4-Dimethylaminopyridine-catalyzed multi-component one-pot reactions for the convenient synthesis of spiro[indoline-3,4′-pyrano[2,3-c]pyrazole] derivatives

Article abstract of DOI:10.1016/j.tet.2013.11.019

An efficient and clean reaction process was developed for the convenient and cheap synthesis of spirooxindole derivatives. One-pot reactions of isatins, malononitrile (or ethyl cyanoacetate), hydrazine hydrate (or phenylhydrazine), and 1,3-dicarbonyl comp

Full text of DOI:10.1016/j.tet.2013.11.019

Tetrahedron 70 (2014) 484e489
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
4-Dimethylaminopyridine-catalyzed multi-component one-pot
reactions for the convenient synthesis of spiro[indoline-3,40-pyrano
[2,3-c]pyrazole] derivatives
*
Jun Feng, Keyume Ablajan , Ahat Sali
Key Laboratory of Oil & Gas Fine Chemicals, Ministry of Education & Xinjiang Uyghur Autonomous Region, College of Chemistry and Chemical
Engineering, Xinjiang University, Urumqi 830046, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 October 2013
Received in revised form 6 November 2013
Accepted 11 November 2013
Available online 15 November 2013
An efficient and clean reaction process was developed for the convenient and cheap synthesis of spi-
rooxindole derivatives. One-pot reactions of isatins, malononitrile (or ethyl cyanoacetate), hydrazine
hydrate (or phenylhydrazine), and 1,3-dicarbonyl compounds were compared with one-pot reactions of
isatins, malononitrile (or ethyl cyanoacetate), and 5-pyrazolone derivatives. Both sets of reaction were
conducted in EtOH in the presence of 4-DMAP catalyst. A series of spiro[indoline-3,40-pyrano[2,3-c]
pyrazole] derivatives were quickly obtained in excellent yields by using the four-component one-pot
reaction method.
Keywords:
4-Dimethylaminopyridine
Spirooxindole
Ó 2013 Elsevier Ltd. All rights reserved.
Multi-component reaction
One-pot synthesis
1. Introduction
their efficiency, low toxicity, unique reaction mechanisms, safety,
lack of cross-resistance, and other characteristics.10 The indole
Multi-component reactions (MCRs) effectively combine three,
or sometimes more, reactants simultaneously in a one-pot syn-
thesis that does not require the separation of intermediate prod-
ucts. These reactions constitute one of the best tools for modern
organic synthesis because they can use most of the constituent
atoms of several reactant molecules to form a product molecule.1
They are also highly selective and are simply operated under mild
conditions; some have been used industrially.2 MCRs have been
widely used in synthetic chemistry to form new carbonecarbon
bonds.3 The earliest example of this is Stercker’s compounding of
moiety, which is probably the most well-known heterocycle, is an
important active feature of a variety of natural products and me-
dicinal agents.12 Sharing of the indole 3-carbon atom in the for-
mation of spiroindoline derivatives has been reported to greatly
enhance the biological activity of the products.11 Spirooxindoles
exhibit a wide range of biological properties; an example is
coerulescine, a simple spirooxindole found in nature, which dis-
plays a local anesthetic effect.13 Another is spirotryprostatin A,
a natural alkaloid isolated from the fermentation broth of Asper-
gillus fumigatus, which has been shown to inhibit the mammalian
cell cycle. The polycyclic alkaloids pteropodine and isopteropodine
have long been used in medicine to modulate the function of
muscarinic serotonin receptors.14 Pyran derivatives exhibit a wide
range of biological and physical properties; for example, benzo-
pyran has been reported to have anti-dysplasia, anti-allergic, hy-
poglycemic, antimicrobial, and anticancer effects. It has been used
for the treatment of allergic bronchitis and diabetes. Another ex-
ample, spiropyran, has excellent optical properties.
