Novel and efficient one-pot synthesis of spiro[indoline-3,4'-pyrano [2,3-c]pyrazole]derivatives catalysed by L-proline in aqueous medium

Article abstract of DOI:10.3184/174751913X13687116634925

An efficient mild one-pot synthesis of spiro[indoline-3,4'-pyrano[2,3-c] pyrazole derivatives by a four-component reaction of hydrazine, a β-keto ester, isatin, and malononitrile catalysed by L-proline in water is reported.

Full text of DOI:10.3184/174751913X13687116634925

JOURNAL OF CHEMICAL RESEARCH 2013
RESEARCH PAPER 365
JUNE, 365–368
Novel and efficient one-pot synthesis of spiro[indoline-3,4’-
pyrano[2,3-c]pyrazole]derivatives catalysed by L-proline in
aqueous medium
Jiangxia Yu, Yongbing Zhou, Tianhua Shen, Wengang Mao, Kang Chen and Qingbao Song*
College of Chemical Engineering and Material Science, Zhejiang University ofTechnology, Hangzhou 310014, P. R. China
An efficient mild one-pot synthesis of spiro[indoline-3,4’-pyrano[2,3-c]pyrazole derivatives by a four-component
reaction of hydrazine, a β-keto ester, isatin, and malononitrile catalysed by L-proline in water is reported.
Keywords: isatin, multicomponent reactions, spirooxindole, aqueous medium
Multicomponent reactions (MCRs) are synthetically useful
organic reactions, in which three or more different starting
materials react to rapidly build up molecular structure and
complexity in a one-pot procedure.1 The advantages offered by
MCRs have been recognised in the past decade.2 MCRs lead-
ing to interesting heterocyclic scaffolds are particularly useful
for the synthesis of biologically active compounds and drug
candidates3. As a result, the discovery of new MCRs is still
of considerable importance. Furthermore, the design of MCRs
in water with a suitable catalyst is another attractive area in
chemistry,4 because water is a cheap, safe and environmentally
friendly solvent.
The indole nucleus is a common heterocycle in nature. Due
to the structural diversity of biologically active indoles, it is not
surprising that the indole ring system has become an important
component of many pharmaceutical agents.5 Compounds
carrying the indole ring often exhibit antifungal and antibac-
terial activities.6 Furthermore, it has been reported that indoles
substituted withheterocyclic rings at the 3-position as spiroin-
doline derivatives increase biological activity.7,8 The spirooxin-
dole system is the core structure of a number of natural
alkaloids and medicinally relevant compounds.9 Therefore,
various methods have been reported for the preparation of
spirooxindole derivatives.10,11
Heterocycles containing the dihydropyrano[2,3-c]pyrazoles
represent an interesting template for medicinal chemistry,
because this fragment is a key moiety in numerous biologi-
cally active compounds.12,13 Compounds have been described
with potential anticancer,14 antibacteria,15 antimicrobial,16
anti-inflammatory17 and molluscicidal activity.18 Furthermore,
dihydropyrano[2,3-c]pyrazoles have also been identified as
promising human Chk1 kinase inhibitors.19 Recently, Shesto-
palov et al.20 reported the synthesis of spiro[indoline-3,4′-
pyrano [2,3-c]pyrazol]-2-ones via one-pot, two steps reaction
of isatin, hydrazine, malononitrile and a β-keto ester catalysed
by Et3N in EtOH. Yi Zou et al.21 reported the synthesis
of spiro[indoline-3,4′-pyrano[2,3-c]pyrazole]derivatives cata-
lysed by pipe-ridine under ultrasound irradiation. However, to
the best of our knowledge, there have beenfew reports about
the synthesis of spirooxindole derivatives in water.22 In
continuation of our work aimed at developing efficient and
environmental friendly methodologies for the preparation of
indole derivatives,23,24 we have investigated a four-component
reaction of hydrazine, β-keto ester, isatin and malononitrile to
afford a series of spiro[indoline-3,4′-pyrano[2,3-c]pyrazole]-
derivatives catalysed by L-proline in water.
ethyl acetoacetate 2, isatin 3 and malononitrile 4 under differ-
ent reaction conditions (Scheme 1). The results are summarised
in Table 1.The effect of the solvent was examined. It was found
that ethanol, acetonitrile, ethyl acetate, DMF or DMSO showed
no superiority to water (entries 1–6) as solvents. Water proved
to be a suitable solvent and was adopted for all future studies.
To further improve the yield and decrease the reaction time,
we tried to raise the reaction temperature. Raising the tempera-
ture from room temperature to 80 °C (entries 7–10) led to an
increase in yield from 73 to 92%, while at temperatures over
80 °C (entry 11) resulted in a slightly decrease in yield (89%).
Next, the effects of catalysts were evaluated for this model
reaction. A series of Lewis acids and bases were used to
optimise the reaction of hydrazine hydrate, ethyl acetoacetate,
isatin and malononitrile and the results are summarised in
Table 2. It was found that when the reaction was carried out
without any catalyst, the yield can reach 74% (entry 1).
Common bases, such as NaOH, Et3N, TBAF and Lewis acids
such as p-TSA, CAN, FeCl3.6H2O, ZnCl2 catalysed this
reaction in low yields (entries 2–9). However, L-proline was
identified as the best catalyst with 5a being isolated in 92%
yield (entry 10). Consequently, we further turned to testing
the effect of catalyst loading. 5 mol%, 10 mol%, 15 mol%,
20 mol%, 30 mol% of L-proline were tested respectively and
the results are summarised in Table 2. It can be seen that
10 mol% loading of L-proline was optimal, while higher
amounts of L-proline led to a slight decrease in yield (entries
12–14). The yield indicated that over-use of the catalyst may
lead to undesired side reactions.
Under the optimised conditions, the reactions of different
isatins with hydrazines, β-keto esters and malononitrile were
examined (Scheme 2). The corresponding spiro[indoline-3,4′-
pyrano[2,3-c]pyranzole] derivatives 5a–p were obtained in
good yields at 80 °C in water in the presence of L-proline.
The results were shown in Table 3. As shown in Table 3, this
method works with a wide variety of substrates, isatins with
either electron-withdrawing (halides) or electron-donating
groups(alkyl) were reactive.
Results and discussion
At first, the effects of solvent and temperature on the reaction
were studied. We studied the reaction of hydrazine hydrate 1,
* Correspondent. E-mail: qbsong@zjut.edu.cn
Scheme 1 Model reaction.

