Efficient one-pot synthesis of spirooxindole derivatives catalyzed by L-proline in aqueous medium

Article abstract of DOI:10.1021/cc9001185

An efficient one-pot synthesis of spirooxindole derivatives by three-component reaction of isatins, malononitrile (cyanoacetic ester) and 1,3-dicarbonyl compounds in water in the presence of L-proline is reported. This new protocol has the advantages of e

Full text of DOI:10.1021/cc9001185

J. Comb. Chem. 2010, 12, 231–237
231
Efficient One-Pot Synthesis of Spirooxindole Derivatives Catalyzed by
L-Proline in Aqueous Medium
Yuling Li, Hui Chen, Chunling Shi, Daqing Shi,* and Shunjun Ji
Key Laboratory of Organic Synthesis of Jiangsu ProVince, College of Chemistry, Chemical Engineering
and Materials Science, Soochow UniVersity, Suzhou 215123, P. R. China
ReceiVed August 5, 2009
An efficient one-pot synthesis of spirooxindole derivatives by three-component reaction of isatins,
malononitrile (cyanoacetic ester) and 1,3-dicarbonyl compounds in water in the presence of L-proline is
reported. This new protocol has the advantages of environmental friendliness, higher yields, shorter reaction
times, low cost, and convenient operation.
1. Introduction
effects could strongly enhance the rate of several organic
reactions, rediscovered the use of water as a solvent in
organic chemistry in the 1980s. There has been growing
recognition that water is an attractive medium for many
organic reactions18 and many MCRs in aqueous medium
have been reported.19 However, to the best of our knowl-
edge,20 there have been few reports about the synthesis of
spirooxindole derivatives in aqueous medium. As a conse-
quence of our interest in the aqueous medium organic
synthesis21 and our continual work on the synthesis of indole
derivatives22 guided by the observation that the presence of
two or more different heterocyclic moieties in a single
molecule often enhances the biocidal profile remarkably, we
investigated an efficient one-pot synthesis spirooxindole
derivatives catalyzed by L-proline in aqueous medium.
Multicomponent reactions (MCRs), in which multiple
reactions are combined into the synthetic operation have been
used extensively to form carbon-carbon bonds in the
synthetic chemistry.1 Such reactions offer a wide range of
possibilities for the efficient construction of highly complex
molecules in a single procedural 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 development in three- and four-
component reactions and great efforts continue to be made
to develop new MCRs.3
The indole nucleus is probably the most well-known
heterocycle, a common and important feature of a variety
of natural products and medicinal agents.4 Compounds
carrying the indol moiety exhibit antibacterial and antifungal
activities.5 Furthermore, it has been reported that sharing of
the indole 3-carbon in the formation of spiroindoline deriva-
tives highly enhances biological activity.6 The spirooxindole
system is the core structure of many pharmacological agents
and natural alkaloids.7
Small organic molecules like cinchona alkaloids, L-proline,
and its derivatives are readily commercially available
catalysts and have been used in various transformations with
excellent yields.8 L-Proline has been found to be very
effective in enamine based direct catalytic asymmetric aldol,9
Mannich,10 Michael,11 Diels-Alder,12 R-amination reac-
tions,13 and Knoevenagel type reaction,14 and unsymmetric
Biginelli reaction.15 More recently, L-proline and its deriva-
tives have been used in multicomponent reactions.16
The need to reduce the amount of toxic waste and
byproduct arising from chemical process requires increasing
emphasis on the use of less toxic and environmentally
compatible materials in the design of new synthetic methods.
One of the most promising approaches is using water as
reaction media. Breslow,17 who showed that hydrophobic
2. Results and Discussion
First, to study the reaction in water, we tested the reaction
of isatin 1{1}, malononitrile 2{1}, and tetronic acid 3{1}
as a simple model substrate in various additives (Scheme
1). The results are shown in Table 1.
We examined this reaction in the absence and presence
of several additives. The results are summarized in Table 1.
It was found that when the reaction was carried out without
any additives only trace product was detected (Table 1, entry
1). p-TSA (p-toluenesulfonic acid) could not catalyze this
reaction (Table 1, entry 2). Some bases such as NaHCO3,
K2CO3 can catalyze this reaction with moderate yields (Table
1, entries 3-4). When some surfactants, for example, SDS
(sodium dodecyl sulfate), TEBA (triethylbenzylammonium
chloride), TBAB (tetrabutylammonium bromide), and CTAB
(cetyltrimethylammonium bromide) were used in this reac-
Scheme 1. Model Reaction
* To whom correspondence should be addressed. E-mail:
dqshi@suda.edu.cn.
10.1021/cc9001185  2010 American Chemical Society
Published on Web 01/19/2010

232 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 2
Table 1. Optimization of Reaction Conditionsa
Li et al.
entry
additive (mol %)
T (°C)
time (min)
yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
none
80
80
80
80
80
80
80
80
80
40
60
70
90
80
80
80
80
80
80
80
80
30
240
120
120
240
30
120
90
15
50
25
15
15
15
15
15
5
10
20
30
60
trace
trace
62
68
72
77
77
83
92
66
74
79
90
73
90
91
51
78
92
91
92
p-TSA (10%)
NaHCO3 (10%)
K2CO3 (10%)
SDS (10%)
TEBA (10%)
TBAB (10%)
CTAB (10%)
L-proline (10%)
L-proline (10%)
L-proline (10%)
L-proline (10%)
L-proline (10%)
L-proline (5%)
L-proline (15%)
L-proline (20%)
L-proline (10%)
L-proline (10%)
L-proline (10%)
L-proline (10%)
L-proline (10%)
a The reaction was carried out with isatin, malononitrile, and tetronic
acid in water. b Isolated yields.
tion system, the products was obtained in moderate yields
(Table 1, entries 5-8). The best result was obtained when
L-proline was used according to the yield and the reaction
time (Table 1, entry 9). So L-proline was chosen as the
catalyst for this reaction.