a
-amino acid with HCN, aldehyde, and ammonia through an a-
cyanamide intermediate.4 Subsequent MCRs include Biginelli,5
Mannich,6 Robinson,7 Passerini,8 and Ugi reactions, which have
been widely used in synthetic, medicinal, and combinatorial
chemistry.9,10
Heterocycles containing pyrazole rings are important target
compounds in synthetic and medicinal chemistry because the ring
is a key moiety in various biologically active compounds. Pyrazole
derivatives have been studied in the development of insecticides,
acaricides, fungicides, herbicides, dyes, and reagents because of
The development of efficient and convenient syntheses of novel
bioactive organic compounds, such as spirooxindoles is an impor-
tant current research area, with MCRs considered the most efficient
method of preparing spirooxindoles. Several MCRs have been used
in various syntheses of spiro[indoline-3,40-pyrano[2,3-c]pyrazole]
* Corresponding author. Tel.: þ86 139 991 35640; fax: þ86 0991 858 3575; e-mail
derivatives in the presence of InCl3,12 TEBA,15 TBAF,16
L-proline,
address: ablajan209@hotmail.com (K. Ablajan).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.11.019

J. Feng et al. / Tetrahedron 70 (2014) 484e489
485
TEA,17 C17H35COONa,18 or EDDA (ethylenediamine diacetate).19 An
electrocatalytic method20 has also been used in the preparation of
spirooxindole-pyrano[2,3-c] pyrazole. However, there are few re-
ported attempts to address MCRs’ prolonged reaction times, use of
toxic solvents, or moderate yields. Improvements of these draw-
backs to develop MCRs that are facile and convenient may be
possible if the reaction methodology was fully understood. Recent
increased environmental awareness has led both academic and
industrial chemists to develop cheap and efficient processes that
use nontoxic reagents, solvents, and catalysts or that operate in
solvent-free conditions. The use of EtOH as a reaction medium can
greatly increase the rates of many organic reactions due to its hy-
drophobic effects.21 It is, therefore, considered an attractive me-
dium for many organic reactions, and many MCRs in EtOH have
been reported.
HN
O
R1COCH2CO2CH3
NH2NH2
R1
R2
O
O
N
H
4-DMAP
EtOH
+
HN
R2CH2CN
O
NH2
N
R1 = CH3, C2H5, n-C3H7, iso-C3H7, Ph
R2 = CN, COOEt
Scheme 3. Four-component reaction for the synthesis of 5fej and 6fej.
Table 1
Optimization of reaction conditions for the synthesis of 5a via three- and four-
component reactions
However, the synthesis of spirooxindole derivatives in EtOH
using 4-DMAP as a catalyst is not well reported. As part of efforts to
develop new selective and environmentally friendly methodologies
for the preparation of bioactive compounds, we investigated one-
pot three-component reactions of isatins, malononitrile (or ethyl
cyanoacetate), and 5-pyrazolone derivatives (Scheme 1), as well as
one-pot four-component reactions of isatin, malononitrile (or ethyl
cyanoacetate), hydrazine hydrate (or phenylhydrazine), and 1,3-
dicarbonyl compounds (Schemes 2 and 3) for the synthesis of
spiro[indoline-3,40-pyrano[2,3-c]pyrazole] derivatives in EtOH
catalyzed by 4-DMAP.
Entry
Solvent
Catalyst
Time (min)
Yielda (%)
Yieldb (%)
1
2
3
4
5
6
7
8
CH2Cl2
THF
H2O
EtOH
MeOH
CH2Cl2
H2O
EtOH
EtOH
H2O
4-DMAP
4-DMAP
4-DMAP
4-DMAP
4-DMAP
Et3N
Et3N
Et3N
Piperidine
Piperidine
N/A
60
60
60
60
60
60
60
60
60
60
60
15
18
63
75
68
10
60
65
55
45
5
15
20
65
80
70
10
65
70
60
50
5
9
10
11
EtOH
a
Isolated yield via a three-component reaction.
Isolated yield via a four-component reaction.
b
R1
HN
Table 2
N
Optimization of reaction time and temperature for the synthesis of 5a via three- and
four-component reactions
R1
O
N
H
O
R2
Entry
Temp (ꢀC)
Time (min)
4-DMAP (mol %)
Yielda (%)
Yieldb (%)
HN
4-DMAP / EtOH
NH2
O
N
1
2
3
4
5
6
7
8
20
40
60
20
40
60
20
40
60
60
60
60
20
20
20
40
40
40
60
60
60
60
60
60
20
20
20
20
20
20
20
20
5
10
25
46
12
38
65
16
40
60
75
68
74
10
30
50
15
40
70
20
45
65
80
70
76
5a-e, 6a-e
HN
O
R1
N
+
R2CH2CN
4a,4b
O
HN
3a
N
O
R1
O
R2
Ph
9
4-DMAP / EtOH
N
NH2
10
11
12
20
10
30
O
N
Ph
5f-j, 6f-j
R1 = CH3, C2H5, n-C3H7, iso-C3H7, Ph
R2 = CN, COOEt
a
Isolated yield for three-component reaction.
Isolated yield for four-component reaction.
b
Scheme 1. Three-component reaction for the synthesis of 5aej and 6aej.
were three-component one-pot reactions of isatins, malononitrile,
and 3-methyl-5-pyrazolone, and four-component reactions of isa-
tins, malononitrile, hydrazine hydrate, and methyl acetoacetate.
The methodology is simple and convenient, and could be applicable
for the synthesis of spiro[indoline-3,40-pyrano[2,3-c]pyrazole] de-
rivatives in good yield (Tables 1 and 2).
