Strategic synthesis and in vitro antimicrobial evaluation of novel difluoromethylated 1-(1, 3-diphenyl-1H-pyrazol-4-yl)-3, 3-difluoro-1, 3-dihydro-indol-2-ones

Article abstract of DOI:10.1007/s00044-016-1658-z

A strategic synthesis of 1-(1,3-diphenyl-1H-pyrazol-4-yl)-3,3-difluoro-1,3-dihydro-indol-2-ones has been achieved by the reaction of indole-2,3-dione (isatin) and substituted bromoacetyl benzene followed by cyclization reaction and evaluated for in vitro antibacterial and antifungal activities. Direct fluorination using diethylaminosulfur trifluoride as a nucleophilic fluorinating reagent was carried out in the present paper. Undoubtedly this methodology gives a facile and straightforward pathway to construct 1-(1,3-diphenyl-1H-pyrazol-4-yl)-3,3-difluoro-1,3-dihydro-indol-2-ones in good yields. The structure of new fluorinated 1-(1,3-diphenyl-1H-pyrazol-4-yl)-3,3-difluoro-1,3-dihydro-indol-2-ones was characterized based on ¹H, ¹³C, and ¹⁹F nuclear magnetic resonance spectroscopy and mass spectrometry data. Structure of target compound was confirmed by Nuclear Overhauser Effect Spectroscopy spectra. Some of the synthesized compounds showed good antimicrobial activities against bacteria and fungi.

Full text of DOI:10.1007/s00044-016-1658-z

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-016-1658-z
ORIGINAL RESEARCH
Strategic synthesis and in vitro antimicrobial evaluation of novel
difluoromethylated 1-(1, 3-diphenyl-1H-pyrazol-4-yl)-3, 3-difluoro-1,
3-dihydro-indol-2-ones
Tejpal Singh Chundawat1,2 Poonam Kumari1 Nutan Sharma1 Sunita Bhagat1
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Received: 23 July 2015 / Accepted: 4 July 2016
© Springer Science+Business Media New York 2016
Abstract A strategic synthesis of 1-(1,3-diphenyl-1H-pyr-
azol-4-yl)-3,3-difluoro-1,3-dihydro-indol-2-ones has been
achieved by the reaction of indole-2,3-dione (isatin) and
substituted bromoacetyl benzene followed by cyclization
reaction and evaluated for in vitro antibacterial and anti-
fungal activities. Direct fluorination using diethylamino-
sulfur trifluoride as a nucleophilic fluorinating reagent was
carried out in the present paper. Undoubtedly this metho-
dology gives a facile and straightforward pathway to con-
struct 1-(1,3-diphenyl-1H-pyrazol-4-yl)-3,3-difluoro-1,3-
dihydro-indol-2-ones in good yields. The structure of new
fluorinated 1-(1,3-diphenyl-1H-pyrazol-4-yl)-3,3-difluoro-
Introduction
Naturally occurring fluorinated molecules are rare
(Hagan and Harper, 1999) and therefore organo fluorine
chemists are interested in the possible effects on biological
properties of molecules after introducing a limited number
of highly electronegative fluorine atoms (Tozer and Herpin,
1996; Smart, 2001). Many studies showed that fluorine
atom and fluoroalkyl group can often bring about many
beneficial effects in a biologically active molecule, such as
the enhancement of metabolic stability, bioavailability,
lipophilicity, and membrane permeability, as well as an
increase of binding affinity (Thayer, 2006; Kirk, 2008;
Hagmann, 2008; Prakash and Chacko, 2008). The drive to
develop methodology allowing improved access to such
compounds has arisen after the demonstration of the useful
physical and chemical properties possessed by this class of
molecules.
1
1,3-dihydro-indol-2-ones was characterized based on H,
13C, and 19F nuclear magnetic resonance spectroscopy and
mass spectrometry data. Structure of target compound was
confirmed by Nuclear Overhauser Effect Spectroscopy
spectra. Some of the synthesized compounds showed good
antimicrobial activities against bacteria and fungi.
Selective fluorination of organic compounds continues to
be a stimulating and exciting area of research. Fluorination
and fluoroalkylation are the two major synthetic methods
to prepare selectively fluorinated organic compounds
(Hiyama, 2000; Kirsch, 2004; Uneyama, 2006). As
compared to trifluoromethylated compounds (Roy et al.,
2011), the analogous difluoro-methylation and mono-
fluoromethylation (selective introduction of a CF2H or CH2F
group into organic molecules) are less studied (Ni et al.,
2007; Uneyama, 2008). It has been realized that a difluor-
omethyl group (CF2H) can act as a more lipophilic hydrogen
bond donor, which makes it an interesting group with respect
to the design of bioactive molecules (Furuya et al., 2008; Wu
et al., 2010; Meanwell, 2011; Rewcastle et al., 2011).
Our interest in applying synthetic methods for introdu-
cing difluoromethyl group in organic compounds and to
develop novel heterocycles encouraged us to explore
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Keywords Isatin Difluoro-methylation Pyrazoles
Heterocycles NOESY Antimicrobial
●
●
Electronic supplementary material The online version of this article
(doi:10.1007/s00044-016-1658-z) contains supplementary material,
which is available to authorized users.
* Sunita Bhagat
sunitabhagat28@gmail.com
1
Organic Synthesis Research Laboratory, Department of
Chemistry, A.R.S.D. College, University of Delhi, New Delhi-
110021, India
2
Department of Applied Sciences, The Northcap University, Sector
23-A, Gurgaon, Haryana, India

