 1H NMR (DMSO-d6,
400 MHz):
1.14 (s, 3H, CH3), 3.20 (d, J¼14.8 Hz, 1H, CH2), 4.48 (d,
258e260 ꢀC. IR (KBr)
n
.
d
J¼14.4 Hz, 1H, CH2), 7.43 (t, J¼6.8 Hz, 1H, ArH), 7.52e7.62 (m, 5H,
ArH), 7.75 (t, J¼7.2 Hz, 1H, ArH), 7.94 (t, J¼7.6 Hz, 1H, ArH), 8.10 (d,
J¼7.6 Hz, 1H, ArH), 8.18 (d, J¼6.4 Hz, 1H, ArH), 8.40 (d, J¼8.0 Hz, 1H,
ArH), 10.04 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6): dC 13.2, 32.0,
53.9,106.9,123.0,125.1,125.6,126.8,128.2,129.8,129.9,130.0,130.3,
130.7,133.4,137.8,137.9,139.0, 139.8,147.3,171.3,198.8. HRMS (ESI):
m/z calcd for C24H17N3O2S: 434.0934 [MþNa]þ, found: 434.0934.
4.2.17. 10,30,5,60-Tetramethyl-60,80-dihydrospiro[indoline-3,40-pyrazolo
[3,4-e][1,4]thiazepine]-2,70 (10H)-dione (4q). Mp: 260e261 ꢀC. IR
(KBr) n: 3195, 2973, 2929, 1702, 1625, 1573, 1538, 1492, 1373, 1236,
1067, 815, 764, 704 cmꢁ1. 1H NMR (400 MHz, DMSO-d6): dH 1.23 (d,
J¼7.2 Hz, 3H, CH3), 1.38 (s, 3H, CH3), 2.20 (s, 3H, CH3), 3.65 (s, 3H,
CH3), 4.51 (q, J¼7.2 Hz, 1H, CH), 6.84 (d, J¼8.0 Hz, 1H, ArH), 6.87 (s,
1H, ArH), 7.08 (d, J¼8.0 Hz, 1H, ArH), 10.16 (s, 1H, NH), 10.69 (s, 1H,
NH). 13C NMR (100 MHz, DMSO-d6): dC 11.8, 15.3, 20.5, 34.8, 35.6,
49.4, 105.0, 110.0, 125.1, 128.1, 130.2, 131.8, 137.1, 138.9, 144.0, 173.1,
178.2. HRMS (ESI): m/z calcd for C17H18N4O2S: 343.1223 [MþH]þ,
found: 343.1238.
4.2.23. 10,30-Dimethyl-60,80-dihydro-2H-spiro[acenaphthylene-1,40-
pyrazolo[3,4-e][1,4]thiazepine]-2,70(10H)-dione (6b). Mp: 268e270 ꢀC.
IR (KBr)
1367, 1256, 1144, 1000, 894, 782, 676 cmꢁ1
400 MHz):
1.03 (s, 3H, CH3), 3.15 (d, J¼14.8 Hz, 1H, CH2), 3.72 (s, 3H,
n
: 3239, 3177, 3055, 2945, 1678, 1572, 1450, 1367, 1256, 1450,
.
1H NMR (DMSO-d6,
d
CH3), 4.27 (d, J¼14.4 Hz, 1H, CH2), 7.50 (d, J¼5.6 Hz, 1H, ArH), 7.72 (t,
J¼6.8 Hz, 1H, ArH), 7.93 (d, J¼6.8 Hz, 1H, ArH), 8.07 (d, J¼7.6 Hz, 1H,
ArH), 8.13 (d, J¼6.0 Hz, 1H, ArH), 8.37 (d, J¼7.6 Hz, 1H, ArH), 10.24 (s,
1H, NH). 13C NMR (75 MHz, DMSO-d6): dC 13.0, 31.6, 36.4, 53.8, 105.2,
122.9, 124.9, 126.7, 129.9, 130.0, 130.1, 130.6, 133.3, 136.0, 139.7, 144.9,
171.5, 199.1. HRMS (ESI): m/z calcd for C19H15N3O2S: 372.0777
[MþNa]þ, found: 372.0782.