HN
O
R1COCH2CO2CH3
PhNH2NH2
R1
R2
O
O
N
H
4-DMAP
EtOH
+
N
R2CH2CN
O
NH2
N
The first set of reactions examined various solvents and catalysts
(Table 1). They were conducted for 60 min at 60 ꢀC using the cat-
alysts at 20 mol % where appropriate. Reactions were first con-
ducted in five different solvents (CH2Cl2, THF, H2O, EtOH, and
MeOH); they were catalyzed by 4-DMAP (entries 1e5, Table 1). The
best yields for both the three- and four-component reactions were
obtained in EtOH (entry 4, Table 1). Different catalytic conditions
were then compared (no catalyst, 4-DMAP, Et3N, and piperidine)
for reactions conducted in EtOH (entries 4, 8, 9, and 11, Table 1). The
other catalysts gave moderate yields in EtOH, but they were below
that achieved using 4-DMAP. The use of no catalyst in EtOH (entry
11, Table 1) or in no solvent (result not shown) resulted in low
yields. Comparison of the catalysts Et3N and piperidine in other
solvents (entries 6e10, Table 1) confirms that EtOH was the optimal
Ph
R1 = CH3, C2H5, n-C3H7, iso-C3H7, Ph
R2 = CN, COOEt
Scheme 2. Four-component reaction for the synthesis of 5aee and 6aee.
2. Results and discussion
The reaction conditions for the synthesis of 5a via three- and
four-component one-pot routes were optimized by testing differ-
ent reaction media and catalysts (Table 1), and different reaction
conditions (Table 2). The results could also be used to compare the
efficiencies of the different systems. The first reactions considered

486
J. Feng et al. / Tetrahedron 70 (2014) 484e489
reaction medium. Overall, the best yields for the three- and four-
component routes (75% and 80%, respectively) were both ob-
tained in EtOH using 4-DMAP as catalyst (Table 1, entry 4).
The next optimization was of catalyst loading: 5, 10, 20, and
30 mol % 4-DMAP were compared (entries 9e12). The optimal
amount of catalyst was found to be 20 mol % (entry 10, Table 2). The
use of more 4-DMAP did not improve the yield (entry 12, Table 2).
The reactions were then compared at different temperatures
(20e60 ꢀC) and for different durations (15e60 min) (entries
1e8 and 10, Table 2). For any given temperature, increasing the
reaction time improved the yield; and for any given reaction du-
ration, hotter reactions led to higher yields. Therefore, the optimal
condition was the reaction conducted at 60 ꢀC for 60 min (entry 10,
Table 2). No improvements were gained from hotter or longer re-
actions (data not shown).
Once the reaction conditions had been optimized, a series of
spiro[indoline-3,40-pyrano[2,3-c]pyrazole] derivatives were syn-
thesized (Table 3). The reactions were conducted at 60 ꢀC for 60 min
in EtOH in the presence of 20 mol % 4-DMAP catalyst. In all cases
excellent yields with good selectivity were obtained. The four-
component reactions appeared to be better despite the three-
component reactions achieving higher actual conversions due to
their having fewer steps.
All of the molecular structures were characterized by 1H NMR,
IR, ESI-MS, and HRMS, and the structures of all products 5ae6j are
in complete agreement with those obtained from spectroscopic
data.23 The results were used to formulate the following mecha-
nism (Scheme 4).
The reaction begins with the isomerization of a molecule of the
1,3-dicarbonyl compound, which leads to the formation of an enol.
Condensation of hydrazine 2 with enol 1 is then proposed to form
intermediate 7. Subsequent intramolecular cyclization of NH2 with
the carboxyl group forms pyrazol-5-one derivative 8 through the
elimination of a MeOH molecule. Deprotonation of 8 in the pres-
ence of the organic base catalyst forms the intermediate anion 9,
which takes part in Knoevenagel condensation with isatin 3 to give
intermediate 10. Intermediate 10 has an H2O molecule eliminated
by the DMAPHþ to restore the catalyst and give an adduct 11.
Malononitrile and DMAP react to give a malononitrile anion, and
a Michael adduct 12 results from the reaction of malononitrile
anion and adduct 11. Finally, the target product 5 results from the
intramolecular cyclization of intermediates 12, 13, and 14.
In summary, a practical and efficient procedure for the synthesis
of spiro[indoline-3,40-pyrano[2,3-c]pyrazole] derivatives was de-
veloped via the one-pot four-component reactions of isatins,
malononitrile (or ethyl cyanoacetate), hydrazine hydrate (or phe-
nylhydrazine), and 1,3-dicarbonyl compounds. The highest yield of
product was obtained at 60 ꢀC in EtOH using 4-DMAP as a catalyst.
This procedure offers several advantages including higher yields,
quicker reactions, and a convenient and simple method.