366 JOURNAL OF CHEMICAL RESEARCH 2013
Table
1 Solvent and temperature optimisation for the
In conclusion, we have described an efficient one pot four-
component reaction of hydrazine, β-keto ester, isatin, and
malononitrile catalysed by L-proline in water. Good to excel-
lent yields have been achieved without further purification.
synthesis of 5aa
Entry
Solvent
Temp./°Cb
Time/min
Yield/%c
1
2
EtOH
CH3CN
DMF
EA
80
80
60
60
60
60
60
60
90
80
60
10
8
45
55
66
43
41
92
73
76
80
92
89
Experimental
3
80
4
80
1H NMR spectra and 13C NMR spectra wererecorded on a Bruker
Avance III 500 MHz spectrometer and using DMSO-d6 (500 MHz for
1H or 125 MHz for 13C, respectively) as solvent. IR spectra were
recorded on a TENSOR 27 spectrometer. Melting points were taken
on a X-4 digital display microscopic melting point apparatus. Mass
spectra were carried out on VARIAN1200. Microanalyses were taken
on a Costech ECS4010 CHNS–O elemental analyser. The reaction
mixture was monitored by on silica gel plates (60F-254).
5
DMSO
H2O
80
6
80
7
H2O
r.t.
40
8
H2O
9
H2O
60
80
100
10
11
H2O
H2O
a Reaction conditions: hydrazine hydrate (1.2 mmol), ethyl ace-
tate (1 mmol), isatin (1 mmol), malononitrile (1mmol), solvent
(5 mL) and L-proline (10 mmol%).
Synthesis of spiropyranyl-oxindole derivatives 5a–p; general
procedure
b r.t., room temperature.
A 50 mL flask charged with hydrazine 1 (1.2 mmol), β-keto ester 2
(1 mmol), isatin 3 (1 mmol), malononitrile 4 (1 mmol) and L-proline
(0.1 mmol) was stirred at 80 °C in water (5 mL). After the completion
of the reaction (monitored by TLC), the reaction mixture was cooled
to room temperature. Then the precipitated product was filtered and
washed with water and cooled ethanol to afford the pure product as a
solid in good to excellent yields.
c Isolated yields.
Table 2 Effects of catalysts on model reactiona
Entry
Catalyst/mol% Temp/°C Time/min Yield/%b
1
2
80
80
80
80
80
80
80
80
80
80
80
80
80
80
60
60
60
60
60
60
60
60
60
10
30
9
74
61
64
68
62
67
65
55
69
92
82
88
86
79
NaO—H(10)
Et3N(10)
6'-Amino-4-bromo-3'-methyl-2-oxo-1'H-spiro[indoline-3,4'-pyrano-
[2,3-c]pyrazole]-5'-carbonitrile (5e): White powder; m.p. >300 °C;
IR (KBr, ν, cm−1): 3371, 3119, 2185, 1730, 1601, 1498, 1383, 1151,
3
4
TBAF(10)
1
1058, 928, 782, 659; H NMR (500 MHz, DMSO) δ 12.29 (s, 1H,
5
p-TSA(10)
CAN(10)
NH), 10.87 (s, 1H, NH), 7.28 (s, 2H, NH2), 7.21 (d, J = 7.8 Hz, 1H,
ArH), 7.15 (d, J = 7.7 Hz, 1H, ArH), 6.96–6.92 (m, 1H, ArH), 1.59
(s, 3H, CH3); 13C NMR (125 MHz, DMSO) δ 177.1, 163.1, 155.9,
143.5, 134.4, 130.9, 129.5, 125.9, 118.5, 126.0, 119.2, 118.5,
109.2,93.1, 53.0; MS m/z 371 (M+). Anal Calcd for C15H10BrN5O2: C,
48.42; H, 2.71; N, 18.82. Found: C, 48.38; H, 2.64; N, 18.56%.
6′-Amino-5-fluoro-1-propyl-2-oxo-3′-methyl-1′H-spiro[indoline-
3,4′-pyrano[2,3-c]pyrazole]-5′-carbonitrile (5m): Light red powder;
m.p. 256–258 °C; IR (KBr, ν, cm−1): 3318, 3171, 2194, 1699, 1587,
1490, 1383, 1259, 1159, 1054, 922, 695; 1H NMR (500 MHz, DMSO)
δ 12.35 (s, 1H, NH), 7.33 (s, 2H, NH2), 7.20 (d, J = 2.1 Hz, 1H, ArH),
7.18 (d, J = 2.3 Hz, 1H, ArH), 7.10–7.06 (m, 1H, ArH), 3.69 (m, 2H,
CH2), 1.63 (m, 2H, CH2), 1.51 (s, 3H, CH3), 0.91 (t, J = 7.4 Hz, CH3);
