Diastereoselective trans Cyclopropanation of 3-Alkylidene Oxindoles with in Situ Generated α-Diazo Carbonyls or α,β-Unsaturated Diazo Compounds

Article abstract of DOI:10.1055/a-1384-1967

An efficient diastereoselective trans cyclopropanation of 3-alkylidene oxindoles with in situ generated α-diazo carbonyl compounds or α,β-unsaturated diazo compounds under metal-free conditions has been developed to synthesize 3-spirocyclopropyl-2-oxindol

Full text of DOI:10.1055/a-1384-1967

SYNTHESIS
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 53, A–M
paper
A
en
S. Pramanik et al.
Paper
Synthesis
Diastereoselective trans Cyclopropanation of 3-Alkylidene Oxindoles
with In Situ Generated -Diazo Carbonyls or ,-Unsaturated Diazo
Compounds
R3
Sayan Pramanika
Suman Rayb
Suvendu Maityc
Prasanta Ghoshc
Chhanda Mukhopadhyay*a
O
R1
O
OH
OH
R3
O
O
R2
N2
Cs2CO3
MeCN
O
R3
+
N
22 examples
70–88% yield
O
TsNHNH2
R
R1
R2
0
0
0
0
-
0
0
0
3
-2
0
6
5
-
3
3
7
8
reflux
R1
a Department of Chemistry, University of Calcutta, 92 APC
Road, Kolkata 700009, India
O
CHO
N
R
cmukhop@yahoo.co.in
R4
O
b Department of Chemistry, Presidency University, Kolkata
700073, India
Cs2CO3
MeCN
N2
R4
+
R4
TsNHNH2
c Department of Chemistry, R. K. Mission Residential College,
Narendrapur, Kolkata 700103, India
R2
O
8 examples
82–90% yield
N
R
CDeMhehpaaiClnrotcdmrmareeuMnskptuhookonhfpdoC@iphnyaegadmhAhiouysotarh.ycyoo,r.Uinniversity of Calcutta, 92 APC Road, Kolkata-700009, India
Received: 11.12.2020
Accepted after revision: 05.02.2021
Published online: 05.02.2021
e.g. in kinase 4 inhibitor as an orally bioavailable antitumor
agent, as an EP4 receptor antagonist, as antagonists for va-
sopressin, and for the treatment of congestive heart failure.8
These unique chemical and biological characteristics of spi-
rocyclopropyl oxindoles have stimulated the development
of new synthetic strategies towards their synthesis.
DOI: 10.1055/a-1384-1967; Art ID: ss-2020-g0639-op
Abstract An efficient diastereoselective trans cyclopropanation of 3-
alkylidene oxindoles with in situ generated -diazo carbonyl com-
pounds or ,-unsaturated diazo compounds under metal-free condi-
tions has been developed to synthesize 3-spirocyclopropyl-2-oxindole
derivatives. The procedure is based on the 1,3-dipolar character of the
corresponding diazo compounds under base-catalyzed conditions. The
method has a wide substrate scope and uses easily available starting
materials.
In the last few decades, great efforts have been devoted
to develop efficient methods for cyclopropanation reac-
tions.9 3-Spirocyclopropyl-2-oxindoles can be traditionally
synthesized in a diastereoselective and enantioselective
manner by treating oxindoles with bromonitroolefins,10
with -chloroacetoacetate esters,11 with pyridinium salts in
the presence of base,12 and with ethyl diazoacetate.13 3-
Chlorooxindole can also be used as a nucleophile, perform-
ing Michael-initiated ring closure between ,-unsaturated
carbonyl compounds, resulting in spirocyclopropyl oxin-
doles.14 Recently, Marinia et al. reported the synthesis of
spirocyclopropyl oxindoles by using vinyl selenone and
substituted and unsubstituted oxindoles.15 In the last few
years, many synthetic approaches have been used for spiro-
cyclopropyl oxindoles, e.g. a 1,3-dipolar cycloaddition reac-
tion of substituted methyleneindolinones with -di-
azomethylphosphonate (Scheme 1a),16 a ring opening/cy-
clopropanation reaction of cyclic sulfur ylides with (E)-3-
(oxyethylidene)-2-oxoindolines (Scheme 1b),17 a sequential
[3 + 2] cycloaddition/ring contraction reaction of 3-ylidene-
oxindoles with 2,2,2-trifluorodiazoethane (Scheme 1c).18
However, the aforementioned strategies use transition met-
als, which results in limited diversification points in the
product. Of environmental concern, CF3CHN2 is explosive
and toxic. Therefore, an alternate approach avoiding the use
of expensive and explosive diazo compounds for the syn-
thesis of these scaffolds is still in great demand. In the last
Key words diastereoselectivity, trans cyclopropanation, diazo com-
pounds, 1,3-dipoles, spiro compounds, oxindoles
There is a great demand for structurally complex cyclo-
propane scaffolds, which have extensive applications in the
pharmaceutical area. Therefore, there is interest in design-
ing and developing expeditious strategies towards the con-
struction of these compounds.1 Among them, the spiro-ox-
indole skeleton is widely found in both natural alkaloids
and synthetic therapeutic agents.2,3 Over the past few de-
cades, numerous elegant transformations have been devel-
oped for the construction of these structures, which usually
employ multistep reactions to construct the spiro-oxindole
skeletons.4
Among the spiro-oxindoles, 3-spirocyclopropyl-2-oxin-
dole is a privileged scaffold with an attractive framework
for both medicinal research and synthetic chemistry. 3-Spiro-
cyclopropyl-2-oxindoles possess a wide spectrum of biolog-
ical activities, such as inotropic3c and herbicidal5,6 proper-
ties. They are also useful in the treatment of congestive
heart failure, hypertension, edema, and hyponatremia.7 Spiro-
cyclopropyl oxindole derivatives are extensively applied,
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–M
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
S. Pramanik et al.
Paper
Synthesis
few decades, -diazo carbonyl compounds have been wide-
ly utilized as 1,3-dipoles in a variety of useful chemical
transformations.19 Construction of -diazo carbonyl com-
pounds from readily available aryl glyoxal monohydrate
and tosylhydrazine encouraged us to further develop an ef-
fective synthetic approach towards spirocyclopropyl oxin-
dole derivatives.20 However, recently, Xiao et al.21 reported
the synthesis of spiro[pyrazolin-3,3′-oxindoles] and 3-aryl-
carbonylmethyl-substituted 3-ylideneoxindoles using the
same starting materials (Scheme 1d); Babu et al.22 also uti-
lized in situ generated -aryldiazomethane with 3-ylidene-
oxindoles towards the synthesis of 3-spirocyclopropyl-2-
oxindole. In continuation to our efforts towards the genera-
tion of new cascade reactions to construct carbo- and het-
erocyclic moieties, we report here the synthesis of 2,3-
dibenzoylspirocyclopropyl oxindole derivatives in a se-
quential [3 + 2] cycloaddition/ring contraction strategy23
starting from 3-ylidene oxindoles and -diazo carbonyl ob-
tained from aryl glyoxal monohydrate. We also noticed that
,-unsaturated diazoalkanes (generated in situ from tosyl-
hydrazine and ,-unsaturated aldehydes) act as 1,3-di-
poles and take part in a similar reaction, providing good ac-
cess to 2-benzoyl-3-styrylspirocyclopropyl oxindoles.
Our preliminary investigation shown in Table 1 com-
menced with the in situ generation of -diazoacetophe-
none from phenylglyoxal monohydrate (2a) and TsNHNH2
(3) in acetonitrile as solvent at room temperature in the
presence of Et3N as base, followed by treatment of this
Previous work
(a) 1,3-Dipolar Cycloaddition of 3- alkylidene oxindoles with alpha-Diazomethylphosphonate towards 3,3'-spirophophonylpyrazoline oxindoles
and furthur transformation into spirophosphonylcyclopropane oxindoles16
(MeO)2OP
R2
R2
PO(OMe)2
N
R2
O
P
X
X
NXS
OMe
OMe
NH
R1
O
+
O
R1
O
N
H
N
N
N2
H
H
(b) Ring opening/ cyclopronation of sulfur ylides with 3-alkylidene oxindoles17
O
O
O
R1
S
R1
R3
catalyst
R4
X
R4
O
O
+
S
R2
R2
O
CHCl3, temp
N
N
Boc
R3
Boc
(c) [3+2] Cycloaddition/ring contraction of 3-alkylidene oxindoles with 2,2,2-trifluorodiazoethane18
R2
R2
CF3
R3
R3
O
N2
O
+
F3C
N
R1
N
R1
(d) 1,3-Dipolar cycloaddtion of 3-alkylidene oxindoles with alphadiazoketone towards spiro [pyrazoline-3,3'-oxindoles]21
O
Ar
R2
O
N
R2
DBU (3 equiv)
DMSO, rt
OH
NH
R3
TsNHNH2
+
O
Ar
+
R3
O
N
R1
OH
N
R1
This work
R1
R3
O
O
N
R1
O
OH
Cs2CO3 (2 equiv)
MeCN, 80 °C
O
TsNHNH2
+
R2
+
+
R3
O
R2
O
OH
N
R
R
R1
O
R1
R2
O
CHO
Cs2CO3 (2 equiv)
R3
TsNHNH2
+
O
R3
MeCN, 80 °C
N
R2
O
N
R
R
Scheme 1 Cyclopropanation of 3-alkylidene oxindoles and -diazo compounds for the synthesis of 3-spirocyclopropyl-2-oxindoles
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–M