Table 3
Three- and four-component one-pot syntheses of spiro[indoline-3,40-pyrano[2,3-c]
pyrazole] derivatives in EtOH catalyzed by 4-DMAP
Entry Product R1
R2
Time Yield (%)a
Yield (%)a
(min) (three-component (four-component
3. Conclusion
reaction)
reaction)
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
CH3e
C2H5e
n-C3H7e CN
iso-C3H7e CN
Phe
CH3e
C2H5e
n-C3H7e CN
iso-C3H7e CN
Phe
CH3e
C2H5e
n-C3H7e COOEt 60
iso-C3H7e COOEt 60
Phe
CH3e
C2H5e
n-C3H7e COOEt 60
iso-C3H7e COOEt 60
CN
CN
60
60
60
60
60
60
60
60
60
60
75
78
80
76
74
77
75
79
82
75
82
83
74
73
69
81
78
72
71
71
80
86
87
85
80
83
82
83
85
80
86
86
78
76
75
85
83
80
76
83
An efficient and simple method for the synthesis of spiro
[indoline-3,40-pyrano[2,3-c]pyrazole] derivatives was developed
via the one-pot four-component reactions of isatins, malononitrile
(or ethyl cyanoacetate), hydrazine hydrate (or phenylhydrazine),
and 1,3-dicarbonyl compounds at 60 ꢀC in EtOH using 4-DMAP as
a catalyst. This method offers several advantages including higher
yields, milder and quicker reactions, and a simple procedure.
CN
CN
CN
9
10
11
12
13
14
15
16
17
18
19
20
5j
CN
COOEt 60
COOEt 60
6a
6b
6c
6d
6e
6f
6g
6h
6i
4. Experimental
4.1. General
COOEt 60
COOEt 60
COOEt 60
All solvents were purified and dried prior to use. Optical rota-
tions were measured on a PerkineElmer 241MC polarimeter in the
solvent indicated. 1H NMR spectra were recorded on a Bruker Ad-
vance 400 MHz machine using TMS internal standard and DMSO-d6
solvent. Chemical shifts were given on the d scale (ppm). MS
spectra were determined on MSD1-MS (LCeMS, ESI source). Silica
6j
Phe
COOEt 60
a
Isolated yield.
O
O
H
1
R
1
N
1
R
O
R
OCH
3
1
1
R
OCH
NH
3
O
1
R
+
O
B
H
N
CH OH
H O
2
3
N
OH
O
O
N
H
+
O
O
N
N
H
O
N
NH
2
O
1
N
3
R
OCH
2
9
3
8
7
10
H
NH NH
2
+
2
NC
BH
H O
2
H
HN
HN
2
4
H
HN
R
HN
N
+
B
O
O
H
O
O
R1
2
1
1
O
R
R
R
+
1
2
R
2
BH
R
R
NC
R2
R
1
HN
N
NH
N
HN
N
N
O
2
O
N
N
OH
N
R
N
O
N
NH2
H
O
N
5
H
14
13
12
H
11
Scheme 4. The reaction mechanism for the one-pot synthesis of compound 5.

J. Feng et al. / Tetrahedron 70 (2014) 484e489
487
gel plates GF254 were used for thin layer chromatography (TLC). IR
spectra were obtained on a Bruker Tensor27 spectrometer (KBr
disks).
z¼322 (MþH)þ, 344 (MþNa)þ; HRMS(ESI) calcd for C17H16N5O2
([MþH]þ): 322.1304. Found: 322.1308.
4.3.5. 60-Amino-2-oxo-30-phenyl-20H-spiro[indoline-3,40-pyrano [2,3-
c]pyrazole]-50-carbonitrile (5e). White solid, lit. mp 219e220 ꢀC;22 1H
4.2. General procedure for the three-component one-pot
synthesis of 60-amino-30-methyl-2-oxo-20H-spiro[indoline-
3,40-pyrano[2,3-c]pyrazole]-50-carbonitrile
NMR (DMSO-d6, 400 MHz)
m, C6H5), 7.25 (2H, s, NH2), 10.49 (1H, s, NH), 12.88 (1H, s, NH); IR
d: 6.74e6.93 (4H, m, C6H4), 7.03e7.27 (5H,
(KBr) n: 3768, 3308, 3238, 2702, 2644, 2186, 1705, 1583, 1473, 1408,
1320, 1208, 1132, 1058, 915, 747, 676 cmꢁ1; ESI-MS: m/z¼356
(MþH)þ, 378 (MþNa)þ; HRMS(ESI) calcd for C20H14N5O2 ([MþH]þ):
356.1148. Found: 356.1144.
A mixture of 3-methyl-5-pyrazolone 1a (1 mmol), isatin 3
(1 mmol), malononitrile 4a (1 mmol), and 4-DMAP (0.1 mmol) in
EtOH (20 mL) was stirred at 60 ꢀC for 60 min. After completion of
the reaction had been confirmed by TLC, the reaction mixture was
cooled to room temperature. The precipitated product was then
filtered and washed successively with water and cooled EtOH (50%)
to afford the pure product 5a in good yield.
