A facile and convenient way to functionalized trifluoromethylated spirocyclic[indole-3,4-pyrano[2,3-c]pyrazole] derivatives

Article abstract of DOI:10.1016/j.tetlet.2013.06.038

An efficient and consecutive one-pot, two-step, four-component reaction for the synthesis of trifluoromethylated spirocyclic[indole-3,4-pyrano[2,3-c] pyrazole] derivatives by the reaction of isatin, malononitrile, ethyl cyanoacetate, or cyanoacetamide, ethyl 4,4,4-trifluoroacetoacetate and hydrazine in the presence of a catalytic amount of piperidine in good yields was described. The structures of new compounds were determined by spectroscopic methods, microanalysis, and X-ray diffraction analysis. In addition, a possible mechanism of the reaction was proposed herein.

Full text of DOI:10.1016/j.tetlet.2013.06.038

Accepted Manuscript
A facile and convenient way to functionalized trifluoromethylated spirocy‐
clic[indole-3,4-pyrano[2,3-c]pyrazole] derivatives
Xiaoqing Liu, Xiaoling Xu, Xu Wang, Wenxin Yang, Qun Qian, Min Zhang,
Liping Song, Hongmei Deng, Min Shao
PII:
S0040-4039(13)01005-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.06.038
TETL 43091
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
8 April 2013
6 June 2013
11 June 2013
Please cite this article as: Liu, X., Xu, X., Wang, X., Yang, W., Qian, Q., Zhang, M., Song, L., Deng, H., Shao, M.,
A facile and convenient way to functionalized trifluoromethylated spirocyclic[indole-3,4-pyrano[2,3-c]pyrazole]
derivatives, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.06.038
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2
Graphical Abstract
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A Facile and convenient way to
functionalized trifluoromethylated
spirocyclic[indole-3,4-pyrano[2,3-c]pyrazole
derivatives
Xiaoqing Liua, Xiaoling Xua, Xu Wanga, Wenxin Yanga, Qun Qiana, Min Zhanga, Liping Songa ,b,*, Hongmei Dengc,
Min Shaoc
Department of Chemistry, School of Science, Shanghai University, Shanghai 200444, China

1
Tetrahedron Letters
journal hom epag e: www.elsevier.com
A facile and convenient way to functionalized trifluoromethylated
spirocyclic[indole-3,4-pyrano[2,3-c]pyrazole] derivatives
Xiaoqing Liua, Xiaoling Xua, Xu Wanga, Wenxin Yanga, Qun Qiana, Min Zhanga, Liping Songa,b∗,
Hongmei Dengc, Min Shaoc
a Department of Chemistry, School of Science, Shanghai University, No. 99, Shangda Road, Shanghai 200444, China
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032,
China
c Laboratory for Microstructures, Shanghai University
ARTICLE INFO
ABSTRACT
Article history:
Received
An efficient and consecutive one-pot, two-step, four-component reaction for synthesis of
trifluoromethylated spirocyclic[indole-3,4-pyrano[2,3-c]pyrazole] derivatives by reaction of
isatin, malononitrile, ethyl cyanoacetate or cyanoacetamide, ethyl 4,4,4-trifluoroacetoacetate and
hydrazine in the presence of a catalytic amount of piperidine in good yields was described. The
structures of new compounds were determined by spectroscopic methods, microanalysis and X-
ray diffraction analysis. In addition, a possible mechanism of the reaction was proposed herein.
Received in revised form
Accepted
Available online
Keywords:
combinatorial synthesis
spirooxindole, multi-component reaction
X-ray crystallographic analysis
synthesis
2009 Elsevier Ltd. All rights reserved.
∗ Corresponding author. Tel.: +86-21-6613-4846; fax: +86-21-6613-4594; e-mail: lpsong@shu.edu.cn