4.2.18. 5-Fluoro-10,30,60-trimethyl-60,80-dihydrospiro[indoline-3,40-
pyrazolo[3,4-e][1,4]thiazepine]-2,70(10H)-dione
(4r). Mp:
300-
202 ꢀC. IR (KBr)
n: 3267, 3118, 3069, 2988, 2934, 2862, 1697, 1571,
1485,1374,1258,1185,1065,1002, 811, 680 cmꢁ1.1H NMR (400 MHz,
DMSO-d6): dH 1.25 (d, J¼7.2 Hz, 3H, CH3),1.41 (s, 3H, CH3), 3.66 (s, 3H,
CH3), 4.53 (q, J¼7.2 Hz,1H, CH), 6.92 (d, J¼6.8 Hz,1H, ArH), 6.95e6.98
(m,1H, ArH), 7.14 (t, J¼8.8 Hz,1H, ArH),10.15 (s,1H, NH),10.81 (s,1H,
NH). 13C NMR (75 MHz, DMSO-d6): dC 12.4, 15.9, 35.4, 36.3, 50.1,
104.9, 111.8, 111.9, 112.6, 112.9, 117.0, 117.3, 130.3, 130.4, 137.8, 138.2,
144.5, 157.3, 160.5, 173.5, 178.7. HRMS (ESI): m/z calcd for
C16H15FN4O2S: 347.0973 [MþH]þ, found: 347.0986.
4.3. Procedure for preparation of intermediate 7
A mixture of 5-amino-1-phenyl-3-methylpyrazole 1a (2 mmol),
isatin 2a (2 mmol), 2-mercaptoacetic acid 3a (2 mmol), and p-TSA
(30 mol %) in CH3CN (5 mL) was stirred at 80 ꢀC for 1 h. The reaction
mixture was cooled to room temperature. Then, the precipitated
product was filtered, dried, and washed by 10 mL hot ethanol to
afford the pure 7 as a white powder.
4.2.19. 5-Bromo-10,30-dimethyl-60,80-dihydrospiro[indoline-3,40-
pyrazolo[3,4-e][1,4]thiazepine]-2,70(10H)-dione (4s). Mp: 220e
222 ꢀC. IR (KBr)
n: 3248,1709,1575,1472,1403,1312,1221,1169,1131,
1057, 865, 816, 709 cmꢁ1. 1H NMR (400 MHz, DMSO-d6): dH 1.39 (s,
3H, CH3), 3.14 (d, J¼14.8 Hz, 1H, CH2), 3.67 (s, 3H, CH3), 4.30 (d,
J¼14.8 Hz,1H, CH2), 6.94 (d, J¼8.4 Hz,1H, ArH), 7.24 (d, J¼2.0 Hz,1H,
ArH), 7.48e7.50 (m, 1H, ArH), 10.15 (s, 1H, NH), 10.98 (s, 1H, NH). 13C
NMR (100 MHz, DMSO-d6): dC 12.3, 30.3, 36.2, 49.0,104.1,112.7,114.5,
127.6, 131.5, 133.1, 137.7, 141.0, 144.4, 171.4, 178.0. HRMS (ESI): m/z
calcd for C15H13BrN4O2S: 393.0015 [MþH]þ, found: 393.0026.
4.3.1. 3-(5-Amino-3-methyl-1-phenyl-1H-pyrazol-4-yl)-3-
hydroxyindolin-2-one (7). Mp: 235e236 ꢀC. IR (KBr)
n: 3439, 3361,
3135, 3073, 2832, 1713, 1619, 1516, 1386, 1187, 1115, 1049, 934, 747,
692 cmꢁ1. 1H NMR (300 MHz, DMSO-d6): dH 1.42 (s, 3H, CH3), 5.28
(s, 2H, NH2), 6.61 (s, 1H, OH), 6.84 (d, J¼7.8 Hz, 1H, ArH), 6.97 (t,
J¼7.5 Hz, 1H, ArH), 7.21e7.30 (m, 3H, ArH), 7.45 (t, J¼7.5 Hz, 2H,
ArH), 7.55 (d, J¼7.5 Hz, 2H, ArH), 10.35 (s, 1H, NH). HRMS (ESI): m/z
calcd for C18H16N4O2: 321.1346 [MþH]þ, found: 321.1347.