4.3.6. 60-Amino-30-methyl-2-oxo-10-phenyl-spiro[indoline-3,40-pyr-
ano[2,3-c]pyrazole]-50-carbonitrile (5f). White solid, lit. mp
238e240 ꢀC;20 1H NMR (DMSO-d6, 400 MHz)
d
:1.56 (3H, d, CH3),
6.95e7.31 (4H, m, C6H4), 7.34e7.81 (5H, m, C6H5), 7.58 (2H, s, NH2),
10.75 (1H, s, NH); IR (KBr) : 3371, 3156, 3033, 2929, 2809, 2095,
n
1703, 1640, 1612, 1505, 1479, 1400, 1341, 1302, 1217, 1045, 920, 865,
824, 768, 626 cmꢁ1; ESI-MS: m/z¼370 (MþH)þ, 392 (MþNa)þ, 480
(MþK)þ; HRMS(ESI) calcd for C21H16N5O2 ([MþH]þ): 370.1304.
Found: 370.1309.
4.3. General procedure for the four-component one-pot re-
action synthesis of ethyl 60-amino-30-methyl-2-oxo-20H-spiro
[indoline-3,40-pyrano[2,3-c]pyrazole]-50-carboxylate
A mixture of ethyl acetoacetate 1 (1 mmol), hydrazine 2
(1 mmol), isatin 3 (1 mmol), ethyl cyanoacetate 4b (1 mmol), and 4-
DMAP (0.1 mmol) in EtOH (20 mL) was stirred at 60 ꢀC for 60 min.
After completion of the reaction had been confirmed by TLC, the
reaction mixture was cooled to room temperature. The precipitated
product was then filtered and washed successively with water and
cooled EtOH (50%) to afford the pure product 6a in good yield.
4.3.7. 60-Amino-30-ethyl-2-oxo-10-phenyl-spiro[indoline-3,40-pyrano
[2,3-c]pyrazole]-50-carbonitrile (5g). White solid, mp 224e225 ꢀC;
1H NMR (DMSO-d6, 400 MHz)
d: 0.68e0.72 (3H, t, CH3), 1.89e1.92
(2H, q, CH2), 6.95e7.31 (4H, m, C6H4), 7.34e7.81 (5H, m, C6H5), 7.59
(s, 2H, NH2), 10.75 (s, 1H, NH); IR (KBr) n: 3291, 3173, 2195, 1700,
1634, 1588, 1496, 1401, 1315, 1204, 1046, 933, 765, 656 cmꢁ1; ESI-
MS: m/z¼431 (MþH)þ, 453 (MþNa)þ; HRMS(ESI) calcd for
C
22H18N5O2 ([MþH]þ): 384.1461. Found: 384.1456.
4.3.1. 60-Amino-30-methyl-2-oxo-20H-spiro[indoline-3,40-pyrano[2,3-
c]pyrazole]-50-carbonitrile
(5a). White
279e280 ꢀC;21 1H NMR (DMSO-d6, 400 MHz)
6.90e7.26 (4H, m, C6H4), 7.23 (2H, s, NH2), 10.59 (1H, s, NH), 12.28
(1H, s, NH); IR (KBr) : 3378, 3338, 3131, 2691, 2577, 2360, 2182,
solid,
lit.
mp
4.3.8. 60-Amino-30-propyl-2-oxo-10-phenyl-spiro[indoline-3,40-pyr-
ano[2,3-c]pyrazole]-50-carbonitrile
(5h). White solid, mp
211e213 ꢀC; 1H NMR (DMSO-d6, 400 MHz)
: 0.61e0.65 (3H, t, CH3),
d: 1.54 (3H, s, CH3),
d
n
1.17e1.24 (2H, m, CH2), 1.84e1.88 (2H, t, CH2), 6.94e7.31 (4H, m,
C6H4), 7.34e7.81 (5H, m, C6H5), 7.56 (2H, s, NH2),10.76 (1H, s, NH); IR
(KBr) n: 3564, 3360, 3310, 3181, 3072, 3035, 2957, 2924, 2865, 2204,
1707, 1656, 1597, 1522, 1468, 1397, 1293, 1215, 1132, 1072, 1028, 930,
744, 683 cmꢁ1; ESI-MS: m/z¼398 (MþH)þ, 420 (MþNa)þ; HRMS(ESI)
calcd for C23H20N5O2 ([MþH]þ): 370.1304. Found: 370.1307.
1711, 1641, 1606, 1583, 1477, 1410, 1318, 1206, 1153, 1052, 929, 755,
696 cmꢁ1; ESI-MS: m/z¼294 (MþH)þ, 316 (MþNa)þ; HRMS(ESI)
calcd for C15H12N5O2 ([MþH]þ): 294.0991. Found: 294.0994.