C
S. Pramanik et al.
Paper
Synthesis
reaction mixture with 1a under reflux. To our delight, cy-
clopropanation occur smoothly to give the corresponding
product 4a in 68% isolated yield with excellent regioselec-
tivity and diastereoselectivity (entry 1). The structure of
the corresponding cyclopropanation product 4a was con-
firmed by NMR and HRMS analyses.
tions were concluded to be the following: 1a (0.5 mmol), 2a
(0.5 mmol), 3 (0.5 mmol) and Cs2CO3 (1 mmol) in MeCN un-
der reflux (80 °C) (Table 1, entry 3).
With these optimized reaction conditions in hand, we
then investigated the substrate scope of this cyclopropana-
tion reaction by varying the substitution pattern of al-
kylidene oxindole 1 and aryl glyoxal monohydrate 2
(Scheme 2). Initially, various aryl glyoxal monohydrates 2
substituted with different functional groups were
screened; these undergo cyclopropanation through 1,3-di-
polar cycloaddition/ring contraction strategy quite easily
and provided the corresponding 3-spirocyclopropyl-2-oxin-
dole scaffolds 4. It was found that both electron-donating
(Me, MeO) and electron-withdrawing (Cl) groups were well
tolerated under the reaction conditions along with phenyl
glyoxal monohydrate (without substitution), affording good
yields. Aryl glyoxal monohydrates 2 with electron-donating
groups provide comparably better yields (4e, 4h, 4i, 4m, 4r,
4v) than those with electron-withdrawing groups (4j, 4s).
When both the 3-alkylidene oxindole 1 and aryl glyoxal 2
are substituted with strong electron-withdrawing groups, a
This interesting result encouraged us to scrutinize other
parameters such as temperature, base and solvent to in-
crease the efficiency of the reaction. Different reaction tem-
peratures were examined and it was found that the reaction
at 80 °C gave a satisfying yield (80%) with reduced reaction
time (Table 1, entry 3). The base used has a remarkable ef-
fect on the reaction efficiency; the reaction occurs in the
presence of various organic and inorganic bases, such as
Et3N, pyridine, DBU, Cs2CO3, and K2CO3, giving the desired
product in moderate to good yield. After optimization using
different bases, Cs2CO3 was shown to be superior, providing
the best yield of 4a (entry 3). Furthermore, a survey was
conducted using solvents such as EtOH, MeCN, MeOH, THF,
DCM, and toluene, which revealed that MeCN is the optimal
solvent. Hence, after a brief screening, the optimal condi-
Table 1 Optimization Study for the Formation of 4aa
O
O
O
O
O
O
OH
base
O
TsNHNH2
+
O
+
OH
N
solvent, temp
N
H
H
1a
2a
3
4a
Entry
Solvent
Base (equiv)
Temp (°C)
Time (h)
Yield (%)b
1
2
EtOH
EtOH
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
THF
Et3N (2)
80
80
80
rt
9
9
68
31
80
–
pyridine (2)
Cs2CO3 (2)
Cs2CO3 (2)
K2CO3 (2)
DBU (2)
3
5
4
10
8
5
80
80
80
50
100
100
80
100
80
80
80
rt
60
42
65
52
trace
34
40
–
6
6
7
Et3N (1)
6
8
Cs2CO3 (1)
pyridine (2)
K2CO3 (1)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
K2CO3 (1)
Et3N (2)
8
9
9
10
11
12
13
14
15
16
17
THF
9
THF
9
toluene
MeOH
MeOH
MeOH
DCM
8
9
65
53
50
–
9
9
Cs2CO3 (1)
Cs2CO3 (1)
6
MeCN
80
5
68
a Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), 3 (0.5 mmol), base, solvent.
b Isolated yields.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–M

D
S. Pramanik et al.
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Synthesis
negligible amount of product is formed, which is too little
to isolate. It is worth mentioning that halo-substituted
products are useful for further functional group intercon-
versions. Products 4 are obtained in excellent diastereo-
selectivity, i.e. >95:5 dr towards trans orientation of the cy-
with coupling constant J = 7.6 Hz as measured by a 400
MHz spectrometer (see Supporting Information, SI), ideal
for trans-oriented CH groups of cyclopropane.24 Additional-
ly, the HPLC data of compound 4j was recorded, ensuring
the good diastereoselectivity (see SI). We also checked a 1H
NMR spectrum of the crude product 4j and noticed a simi-
lar coupling constant of the two cyclopropane CH groups
1
clopropane ring. This was shown by H NMR spectroscopy
of pure compound 4j having two doublets at  = 4.37, 4.12
R3
O
O
R1
R1
O
O
OH
Cs2CO3 (2 equiv)
R2
O
R3
TsNHNH2
+
R2
O
+
OH
N
MeCN, 80 °C
N
R
R
4
1
3
2
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
N
N
H
N
H
N
N
H
H
H
4b, 78%
4e, 79%
4a, 80%
4c, 76%
4d, 80%
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
N
N
N
N
4i, 88%
4g, 85%
4h, 87%
4f, 83%
O
Cl
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
N
O
O
N
N
N
N
4n, 73%
4m, 88%
4k, 75%
4l, 88%
4j, 80%
O
O
O
O
O
Cl
O
O
Cl
O
O
O
O
O
O
O
N
N
N
N
4r, 80%
4q, 72%
4o, 70%
4p, 85%
Cl
O
O
O
O
O
O
Br
O
Cl
O
O
O
O
O
O
N
O
N
N
N
4v, 78%
4u, 82%
4t, 84%
4s, 78%
Scheme 2 Substrate scope for the formation of product 4. Reagents and conditions: 1 (0.5 mmol), 2 (0.5 mmol), 3 (0.5 mmol), anhyd Cs2CO3 (1 mmol),
MeCN (6 mL), 70–80 °C, 5 h.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–M

E
S. Pramanik et al.
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Synthesis
1
compared with the pure compound’s H NMR data (Figure
1). X-ray crystallographic analysis of compound 4j con-
firmed the trans orientation of the cyclopropane group
(Figure 2)
Figure 2 ORTEP diagrams of 4j and 6b
conditions. In addition, the electronic nature of the substit-
uent on the aryl ring of 1 appears to have a subtle influence
on the yield of product 4. It was observed, here also, that an
electron-donating group (MeO) on the aryl ring produced
higher yields (4a, 4d, 4e, 4g, 4i, 4j, 4l, 4m, 4p, 4r, 4t, 4u)
compared to an electron-withdrawing group (4o, 4q). Then
the effect of N-protecting groups on the indoline ring was
also investigated. Various N-protected (Me, Et, Pr, Bn, All)
alkylidene oxindoles 1 were used; N-protected oxindoles 1
gave better yields compared to the unprotected substrates
(4f–v). Moreover, the halo-substituted products 4 can be
further used for transition-metal catalyzed cross-coupling
reactions, thus allowing further application of such
products. In all cases, the functional complexity of the re-
sulting products demonstrates the remarkable chemo- and
Figure 1 Crude NMR spectrum of compound 4j
With these satisfactory results in hand, we then investi-
gated the substrate variation of alkylidene oxindoles 1 in
this cyclopropanation reaction (Scheme 2). Both electron-
withdrawing (4u, 4v) and electron-donating (4d) substitu-
tion on the indoline ring were compatible with the reaction
Table 2 Optimization Study for the Formation of 6aa
O
O
O
O
CHO
base
TsNHNH2
+
O
+
O
solvent, temp
N
N
H
H
1a
5a
3
6a
Entry
Solvent
Base (equiv)
Temp (°C)
Time (h)
Yield (%)b
1
2
MeCN
MeCN
MeCN
MeCN
MeCN
EtOH
Cs2CO3 (2)
K2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
K2CO3 (1)
Cs2CO3 (1)
Et3N (2)
80
80
80
rt
4
6
88
72
70
–
3
12
9
4
5
50
80
80
80
110
rt
4
57
62
74
56
30
–
6
6
7
EtOH
6
8
MeOH
toluene
DCM
6
9
Et3N (2)
7
10
11
Cs2CO3 (2)
Cs2CO3 (1)
6
MeCN
80
4
73
a Reaction conditions: 1a (0.5 mmol), 5a (0.5 mmol), 3 (0.5 mmol), base, solvent.
b Isolated yields.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–M