Figure 1. Diversity of reagents.
Table 2. Synthesis of Spirooxindole Derivatives 4 in Aqueous
Medium Catalyzed by L-Proline
To optimize the reaction temperature, the reactions were
carried out at different temperatures ranging from 40 to 90
°C. We found that the yield of product 4{1,1,1} was
improved and the reaction time was shortened as the
temperature was increased to 80 °C. The yield plateau when
temperature was further increased to 90 °C (Table 1, entries
10-13). Therefore, the most suitable reaction temperature
is 80 °C.
We also evaluated the amount of L-proline required for
this reaction. It was found that when increasing the amount
of the L-proline from 5 to 10, 15, and 20 mol %, the yields
increased from 73 to 92, 90, and 91%, respectively (Table
1, entries 14-16). Using 10 mol % L-proline in water is
sufficient to push this reaction forward. More amounts of
the additive did not improve the yields.
Finally, we studied the yields according to reaction times.
It can be seen from the Table 1 that this reaction was
completed within 15 min. (Table 1, entries 17-21).
After optimization of the conditions, to delineate this
approach, particularly in regard to library construction, this
methodology was evaluated by using different isatins, 1,3-
dicarbonyl compounds and malononitrile or cyanoacetic
ester. Three substituted isatins 1{1-3}, four malononitrile
or cyanoacetic esters 2{1-4}, and eight 1,3-dicarbonyl
compounds 3{1-8} were chosen for the library validation
(Figure 1). Corresponding spirooxindole derivatives 4 were
synthesized by the one-pot, three-component reaction of
isatin 1, malononitrile (cyanoacetic ester) 2 and 1,3-dicar-
bonyl compound 3 in good yields at 80 °C in water in the
presences of L-proline. The results are shown in Table 2. As
shown in Table 2, it was found that this method works with
a wide variety of substrates. A series of substituted isatins
and different 1,3-dicarbonyl compounds were used in this
.
entry
products 4
time (min)
yield (%)
mp (°C)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
4{1,1,1}
4{1,1,2}
4{1,1,3}
4{1,1,4}
4{1,1,5}
4{1,1,6}
4{1,1,7}
4{1,2,2}
4{1,2,3}
4{1,2,6}
4{1,2,7}
4{1,2,8}
4{1,3,2}
4{1,4,2}
4{2,1,1}
4{2,1,2}
4{2,1,3}
4{2,1,4}
4{2,1,5}
4{2,1,6}
4{2,1,7}
4{3,1,1}
4{3,1,2}
4{3,1,3}
4{3,1,4}
4{3,1,5}
4{3,1,6}
4{3,1,7}
15
20
11
38
20
12
15
30
45
45
60
60
30
30
15
17
18
40
17
20
24
10
11
20
42
10
17
24
92
94
93
94
90
95
94
81
76
79
83
85
78
80
94
95
94
94
91
94
95
94
93
93
93
90
94
93
238-240
290-292
298-299
278-280
258-260
236-237
>300
256-258
253-255
235-237
251-253
>300
230-232
251-253
252-254
>300
294-296
>300
256-258
226-228
>300
266-268
>300
290-292
>300
262-264
225-226
>300
reaction. Additionally, the reaction with malononitrile or
cyanoacetic esters also proceeded smoothly; however, the
reaction time of cyanoacetic esters with isatins and 1,3-
dicarbonyl compounds was longer than those of malononi-

One-Pot Synthesis of Spirooxindole Derivatives
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 2 233
Table 3. Studies on the Reuse of Reaction Solution in the
Preparation of 4{1,1,1}
4. Experimental Section
Typical Procedure for Preparation of Spirooxindole
Derivatives (4{1-2-3}). A mixture of isatin 1{1-3} (1
mmol), malononitrile or cyanoacetic esters 2{1-4} (1
mmol), 1,3-dicarbonyl compounds 3{1-8} (1 mmol), and
L-proline (0.1 mmol) in water (2 mL) was stirred at 80 °C
for 15-60 min. After completion of the reaction confirmed
by TLC, the reaction mixture was cooled to room temper-
ature. Then, the precipitated product was filtered and washed
with water and cooled ethanol to afford the pure 4{1-2-3}.
2-Amino-2′,5-dioxo-5,7-dihydrospiro[furo[3,4-b]pyran-
4,3′-indoline]-3-carbonitrile 4{1,1,1}. mp: 238-240 °C. IR
(KBr) ν: 3341, 3247, 3147, 2198, 1748, 1653, 1619, 1472,
round
1
2
3
4
5
6
7
8
9 10 11 12 13
yield (%) 92 93 92 91 93 92 90 90 91 89 88 84 79
trile, which is probably due to the lower reactivities of the
cyanoacetic esters.
Given the large number of commercially available isatins,
malononitrile or cyanoacetic esters, and 1,3-dicarbonyl
compounds, the present method should be applicable to
synthesis of libraries with high diversity. We expect this
method to find extensive application in the filed of combi-
natorial chemistry and drug discovery.