4.3.2. 60-Amino-30-ethyl-2-oxo-10-phenyl-20H-spiro[indoline-3,40-
pyrano[2,3-c]pyrazole]-50-carbonitrile (5b). White solid, mp
273e274 ꢀC; 1H NMR (DMSO-d6, 400 MHz)
d
: 0.68e0.72 (3H, t,
CH3), 1.87e1.96 (2H, q, CH2), 6.90e7.26 (4H, m, C6H4), 7.22 (2H, s,
NH2), 10.61 (1H, s, NH), 12.31 (1H, s, NH); IR (KBr) : 3371, 3345,
4.3.9. 60-Amino-30-isopropyl-2-oxo-10-phenyl-spiro[indoline-3,40-
pyrano[2,3-c]pyrazole]-50-carbonitrile
(5i). White
solid,
mp
n
198e200 ꢀC; 1H NMR (DMSO-d6, 400 MHz)
d: 0.66e0.68 (3H, d,
3115, 2991, 2940, 2176, 1717, 1635, 1583, 1468, 1402, 1314, 1204,
CH3), 0.95e0.97 (3H, d, CH3), 2.05e2.12 (1H, m, CH), 6.95e7.30 (4H,
m, C6H4), 7.34e7.82 (5H, m, C6H5), 7.54 (2H, s, NH2), 10.75 (1H, s,
1055, 928, 755, 647 cmꢁ1
;
ESI-MS: m/z¼308 (MþH)þ, 330
(MþNa)þ; HRMS(ESI) calcd for C16H14N5O2 ([MþH]þ): 308.1148.
NH); IR (KBr) n: 3362, 3320, 3188, 2895, 2923, 2867, 2212, 1710,
Found: 308.1151.
1664, 1589, 1520, 1409, 1304, 1219, 1132, 1078, 934, 745, 621 cmꢁ1
;
ESI-MS: m/z¼398 (MþH)þ, 420 (MþNa)þ; HRMS(ESI) calcd for
4.3.3. 60-Amino-30-propyl-2-oxo-20H-spiro[indoline-3,40-pyrano
C
23H20N5O2 ([MþH]þ): 370.1304. Found: 370.1300.
[2,3-c]pyrazole]-50-carbonitrile
(5c). White
solid,
: 0.51e0.55 (3H, t,
lit.
mp
268e270 ꢀC;21 1H NMR (DMSO-d6, 400 MHz)
d
4.3.10. 60-Amino-2-oxo-10,30-diphenyl-spiro[indoline-3,40-pyrano
CH3), 0.99e1.14 (2H, m, CH2), 1.84e1.88 (2H, m, CH2), 6.90e7.27
[2,3-c]pyrazole]-50-carbonitrile (5j). White solid, mp 115e117 ꢀC; 1H
(4H, m, C6H4), 7.20 (2H, s, NH2), 10.60 (1H, s, NH), 12.28 (1H, s, NH);
NMR (DMSO-d6, 400 MHz)
(5H, m, C6H5), 6.94e7.31 (4H, m, C6H4), 7.32e7.79 (5H, m, C6H5),
7.23 (2H, s, NH2), 10.60 (1H, s, NH), 12.29 (1H, s, NH); IR (KBr) n:
3383, 3305, 3228, 2196, 1706, 1588, 1406, 1322, 1201, 1023, 920, 747,
673 cmꢁ1; ESI-MS: m/z¼431 (MþH)þ, 453 (MþNa)þ ESI-MS: m/
z¼322 (MþH)þ, 344 (MþNa)þ; HRMS(ESI) calcd for C26H18N5O2
([MþH]þ): 432.1461. Found: 432.1465.
d: 6.73e6.92 (4H, m, C6H4), 7.01e7.25
IR (KBr) n: 3518, 3442, 3143, 2979, 2889, 2815, 2801, 2343, 1092,
1713, 1637, 1589, 1488, 1417, 1300, 1211, 1069, 917, 742, 618 cmꢁ1
;
ESI-MS: m/z¼322 (MþH)þ, 344 (MþNa)þ; HRMS(ESI) calcd for
C
17H16N5O2 ([MþH]þ): 322.1304. Found: 322.1301.