Med Chem Res
diethylaminosulfur trifluoride (DAST) as key nucleophilic
fluorinating reagent.
Results and discussion
Chemistry
Pyrazoles and isatin are important heterocyclic com-
pounds demonstrated to be versatile building blocks in
organic synthesis and possess remarkable pharmaceutical
applications. The pyrazole derivatives are important five-
membered aza-heterocycles, which are present in a wide
range of bioactive compounds with anti-inflammatory
(Nasr and Said, 2003), antidepressant (Gokhan et al.,
2003) hypotensive (Du et al., 2002) anticancer, anti-
bacterial, and antiviral activities (Havrylyuk et al., 2009;
Shaharyar et al., 2010). In addition, isatin (1H-indol-2,3-
dione) analogues, due to indole backbone have shown a
variety of biological activities such as antibacterial, anti-
fungal, anti-HIV, and anticonvulsant (Pandeya et al., 2000;
Pandeya et al., 2005; Dandia et al., 2006; Yamamoto and
Kurazono, 2007).
Considering the significance of fluorine incorporation in
heterocycles and taking an overview on the biological
activities and commercial uses of different natural and
synthetic pyrazoles, the synthesis of some new fluorine
containing heterocyclic systems using pyrazole as basic
moiety and coupling it with other bioactive fluorinated
nuclei viz., isatin and phenyl hydrazine for antibacterial and
antifungal activities were aimed in this study.
In order to explore the synthetic utility of difluoromethyl
chemistry, in the present work a study was initiated in
which potentially useful α,α-difluoromethyl ketones were
targeted for the synthesis of 1-(1,3-diphenyl-1H-pyrazol-4-
yl)-3,3-difluoro indolin-2-one 9 in an efficient method. In
order to develop the target compound 9, ketal protection 1
of indole-2,3-dione was readily prepared by refluxing
reaction of indole-2,3-dione with ethylene glycol according
to the method described in the literature (Bhattacharya and
Chakraborti, 1998). Further N-alkylation of 1 with sub-
stituted bromoacetophenone 3a–g yielded compound 4.
Purification of compound 4 was done by recrystalisation
process followed by washing with water. Compounds 3a–g
were obtained from the bromination reaction of 2a–g with
N-bromosuccinimide and a catalytic amount of p-toluene-
sulfonic acid (5–10 mol %) in acetonitrile (Scheme 1).
The reaction of 4a–g with dimethylformamide dime-
thylacetal (DMF-DMA) yielded intermediated compound 5
in situ, which was further cyclized with substituted phenyl
hydrazine hydrochloride 6a–c in ethanol:water (9:1) ratio to
give cyclized compound 7a–t (Scheme 2). As compound 5
Scheme 1 N-alkylation reaction
of protected compound 1
Scheme 2 Synthesis of 7a–t by in situ cyclization