Apart from the mild conditions of the process and its
excellent results, the simplicity of product isolation and the
possibility to recover and recycle the L-proline as catalyst
offer a significant advantage. Because L-proline is soluble
in reaction mediumswater and the desired products is less
soluble in water, the products can be directly separated by
cooling to room temperature and filtering after the reaction
was completed. The filtrate containing L-proline can directly
be recovered and recycled. Studies using 1{1}, 2{1}, and
3{1} as model substrates showed that the recovered filterate
could be successively recycled in subsequent reactions
without any decrease of yields (Table 3). It is shown that
reaction solution have been recovered nineth rounds, catalytic
efficiency of L-proline in reaction solution still be noted that
even in the nineth round. While when the filterate was
recovered thirteenth the catalyst started to lose effect because
of the losing of the catalyst.
Proposed mechanism for the synthesis of spirooxindole
derivative 4{1,1,1} was described in Scheme 2. We suggest
that L-proline catalyze the formation of iminium ion 5 in a
reversible reaction with isatin 1{1}. The higher reactivity
of the iminium ion compared to the carbonyl species could
facilitate Knoevenagel condensation between isatin 1{1} and
malononitrile 2{1}, via intermediate 6 and after the elimina-
tion of L-proline, 7 might be produced as an intermediate.
Then, 7 is attacked via Michael addition of tetronic acid 3{1}
to give the intermediate 8, followed by the cycloaddition of
hydroxyl group up to the cyano moiety to form the desired
produst 4{1,1,1}.
1
1378, 1030, 918 cm-1. H NMR (DMSO-d6, 400 MHz) δ:
5.10 (d, J ) 16.8 Hz, 1H, CH2), 5.20 (d, J ) 16.8 Hz, 1H,
CH2), 6.88 (d, J ) 7.6 Hz, 1H, ArH), 7.01 (d, J ) 7.6 Hz,
1H, ArH), 7.20 (d, J ) 7.6 Hz, 1H, ArH), 7.26 (t, J ) 7.6
Hz, 1H, ArH), 7.70 (s, 2H, NH2), 10.71 (s, 1H, NH). HRMS
[Found m/z 295.0609 (M+); Calcd for C15H9N3O4 M,
295.0593].
2-Amino-7,7-dimethyl-2′,5-dioxo-5,6,7,8-tetrahydrospi-
ro[chromene-4,3′-indoline]-3-carbonitrile 4{1,1,2}. mp:
290-292 °C. IR (KBr) ν: 3377, 3312, 3144, 2192, 1723,
1683, 1656, 1472, 1348, 1223, 1055 cm-1. 1H NMR (DMSO-
d6, 400 MHz) δ: 1.01 (s, 3H, CH3), 1.04 (s, 3H, CH3), 2.10
(d, J ) 16.0 Hz, 1H, CH2), 2.18 (d, J ) 16.0 Hz, 1H, CH2),
2.54 (d, J ) 18.0 Hz, 1H, CH2), 2.59 (d, J ) 18.0 Hz, 1H,
CH2), 6.79 (d, J ) 7.6 Hz, 1H, ArH), 6.89 (t, J ) 7.2 Hz,
1H, ArH), 6.98 (d, J ) 7.2 Hz, 1H, ArH), 7.14 (t, J ) 7.6
Hz, 1H, ArH), 7.24 (s, 2H, NH2), 10.40 (s, 1H, NH). HRMS
[Found m/z 335.1281 (M+); Calcd for C19H17N3O3 M,
335.1270].
2-Amino-2′,5-dioxo-5,6,7,8-tetrahydrospiro[chromene-
4,3′-indoline]-3-carbonitrile 4{1,1,3}. mp: 298-299 °C. IR
(KBr) ν: 3370, 3286, 3134, 2191, 1709, 1679, 1655, 1604,
1
1471, 1351, 1211, 1076, 1011 cm-1. H NMR (DMSO-d6,
400 MHz) δ: 1.91-1.95 (m, 2H, CH2), 2.20-2.25 (m, 2H,
CH2), 2.66 (t, J ) 6.0 Hz, 2H, CH2), 6.78 (d, J ) 7.6 Hz,
1H, ArH), 6.89 (t, J ) 7.6 Hz, 1H, ArH), 7.00 (d, J ) 7.2
Hz, 1H, ArH), 7.14 (t, J ) 7.6 Hz, 1H, ArH), 7.22 (s, 2H,
NH2), 10.40 (s, 1H, NH). 13C NMR (DMSO-d6, 400 MHz)
δ: 20.48, 27.44, 37.07, 47.58, 58.23, 109.84, 112.56, 118.06,
122.35, 123.88, 128.83, 135.22, 142.66, 159.32, 166.74,
178.84, 195.72. HRMS [Found m/z 307.0957 (M+); Calcd
for C17H13N3O3 M, 307.0957].
It is noticed that the compounds obtained are racemic ones.
L-Proline plays a key role in this reaction. According to above
proposed mechanism L-proline only catalyzes the formation
of intermediate 7 and not takes part in the generation of this
spiranic stereocenter. So the stereoselection is not achieved.
In this study, all the products were characterized by
2′-Amino-7′-methyl-2,5′-dioxo-5′H-spiro[indoline-3,4′-
pyrano[4,3-b]pyran]-3′-carbonitrile 4{1,1,4}. mp: 278-280
°C. IR (KBr) ν: 3378, 3184, 2198, 1743, 1699, 1664, 1612,
1
melting point, IR, and H NMR spectral data, as well as
1
1472, 1370, 1170, 1094 cm-1. H NMR (DMSO-d6, 400
HRMS.
MHz) δ: 2.24 (s, 3H, CH3), 6.36 (s, 1H, CH), 6.82 (d, J )
7.6 Hz, 1H, ArH), 6.93 (t, J ) 7.2 Hz, 1H, ArH), 7.11 (d, J
) 7.6 Hz, 1H, ArH), 7.20 (t, J ) 8.0 Hz, 1H, ArH), 7.46 (s,
2H, NH2), 10.59 (s, 1H, NH). HRMS [Found m/z 321.0750
(M+); Calcd for C17H11N3O4 M, 321.0750].