2
Indole and indoline fragments are a class of important
structural motif central to a large number of natural biologically
active compounds.1 Compounds bearing the 2-oxindole nucleus
moiety exhibit different pharmacological activities2 and C-3
spiroindoline derivatives dramatically enhance biological
activity.3 Therefore, searching for efficient methods for the
preparation of those compounds has aroused great interest in
organic synthesis, and developments in the synthesis of diversely
structured spirocyclic derivatives have made a tremendous
progress, such as Heck reactions,4 cyclopropane expansions,5
Diels-Alder reactions6 and [3+2] cycloadditions.7
optimal catalyst, which afforded the product 5{1,1,1,1} in 93%
yield (Table 1, entry 7). Next, we screened the effect of catalyst
loading, the solvent factors and the reaction time. We observed
that the reaction in protic solvents could generally give a higher
yield than that in aprotic solvents (Table 1, entries 7-11). Also
higher amounts of catalyst and prolonged reaction time did not
further improve the yield obviously (Table 1, entries 12-14).
Consequently, the best result was obtained by using 25 mol % of
piperidine as the catalyst and ethanol as the solvent (Table 1,
entry 7).
Multicomponent reactions (MCRs) have attracted much
attention for the construction of bioactive heterocyclic
compounds by virtue of their convergence, productivity, facile
execution, and generally high yields of products.8 In recent years,
literatures showed a series of simple and convenient methods for
synthesis of spirocyclic compound via multicomponent
condensation reactions in good to excellent yields catalyzed by
InCl3,9 K2CO3,10 quaternary cationics,11 β-CD,12 sodium
stearate,13 L-proline14 etc. Other effective synthetic methods were
microwave irradiation15 and the use of electrogenerated base.16 It
is widely recognized that the introduction of fluorine to organic
molecules can often significantly improve their physical,
chemical and boilogical properties.17 However, to the best of our
knowledge, tremendous progress has been achieved in the
synthesis of spirocyclic compounds, while the preparation of
trifluoromethylated spirooxindole derivatives has been
considerably less studied.
Table 1. Optimization of the reaction conditionsa
Yield of
5{1,1,1,1} b (%)
Entry
Base/equiv.
Solvent
Time/h
1
2
Et3N/0.25
Pyridine/0.25
DABCO/0.25
Morpholine /0.25
DBU/0.25
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
DME
6
6
70
50
71
70
87
65
93
83
50
35
40
91
91
90
3
6
4
6
5
6
6
DMAP/0.25
6
7
Piperidine/0.25
Piperidine/0.25
Piperidine/0.25
Piperidine/0.25
Piperidine/0.25
Piperidine/0.5
Piperidine/1
6
8
6
9
6
As part of our ongoing research programs directed at the
development of efficient methodologies for the preparation of the
fluorine-containing heterocyclic compounds and our continued
work on the synthesis of fluorine-containing heterocyclic
compounds via MCRs based on the trifluoromethyl-1,3-
dicarbonyl compounds, a versatile fluorine-containing building-
block,18 herein, we investigated a facile and convenient way to
functionalized trifluoromethylated spirocyclic[indole-3,4-pyra-
no[2,3-c]pyrazole] derivatives.
10
11
12
13
14
CH2Cl2
CH3CN
EtOH
EtOH
EtOH
24
24
6
6
Piperidine/0.25
12
a
Reaction conditions: 1{1} (1.5 mmol), 2{1} (1.5 mmol), 3{1} (1.5 mmol),
4{1} (1.5 mmol), solvent: 10.0 mL EtOH, refluxing.
b Isolated yield.
Initially, we carried out the one-pot, two-step, four-component
reaction of isatin 1{1}, malononitrile 2{1}, ethyl 4,4,4-trifluo-
roacetoacetate 3{1} and hydrazine 4{1} as a model reaction. A
stirring solution of 3{1} (1.5 mmol) and 4{1} (1.5 mmol) in
o
ethanol (10 mL) was refluxed at 78 C for 30 mins. Then 1{1}
(1.5 mmol), 2{1} (1.5 mmol) and a catalytic amount of Et3N (25
mol%, 0.375 mmol) were added. The resulting mixture was
continued to stir at 78 oC for 6h. TLC analysis showed that the
reaction was completed. General workup afforded the major pure
product 5{1,1,1,1} in 70% yield as a white solid (Scheme 1).
Figure 1. Diversity of Reagents
Scheme 1. Model Reaction
O
O
O
H2N
NC
O
O
F3C
OEt
NH
N
N
H
1{1}
3{1}
Et3N
CF3
O
EtOH,ref
N
CN
CN
H
H2N NH2
4{1}
2{1}
5{1,1,1,1}
Based on the above results, a series of commercially available
bases and solvents were investigated in order to find the optimal
condition for the envisaged one-pot, two-step, four-component
reaction for synthesis of trifluoromethylated spirooxindole
derivatives (Table 1). It was found that pyridine catalyzed this
reaction with moderate yield (Table 1, entry 2) and other
common bases, such as Et3N, DABCO, DMAP, Morpholine and
DBU, gave a little bit higher yields (Table 1, entries 1, 3-6).
Among those bases examined, piperidine was identified as the