4.2.20. 6-Bromo-10,30-dimethyl-60,80-dihydrospiro[indoline-3,40-
pyrazolo[3,4-e][1,4]thiazepine]-2,70(10H)-dione (4t). Mp: 296e
Acknowledgements
298 ꢀC. IR (KBr)
n: 3228, 3162, 3045, 2925, 1708, 1677, 1608, 1574,
1480, 1447, 1371, 1315, 1223, 1056, 993, 860, 806, 684 cmꢁ1. 1H NMR
We acknowledge the financial support from the Foundation of
(400 MHz, DMSO-d6): dH 1.39 (s, 3H, CH3), 3.11 (d, J¼15.2 Hz, 1H,
the Natural Science Foundation of China (No. 21072144), the Major

5692
H. Chen, D. Shi / Tetrahedron 67 (2011) 5686e5692
Mabuchi, H.; Tozawa, R.; Nakamura, M.; Sugiyama, Y.; Yukimasa, H. Bioorg. Med.
Chem. 2002, 10, 385e400; (h) Pei, Y. Z.; Lilly, M. J.; Owen, D. J.; D’Souza, L. J.;
Tang, X. Q.; Yu, J. H.; Nazarbaghi, R.; Hunter, A.; Anderson, C. M.; Glasco, S.; Ede,
N. J.; James, I. W.; Maitra, U.; Chandrasekaran, S.; Moos, W. H.; Ghosh, S. S. J. Org.
Chem 2003, 68, 92e103; (i) Elmaati, T. M. A.; El-Taweel, F. M. J. Chin. Chem. Soc.
2003, 59, 413e418 (Taipei, Taiwan); (j) Angibaud, P.; Bourdrez, X.; Devine, A.;
End, D. W.; Freyne, E.; Ligny, Y.; Muller, P.; Mannens, G.; Pilatte, I.; Poncelet, V.;
Skrzat, S.; Smets, G.; Van Dun, J.; Van Remoortere, P.; Venet, M.; Wouters, W.
Bioorg. Med. Chem. Lett. 2003, 13, 1543e1547; (k) Neo, A. G.; Marcos, C. F.;
Marcaccinib, S.; Pepino, R. Tetrahedron Lett. 2005, 46, 7977e7979; (l) Ilyn, A. P.;
Loseva, M. V.; Vvedensky, V. Y.; Putsykina, E. B.; Tkachenko, S. E.; Kravchenko,
D. V.; Khvat, A. V.; Krasavin, M. Y.; Ivachtchenko, A. V. J. Org. Chem. 2006, 71,
Basic Research Project of the Natural Science Foundation of the
Jiangsu Higher Education Institutions (No. 10KJA150049), A Project
Funded by the Priority Academic Project Development of Jiangsu
Higher Education Institutions and the Foundation of Key Laboratory
of Organic Synthesis of Jiangsu Province (No. JSK0812).
References and notes
1. (a) Orru, R. V. A.; de Greef, M. Synthesis 2003, 1471e1499; (b) Balme, G.; Bos-
€
sharth, E.; Monteiro, N. Eur. J. Org. Chem. 2003, 4101e4111; (c) Brase, S.; Gil, C.;
ꢀ
€
2811e2819; (m) Sarabia, F.; Chammaa, S.; García-Castro, M.; Martín-Galvez, F.
Knepper, K. Bioorg. Med. Chem. 2002, 10, 2415e2437; (d) Domling, A.; Ugi, I.
Chem. Commun. 2009, 5763e5765; (n) Tu, S. J.; Cao, X. D.; Hao, W. J.; Zhang, X.
H.; Yan, S.; Wu, S. S.; Han, Z. G.; Shi, F. Org. Biomol. Chem. 2009, 7, 557e563.
8. Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209e2219.
9. Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46, 8748e8758.
10. Trost, B. M.; Brennan, M. K. Synthesis 2009, 3003e3025.
Angew. Chem., Int. Ed. 2000, 39, 3168e3210.
2. Terrett, N. K. Combinatorial Chemistry; Oxford University: New York, NY, 1998.
3. (a) Nair, V.; Vinod, A. U.; Rajesh, C. J. Org. Chem. 2001, 66, 4427e4429; (b) List,
B.; Castello, C. Synlett 2001, 1687e1689; (c) Shestopalov, A. M.; Emeliyanova, Y.
M.; Shestopalov, A. A.; Rodinovskaya, L. A.; Niazimbetova, Z. I.; Evans, D. H. Org.
Lett. 2002, 4, 423e425; (d) Bertozzi, F.; Gustafsson, M.; Olsson, R. Org. Lett.