3. Conclusion
In conclusion, we have described an efficient one-pot
three-component reaction of isatin, malononitrile (cyanoacetic
ester) and 1,3-dicarbonyl compound for the synthesis of
spirooxindole derivatives catalyzed by L-proline in aqueous
medium. This new method has the advantages of higher
yields, mild reaction conditions, shorter reaction time,
convenient procedure and environmental friendliness.
Ethyl 2′-Amino-3′-cyano-6′-methyl-2-oxospiro[indoline-
3,4′-pyran]-5′-carboxylate 4{1,1,5}. mp: 258-260 °C. IR
(KBr) ν: 3482, 3282, 3159, 2192, 1712, 1619, 1597, 1471,
1
1382, 1289, 1212, 1073 cm-1. H NMR (DMSO-d6, 400
MHz) δ: 0.78 (t, J ) 6.8 Hz, 3H, CH3), 2.32 (s, 3H, CH3),

234 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 2
Li et al.
Scheme 2. Plausible Mechanism for the Reaction of Isatin and Malononitrile with Tetronic Acid
3.75-3.79 (m, 2H, CH2), 6.80 (d, J ) 7.6 Hz, 1H, ArH),
6.93 (t, J ) 7.2 Hz, 1H, ArH), 7.06 (d, J ) 7.2 Hz, 1H,
ArH), 7.15 (s, 2H, NH2), 7.18 (t, J ) 7.6 Hz, 1H, ArH),
10.40 (s, 1H, NH). 13C NMR (DMSO-d6, 100 MHz) δ: 13.66,
19.24, 49.63, 57.18, 60.94, 105.31, 110.01, 118.18, 122.54,
124.06, 129.23, 135.22, 142.81, 159.21, 159.61, 165.17,
179.28. HRMS [Found m/z 325.1065 (M+); Calcd for
C17H15N3O4 M, 325.1063].
1688, 1670, 1648, 1617, 1526, 1470, 1347, 1316, 1291, 1222,
1
1166, 1053, 901, 786, 745, cm-1. H NMR (DMSO-d6, δ,
400 MHz): 0.80 (t, J ) 7.2 Hz, 3H, CH3), 0.95 (s, 3H, CH3),
1.02 (s, 3H, CH3), 1.96-2.18 (m, 2H, CH2), 2.46-2.61 (m,
2H, CH2), 3.63-3.73 (m, 2H, CH2O), 6.67 (d, J ) 7.6 Hz,
1H, ArH), 6.76 (t, J ) 7.2 Hz, 1H, ArH), 6.84 (d, J ) 7.2
Hz, 1H, ArH), 7.03-7.07 (m, 1H, ArH), 7.87 (br s, 2H,
NH2), 10.15 (s, 1H, NH). 13C NMR (DMSO-d6, 100 MHz)
δ: 13.79, 27.35, 28.47, 32.23, 47.29, 51.32, 59.53, 76.99,
108.81, 113.77, 121.22, 122.91, 127.86, 136.66, 144.71,
159.79, 160.88, 163.09, 168.32, 180.49, 195.34. HRMS
(ESI): m/z calcd for C21H22N2O5 405.1426 [M + Na]+; found
405.1430.
6′-Amino-3′-methyl-2-oxo-1′-phenyl-1′H-spiro[indoline-
3,4′-pyrano[2,3-c]pyrazole]-5′-carbonitrile 4{1,1,6}. mp:
236-237 °C. IR (KBr) ν: 3461, 3274, 3176, 2196, 1703,
1
1655, 1594, 1469, 1391, 1331, 1220, 1127, 1070 cm-1. H
NMR (DMSO-d6, 400 MHz) δ: 1.55 (s, 3H, CH3), 6.95 (d,
J ) 7.6 Hz, 1H, ArH), 7.04 (t, J ) 7.6 Hz, 1H, ArH), 7.19
(d, J ) 7.2 Hz, 1H, ArH), 7.29 (t, J ) 7.6 Hz, 1H, ArH),
7.36 (t, J ) 7.6 Hz, 1H, ArH), 7.53 (t, J ) 8.0 Hz, 2H,
ArH), 7.59 (s, 2H, NH2), 7.80 (d, J ) 7.6 Hz, 2H, ArH),
10.76 (s, 1H, NH). HRMS [Found m/z 369.1223 (M+); Calcd
for C21H15N5O2 M, 369.1226].
Ethyl
2-Amino-2′,5-dioxo-5,6,7,8-tetrahydrospiro-
[chromene-4,3′-indoline]-3-carboxylate4{1,2,3}.mp:253-255
°C. IR (KBr) ν: 3361, 3257, 3188, 2902, 1715, 1692, 1659,
1644, 1524, 1471, 1349, 1294, 1251, 1224, 1133, 1082, 933,
742, 679 cm-1. 1H NMR (DMSO-d6, δ, 300 MHz): 0.77 (t,
J ) 7.2 Hz, 2H, CH2), 1.83-1.88 (m, 2H, CH2), 2.13-2.20
(m, 3H, CH3), 2.58-2.64 (m, 2H, CH2), 3.66-3.69 (m, 2H,
CH2O), 6.63-6.84 (m, 3H, ArH), 7.00-7.11 (m, 1H, ArH),
7.86 (br s, 2H, NH2), 10.15 (s, 1H, NH). HRMS [Found m/z
354.1214 (M+); calcd for C19H18N2O5 M, 354.1216].