4.3.4. 60-Amino-30-isopropyl-2-oxo-20H-spiro[indo-line-3,40-pyrano
[2,3-c]pyrazole]-50-carbonitrile (5d). White solid, mp 257e259 ꢀC;
1H NMR (DMSO-d6, 400 MHz)
d
: 0.66e0.68 (3H, d, CH3), 0.95e0.97
(3H, d, CH3), 2.05e2.12 (1H, m, CH), 6.89e7.26 (4H, m, C4H6), 7.18
(2H, s, NH2), 10.61 (1H, s, NH), 12.31 (1H, s, NH); IR (KBr) : 3504,
4.3.11. Ethyl 60-amino-30-methyl-2-oxo-20H-spiro[indoline-3,40-pyr-
ano[2,3-c]pyrazole]-50-carboxylate (6a). White solid; 1H NMR
n
(DMSO-d6, 400 MHz)
3.65e3.75 (2H, m, CH2), 6.81e7.15 (4H, m, C6H4), 8.02 (2H, s, NH2),
10.37 (1H, s, NH), 12.15 (1H, s, NH); IR (KBr) : 3385, 3281, 3188,
d: 0.70e0.73 (3H, t, CH3), 1.58 (3H, s, CH3),
3463, 3156, 2966, 2908, 2874, 2825, 2362, 2192, 1702, 1640, 1610,
1494, 1468, 1402, 1307, 1216, 1010, 928, 750, 626 cmꢁ1; ESI-MS: m/
n

488
J. Feng et al. / Tetrahedron 70 (2014) 484e489
3084, 3028, 2977, 2898, 2838, 2578, 1974, 1715, 1666, 1614, 1539,
1471, 1401, 1290, 1221, 1155, 1097, 1035, 923, 884, 768, 713, 679, 618,
558 cmꢁ1; ESI-MS: m/z¼431 (MþH)þ, 453 (MþNa)þ; HRMS(ESI)
calcd for C17H17N4O4 ([MþH]þ): 431.1250. Found: 431.1254.
256e258 ꢀC; 1H NMR (DMSO-d6, 400 MHz)
d: 0.64e0.68 (3H, t, CH3),
0.74e0.77 (3H, t, CH3), 1.88e2.02 (2H, m, CH2), 3.70e3.80 (2H, m,
CH2), 6.86e7.20 (4H, m, C6H4), 7.33e7.84 (5H, m, C6H5), 8.21 (2H, s,
NH2),10.53(1H, s, NH); IR (KBr)n: 3364, 3261, 3178, 3075, 3032, 2960,
2931, 2871, 2834, 2738,1696,1635,1514,1469,1381,1284,1168,1135,
1072, 1039, 935, 785, 760, 747, 682, 617 cmꢁ1; ESI-MS: m/z¼445
(MþH)þ, 467 (MþNa)þ; HRMS(ESI) calcd for C28H23N4O4 ([MþH]þ):
445.1876. Found: 445.1872.
4.3.12. Ethyl 60-amino-30-ethyl-2-oxo-20H-spiro[indoline-3,40-pyrano
[2,3-c]pyrazole]-50-carboxylate (6b). White solid; 1H NMR (DMSO-
d6, 400 MHz) d: 0.62e0.66 (3H, t, CH3), 0.70e0.74 (3H, t, CH3),
1.93e2.07 (2H, m, CH2), 3.65e3.75 (2H, m, CH3), 6.81e7.15 (4H, m,
C6H4), 8.02 (2H, s, NH2), 10.39 (1H, s, NH), 12.16 (1H, s, NH); IR (KBr)
4.3.19. Ethyl 60-amino-30-isopropyl-2-oxo-10-phenyl-spiro [indoline-
n
: 3396, 3341, 3181, 2979, 2908, 1708, 1616, 1545, 1469, 1400, 1287,
3,40-pyrano[2,3-c]pyrazole]-50-carboxylate (6i). White solid, mp
1162, 923, 770, 677, 620 cmꢁ1; ESI-MS: m/z¼355 (MþH)þ, 377
(MþNa)þ, 393 (MþK)þ; HRMS(ESI) calcd for C18H19N4O4 ([MþH]þ):
355.1406. Found: 355.1411.
258e259 ꢀC; 1H NMR (DMSO-d6, 400 MHz)
d: 0.52e0.54 (3H, d,
CH3), 0.74e0.78 (3H, t, CH3), 1.07e1.09 (3H, d, CH3), 2.31e2.35 (1H,
m, CH), 3.70e3.79 (2H, m, CH2), 6.84e7.19 (4H, m, C6H4), 7.33e7.84
(5H, m, C6H5), 8.20 (2H, s, NH2), 10.51 (1H, s, NH); IR (KBr) n: 3379,
4.3.13. Ethyl 60-amino-30-propyl-2-oxo-20H-spiro[indoline-3,40-pyr-
3203, 3190, 3024, 2938, 1678, 1628, 1523, 1434, 1376, 1285, 1150,
1072, 955, 783, 746, 688, 627 cmꢁ1; ESI-MS: m/z¼445 (MþH)þ, 467
(MþNa)þ; HRMS(ESI) calcd for C25H25N4O4 ([MþH]þ): 445.1876.