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S. Pramanik et al.
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Synthesis
O
O
R1
R3
R1
R2
Cs2CO3 (2 equiv)
MeCN, 80 °C
CHO
R2
O
R3
TsNHNH2
+
O
+
N
N
R
R
1
5
3
6
O
O
O
O
O
O
N
O
N
O
N
H
6a, 88%
6b, 87%
6c, 85%
O
O
O
O
O
N
N
Cl
6d, 88%
6e, 90%
O
O
O
Cl
O
O
O
N
N
H
N
6f, 86%
6g, 86%
6h, 82%
Scheme 3 Substrate scope for the formation of product 6. Reagents and conditions: 1 (0.5 mmol), 5 (0.5 mmol), 3 (0.5 mmol), anhyd Cs2CO3 (1 mmol),
MeCN (6 mL), 70–80 °C, 4–6 h.
regiospecificity of the sequence starting from easily acces-
sible starting materials. The structures were unambiguous-
ly elucidated by NMR spectroscopic analysis. A single crys-
tal of 4j was successfully obtained by slow evaporation of
the solvent and the structure was unequivocally confirmed
by X-ray diffraction analysis (Figure 2).
During further study of the reaction, we observed that
(E)-(3-diazoprop-1-enyl)benzene, which is generated in
situ from trans-cinnamaldehyde and TsNHNH2 under base
O
O
O
Cs2CO3 (2 equiv)
no desired product
MeCN, 80 °C
OH
OH
O
O
+
N
H
2a
1a
O
O
N
Ts
MeCN, 80 °C
+
N
no desired product
O
H
N
H
7
1a
O
O
O
O
O
O
N2
Cs2CO3 (2 equiv)
MeCN, 80 °C
O
O
+
N
H
N
H
1a
4a, 76%
Scheme 4 Control experiments
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–M

G
S. Pramanik et al.
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Synthesis
catalysis, can also perform similar cyclopropanation with
alkylidene oxindoles 1 (Table 2). In our preliminary investi-
gation we treated trans-cinnamaldehyde (5a) and TsNHNH2
(3) in acetonitrile at room temperature in the presence of
Cs2CO3 as base with alkylidene oxindole 1a under reflux. As
expected, cyclopropanation occurred, to give the corre-
R3
O
N
O
O
N
N
Ts
Cs2CO3
– TsH
OH
OH
O
N
TsNHNH2
– H2O
O
R3
H
N
R3
R3
R1
N
B
2
A
O
R2
N
R
1,3-dipolar
[3+2] cycloaddition
R3
R3
R1
R1
N
R3
O
O
O
R1
H
O
N
O
N
H
ring contraction
– N2
R1
N
O
O
or
O
N
H
O
R3
O
H
H
N
N
N
R2
O
R2
O
R
R
N
R
N
4
R
C
R2
R2
trans intermediate
cis intermediate
not obtained
R4
1. TsNHNH2
R4
R4
N
N
CHO 2. Cs2CO3
5
D
O
N
N
O
R1
N
R2
R
1,3-dipolar
[3+2] cycloaddition
R4
R1
R1
R1
O
O
O
H
N
N
O
R1
ring
contraction
H
R4
N
N
N
N
O
O
O
R4
or
H
R2
O
– N2
R2
H
H
N
N
R
N
R
N
6
R
R
E
R4
R2
trans intermediate
R2
cis intermediate
not obtained
Scheme 5 Plausible mechanism of the reaction
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–M

H
S. Pramanik et al.
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Synthesis
sponding spiro[cyclopropane-1,3′-indolin]-2′-one 6a in 88%
yield with excellent regiospecificity and diastereoselectivi-
ty (entry 1). The structure of the corresponding product 6a
was confirmed by NMR and HRMS analysis (see SI). There-
fore, we investigated other reaction parameters for further
improvement. After a brief optimization of temperature,
solvent, and base, the optimal conditions were determined
to be the following: 1a (0.5 mmol), 5a (0.5 mmol), 3 (0.5
mmol), Cs2CO3 (1 mmol), in MeCN as medium under reflux-
ing conditions (80 °C) (entry 1).
Next, we examined the substrate scope by varying both
alkylidene oxindole 1 and ,-unsaturated aldehyde 5
(Scheme 3). We found that ,-unsaturated aldehyde 5 with
4-MeO substitution gave the corresponding cyclopropana-
tion product 6e in good yield. Different substituents R1 and
R2 on 1 were also investigated. All the products 6 were ob-
tained in >95:5 dr, as confirmed by NMR and single-crystal
X-ray analysis of 6b (Figure 2).
To gain some insight into the mechanism of this reac-
tion, we conducted some control experiments as shown in
Scheme 4. In our first experiment, the reaction was carried
out with 2a (0.5 mmol) and 1a (0.5 mmol) in the presence
of Cs2CO3 (2 equiv) in refluxing MeCN; we did not obtain
our desired product and both starting materials remained
unchanged. Therefore, we can say that this cyclopropana-
tion requires a 1,3-dipole to initiate a dipolar cycloaddition
and subsequent ring contraction. Then, tosylhydrazone 7 of
phenyl glyoxal monohydrate (0.5 mmol) was subjected to
1a (0.5 mmol) in MeCN as medium without any base, and,
as expected, we did not obtain the cyclopropanation prod-
uct. Therefore, base-catalyzed elimination of the tosyl
group is required to generate the active diazo compound.
We also carried out the reaction with -diazoacetophe-
none, instead of in situ generation of this, under the opti-
mal conditions; the desired product 4a was obtained in 76%
yield.
On the basis of the above results and some previous re-
ports,18,21,22 a plausible mechanism of the reaction is shown
in Scheme 5. Initially, the condensation of arylglyoxal
monohydrate 2 and tosylhydrazine afforded the corre-
sponding tosylhydrazone intermediate A, which subse-
quently generated -diazoarylethanone B in the presence of
Cs2CO3 by elimination of the tosyl group. Then alkylidene
oxindole 1, which has dual Michael acceptor ability, under-
goes 1,3-dipolar cycloaddition with -diazoarylethanone,
acting as 1,3-dipolarophile. The observed diastereoselectiv-
ity of the reaction might be explained by severe steric re-
pulsion in the formation of a cis five-membered intermedi-
ate, rejecting the possibility of cis cyclopropanation. The in-
termediate C decomposes under refluxing conditions by
elimination of N2 to deliver the corresponding trans-spiro-
cyclopropyl oxindole derivative 4. In a similar mechanistic
pathway, 6 can be generated from D (formed in situ from
trans-cinnamaldehyde 5 and TsNHNH2) (Scheme 5).
In conclusion, we have successfully developed a simple
and efficient methodology for the one-pot synthesis of spiro-
cyclopropyl oxindole derivatives through 1,3-dipolar cyclo-
addition/ring contraction of in situ generated -diazocar-
bonyl or ,-unsaturated diazo compounds with 3-alkyli-
dine oxindoles, which were synthesized by a reported
procedure.25 The notable advantage of this method is that
cyclopropanation is achieved without the use of transition
metals or expensive reagents. Further studies towards the
application of this methodology and structural diversifica-
tion of this moiety are underway in our laboratory.
All commercially available chemicals were purchased from Aldrich,
USA, or Spectrochem, India, and used without further purification. All
solvents were used as received. The progress of the reactions were
monitored by TLC (glass sheets pre-coated with silica gel, with binder,
300 mesh, Spectrochem) and column chromatography was per-
formed using silica gel (100–200 mesh). Bruker instruments were
used for 1H (300 and 400 MHz) and 13C (75 and 100 MHz) NMR spec-
troscopy. Chemical shifts are reported in ppm downfield from an in-
ternal TMS reference. HRMS with an ESI source was carried out on a
Waters XEVO-G2S Q TOF mass spectrometer. A 2400 Series II CHNS
Analyzer, Perkin Elmer, USA, was used for elemental analyses. HPLC
spectra were recorded by using an Agilent 1200 Series auto sampler
HPLC system. Melting points were recorded with an open capillary on
an electrical melting point apparatus and the single-crystal structures
of the synthesized compounds were confirmed by an X-ray crystal-
lography experiment on a Bruker SMART diffractometer.
CCDC 1967554 (4j) and 1967819 (6b) contain the supplementary
crystallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/structures.
Spiro[cyclopropane-1,3′-indolin]-2′-ones 4 and 6; General Proce-
dure
The appropriate 3-alkylidene oxindole 1 (0.5 mmol), aryl glyoxal
monohydrate 2 or trans-cinnamaldehyde 5 (0.5 mmol), tosylhydra-
zine (3; 0.5 mmol), and Cs2CO3 (1 mmol) were added with MeCN (6
mL) to a dry 10 mL round-bottomed flask equipped with a reflux con-
denser. Then the reaction mixture was stirred under reflux for 5 h. Af-
ter the reaction had reached completion, as monitored by TLC, the re-
action mixture was cooled to rt, diluted with water (10 mL), and ex-
tracted with EtOAc (3 × 10 mL). The organic layer was combined,
washed with brine, and dried over anhyd Na2SO4. After the solvent
had been removed under reduced pressure, the crude product was
purified by column chromatography (silica gel, PE–EtOAc); this af-
forded the desired product 4 or 6.
2-Benzoyl-3-(4-methoxybenzoyl)spiro[cyclopropane-1,3′-indo-
lin]-2′-one (4a)
White solid; yield: 158.8 mg, 80%; Rf = 0.3 (EtOAc–PE, 25:75); mp
198–200 °C.
1H NMR (300 MHz, CDCl3):  = 8.91 (br s, 1 H), 7.85–7.73 (m, 4 H),
7.43–7.36 (m, 1 H), 7.27–7.15 (m, 4 H), 6.96–6.88 (m, 2 H), 6.70 (d, J =
8.4 Hz, 2 H), 4.29 (d, J = 8.7 Hz, 1 H), 4.09 (d, J = 8.7 Hz, 1 H), 3.70 (s, 3
H).
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–M