3
groups on isatins. The protocol was also effective with isatins
bearing N-methyl group (Table 2, entries 11-12) or N-phenyl
group (Table 2, entries 13-14).
isatins 1
O
O
O
H3C
O2N
O
O
O
N
H
N
H
N
H
{3}
{1}
{4}
{2}
O
O
O
Cl
F
O
O
O
N
N
H
N
H
{6}
{5}
malononitrile or ethyl cyanoacetate or cyanoacetamide 2
CN
CN
{1}
CN
CN
COOEt
{2}
CONH2
{3}
Ethyl 4,4,4-trifluoroacetoacetate 3
O
O
F3C
OEt
{1}
hydrazines 4
H2N NH2
H2O
NHNH2
{1}
{2}
To investigate the scope and limitation of this process, six
isatins 1{1-6}, three acetonitrile derivatives 2{1-3}, ethyl 4,4,4-
trifluoroacetoacetate 3{1} and two hydrazines 4{1-2} were
chosen for the library validation (Figure 1). The corresponding
trifluoromethylated
spirocyclic
[indole-3,4-pyrano[2,3-
c]pyrazole] derivatives 5{(1-6),(1-2),1,(1-2)} were obtained in
excellent yields. The reaction facilitated various isatins bearing
either electron-withdrawing substituents, such as fluoro, chloro
and nitro (Table 2, entries 3-4,7-10), or electron-donating
substituents such as alkyl (Table 2, entries 5-6). Gratifyingly, it
was found that nearly all of the corresponding products were
obtained in excellent yields, regardless the effect of substituted
Table 2. Synthesis of trifluoromethylated spirocyclic[indole-3,4-pyrano[2,3,-c] pyrazole] derivatives by using malononitrile or ethyl
cyanoacetate a, 20,21