2′-Amino-2,5′-dioxo-5′H-spiro[indoline-3,4′-pyrano[3,2-
c]chromene]-3′-carbonitrile 4{1,1,7}. mp: >300 °C. IR
(KBr) ν: 3473, 3357, 3117, 2194, 1738, 1681, 1621, 1471,
1
1366, 1069 cm-1. H NMR (DMSO-d6, 400 MHz) δ: 6.86
(d, J ) 7.6 Hz, 1H, ArH), 6.94 (t, J ) 7.6 Hz, 1H, ArH),
7.22 (t, J ) 7.2 Hz, 2H, ArH), 7.49 (d, J ) 8.4 Hz, 1H,
ArH), 7.54 (t, J ) 8.0 Hz, 1H, ArH), 7.68 (s, 2H, NH2),
7.77 (t, J ) 8.0 Hz, 1H, ArH), 7.95 (d, J ) 7.6 Hz, 1H,
ArH), 10.69 (s, 1H, NH). HRMS [Found m/z 357.0750 (M+);
Calcd for C20H11N3O4 M, 357.0750].
Ethyl 2-Amino-7,7-dimethyl-2′,5-dioxo-5,6,7,8-tetrahy-
drospiro[chromene-4,3′-indoline]-3-carboxylate 4{1,2,2}.
mp: 256-258 °C. IR (KBr) ν: 3372, 3236, 3181, 2956, 1715,
Ethyl 6′-Amino-3′-methyl-2-oxo-1′-phenyl-1′H-spiro[in-
doline-3,4′-pyrano[2,3-c]pyrazole]-5′-carboxylate 4{1,2,6}.
mp: 235-237 °C. IR (KBr) ν: 3381, 3233, 3174, 1718, 1692,
1663, 1612, 1534, 1470, 1353, 1283, 1116, 1030, 966, 762,
1
678 cm-1. H NMR (DMSO-d6, δ, 300 MHz): 0.72 (t, J )
7.2 Hz, 3H, CH3), 1.56 (s, 3H, CH3), 3.70-3.74 (m, 2H,
CH2O), 6.82-6.96 (m, 3H, ArH), 7.13-7.18 (m, 1H, ArH),
7.32 (t, J ) 7.2 Hz, 1H, ArH), 7.49 (t, J ) 7.8 Hz, 2H,
ArH), 7.78 (d, J ) 7.8 Hz, 2H, ArH), 8.20 (br s, 2H, NH2),

One-Pot Synthesis of Spirooxindole Derivatives
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 2 235
10.50 (s, 1H, NH). HRMS [Found m/z 416.1483 (M+); calcd
for C23H20N4O4 M, 416.1485].
δ: 5.05 (d, J ) 16.8 Hz, 1H, CH2), 5.21 (d, J ) 16.8 Hz,
1H, CH2), 6.89 (d, J ) 8.4 Hz, 1H, ArH), 7.31 (d, J ) 8.0
Hz, 1H, ArH), 7.38 (s, 1H, ArH), 7.77 (s, 2H, NH2), 10.85
(s, 1H, NH). HRMS [Found m/z 329.0210 (M+); calcd for
C15H8N3O435Cl M, 329.0203].
Ethyl 2′-Amino-2,5′-dioxo-5′H-spiro[indoline-3,4′-pyr-
ano[3,2-c]chromene]-3′-carboxylate 4{1,2,7}. mp: 251-254
°C. IR (KBr) ν: 3358, 3261, 2981, 1696, 1641, 1514, 1491,
1472, 1396, 1380, 1289, 1135, 1074, 929, 747, 684 cm-1.
1H NMR (DMSO-d6, δ, 300 MHz): 0.81 (t, J ) 7.2 Hz, 3H,
CH3), 3.73-3.77 (m, 2H, CH2O), 6.71-6.81 (m, 2H, ArH),
7.00 (d, J ) 6.9 Hz, 1H, ArH), 7.10 (t, J ) 7.8 Hz, 1H,
ArH), 7.42-7.53 (m, 2H, ArH), 7.73 (t, J ) 8.1 Hz, 1H,
ArH), 8.01 (d, J ) 8.4 Hz, 1H, ArH), 8.13 (br s, 2H, NH2),
10.42 (s, 1H, NH). HRMS [Found m/z 404.1011 (M+); calcd
for C22H16N2O6 M, 404.1008].
2-Amino-5′-chloro-7,7-dimethyl-2′,5-dioxo-5,6,7,8-tet-
rahydrospiro[chromene-4,3′-indoline]-3-carbonitrile
4{2,1,2}. mp: >300 °C. IR (KBr) ν: 3372, 3290, 3156, 2193,
1
1726, 1680, 1654, 1602, 1478, 1350, 1225, 1057 cm-1. H
NMR (DMSO-d6, 400 MHz) δ: 1.02 (s, 6H, 2 × CH3), 2.16
(t, J ) 16.4 Hz, 2H, CH2), 2.52 (d, J ) 18.0 Hz, 1H, CH2),
2.59 (d, J ) 18.0 Hz, 1H, CH2), 6.81 (d, J ) 8.4 Hz, 1H,
ArH), 7.11 (s, 1H, ArH), 7.19 (d, J ) 8.4 Hz, 1H, ArH),
7.33 (s, 2H, NH2), 10.55 (s, 1H, NH).13C NMR (DMSO-d6,
100 MHz) δ: 27.91, 28.19, 32.66, 47.79, 50.63, 57.40,
110.87, 111.34, 117.92, 123.96, 126.33, 128.77, 137.11,
141.71, 141.79, 159.56, 165.30, 178.51, 195.79. HRMS
[Found m/z 369.0877 (M+); calcd for C19H16N3O335Cl M,
369.0880].