I
S. Pramanik et al.
Paper
Synthesis
13C NMR (75 MHz, CDCl3):  = 190.3, 190.1, 164.2, 141.2, 136.2, 133.6,
131.0, 129.8, 128.8, 128.4, 124.6, 122.8, 122.7, 114.4, 114.0, 110.1,
55.5, 40.8, 39.7, 38.7.
13C NMR (100 MHz, CDCl3):  = 190.3, 190.2, 173.6, 164.0, 144.6,
141.3, 133.6, 132.3, 130.9, 130.7, 129.6, 129.4, 129.3, 128.6, 128.5,
124.5, 122.6, 122.5, 113.8, 110.3, 55.5, 40.9, 39.5, 38.7, 21.6.
HRMS (ESI): m/z [M + H]+ calcd for C25H19NO4: 398.1392; found:
HRMS (ESI): m/z [M + H]+ calcd for C26H21NO4: 412.1549; found:
398.1376.
412.1583.
2′-Oxospiro[cyclopropane-1,3′-indoline]-2,3-diylbis(phenylmeth-
1′-Ethyl-2′-oxospiro[cyclopropane-1,3′-indoline]-2,3-diyl-
anone) (4b)
bis(phenylmethanone) (4f)
White solid; yield: 143.7 mg, 78%; Rf = 0.3 (EtOAc–PE, 25:75); mp
White solid; yield: 163.3 mg, 83%; Rf = 0.3 (EtOAc–PE, 2:8); mp 208–
200–202 °C.
210 °C.
1H NMR (300 MHz, CDCl3):  = 8.76 (s, 1 H), 7.98 (d, J = 7.8 Hz, 2 H),
7.83 (d, J = 7.8 Hz, 2 H), 7.57–7.33 (m, 7 H), 7.28–7.23 (m, 1 H), 7.04 (t,
J = 7.5 Hz, 1 H), 6.95 (d, J = 7.5 Hz, 1 H), 4.43 (d, J = 7.8 Hz, 1 H), 4.19 (d,
J = 7.8 Hz, 1 H).
1H NMR (300 MHz, CDCl3):  = 8.00 (d, J = 7.8 Hz, 2 H), 7.80 (d, J = 7.8
Hz, 2 H), 7.59–7.28 (m, 8 H), 7.06 (t, J = 7.8 Hz, 1 H), 6.92 (d, J = 7.8 Hz,
1 H), 4.42 (d, J = 7.8 Hz, 1 H), 4.13 (d, J = 7.8 Hz, 1 H), 3.82–3.63 (m, 2
H), 1.10 (t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3):  = 192.0, 190.4, 173.3, 141.4, 136.7, 136.1,
133.8, 133.6, 128.8, 128.6, 128.5, 128.4, 124.3, 122.8, 122.6, 110.3,
41.1, 39.6, 38.7.
13C NMR (75 MHz, CDCl3):  = 192.4, 190.7, 170.8, 143.3, 136.8, 136.3,
135.8, 133.4, 128.7, 128.6, 128.5, 128.4, 124.2, 122.6, 122.5, 108.4,
40.8, 39.7, 38.5, 35.1, 12.6.
HRMS (ESI): m/z [M + H]+ calcd for C24H17NO3: 368.1287; found:
HRMS (ESI): m/z [M + H]+ calcd for C26H21NO3: 396.1600; found:
368.1299.
396.1680.
2-Benzoyl-3-(4-methylbenzoyl)spiro[cyclopropane-1,3′-indolin]-
2′-one (4c)
2-Benzoyl-1′-ethyl-3-(4-methoxybenzoyl)spiro[cyclopropane-
1,3′-indolin]-2′-one (4g)
White solid; yield: 144.0 mg, 76%; Rf = 0.3 (EtOAc–PE, 25:75); mp
White solid; yield: 180.9 mg, 85%; Rf = 0.3 (EtOAc–PE, 2:8); mp 204–
201–203 °C.
206 °C.
1H NMR (400 MHz, CDCl3):  = 8.45 (s, 1 H), 7.87–7.81 (m, 4 H), 7.49
(t, J = 7.2 Hz, 1 H), 7.42–7.30 (m, 3 H), 7.24–7.18 (m, 3 H), 7.02 (t, J =
7.6 Hz, 1 H), 6.90 (d, J = 8 Hz, 1 H), 4.38 (d, J = 8 Hz, 1 H), 4.16 (d, J = 8
Hz, 1 H), 2.35 (s, 3 H).
1H NMR (300 MHz, CDCl3):  = 7.98 (d, J = 8.4 Hz, 2 H), 7.80 (d, J = 7.5
Hz, 2 H), 7.52 (t, J = 6.3 Hz, 2 H), 7.39–7.28 (m, 4 H), 7.05 (t, J = 7.8 Hz,
1 H), 6.92–6.89 (m, 3 H), 4.4 (d, J = 7.5 Hz, 1 H), 4.12 (d, J = 7.5 Hz, 1 H),
3.85–3.65 (m, 1 H), 1.09 (t, J = 6.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 191.5, 190.5, 173.2, 144.9, 141.2,
136.1, 134.2, 133.6, 131.2, 129.4, 128.7, 128.6, 128.5, 128.4, 124.4,
122.8, 122.6, 110.2, 40.9, 39.5, 38.7, 21.6.
13C NMR (75 MHz, CDCl3): 190.8, 190.5, 170.9, 164.1, 143.2, 136.3,
133.4, 131.0, 129.9, 128.6, 128.4, 124.4, 122.6, 122.5, 113.9, 108.4,
55.5, 40.5, 39.6, 38.3, 35.0, 12.5.
HRMS (ESI): m/z [M + H]+ calcd for C25H19NO3: 382.1443; found:
HRMS (ESI): m/z [M + H]+ calcd for C27H23NO4: 426.1706; found:
382.1496.
426.1757.
2-Benzoyl-5′-methoxy-3-(4-methoxybenzoyl)spiro[cyclopropane-
1,3′-indolin]-2′-one (4d)
2-Benzoyl-1′-ethyl-3-(4-methoxybenzoyl)spiro[cyclopropane-
1,3′-indolin]-2′-one (4h)
White solid; yield: 171.1 mg, 80%; Rf = 0.3 (EtOAc–PE, 3:7); mp 194–
White solid; yield: 185.8 mg, 87%; Rf = 0.3 (EtOAc–PE, 2:8); mp 180–
196 °C.
182 °C.
1H NMR (300 MHz, CDCl3):  = 8.26 (br s, 1 H), 7.99–7.94 (m, 2 H),
7.83–7.78 (m, 2 H), 7.52–7.48 (m, 1 H), 7.43–7.39 (m, 1 H), 7.36–7.34
(m, 1 H), 6.94–6.92 (m, 1 H), 6.86–6.81 (m, 2 H), 6.79–6.77 (m, 2 H),
4.37 (d, J = 7.6 Hz, 1 H), 4.12 (d, J =48 Hz, 1 H), 3.85–3.83 (m, 6 H).
1H NMR (400 MHz, CDCl3):  = 7.97 (d, J = 7.6 Hz, 2 H), 7.76 (d, J = 8.8
Hz, 2 H), 7.54–7.52 (m, 1 H), 7.44–7.26 (m, 4 H), 7.03 (t, J = 7.6 Hz, 1
H), 6.90–6.81 (m, 3 H), 4.39 (d, J = 8 Hz, 1 H), 4.08 (d, J = 8 Hz, 1 H),
3.83–3.76 (m, 4 H), 3.70–3.66 (m, 1 H), 1.13–1.06 (m, 3 H).
13C NMR (100 MHz, CDCl3):  = 192.1, 190.1, 173.1, 163.9, 155.8,
136.7, 136.1, 134.5, 133.8, 130.7, 129.7, 128.7, 128.6, 128.4, 125.7,
125.6, 114.0, 110.5, 109.2, 55.7, 55.4, 41.0, 39.8, 38.5.
13C NMR (100 MHz, CDCl3):  = 192.6, 189.3, 171.0, 164.0, 143.4,
137.0, 133.9, 130.8, 129.8, 128.9, 128.8, 128.5, 124.5, 122.8, 114.1,
108.6, 55.7, 40.9, 39.9, 38.8, 35.2, 12.8.
HRMS (ESI): m/z [M + H]+ calcd for C26H21NO5: 428.1498; found:
HRMS (ESI): m/z [M + H]+ calcd for C27H23NO4: 426.1706; found:
428.1465.
426.1708.
2-(4-Methoxybenzoyl)-3-(4-methylbenzoyl)spiro[cyclopropane-
1′-Methyl-2′-oxospiro[cyclopropane-1,3′-indoline]-2,3-diylbis((4-
1,3′-indolin]-2′-one (4e)
methoxyphenyl)methanone) (4i)
White solid ; yield: 162.0 mg, 79%; Rf = 0.3 (EtOAc–PE, 25:75); mp
White solid; yield: 194.2 mg, 88%; Rf = 0.3 (EtOAc–PE, 25:75); mp
196–198 °C.
178–180 °C.
1H NMR (400 MHz, CDCl3):  = 8.87 (br s, 1 H), 7.90 (d, J = 8.8 Hz, 1 H),
7.81 (dd, J1 = 8 Hz, J2 = 22.8 Hz, 2 H), 7.71 (d, J = 8 Hz, 1 H), 7.29 (d, J =
7.6 Hz, 1 H), 7.23–7.19 (m, 1 H), 7.15–7.11 (m, 2 H), 7.02–6.98 (m, 1
H), 6.91 (d, J = 7.6 Hz, 1 H), 6.80–6.76 (m, 3 H), 4.35 (d, J = 7.6 Hz, 1 H),
4.14 (d, J = 7.6 Hz, 1 H), 3.77 (s, 3 H), 2.31 (s, 3 H).
1H NMR (400 MHz, CDCl3):  = 7.90 (d, J = 8.8 Hz, 2 H), 7.71 (d, J = 8.8
Hz, 2 H), 7.28 (d, J = 7.6 Hz, 1 H), 7.23–7.19 (m, 1 H), 6.97 (t, J = 7.6 Hz,
1 H), 6.81–6.74 (m, 5 H), 4.31 (d, J = 7.6 Hz, 1 H), 4.05 (d, J = 7.6 Hz, 1
H), 3.76–3.73 (m, 6 H), 3.11 (s, 3 H).
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–M