Found: 445.1879.
ano[2,3-c]pyrazole]-50-carboxylate (6c). White solid; 1H NMR
(DMSO-d6, 400 MHz) d: 0.60e0.65 (3H, t, CH3), 0.69e0.73 (3H, t,
CH3), 0.99e1.14 (2H, m, CH2), 1.83e1.88 (2H, t, CH2), 6.80e7.14 (4H,
m, C6H4), 8.02 (2H, s, NH2), 10.37 (1H, s, NH), 12.17 (1H, s, NH); IR
(KBr) n: 3390, 3343, 3181, 3075, 3012, 2884, 2848, 2802, 2725, 1709,
4.3.20. Ethyl 60-amino-2-oxo-10,30-diphenyl-spiro[indoline-3,40-pyr-
1618, 1471, 1420, 1284, 1086, 924, 777, 673, 625 cmꢁ1; ESI-MS: m/
z¼369 (MþH)þ, 391 (MþNa)þ; HRMS(ESI) calcd for C19H21N4O4
([MþH]þ): 369.1563. Found: 369.1566.
ano[2,3-c]pyrazole]-50-carboxylate
(6j). White
solid,
mp
128e130 ꢀC; 1H NMR (DMSO-d6, 400 MHz)
d: 0.71e0.75 (3H, t,
CH3), 3.67e3.77 (2H, m, CH2), 6.86e7.36 (4H, m, C6H4), 7.06e7.32
(5H, m, C6H5), 7.33e7.84 (5H, m, C6H5), 8.25 (2H, s, NH2), 10.08 (1H,
4.3.14. Ethyl
pyrano[2,3-c]pyrazole]-50-carboxylate (6d). White solid; 1H NMR
(DMSO-d6, 400 MHz) : 0.50e0.51 (3H, d, CH3), 0.70e0.74 (3H, t, CH3),
60-amino-30-isopropyl-2-oxo-20H-spiro[indoline-3,40-
s, NH); IR (KBr) n: 3373, 3315, 3256, 3046, 3092, 2973, 1710, 1656,
1576, 1527, 1465, 1340, 1283, 1127, 1047, 973, 775, 628 cmꢁ1; ESI-
d
MS: m/z¼479 (MþH)þ, 501 (MþNa)þ; HRMS(ESI) calcd for
1.03e1.05 (3H, d,CH3), 2.33e2.37 (1H, m, CH), 3.65e3.75(2H, m, CH2),
6.80e7.14 (4H, m, C6H4), 8.02 (2H, s, NH2), 10.39 (1H, s, NH), 12.15 (1H,
C
25H25N4O4 ([MþH]þ): 479.1719. Found: 479.1714.
s, NH); IR (KBr) n: 3280, 3085, 2971, 2931, 2932,1965,1701,1614,1537,
1471, 1397, 1291, 1207, 1158, 1093, 1051, 927, 756, 678, 611 cmꢁ1; ESI-
MS: m/z¼369 (MþH)þ, 391 (MþNa)þ, 407 (MþK)þ; HRMS(ESI) calcd
for C19H21N4O4 ([MþH]þ): 369.1563. Found: 369.1559.
Acknowledgements
This work was supported by the Natural Science Foundation of
China (No. 21162028), the Natural Science Foundation of the Xin-
jiang Science Technology Agency (No. 2009 211A02), and the Nat-
ural Science Foundation of the Education Department of Xinjiang
Uyghur Autonomous Region (No. XJEDU2009S18).
4.3.15. Ethyl 60-amino-2-oxo-30-phenyl-20H-spiro[indoline-3,40-pyr-
ano[2,3-c]pyrazole]-50-carboxylate (6e). White solid, lit. mp
242e243 ꢀC;21 1H NMR (DMSO-d6, 400 MHz)
d: 0.66e0.70 (3H, t,
CH3), 3.64e3.72 (2H, m, CH2), 6.49e6.97 (4H, m, C6H4), 7.06e7.32
(5H, m, C6H5), 8.06 (2H, s, NH2), 9.94 (1H, s, NH), 12.60 (1H, s, NH);
IR (KBr) n: 3508, 3391, 3181, 3059, 2977, 2908,1884,1717,1677,1616,
Supplementary data
1541, 1473, 1402, 1287, 1216, 1096, 1036, 925, 767, 735, 691,
618 cmꢁ1; ESI-MS: m/z¼403 (MþH)þ, 425 (MþNa)þ; HRMS(ESI)
calcd for C22H19N4O4 ([MþH]þ): 403.1406. Found: 403.1403.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.11.019.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
4.3.16. Ethyl 60-amino-30-methyl-2-oxo-10-phenyl-spiro [indoline-3,40-
pyrano[2,3-c]pyrazole]-50-carboxylate (6f). White solid, lit. mp
236e237 ꢀC;12 1H NMR (DMSO-d6, 400 MHz)
d: 0.73e0.77 (3H, t,
References and notes
CH3), 1.60 (3H, s, CH3), 3.72e3.78 (2H, m, CH2), 6.86e7.36 (4H, m,
C6H4), 7.33e7.83 (5H, m, C6H5), 8.22 (2H, s, NH2),10.52 (1H, s, NH); IR
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248e249 ꢀC; 1H NMR (DMSO-d6, 400 MHz)
d: 0.74e0.78 (6H, m,
2CH3), 1.85e2.11 (2H, m, CH2), 3.70e3.79 (2H, m, CH2), 6.85e7.19
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