2002, 4, 3147e3150; (e) Yuan, Y.; Li, X.; Ding, K. Org. Lett. 2002, 4, 3309e3311;
(f) Cheng, J. F.; Chen, M.; Arrhenius, T.; Nadzen, A. Tetrahedron Lett. 2002, 43,
6293e6295; (g) Huma, H. Z. S.; Halder, R.; Kalra, S. S.; Das, J.; Iqbal, J. Tetra-
hedron Lett. 2002, 43, 6485e6488; (h) Bora, U.; Saikia, A.; Boruah, R. C. Org. Lett.
2003, 5, 435e438; (i) Dallinger, D.; Gorobets, N. Y.; Kappe, C. O. Org. Lett. 2003,
5, 1205e1208.
4. (a) Skiles, J. W.; Suh, J. T.; Williams, B. E.; Menard, P. R.; Barton, J. N.; Love, B.;
Jones, H.; Neiss, E. S.; Schwab, A.; Mann, W. S. J. Med. Chem. 1986, 29, 784e796;
(b) Crescenza, A.; Botta, M.; Corelli, F.; Santini, A.; Tafi, A. J. Org. Chem. 1999, 64,
3019e3025; (c) Umemiya, H.; Fukasawa, H.; Ebisawa, M.; Eyrolles, L.; Kawachi,
E.; Eisenmann, G.; Gronemeyer, H.; Hashimoto, Y.; Shudo, K.; Kagechika, H.
J. Med. Chem. 1997, 40, 4222e4234; (d) Venkatesan, A. M.; Gu, Y.; Dos Santos, O.;
Abe, T.; Agarwal, A.; Yang, Y.; Petersen, P. J.; Weiss, W. J.; Mansour, T. S.; Nukaga,
M.; Hujer, A. M.; Bonomo, R. A.; Knox, J. R. J. Med. Chem. 2004, 47, 6556e6568.
5. (a) Malli, R.; Frieden, M.; Trenker, M.; Graier, W. F. J. Biol. Chem. 2005, 280,
12114e12122; (b) Neamati, N.; Turpin, J. A.; Winslow, H. E.; Christensen, J. L.;
Williamson, K.; Orr, A.; Rice, W. G.; Pommier, Y.; Garofalo, A.; Brizzi, A.; Cam-
piani, G. J. Med. Chem. 1999, 42, 3334e3341; (c) Maruenda, H.; Johnson, F.
J. Med. Chem. 1995, 38, 2145e2151; (d) Garofalo, A.; Campiani, G.; Fiorini, I.;
Nacci, V. Farmaco 1993, 48, 275e283.
11. (a) Fensome, A.; Adams, W. R.; Adams, A. L.; Berrodin, T. J.; Cohen, J.; Huselton,
C.; Illenberger, A.; Kern, J. C.; Hudak, V. A.; Marella, M. A.; Melenski, E. G.;
McComas, C. C.; Mugford, C. A.; Slayden, O. D.; Yudt, M.; Zhang, Z.; Zhang, P.;
Zhu, Y.; Winneker, R. C.; Wrobel, J. E. J. Med. Chem. 2008, 51, 1861e1873; (b)
Teno, N.; Masuya, K.; Ehara, T.; Kosaka, T.; Miyake, T.; Irie, O.; Hitomi, Y.; Mat-
suura, N.; Umemura, I.; Iwasaki, G.; Fukaya, H.; Toriyama, K.; Uchiyama, N.;
Nonomura, K.; Sugiyama, I.; Kometani, M. J. Med. Chem. 2008, 51, 5459e5462.
12. Numata, A.; Takahashi, C.; Ito, Y.; Takada, T.; Kawai, K.; Usami, Y.; Matsumura,
E.; Imachi, M.; Ito, T.; Hasegawa, T. Tetrahedron Lett. 1993, 34, 2355e2358.
13. Tsuda, M.; Kasai, Y.; Komatsu, K.; Sone, T.; Tanaka, M.; Mikami, Y.; Kobayashi, J.
Org. Lett. 2004, 6, 3087e3089.
14. Mugishima, T.; Tsuda, M.; Kasai, Y.; Ishiyama, H.; Fukushi, E.; Kawabata, J.;
Watanabe, M.; Akao, K.; Kobayashi, J. J. Org. Chem. 2005, 70, 9430e9435.