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S. Pramanik et al.
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Synthesis
13C NMR (100 MHz, CDCl3):  = 190.4, 189.0, 171.4, 164.0, 163.7,
144.1, 131.0, 130.7, 129.8, 129.3, 128.3, 124.2, 122.6, 122.3, 113.9,
113.8, 108.2, 55.5, 40.5, 39.4, 38.5, 30.9, 26.7.
13C NMR (100 MHz, CDCl3):  = 183.5, 182.2, 164.3, 157.0, 156.6,
136.5, 123.9, 123.6, 122.8, 122.4, 121.2, 117.2, 115.3, 106.8, 106.7,
101.4, 48.4, 48.3, 34.7, 33.3, 32.3, 31.5, 13.6, 4.0.
HRMS (ESI): m/z [M + H]+ calcd for C27H23NO5: 4412.1654; found:
HRMS (ESI): m/z [M + H]+ calcd for C29H27NO5: 470.1968; found:
4412.1693.
470.1983.
2-(4-Chlorobenzoyl)-3-(4-methoxybenzoyl)-1′-methylspiro[cyclo-
propane-1,3′-indolin]-2′-one (4j)
2-Benzoyl-3-(4-methylbenzoyl)-1′-propylspiro[cyclopropane-1,3′-
indolin]-2′-one (4n)
White solid; yield: 178.0 mg, 80%; Rf = 0.3 (EtOAc–PE, 25:75); mp
White solid; yield: 158.6 mg, 73%; Rf = 0.3 (EtOAc–PE, 15:85); mp
204–206 °C.
200–202 °C.
1H NMR (400 MHz, CDCl3):  = 7.95 (d, J = 9.2 Hz, 1 H), 7.79–7.73 (m, 2
H), 7.38 (d, J = 8.4 Hz, 1 H), 7.35–7.31 (m, 3 H), 7.30–7.28 (m, 1 H),
7.07–7.03 (m, 1 H), 6.89–6.82 (m, 3 H), 4.37 (d, J = 7.6 Hz, 1 H), 4.12
(d, J = 7.6 Hz, 1 H), 3.83 (s, 3 H), 3.18 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 190.1, 189.5, 171.2, 164.1, 163.9,
144.1, 140.0, 134.9, 131.0, 130.7, 130.0, 129.8, 129.1, 128.5, 123.8,
122.8, 113.9, 108.3, 55.5, 40.5, 39.1, 38.4, 26.7.
1H NMR (300 MHz, CDCl3):  = 7.99 (d, J = 7.5 Hz, 1 H), 7.89 (d, J = 8.1
Hz, 1 H), 7.82 (d, J = 7.8 Hz, 1 H), 7.71 (d, J = 8.1 Hz, 1 H), 7.54–7.15 (m,
7 H), 7.07–7.04 (m, 1 H), 6.89 (d, J = 7.8 Hz, 1 H), 4.41 (d, J = 7.8 Hz, 1
H), 4.15 (d, J = 7.8 Hz, 1 H), 3.71–3.66 (m, 2 H), 2.38 (s, 3 H), 1.59–1.55
(m, 2 H), 0.77 (t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3):  = 191.7, 190.7, 171.3, 144.8, 143.7, 136.3,
134.3, 133.7, 133.4, 129.4, 128.9, 128.7, 128.6, 128.5, 128.4, 124.2,
122.5, 108.5, 41.8, 40.5, 39.4, 38.7, 21.6, 20.6, 11.0.
HRMS (ESI): m/z [M + H]+ calcd for C26H21ClNO4: 446.1160; found:
446.1199.
HRMS (ESI): m/z [M + H]+ calcd for C28H25NO3: 424.1912; found:
424.2745.
2-Benzoyl-1′-methyl-3-(4-methylbenzoyl)spiro[cyclopropane-
1,3′-indolin]-2′-one (4k)
2-Benzoyl-3-(4-chlorobenzoyl)-1′-propylspiro[cyclopropane-1,3′-
indolin]-2′-one (4o)
White solid; yield: 148.5 mg, 75%; Rf = 0.3 (EtOAc–PE, 2:8); mp 190–
192 °C.
Yellow liquid; yield: 70%; Rf = 0.3 (EtOAc–PE, 15:85).
1H NMR (400 MHz, CDCl3):  = 7.98 (d, J = 7.6 Hz, 1 H), 7.85 (dd, J1 = 8
Hz, J2 = 24 Hz, 2 H), 7.71 (d, J = 8 Hz, 1 H), 7.52–7.51 (m, 2 H), 7.42–
7.35 (m, 2 H), 7.32–7.26 (m, 1 H), 7.22–7.15 (m, 2 H), 7.05–7.04 (m, 1
H), 6.87 (t, J = 7.6 Hz, 1 H), 4.44 (d, J = 8 Hz, 1 H), 4.18 (d, J = 8 Hz, 1 H),
3.18 (s, 3 H), 2.36 (s, 3 H).
1H NMR (300 MHz, CDCl3):  = 7.99–7.91 (m, 1 H), 7.82–7.73 (m, 1 H),
7.61 (d, J = 8.4 Hz, 1 H), 7.57–7.53 (m, 1 H), 7.50–7.34 (m, 7 H), 7.06 (t,
J = 7.5 Hz, 1 H), 6.91 (d, J = 7.8 Hz, 1 H), 4.39 (t, J = 8.1 Hz, 1 H), 4.13 (t,
J = 7.5 Hz, 1 H), 3.74–3.59 (m, 2 H), 1.63–1.52 (m, 2 H), 0.76 (q, J = 9
Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 191.6, 190.5, 171.3, 144.9, 144.1,
136.0, 134.1, 133.8, 133.6, 129.4, 128.7, 128.6, 128.5, 128.4, 123.9,
122.7, 122.4, 108.3, 40.7, 39.3, 38.5, 26,7, 21.7.
13C NMR (75 MHz, CDCl3):  = 191.2, 190.5, 171.0, 143.7, 140.4, 136.1,
135.0, 133.5, 130.1, 130.0, 129.7, 129.1, 129.0, 128.9, 128.7, 128,6,
128,5, 123.8, 122.6, 108.7, 41.9, 40.7, 39.5, 38.5, 30.9, 20.6, 11.0.
HRMS (ESI): m/z [M + H]+ calcd for C26H21NO3: 396.1599; found:
396.1676.
2-Benzoyl-1′-benzyl-3-(4-methoxybenzoyl)spiro[cyclopropane-
1,3′-indolin]-2′-one (4p)
White solid; yield: 206.9 mg, 85%; Rf = 0.3 (EtOAc–PE, 2:8); mp 172–
174 °C.
2-Benzoyl-3-(4-methoxybenzoyl)-1′-methylspiro[cyclopropane-
1,3′-indolin]-2′-one (4l)
White solid; yield: 180.8 mg, 88%; Rf = 0.3 (EtOAc–PE, 2:8); mp 199–
201 °C.
1H NMR (300 MHz, CDCl3):  = 7.99 (d, J = 7.8 Hz, 2 H), 7.88–7.81 (m, 2
H), 7.58 (t, J = 7.5 Hz, 1 H), 7.47–7.35 (m, 3 H), 7.21–7.16 (m, 4 H),
7.07–6.99 (m, 3 H), 6.90 (d, J = 9 Hz, 2 H), 6.78–6.74 (m, 1 H), 5.09 (d,
J = 15.6 Hz, 1 H), 4.69 (d, J = 15.6 Hz, 1 H), 4.46 (d, J = 7.8 Hz, 1 H), 4.22
(d, J = 7.8 Hz, 1 H), 3.86 (s, 3 H).
13C NMR (75 MHz, CDCl3):  = 190.7, 190.3, 171.5, 164.1, 143.2, 136.2,
135.5, 133.5, 131.0, 130.8, 129.8, 128.8, 128.5, 128.3, 127.5, 127.1,
127.0, 124.1, 122.8, 122.4, 114.0, 109.3, 55.5, 44.0, 40.3, 39.6, 38.7.
1H NMR (400 MHz, CDCl3):  = 7.98–7.95 (m, 2 H), 7.82–7.77 (m, 2 H),
7.53–7.49 (m, 1 H), 7.43–7.39 (m, 1 H), 7.38–7.34 (m, 2 H), 7.31–7.26
(m, 1 H), 7.05 (t, J = 7.6 Hz, 1 H), 6.90–6.82 (m, 3 H), 4.40 (d, J = 8 Hz, 1
H), 4.16 (d, J = 8 Hz, 1 H), 3.88 (s, 3 H), 3.18 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 190.5, 190.3, 171.3, 164.1, 144.1,
136.1, 133.5, 131.0, 130.7, 128.7, 128.4, 124.0, 122.7, 122.4, 113.9,
108.2, 55.5, 40.6, 39.4, 38.4, 26.7.
HRMS (ESI): m/z [M + H]+ calcd for C32H25NO4: 488.1862; found:
488.1889.
HRMS (ESI): m/z [M + H]+ calcd for C26H21NO4: 412.1550; found:
412.1584.
2-Benzoyl-1′-benzyl-3-(4-chlorobenzoyl)spiro[cyclopropane-1,3′-
indolin]-2′-one (4q)
2′-Oxo-1′-propylspiro[cyclopropane-1,3′-indoline]-2,3-diylbis((4-
Yellow liquid; yield: 176.7 mg, 72%; Rf = 0.3 (EtOAc–PE, 2:8).
methoxyphenyl)methanone (4m)
White solid; yield: 206.3 mg, 88%; Rf = 0.3 (EtOAc–PE, 2:8); mp 188–
190 °C.
1H NMR (400 MHz, CDCl3):  = 7.96 (d, J = 7.6 Hz, 1 H), 7.91 (d, J = 8.8
Hz, 1 H), 7.75 (d, J = 7.6 Hz, 1 H), 7.72 (d, J = 8.8 Hz, 1 H), 7.45–7.29 (m,
6 H), 7.22–7.14 (m, 4 H), 7.03–7.01 (m, 1 H), 6.97–6.96 (m, 2 H), 6.76
(t, J = 7.6 Hz, 1 H), 5.27 (d, J = 15 Hz, 1 H), 5.08 (d, J = 15 Hz, 1 H), 4.44
(d, J = 8 Hz, 1 H), 4.15 (d, J = 8 Hz, 1 H).
1H NMR (400 MHz, CDCl3):  = 7.87 (d, J = 8.8 Hz, 2 H), 7.69 (d, J = 8.8
Hz, 2 H), 7.25 (d, J = 7.2 Hz, 1 H), 7.18 (t, J = 7.2 Hz, 1 H), 6.93 (t, J = 7.6
Hz, 1 H), 6.80–6.77 (m, 3 H), 6.73 (d, J = 8.8 Hz, 2 H), 4.27 (d, J = 7.6 Hz,
1 H), 4.01 (d, J = 7.6 Hz, 1 H), 3.73–3.71 (m, 6 H), 3.61 (q, J = 7.2 Hz, 1
H), 3.42 (q, J = 6.8 Hz, 1 H), 1.54–1.41 (m, 2 H), 0.68 (t, J = 7.2 Hz, 3 H).
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–M