13C NMR (125 MHz, DMSO) δ 176.2, 162.5, 158.9 (J = 237.3 Hz),
155.3, 138.6, 134.7, 133.8 (J = 7.5 Hz), 118.4, 115.4 (J = 25.0 Hz),
112.3 (J = 25.0 Hz), 111.0 (J = 7.6 Hz), 94.7, 54.6, 47.2, 41.3, 20.4,
11.1, 9.0; MS m/z 353 (M+). Anal Calcd for C18H16N5O2F: C, 61.16; H,
4.56; N, 19.82. Found: C, 61.28; H, 4.29; N, 19.51%.
6′-Amino-5-fluoro-1-propyl-2-oxo-3′-phenyl-1′H-spiro[indoline-
3,4′-pyrano[2,3-c]pyrazole]-5′-carbonitrile (5n): White powder; m.p.
262–265°C; IR (KBr, ν, cm−1): 3468, 3290, 3156, 2970, 2197, 1696,
1599, 1488, 1352, 1260, 1130, 1048, 920, 823, 700; 1H NMR
(500 MHz, DMSO) δ 12.94 (s, 1H, NH), 7.37 (s, 2H, NH2), 7.27 (t,
J = 7.4 Hz, 1H, ArH), 7.18 (t, J = 7.6 Hz, 2H, ArH), 7.12–7.06 (m, 2H,
ArH), 6.98 (m, 1H, ArH), 6.78–6.72 (m, 2H, ArH), 3.54–3.37 (m, 2H,
CH2), 1.47–1.27 (m, 2H, CH2), 0.77 (t, J = 7.3 Hz, 3H, CH3); 13C NMR
(125 MHz, DMSO) δ 176.3, 162.0, 158.8 (J = 237.7 Hz), 155.7, 139.0,
138.8, 134.8 (J = 7.5 Hz), 128.8, 128.2, 127.3, 118.1, 115.3 (J = 25.0
Hz), 113.4, 112.1 (J = 25.0 Hz), 109.8 (J = 7.5 Hz), 94.9, 56.0, 55.5,
47.5, 41.3, 20.0, 18.5, 11.0; MS m/z 415 (M+). Anal Calcd for
C23H18N5O2F: C, 66.50; H, 4.37; N, 16.86. Found: C, 66.35; H, 4.29;
N, 16.57%.
6
7
FeCl3.6H2O(10)
CuBr(10)
8
9
ZnCl2(10)
10
11
12
13
14
L-proline(10)
L-proline(5)
L-proline(15)
L-proline(20)
L-proline(30)
8
8
a Reaction conditions: hydrazine hydrate (1.2mmol), ethyl ace-
tate (1mmol), isatin (1 mmol), malononitrile (1 mmol), solvent
(5 mL) and L-proline (10 mmol%).
b Yields of isolated products.
The proposed mechanism for the synthesis of spirooxin-
dole derivatives 5 is described in Scheme 3. Firstly, a conden-
sation between hydrazine 1 and β-keto esters 2 is proposed
to give the intermediate 6. Furthermore, it is possible that
L-proline, due to its high solubility and amphoteric nature,
ionizes in water to its zwitterionic form 7 which facilitates the
formation of enolate 9. Subsequent deprotonation and attack
on the Knoevenagel moiety 10 gives the Michael adduct 11,
which finally undergoes a Thorpe–Ziegler type of intra-
molecular cyclisation followed by tautomerisation to afford
the product 5.
In this study, the structures of all products 5a–p were
characterised by melting point, IR and 1H NMR spectral data
as well as MS. Some new compounds were also examined by
13C NMR spectroscopy.
6′-Amino-5-fluoro-1-ethyl-2-oxo-3′-methyl-1′H-spiro[indoline-
3,4′-pyrano[2,3-c]pyrazole]-5′-carbonitrile (5p): White powder; m.p.
264–266°C; IR (KBr, ν, cm−1): 3385, 3119, 2188, 1705, 1587, 1491,
1339, 1259, 1128, 1047, 923, 697; 1H NMR (500 MHz, DMSO)
δ 12.35 (s, 1H, NH), 7.33 (s, 2H, NH2), 7.20 (d, J = 7.2 Hz, 2H, ArH),
7.08 (d, J = 7.3 Hz, 1H, ArH), 3.84–3.71 (m, 2H, CH2), 1.52 (s, 3H,
CH3), 1.17 (t, J = 6.8 Hz, 3H, CH3,); 13C NMR (125 MHz, DMSO)
δ 175.7, 162.5, 158.9 (J = 237.1 Hz), 155.2, 138.0, 134.8, 134.0
(J = 7.4 Hz), 118.4, 115.4 (J = 25.0 Hz), 112.3 (J = 25.0 Hz), 109.8
(J = 7.5 Hz), 94.6, 54.5, 47.2, 34.6, 12.5, 9.0; MS m/z 339 (M+). Anal
Calcd for C17H14N5O2F: C, 60.17; H, 4.16; N, 20.64; Found: C, 60.11;
H, 4.04; N, 20.39%.
Scheme 2 Preparation of product 5.