Ethyl 2′-Amino-6′-methyl-2,5′-dioxo-5′,6′-dihydrospiro[in-
doline-3,4′-pyrano[3,2-c]quinoline]-3′-carboxylate
4{1,2,8}. mp: >300 °C. IR (KBr) ν: 3379, 3257, 3200, 2970,
1718, 1701, 1598, 1534, 1483, 1361, 1273, 1160, 1110, 1031,
961, 931, 760, 680 cm-1. 1H NMR (DMSO-d6, δ, 300 MHz):
0.83 (t, J ) 7.2 Hz, 3H, CH3), 3.43 (s, 3H, CH3), 3.72-3.76
(m, 2H, CH2O), 6.71 (t, J ) 8.4 Hz, 2H, ArH), 6.83 (t, J )
8.4 Hz, 1H, ArH), 7.05 (t, J ) 7.5 Hz, 1H, ArH), 7.39 (t, J
) 7.5 Hz, 1H, ArH), 7.52 (d, J ) 8.4 Hz, 1H, ArH), 7.71 (t,
J ) 7.8 Hz, 1H, ArH), 8.05 (br s, 2H, NH2), 8.13 (d, J )
8.1 Hz, 1H, ArH), 10.26 (s, 1H, NH). 13C NMR (DMSO-d6,
100 MHz) δ: 13.85, 29.81, 48.66, 59.62, 76.70, 108.79,
109.68, 112.87, 115.36, 121.24, 122.84, 123.25, 123.37,
128.03, 132.64, 136.26, 139.09, 145.30, 150.97, 159.34,
159.83, 168.27, 180.37. HRMS (ESI): m/z calcd for
C23H19N3O5 440.1222 [M + Na]+; found 440.1222.
Methyl 2-Amino-7,7-dimethyl-2′,5-dioxo-5,6,7,8-tet-
rahydrospiro[chromene-4,3′-indoline]-3-carboxylate
4{1,3,2}. mp: 230-232 °C. IR (KBr) ν: 3366, 3257, 3195,
2955, 1714, 1692, 1650, 1621, 1472, 1442, 1347, 1313, 1224,
2-Amino-5′-chloro-2′,5-dioxo-5,6,7,8-tetrahydrospiro-
[chromene-4,3′-indoline]-3-carbonitrile4{2,1,3}.mp:294-296
°C. IR (KBr) ν: 3364, 3247, 3175, 2193, 1719, 1681, 1477,
1
1350, 1219, 1079, 1011 cm-1. H NMR (DMSO-d6, 400
MHz) δ: 1.90-2.00 (m, 2H, CH2), 2.25 (t, J ) 6.8 Hz, 2H,
CH2), 2.65 (t, J ) 6.4 Hz, 2H, CH2), 6.80 (d, J ) 8.4 Hz,
1H, ArH), 7.15 (d, J ) 2.0 Hz, 1H, ArH), 7.19 (dd, J1 )
2.0 Hz, J2 ) 8.0 Hz,1H, ArH), 7.31 (s, 2H, NH2), 10.54 (s,
1H, NH). HRMS [Found m/z 341.0564 (M+); calcd for
C17H12N3O335Cl M, 341.0567].
2′-Amino-5-chloro-7′-methyl-2,5′-dioxo-5′H-spiro[indo-
line-3,4′-pyrano[4,3-b]pyran]-3′-carbonitrile 4{2,1,4}. mp:
>300 °C. IR (KBr) ν: 3412, 3300, 3184, 2201, 1721, 1670,
1
1609, 1475, 1367, 1345, 1241, 1174, 1050 cm-1. H NMR
1
1167, 1138, 1054, 988, 901, 787, 748, 668 cm-1. H NMR
(DMSO-d6, 400 MHz) δ: 2.25 (s, 3H, CH3), 6.37 (s, 1H,
CH), 6.84 (d, J ) 8.4 Hz, 1H, ArH), 7.25 (d, J ) 8.4 Hz,
1H, ArH), 7.32 (s, 1H, ArH), 7.55 (s, 2H, NH2), 10.74 (s,
1H, NH). 13C NMR (DMSO-d6, 100 MHz) δ: 19.97, 47.96,
56.95, 98.50, 98.76, 111.52, 117.75, 124.93, 126.75, 129.37,
135.75, 141.79, 159.46, 160.57, 160.84, 164.58, 177.82.
HRMS [Found m/z 355.0360 (M+); calcd for C17H10N3O435Cl
M, 355.0360].
(DMSO-d6, δ, 300 MHz): 0.92 (s, 3H, CH3), 1.00 (s, 3H,
CH3), 1.98 (d, J ) 15.9 Hz, 1H, CH), 2.14 (d, J ) 15.9 Hz,
1H, CH), 2.42-2.61 (m, 2H, CH2), 3.23 (s, 3H, CH3O), 6.66
(d, J ) 7.5 Hz, 1H, ArH), 6.74 (t, J ) 7.2 Hz, 1H, ArH),
6.81 (d, J ) 6.9 Hz, 1H, ArH), 7.02 (t, J ) 7.5 Hz, 1H,
ArH), 7.80 (br s, 2H, NH2), 10.14 (s, 1H, NH). HRMS (ESI):
m/z calcd for C20H20N2O5 369.1450 [M + H]+; found
369.1469.