15. (a) Reifschneider, W.; Bisabari-Ershadi, B.; Dripps, J. E.; Bonron, J. B. U.S. Patent
5,075,293, 1991; Chem. Abstr. 1991, 116, 129249f; (b) Rovnyak, G. C.; Narayanan,
V. L.; Haugwitz, R. D. U.S. Patent 4,053,613, 1975; Chem. Abstr. 1978, 88, 22892;
(c) Ali, S.; Alam, M. Arch. Pharmacal Res. 1994, 17, 131e133.
16. (a) Rajopadhye, M.; Popp, F. D. J. Heterocycl. Chem. 1984, 21, 289e291; (b) Ra-
jopadhye, M.; Popp, F. D. J. Heterocycl. Chem. 1985, 22, 93e96; (c) Popp, F. D.;
Rajopadhye, M.; Brown, D. S.; Waddington, D.; Uff, B. C. J. Heterocycl. Chem.
1987, 24, 261e265; (d) Rajopadhye, M.; Popp, F. D. J. Heterocycl. Chem. 1987, 24,
1637e1642; (e) Azizian, J.; Morady, A. V.; Jadidi, K.; Mehrdad, M.; Sarrafi, Y.
Synth. Commun. 2000, 30, 537e542; (f) Jain, S. C.; Sinha, J.; Bhagat, S.; Errington,
W.; Olsen, C. E. Synth. Commun. 2003, 33, 563e577; (g) Dandia, A.; Singh, R.;
Arya, K. Org. Prep. Proced. Int. 2003, 35, 401e408; (h) Dandia, A.; Arya, K.; Sati,
M.; Gautam, S. Tetrahedron 2004, 60, 5253e5258; (i) Jain, M.; Khanna, P.;
Saxena, A.; Bhagat, S.; Olsen, C. E.; Jain, S. C. Synth. Commun. 2006, 36,
1863e1872; (j) Mashelkar, U. C.; Rane, D. M.; Kenny, R. S. J. Heterocycl. Chem.
2008, 45, 865e872; (k) Pandey, M.; Raghuvanshi, D. S.; Singh, K. N. J. Heterocycl.
Chem. 2009, 46, 49e53.
6. (a) Boulware, S. L.; Bronstein, J. C.; Nordby, E. C.; Weber, P. C. Antiviral Res. 2001, 51,
111e125; (b) Cale, A. D.; Gero, T. W.; Walker, K. R.; Lo, Y. S.; Welstead, W. J.; Jaques,
L. W.; Johnson, A. F.; Leonard, C. A.; Nolan, J. C.; Johnson, D. N. J. Med. Chem. 1989,
32, 2178e2199; (c) Nakao, T.; Tanaka, H.; Yamato, H.; Akagi, T.; Takehara, S. U.S.
Patent 5,141,930, 1991; Chem. Abstr. 1992, 116, 194290b; (d) Schlosser, K. M.;
Krasutsky, A. P.; Hamilton, H. W.; Reed, J. E.; Sexton, K. Org. Lett. 2004, 6, 819e821.
ꢀ
7. (a) Uskokovic, M.; Grethe; Iacobelli, J.; Wenner, W. J. Org. Chem. 1965, 30,
3111e3114; (b) Swett, L. R.; Ratajczyk, J. D.; Nordeen, C. W.; Aynilian, G. H.
J. Heterocycl. Chem. 1975, 12, 1137e1142; (c) Joshi, K. C.; Pathak, V. N.; Garg, U.
J. Heterocycl. Chem. 1980, 17, 789e791; (d) Joshi, K. C.; Dubey, K.; Dandia, A.
Heterocycles 1981, 16, 71e76; (e) Yang, X. J.; Buzon, L.; Hamanaka, E.; Liu, K. K.-C.
Tetrahedron: Asymmetry 2000, 11, 4447e4450; (f) Manthorpe, J. M.; Gleason, J. L.
J. Am. Chem. Soc. 2001, 123, 2091e2092; (g) Miki, T.; Kori, M.; Fujishima, A.;
17. Chen, H.; Shi, D. Q. J. Comb. Chem. 2010, 12, 571e576.
18. (a) Li, Y. L.; Chen, H.; Shi, C. L.; Shi, D. Q.; Ji, S. J. J. Comb. Chem. 2010, 12,
231e237; (b) Liu, H.; Dou, G. L.; Shi, D. Q. J. Comb. Chem. 2010, 12, 292e294; (c)
Liu, H.; Dou, G. L.; Shi, D. Q. J. Comb. Chem. 2010, 12, 633e637.