JOURNAL OF CHEMICAL RESEARCH 2013 367
Table 3 Synthesis of spiro[indoline-3,4'-pyrano[2,3-c]pyrazole] derivatives 5a
Entry
Product
R1
R2
R3
R4
M.p/°C
M.p./°Cb
Yield/%c
1
2
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
Ph
H
H
H
5-F
285
273
297–298
281
275
92
90
88
85
83
91
84
86
83
81
89
90
87
82
78
85
H
274–275
306–307
>300
3
H
H
5-Cl
5-Br
4-Br
5-CH3
5-NO2
5-F
4
H
H
5
H
H
>300
281
6
H
H
269–271
266
255–257
258–259
>300
247–249
267
7
H
H
274
8
H
H
255
9
H
Ph
H
5-Br
4-Br
5-CH3
H
254
10
11
12
13
14
15
16
H
Ph
Ph
CH3
CH3
Ph
CH3
CH3
H
292
H
H
245
H
C2H5
n-Pr
n-Pr
H
274
H
5-F
256–258
262–265
265
H
4-OMePh
H
5-F
H
270–272
C2H5
5-F
264–266
a Reaction of hydrazines, β-keto esters, isatins and malononitrile at 80 °C for 10–30 min in water in the presences of L-proline
(10 mmol%).
b Already reported in literature21,25,26
c Yields of isolated products.
.
Scheme 3 Proposed mechanism.

368 JOURNAL OF CHEMICAL RESEARCH 2013
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Received 23 January 2013; accepted 12 April 2013
Paper 1301742 doi: 10.3184/174751913X13687116634925
Published online: 12 June 2013
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