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13C NMR (100 MHz, CDCl3):  = 191.2, 190.8, 175.0, 143.1, 138.7,
138.1, 136.0, 133.2, 133.1, 132.5, 129.5, 129.4, 129.3, 129.2, 129.0,
128.1, 127.6, 127.3, 124.2, 123.0, 122.5, 114.0, 109.3, 44.5, 40.2, 39.5,
38.7.
6.83–6.80 (m, 2 H), 6.74–6.70 (m, 1 H), 4.29 (d, J = 8 Hz, 1 H), 4.00 (d,
J = 8 Hz, 1 H), 3.76 (s, 3 H), 3.68–3.60 (m, 1 H), 3.55–3.51 (m, 1 H),
2.08 (s, 3 H), 0.95 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 190.5, 190.1, 170.5, 164.2, 141.7,
136.1, 134.6, 132.3, 131.1, 128.7, 128.6, 128.4, 128.3, 126.1, 123.2,
113.9, 109.3, 55.4, 39.9, 38.3, 35.1, 30.9, 12.4.
1′-Allyl-2-(4-methoxybenzoyl)-3-(4-methylbenzoyl)spiro[cyclo-
propane-1,3′-indolin]-2′-one (4r)
HRMS (ESI): m/z [M + H]+ calcd for C27H22ClNO4: 460.1315; found:
460.1341.
White solid; yield: 180.4 mg, 80%; Rf = 0.3 (EtOAc–PE, 2:8); mp 191–
192 °C.
1H NMR (400 MHz, CDCl3):  = 7.99–7.97 (m, 1 H), 7.84 (dd, J1 = 8.4
Hz, J2 = 36.8 Hz, 1 H), 7.72 (d, J = 8 Hz, 1 H), 7.37–7.34 (m, 1 H), 7.28–
7.27 (m, 1 H), 7.26–7.21 (m, 1 H), 7.17 (d, J = 8 Hz, 1 H), 7.06–7.02 (m,
1 H), 6.89 (d, J = 9.2 Hz, 2 H), 6.87–6.83 (m, 2 H), 5.70–5.66 (m, 1 H),
5.10–5.07 (m, 1 H), 5.03–4.99 (m, 1 H), 4.42 (d, J = 8 Hz, 1 H), 4.36–
4.35 (m, 1 H), 4.28–4.26 (m, 1 H), 4.15 (d, J = 8 Hz, 1 H), 3.84 (s, 3 H),
2.36 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 190.4, 190.3, 171.2, 164.1, 144.4,
143.3, 131.1, 130.8, 129.9, 129.4, 128.8, 128.6, 128.3, 124.2, 122.7,
122.5, 117.2, 113.9, 109.2, 55.5, 42.6, 40.6, 40.4, 39.6, 38.8, 38.6, 21.7.
2-Benzoyl-5′-bromo-1′-ethyl-3-(4-methylbenzoyl)spiro[cyclopro-
pane-1,3′-indolin]-2′-one (4v)
White solid; yield: 189.9 mg, 78%; Rf = 0.3 (EtOAc–PE, 2:8); mp 214–
215 °C.
1H NMR (400 MHz, CDCl3):  = 7.90 (d, J = 8.4 Hz, 2 H), 7.77 (d, J = 8 Hz,
2 H), 7.54–7.45 (m, 3 H), 7.40–7.26 (m, 4 H), 6.80 (d, J = 8.4 Hz, 1 H),
4.39 (d, J = 8 Hz, 1 H), 4.08 (d, J = 8 Hz, 1 H), 3.78–3.73 (m, 1 H), 3.64–
3.59 (m, 1 H), 2.39 (s, 3 H), 1.06 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 190.7, 190.1, 170.5, 164.2, 141.8,
136.1, 134.1, 133.6, 129.5, 128.8, 128.7, 128.4, 128.3, 128.0, 126.0,
123.2, 113.9, 113.2, 109.2, 40.3, 39.9, 38.5, 35.2, 21.7, 12.4.
HRMS (ESI): m/z [M + H]+ calcd for C29H25NO4: 452.1863; found:
452.1898.
HRMS (ESI): m/z [M + H]+ calcd for C28H24BrNO3: 502.1018; found:
502.1139.
1′-Allyl-2-(4-chlorobenzoyl)-3-(4-methylbenzoyl)spiro[cyclopro-
pane-1,3′-indolin]-2′-one (4s)
2-(4-Methoxybenzoyl)-3-styrylspiro[cyclopropane-1,3′-indolin]-
2′-one (6a)
White solid; yield: 177.4 mg, 78%; Rf = 0.3 (EtOAc–PE, 2:8); mp 205–
207 °C.
White solid; yield: 173.8 mg, 88%; Rf = 0.3 (EtOAc–PE, 15:85); mp
165–166 °C.
1H NMR (400 MHz, CDCl3):  = 7.98 (d, J = 7.6 Hz, 1 H), 7.84 (dd, J1 =
7.6 Hz, J2 = 27.2 Hz, 2 H), 7.70 (d, J = 8 Hz, 1 H), 7.55–7.49 (m, 1 H),
7.44–7.34 (m, 2 H), 7.23–7.15 (m, 2 H), 7.05–7.03 (m, 1 H), 6.84 (d, J =
8 Hz, 1 H), 5.69–5.62 (m, 1 H), 5.08–4.97 (m, 2 H), 4.42–4.34 (m, 2 H),
4.26–4.15 (m, 2 H), 2.37 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 191.8, 190.7, 171.2, 145.1, 144.6,
143.5, 136.5, 134.5, 133.6, 131.2, 129.6, 128.9, 128.8, 128.7, 128.6,
128.5, 124.2, 122.6, 117.4, 109.3, 42.7, 40.7, 39.8, 39.0, 21.8.
1H NMR (400 MHz, CDCl3):  = 8.61 (br s, 1 H), 7.89 (d, J = 8.7 Hz, 2 H),
7.33 (d, J = 7.5 Hz, 2 H), 7.29–7.25 (m, 3 H), 7.19 (t, J = 7.2 Hz, 1 H),
7.14 (t, J = 7.6 Hz, 1 H), 6.96 (t, J = 7.6 Hz, 1 H), 6.90 (d, J = 7.6 Hz, 1 H),
6.80–6.70 (m, 4 H), 3.98 (d, J = 7.6 Hz, 1 H), 3.77 (s, 3 H), 3.59 (t, J = 7.9
Hz, 1 H).
13C NMR (100 MHz, CDCl3):  = 190.8, 175.4, 163.8, 140.9, 136.7,
133.7, 130.6, 129.9, 128.5, 127.5, 126.3, 126.2, 123.2, 122.3, 113.8,
109.8, 55.4, 42.8, 41.8, 39.1.
HRMS (ESI): m/z [M + H]+ calcd for C28H22ClNO3: 456.1366; found:
456.1476.
HRMS (ESI): m/z [M + H]+ calcd for C26H21NO3: 396.1599; found:
396.1671.
1′-Allyl-2-benzoyl-3-(4-methoxybenzoyl)spiro[cyclopropane-1,3′-
indolin]-2′-one (4t)
2-Benzoyl-1′-ethyl-3-styrylspiro[cyclopropane-1,3′-indolin]-2′-
one (6b)
White solid; yield: 183.5 mg, 84%; Rf = 0.3 (EtOAc–PE, 25:75); mp
195–196 °C.
White solid; yield: 170.9 mg, 87%; Rf = 0.3 (EtOAc–PE, 15:85); mp
162–164 °C.
1H NMR (300 MHz, CDCl3):  = 7.99 (d, J = 8.7 Hz, 2 H), 7.85–7.79 (m, 2
H), 7.53 (t, J = 7.2 Hz, 1 H), 7.40–7.37 (m, 3 H), 7.28 (t, J = 6.6 Hz, 1 H),
7.03–6.99 (m, 1 H), 6.90–6.84 (m, 3 H), 5.72–5.63 (m, 1 H), 5.12–4.97
(m, 2 H), 4.46–4.38 (m, 2 H), 4.28–4.15 (m, 2 H), 3.85 (s, 3 H).
13C NMR (75 MHz, CDCl3):  = 190.7, 190.3, 171.1, 164.1, 143.3, 136.1,
133.5, 131.0, 130.7, 129.8, 128.7, 128.6, 128.4, 128.3, 124.0, 122.7,
122.4, 117.2, 113.9, 109.2, 55.5, 55.4, 42.5, 40.4, 39.5, 38.5.
1H NMR (400 MHz, CDCl3):  = 7.93 (d, J = 7.6 Hz, 2 H), 7.53 (t, J = 7.2
Hz, 1 H), 7.44–7.39 (m, 4 H), 7.33–7.20 (m, 5 H), 6.99 (t, J = 7.6 Hz, 1
H), 6.88–6.81 (m, 2 H), 6.73 (d, J = 16 Hz, 1 H), 4.03 (d, J = 7.6 Hz, 1 H),
3.88 (q, J = 7.2 Hz, 2 H), 3.60 (t, J = 8.4 Hz, 1 H), 1.31 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 193.0, 172.5, 142.9, 137.3, 137.0,
133.8, 133.7, 128.8, 128.7, 128.5, 127.6, 127.5, 126.4, 125.9, 123.6,
122.6, 122.4, 108.3, 43.0, 42.0, 39.4, 35.3, 13.1.
HRMS (ESI): m/z [M + H]+ calcd for C28H23NO4: 438.1705; found:
438.1761.
HRMS (ESI): m/z [M + H]+ calcd for C27H23NO2: 394.1808; found:
394.1832.
2-Benzoyl-5′-chloro-1′-ethyl-3-(4-methoxybenzoyl)spiro[cyclo-
propane-1,3′-indolin]-2′-one (4u)
1′-Ethyl-2-(2-methoxybenzoyl)-3-styrylspiro[cyclopropane-1,3′-
indolin]-2′-one (6c)
White solid; yield: 188.2 mg, 82%; Rf = 0.3 (EtOAc–PE, 2:8); mp 211–
213 °C.
1H NMR (400 MHz, CDCl3):  = 7.92–7.90 (m, 2 H), 7.68 (d, J = 7.2 Hz, 2
H), 7.43 (t, J = 7.2 Hz, 1 H), 7.31–7.26 (m, 3 H), 7.19–7.17 (m, 1 H),
White solid; yield: 179.7 mg, 85%; Rf = 0.3 (EtOAc–PE, 15:85); mp
174–175 °C.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–M