4
H2N
R3
R4
O
N
O
O
O
N
R1
CN
R3
H
N
R1
Piperidine
CF3
H2N
O
O
F3C
OEt
R4 EtOH,ref
N
N
R2
R2
1{1-6}
2{1-2}
3{1}
4{1-2}
5{(1-6),(1-2),1,(1-2)}
Entry
1
Product 5
Time/h
M.p.b
Yield/ %c
o
>222 C
5{1,1,1,1}
5{1,2,1,1}
5{2,1,1,1}
5{2,2,1,1}
5{3,1,1,1}
5{3,2,1,1}
5{4,1,1,1}
5{4,2,1,1}
5{5,1,1,1}
5{5,2,1,1}
5{6,1,1,1}
5{6,2,1,1}
5{1,1,1,2}
5{1,2,1,2}
6
8
93
90
90
87
96
91
93
90
94
90
95
93
94
91
>210 oC
>236 oC
>190 oC
>246 oC
>214 oC
>255 oC
>220 oC
>244 oC
>212 oC
>240 oC
>210 oC
>227 oC
>202 oC
2
3
7
4
9
5
4
6
7
7
6
8
9
9
6
10
11
12
13
14
9
7
10
7
10
a Reaction conditions: 1{(1-6)} (1.5 mmol), 2{(1-2)} (1.5 mmol), 3{1} (1.5 mmol), 4{(1-2)} (1.5 mmol), solvent: 10.0 mL EtOH, refluxing.
b Decomposed.
c Isolated yield.
It should be noted that the reaction with ethyl cyanoacetate
afforded a lower yield than that with malonanitrile, which was
probably due to the lower reactivity of ethyl cyanoacetate,
resulting in the requirement of prolonged reaction time. To our
surprise, in the case of cyanoacetamide instead of malononitrile
or ethyl cyanoacetate, we could not obtain the corresponding
products bearing carbamoyl group 5{(1-6),3,1,1}. As a result,
products bearing ethoxycarbonyl group 5{(1-6),2,1,1} were
obtained in moderate yields (Table 3, Scheme 2) and a yellow
precipitate was formed, which showed no fluorine signal in 19F
NMR. Apparently, the envisaged products were ethanolyzed
under the present reaction conditions.
materialsa
Entry
Product
Time/h
Yield (%)
1
2
3
4
5
6
5{1,2,1,1}
5{2,2,1,1}
5{3,2,1,1}
5{4,2,1,1}
5{5,2,1,1}
5{6,2,1,1}
5
6
50
48
53
51
52
50
5
6
6
12
a
Reaction conditions: 1{1-6} (1.5 mmol), 2{3} (1.5 mmol), 3{1} (1.5
mmol), 4{1} (1.5 mmol), solvent: 10.0 mL EtOH, refluxing
Scheme 2. Unexpected reaction results by using cyanoacetami-
de as the starting materials
The structure of all products 5{(1-6),(1-2),1,(1-2)} was fully
1
characterized by IR, H, 19F, 13C NMR spectroscopies, MS and
elemental analysis or HRMS. It should be noted that, in some
cases, the CF3 signals in 19F NMR displayed a major peak and a
minor peak respectively, indicating the tautomeric structures of
trifluoromethylated pyrazole ring in solvent. Thus, with all the
information at hand, we were hard to deduce which of the
tautomeric structures (A or B) the resulting compounds
correspond (Scheme 3). To unambiguously establish the
regioselectivity of the products obtained by one-pot, two-step,
four-component reaction, the structure of 5{5,2,1,1} was further
confirmed by X-ray diffraction analysis (Figure 2).19 The fine
crystal suitable for XRD analysis was obtained from acetone. As
shown in Figure 2, the tautomeric structure of 5{5,2,1,1} was 2H
isomers in solid state.
H2N
O
NH
H2NOC
O
O
O
N
R1
R1
CF3
O
F3C
OEt
O
N
N
R2
Piperidine
EtOH,ref
R2
1{1-6}
5{(1-6),3,1,1}
3{1}
H2N
O
CN
NH
N
EtOOC
R1
H2N NH2
4{1}
CONH2
2{3}
CF3
O
N
R2
5{(1-6),2,1,1}
Table 3. Reaction results by using cyanoacetamide as the starting