Ethyl
2′-Amino-5-chloro-3′-cyano-6′-methyl-2-ox-
Isopropyl 2-Amino-7,7-dimethyl-2′,5-dioxo-5,6,7,8-tet-
rahydrospiro[chromene-4,3′-indoline]-3-carboxylate
4{1,4,2}. mp: 251-253 °C. IR (KBr) ν: 3388, 3250, 3199,
2985, 1715, 1688, 1672, 1617, 1527, 1471, 1351, 1285, 1103,
ospiro[indoline-3,4′-pyran]-5′-carboxylate 4{2,1,5}. mp:
256-258 °C. IR (KBr) ν: 3389, 3300, 3170, 2205, 1716,
1666, 1591, 1476, 1380, 1280, 1221, 1079 cm-1. H NMR
1
(DMSO-d6, 400 MHz) δ: 0.83 (t, J ) 7.2 Hz, 3H, CH3),
2.33 (s, 3H, CH3), 3.76-3.86 (m, 2H, CH2O), 6.81 (d, J )
8.4 Hz, 1H, ArH), 7.19 (s, 1H, ArH), 7.23 (d, J ) 6.8 Hz,
1H, ArH), 7.24 (s, 2H, NH2), 10.55 (s, 1H, NH). HRMS
[Found m/z 359.0673 (M+); calcd for C17H14N3O435Cl M,
359.0673].
6′-Amino-5-chloro-3′-methyl-2-oxo-1′-phenyl-1′H-
spiro[indoline-3,4′-pyrano[2,3-c]pyrazole]-5′-carboni-
trile 4{2,1,6}. mp: 226-228 °C. IR (KBr) ν: 3467, 3305,
3138, 2191, 1736, 1645, 1526, 1476, 1384, 1211, 1072 cm-1.
1H NMR (DMSO-d6, 400 MHz) δ: 1.60 (s, 3H, CH3), 6.96
(d, J ) 8.4 Hz, 1H, ArH), 7.33-7.36 (m, 3H, ArH), 7.52 (t,
J ) 8.0 Hz, 2H, ArH), 7.64 (s, 2H, NH2), 7.79 (d, J ) 8.0
Hz, 2H, ArH), 10.89 (s, 1H, NH). 13C NMR (DMSO-d6, 100
1
1052, 915, 746, 674 cm-1. H NMR (DMSO-d6, δ, 300
MHz): 0.53 (d, J ) 6.0 Hz, 3H, CH3), 0.93-1.00 (m, 9H, 3
× CH3), 2.00 (d, J ) 15.9 Hz, 1H, CH), 2.13 (d, J ) 15.9
Hz, 1H, CH), 2.43-2.59 (m, 2H, CH2), 4.55-4.64 (m, 1H,
CHO), 6.66 (d, J ) 4.5 Hz, 1H, ArH), 6.74 (t, J ) 7.2 Hz,
1H, ArH), 6.81 (d, J ) 6.9 Hz, 1H, ArH), 7.03 (t, J ) 7.5
Hz, 1H, ArH), 7.83 (br s, 2H, NH2), 10.09 (s, 1H, NH).
HRMS [Found m/z 396.1667 (M+); calcd for C22H24N2O5
M, 396.1685].
2-Amino-5′-chloro-2′,5-dioxo-5,7-dihydrospiro[furo[3,4-
b]pyran-4,3′-indoline]-3-carbonitrile 4{2,1,1}. mp: 252-254
°C. IR (KBr) ν: 3374, 3337, 3199, 2203, 1778, 1694, 1597,
1480, 1375, 1027, 824 cm-1. 1H NMR (DMSO-d6, 400 MHz)

236 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 2
Li et al.
MHz) δ: 12.45, 48.77, 56.29, 96.40, 105.00, 112.08, 118.64,
120.98, 125.88, 127.33, 127.46, 127.51, 130.12, 135.04,
137.95, 141.12, 144.51, 145.77, 161.81, 163.02, 178.04.
HRMS [Found m/z 403.0836 (M+); calcd for C21H14N5O235Cl
M, 403.0836].
Ethyl
2′-Amino-5-bromo-3′-cyano-6′-methyl-2-ox-
ospiro[indoline-3,4′-pyran]-5′-carboxylate 4{3,1,5}. mp:
262-264 °C. IR (KBr) ν: 3384, 3314, 3190, 2207, 1716,
1661, 1596, 1476, 1417, 1380, 1282, 1222, 1073 cm-1. H
1
NMR (DMSO-d6, 400 MHz) δ: 0.84 (t, J ) 6.8 Hz, 3H,
CH3), 2.33 (s, 3H, CH3), 3.80-3.84 (m, 2H, CH2), 6.77 (d,
J ) 8.0 Hz, 1H, ArH), 7.23 (s, 2H, NH2), 7.29 (s, 1H, ArH),
7.36 (d, J ) 8.4 Hz, 1H, ArH), 10.55 (s, 1H, NH). HRMS
[Found m/z 403.0172 (M+); calcd for C17H14N3O479Br M,
403.0168].
2′-Amino-5-chloro-2,5′-dioxo-5′H-spiro[indoline-3,4′-
pyrano[3,2-c]chromene]-3′-carbonitrile 4{2,1,7}. mp: >300
°C. IR (KBr) ν: 3319, 3207, 2199, 1741, 1677, 1608, 1475,
1360, 1222, 1090, 972 cm-1. 1H NMR (DMSO-d6, 400 MHz)
δ: 6.87 (d, J ) 8.4 Hz, 1H, ArH), 7.25-7.28 (m, 1H, ArH),
7.44 (s, 1H, ArH), 7.50 (d, J ) 8.4 Hz, 1H, ArH), 7.55 (t,
J ) 7.6 Hz, 1H, ArH), 7.74 (s, 2H, NH2), 7.78 (d, J ) 8.4
Hz, 1H, ArH), 7.94 (d, J ) 7.6 Hz, 1H, ArH), 10.82 (s, 1H,
NH). 13C NMR (DMSO-d6, 100 MHz) δ: 48.60, 57.11,
101.47, 111.62, 113.24, 117.30, 117.67, 123.42, 125.27,
125.61, 126.86, 129.53, 134.32, 135.73, 141.81, 152.76,
156.13, 159.20, 159.29, 177.78. HRMS [Found m/z 391.0376
(M+); calcd for C20H10N3O435Cl M, 391.0360].