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1H NMR (400 MHz, CDCl3):  = 7.74 (d, J = 7.6 Hz, 1 H), 7.44–7.39 (m, 3
H), 7.35 (d, J = 7.2 Hz, 1 H), 7.29 (t, J = 7.6 Hz, 2 H), 7.24–7.18 (m, 2 H),
7.02–7.00 (m, 1 H), 6.98–6.94 (m, 1 H), 6.90–6.89 (m, 1 H), 3.87 (dd,
J1 = 2.4 Hz, J2 = 6.4 Hz, 2 H), 3.84 (s, 1 H), 6.71 (d, J = 16 Hz, 1 H), 4.11
(d, J = 8 Hz, 1 H), 3.93–3.85 (m, 2 H), 3.75 (s, 3 H), 3.67 (dd, J1 = 8 Hz,
J2 = 9.2 Hz, 1 H), 1.35–1.27 (m, 3 H).
13C NMR (100 MHz, CDCl3):  = 192.6, 172.8, 159.2, 152.8, 142.5,
136.8, 134.3, 132.7, 131.1, 130.7, 130.5, 128.9, 127.3, 127.2, 127.0,
126.3, 124.0, 122.3, 121.9, 120.4, 111.5, 107.8, 55.4, 48.4, 41.5, 39.6,
34.9, 12.9.
2-Benzoyl-1′-propyl-3-styrylspiro[cyclopropane-1,3′-indolin]-2′-
one (6g)
White solid; yield: 175.0 mg, 86%; Rf = 0.3 (EtOAc–PE, 15:85); mp
163–164 °C.
1H NMR (400 MHz, CDCl3):  = 7.94 (d, J = 7.8 Hz, 2 H), 7.55–7.51 (m, 1
H), 7.44–7.40 (m, 4 H), 7.33–7.29 (m, 3 H), 7.24–7.19 (m, 2 H), 7.01–
6.98 (m, 1 H), 6.89–6.83 (m, 2 H), 6.74 (d, J = 16 Hz, 1 H), 4.06 (d, J =
7.6 Hz, 1 H), 3.85–3.75 (m, 2 H), 3.63 (dd, J1 = 7.6 Hz, J2 = 9.2 Hz, 1 H),
1.78–1.71 (m, 2 H), 0.99 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 192.8, 172.6, 143.0, 136.9, 136.8,
133.5, 133.4, 128.6, 128.4, 128.3, 127.4, 127.3, 126.2, 125.6, 123.3,
122.2, 122.1, 108.3, 42.9, 41.9, 39.1, 30.8, 20.8, 11.3.
2-Benzoyl-1′-methyl-3-styrylspiro[cyclopropane-1,3′-indolin]-2′-
one (6d)
HRMS (ESI): m/z [M + H]+ calcd for C28H25NO2: 408.1964; found:
408.1987.
White solid; yield: 166.7 mg, 88%; Rf = 0.3 (EtOAc–PE, 15:85); mp
167–168 °C.
1H NMR (400 MHz, CDCl3):  = 7.84–7.82 (m, 2 H), 7.42–7.38 (m, 1 H),
7.31–7.28 (m, 4 H), 7.23–7.20 (m, 2 H), 7.17 (d, J = 8 Hz, 1 H), 7.12–
7.09 (m, 2 H), 6.91–6.89 (m, 1 H), 6.76–6.70 (m, 2 H), 6.62 (d, J = 16
Hz, 1 H), 3.95 (d, J = 7.6 Hz, 1 H), 3.51 (dd, J1 = 7.6 Hz, J2 = 9.2 Hz, 1 H),
3.24 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 192.7, 172.6, 143.6, 136.9, 136.7,
133.6, 133.5, 128.6, 128.4, 128.3, 127.4, 126.2, 125.5, 123.3, 122.4,
122.2, 107.9, 42.6, 41.8, 39.2, 26.6.
2-Benzoyl-5′-chloro-3-styrylspiro[cyclopropane-1,3′-indolin]-2′-
one (6h)
White solid; yield: 163.5 mg, 82%; Rf = 0.3 (EtOAc–PE, 15:85); mp
195–196 °C.
1H NMR (400 MHz, CDCl3):  = 8.62 (s, 1 H), 7.96 (d, J = 7.2 Hz, 2 H),
7.56 (t, J = 7.6 Hz, 1 H), 7.44 (t, J = 7.6 Hz, 2 H), 7.37 (d, J = 7.2 Hz, 2 H),
7.32–7.31 (m, 1 H), 7.29–7.26 (m, 2 H), 7.23–7.20 (m, 1 H), 7.13 (dd,
J1 = 2 Hz, J2 = 8.4 Hz, 1 H), 6.82 (d, J = 8.4 Hz, 1 H), 6.74–6.70 (m, 2 H),
4.05 (d, J = 8 Hz, 1 H), 3.61–3.57 (m, 1 H).
13C NMR (100 MHz, CDCl3):  = 192.4, 174.4, 139.2, 136.8, 136.6,
134.3, 128.8, 128.6, 128.4, 127.9, 127.8, 127.7, 127.5, 126.3, 123.1,
122.5, 110.6, 42.9, 42.0, 40.0.
HRMS (ESI): m/z [M + H]+ calcd for C26H21NO2: 380.1651; found:
380.1705.
2-(4-Methoxystyryl)-1′-methyl-3-(4-methylbenzoyl)spiro[cyclo-
propane-1,3′-indolin]-2′-one (6e)
HRMS (ESI): m/z [M + H]+ calcd for C25H18ClNO2: 400.1104; found:
400.1159.
White solid; yield: 190.3 mg, 90%; Rf = 0.3 (EtOAc–PE, 15:85); mp
162–164 °C.
1H NMR (400 MHz, CDCl3):  = 7.85 (d, J = 6.4 Hz, 2 H), 7.36–7.30 (m, 3
H), 7.22–7.16 (m, 3 H), 6.99 (t, J = 7.2 Hz, 1 H), 6.85–6.83 (m, 3 H),
6.70–6.69 (m, 2 H), 4.04 (d, J = 7.2 Hz, 1 H), 3.79 (s, 3 H), 3.62–3.60 (m,
1 H), 3.24 (s, 3 H), 2.37 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 192.2, 172.5, 159.0, 144.5, 142.6,
134.5, 133.0, 131.4, 129.6, 129.3, 128.4, 127.4, 127.2, 125.6, 122.3,
122.1, 120.9, 117.4, 113.8, 108.8, 55.2, 42.9, 42.6, 41.5, 39.4, 21.6.
Conflict of Interest
The authors declare no conflict of interest.
Funding Information
SP thanks the Council of Scientific and Industrial Research (CSIR),
New Delhi, for a fellowship (SRF). We also are grateful to CAS-V, DST-
FIST, and DST-PURSE Department of Chemistry, University of Calcut-
HRMS (ESI): m/z [M + H]+ calcd for C28H25NO3: 424.1913; found:
424.1942.
ta, for funding as departmental projects.
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Calcuta()
2-(4-Chlorobenzoyl)-1′-propyl-3-styrylspiro[cyclopropane-1,3′-
indolin]-2′-one (6f)
Supporting Information
White solid; yield: 189.6 mg, 86%; Rf = 0.3 (EtOAc–PE, 15:85); mp
177–178 °C.
Supporting information for this article is available online at
1H NMR (400 MHz, CDCl3):  = 7.86 (d, J = 8.8 Hz, 2 H), 7.39–7.34 (m, 1
H), 7.31–7.19 (m, 5 H), 6.98 (t, J = 7.6 Hz, 1 H), 6.87–6.84 (m, 1 H),
6.82–6.78 (m, 1 H), 6.72 (d, J = 16 Hz, 1 H), 3.96 (d, J = 7.6 Hz, 1 H),
3.83–3.74 (m, 2 H), 3.58 (dd, J1 = 7.6 Hz, J2 = 8.8 Hz, 1 H), 1.77–1.70 (m,
2 H), 0.97 (t, J = 7.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 191.7, 172.6, 143.0, 140.1, 136.7,
135.3, 133.7, 129.7, 129.0, 128.5, 127.5, 126.3, 125.4, 123.1, 122.2,
122.1, 108.4, 42.8, 42.0, 41.7, 39.1, 20.9, 11.3.
https://doi.org/10.1055/a-1384-1967. Su
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© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–M

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S. Pramanik et al.
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Synthesis
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