5
Based on the above results, a plausible mechanism for
theformation of 5 was illustrated in Scheme 4. In the first step, a
condensation of hydrazine with ethyl 4,4,4-
Scheme 3. Two isomers formation of products
4
trifluoroacetoacetate 3 was proposed to give the intermediate 6.
In the second step, Isatins 1 condensed with malononitrile
derivatives to give unsaturated nitriles 8 via Knoevenagel
condensation reaction in the presence of a catalytic amount of
piperidine. Under the present reaction conditions, the resulting
intermediate 6 reacted with intermediate 8 by Michael addition
reaction to afford the intermediate 9, which then underwent the
intra-molecular cyclization via Thorpe-Ziegler like reaction to
afford the final product 5.
In conclusion, we have showed that the one-pot, two-step,
four-component reaction provides a facile and convenient way to
functionalized trifluoromethylated spirocyclic[indole-3,4-pyran
o[2,3-c]pyrazole] derivatives from readily available starting
materials in the presence of a catalytic amount of piperidine.
Excellent chemical yields have been achieved and the reaction
may be considered as a useful synthetic method of fluorine-
containing heterocyclic compounds with potential biological
activity.
Figure 2. X-Ray crystal structure of 5{5,2,1,1}
Acknowledgments
The authors thank the National Natural Science Foundation of
China (NNSFC) (Nos. 21072128, 21272153), the Key
Laboratory of Organofluorine Chemistry, Shanghai Institute of
Organic Chemistry for financial support.
.
Scheme 4. Plausible Mechanism for the Formation of 5
O
NH2-NH-R4
O
O
O
4
-H2O
F3C
OEt
NHR4
F3C
N
-EtOH
EtO
CF3
N
N
R4
EtOH,reflux
6
3
-H+
N
H
N
R3
R4
O
O
CN
O
O
N
R3
7
R1
CN
R3
N
Knoevenagel
reaction
R1
N
R1
N
R4
O
F3C
Michael reaction
CF3
N
O
N
R2
N
R2
R2
1
2
8
9
+H+
N
H
O
N
HN
OH
O
R4
R4
R4
N
O
N
N
R3
R3
R3
N
N
N
R1
R1
R1
Thorpe-Ziegler
like reaction
CF3
CF3
CF3
O
O
N
N
N
R2
R2
10
R2
12
11
H2N
R3
R4
N
O
N
R1
CF3
O
N
R2
5
References and notes

6
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of ethyl 4,4,4-trifluoroacetoacetate 3 (276.0mg, 1.5mmol) and 85%
hydrazine hydrate 4 (88.4 mg,1.5 mmol,) was refluxed in 10ml EtOH
for 30min. Then isatin 1 (220.5 mg, 1.5 mmol), malononitrile 2 (99 mg,
1.5 mmol) and piperdine (21.3 mg, 25 mol %, 0.25 mmol) were added.
The mixture was continuously stirred at 78 oC for 6h. After the
completion of the reaction (monitored by TLC), the solvent was
evaporated under reduced pressure and the residue was
chromatographed on a silica column using petroleum ether-ethyl acetate
(1/1, v/v) as eluent to afford the final product 5{1,1,1,1}, 484.1mg, 93%
yield.
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2011, 41, 441–450.
21. Spectroscopic data for products 5{1,1,1,1}: compound 5{1,1,1,1}, white
solid, yield: 93%. M. p.: >222 oC (decomposed). IR (KBr) ꢀ: 3470,
3313, 3177, 3095, 2205, 1717, 1646, 1620, 1498, 1402, 1334, 1146,
1014, 928, 754, 699 cm-1. 1H NMR (500 MHz, acetone-d6): ꢁ 2.09 (s,
6H, CH3, solvent), 6.67 (s, 2H, NH2), 6.99 (d, J = 7.0 Hz , 1H, Ar-H),
7.03 (dt, J1 = 7.5 Hz, J2 = 0.5 Hz, 1 H, Ar-H), 7.20 (d, J = 7.0 Hz, 1H,
Ar-H), 7.28 (dt, J1 = 7.5 Hz, J2 = 1.0 Hz 1H, Ar-H), 9.64 (s, 1H, NH),
13.12 (br, s, 1H, NH). 13C NMR (100 MHz, acetone-d6): ꢁ 30.95
(acetone-C), 48.55, 59.72, 99.41, 111.02, 111.07, 117.98, 120.70 (q, 1JC-F
= 267.0 Hz), 123.88, 126.00, 130.84, 142.77, 142.89, 162.42, 178.30,
207.06 (acetone-C). 19F NMR (470 MHz, acetone-d6): ꢁ -61.81 (s, 3F).
ESI-MS: 348 [M+H]+ . Anal. Calcd for C18H14F3N5O3: C, 53.34; H,
3.48; N,17.28. Found: C, 52.95; H, 3.62; N, 17.20. (Recrystallized from
acetone. The product contains a molecular of acetone).
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