6′-Amino-5-bromo-3′-methyl-2-oxo-1′-phenyl-1′H-
spiro[indoline-3,4′-pyrano[2,3-c]pyrazole]-5′-carboni-
trile 4{3,1,6}. mp: 225-226 °C. IR (KBr) ν: 3365, 3189,
2204, 1705, 1659, 1521, 1398, 1220, 1132, 1070 cm-1. H
1
NMR (DMSO-d6, 400 MHz) δ: 1.59 (s, 3H, CH3), 6.92 (d,
J ) 8.4 Hz, 1H, ArH), 7.36 (t, J ) 6.8 Hz, 1H, ArH),
7.46-7.54 (m, 4H, ArH), 7.64 (s, 2H, NH2), 7.79 (d, J )
7.6 Hz, 2H, ArH), 10.90 (s, 1H, NH).
2′-Amino-5-bromo-2,5′-dioxo-5′H-spiro[indoline-3,4′-
pyrano[3,2-c]chromene]-3′-carbonitrile 4{3,1,7}. mp: >300
°C. IR (KBr) ν: 3315, 3190, 2200, 1745, 1681, 1614, 1473,
2-Amino-5′-bromo-2′,5-dioxo-5,7-dihydrospiro[furo[3,4-
b]pyran-4,3′-indoline]-3-carbonitrile 4{3,1,1}. mp: 266-268
°C. IR (KBr) ν: 3339, 3308, 3182, 2201, 1774, 1697, 1634,
1
1362, 1084 cm-1. H NMR (DMSO-d6, 400 MHz) δ: 6.83
1
1598, 1478, 1373, 1026, 814 cm-1. H NMR (DMSO-d6,
(d, J ) 8.0 Hz, 1H, ArH), 7.40 (d, J ) 8.0 Hz, 1H, ArH),
7.50 (d, J ) 8.4 Hz, 1H, ArH), 7.55 (t, J ) 8.0 Hz, 2H,
ArH), 7.75 (s, 2H, NH2), 7.79 (d, J ) 7.6 Hz, 1H, ArH),
7.94 (d, J ) 8.0 Hz, 1H, ArH), 10.83 (s, 1H, NH). HRMS
[Found m/z 434.9863 (M+); calcd for C20H10N3O479Br M,
434.9855].
400 MHz) δ: 5.04 (d, J ) 16.8 Hz, 1H, CH2), 5.20 (d, J )
16.8 Hz, 1H, CH2), 6.85 (d, J ) 8.4 Hz, 1H, ArH), 7.44 (d,
J ) 8.4 Hz, 1H, ArH), 7.49 (s, 1H, ArH), 7.77 (s, 2H, NH2),
10.86 (s, 1H, NH). 13C NMR (DMSO-d6, 100 MHz) δ: 46.99,
56.51, 66.78, 101.50, 112.49, 114.76, 117.87, 128.38, 132.90,
134.04, 141.87, 161.27, 168.78, 170.37, 176.47. HRMS
[Found m/z 372.9696 (M+); Calcd for C15H8N3O479Br M,
372.9698].
2-Amino-5′-bromo-7,7-dimethyl-2′,5-dioxo-5,6,7,8-tet-
rahydrospiro[chromene-4,3′-indoline]-3-carbonitrile
4{3,1,2}. mp: >300 °C. IR (KBr) ν: 3365, 3290, 3161, 2957,
2194, 1726, 1681, 1656, 1603, 1475, 1350, 1223, 1056 cm-1.
1H NMR (DMSO-d6, 400 MHz) δ: 1.02 (s, 6H, 2 × CH3),
2.13 (d, J ) 16.8 Hz, 1H, CH2), 2.20 (d, J ) 16.8 Hz, 1H,
CH2), 2.51 (d, J ) 17.6 Hz, 1H, CH2), 2.60 (d, J ) 17.6
Hz, 1H, CH2), 6.76 (d, J ) 8.4 Hz, 1H, ArH), 7.21 (s, 1H,
ArH), 7.32 (d, J ) 7.2 Hz, 1H, ArH), 7.33 (s, 2H, NH2),
10.56 (s, 1H, NH). HRMS [Found m/z 413.0367 (M+); calcd
for C19H16N3O379Br M, 413.0375].
Acknowledgment. We gratefully acknowledge financial
support from the Foundation of Key Laboratory of Organic
Synthesis of Jiangsu Province.
Supporting Information Available. Experimental details
and spectroscopic characterization for compound 4. This
material is available free of charge via the Internet at http://
pubs.acs.org.
References and Notes
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1474, 1352, 1217, 1079, 1010 cm-1. H NMR (DMSO-d6,
400 MHz) δ: 1.91-1.98 (m, 2H, CH2), 2.22-2.26 (m, 2H,
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line-3,4′-pyrano[4,3-b]pyran]-3′-carbonitrile 4{3,1,4}. mp:
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1474, 1376, 1235, 1169, 1049 cm-1. H NMR (DMSO-d6,
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