Med Chem Res
Scheme 3 Synthesis of compounds 9a–t via nucleophilic fluorination using DAST
Table 1 A series of 1-(1,3-
diphenyl-1H-pyrazol-4-yl)-3, 3
difluoroindolin-2-ones 9a–t
Entry
R
R′
Yield (%)
Entry
R
R1
Yield (%)
9a
9b
9c
9d
9e
9f
H
H
82
85
86
84
86
78
84
87
82
76
9k
9l
4-CH3
4-CH3
4-Br
4-CH3
4-CN
H
75
79
80
81
85
87
85
86
74
76
H
4-CH3
4-CN
H
H
9m
9n
9o
9p
9q
9r
4-OCH3
4-OCH3
4-OCH3
4-Cl
4-Br
4-CH3
4-CN
H
4-CH3
4-CN
H
4-Br
4-F
9g
9h
9i
4-F
4-CH3
4-CN
H
4-Cl
4-CH3
4-CN
H
4-F
4-Cl
9s
9t
2-Cl,4-Cl
2-Cl,4-Cl
9j
4-CH3
4-CN
was difficult to purify the above in situ reaction was carried
out for synthesis of compound 7.
After the successful synthesis of compound 7a–t,
deprotection reaction of 7 was carried out using con-
centrated HCl and acetic acid to give the keto compound
8a–t. For the synthesis of target compound we used the
nucleophilic fluorinating reagent. The nucleophilic fluor-
ination reaction of 8a–t with DAST gave the target com-
pound 9a–t (Scheme 3).
It was found that a variety of structurally diverse het-
erocyclic ketones 8a–t can be readily difluoromethylated in
good yields by using this fluorinating reagent (DAST).The
results are summarized in Table 1.
The structure of all synthesized compounds was con-
firmed by elemental analyses, ESI-MS, infrared (IR),
1H-nuclear magnetic resonance (NMR), 13C-NMR, 19F-
NMR, COSY, and Nuclear Overhauser Effect Spectroscopy
(NOESY) spectral data. Mass spectra of all compounds
showed [M + 1] peak corresponding to their molecular ion
peak. IR spectra of compounds 9a–t showed C=O bands in
the region 1685–1660 cm−1. The C=N bands of compound
9 observed at 1625–1610 cm−1, respectively. 1H-NMR
spectra of compound 4 showed triplet and multiplet of
CH2 protons (3–4 ppm) which confirmed the ketal forma-
tion of isatin. A singlet was observed at (7.80 ppm) showing
that the cyclized product was formed. LC-MS showed that
the 90 % purity of the isolated compound.
19F-NMR spectra of 9a showed peak at (δ = −110.1 ppm) of
Fig. 1 Confirmation between 9 and 10 was confirmed by NOESY
CF2 which confirmed the fluorination of keto group. Dif-
ferentiation between the structure 9 and 10 was done by
NOESY spectra and on the basis of NOESY spectra the
final structure was confirmed to be 9 (Fig. 1). The spectral
data for final compounds and intermediates are mentioned
in supplementary information.
Biology
Newly synthesized difluoromethylated 1-(1,3-diphenyl-1H-
pyrazol-4-yl)-3,3-difluoro-1,3-dihydro-indol-2-ones (9a–t)
were evaluated for in vitro antibacterial and antifungal
activity against the Staphylococcus aureus, Bacillus subtilis,
Escherichia coli, S. typhi, Candida albicans, and Asper-
gillus niger. The primary screen was carried out by broth
dilution method using nutrient Muller Hinton Broth culture

Med Chem Res
medium (MHB). Minimum inhibitory concentration (MIC)
in µg/ml values are mentioned in Table 2.
Thin layer chromatography (TLC) analysis was performed
on commercially prepared 60 F254 silica gel plates. Visua-
lization of spots on TLC plate was accomplished with
ultraviolet (UV) light (254 nm) and staining over I2 cham-
ber. IR spectra was recorded in KBr on a Perkin Elmer
Spectrum RX-1 fourier transform infrared (FT-IR) spectro-
Twenty new synthesized compounds (9a–t) were tested
for antimicrobial activity. The results revealed that majority
of the synthesized compounds showed varying degrees of
inhibition against the tested microorganisms. For example,
compound 9d, 9q, 9r, and 9t showed better antibacterial
activity against S. aureus, B. subtilis, and E. coli than the
reference sample ampicilin than other synthesized com-
pounds. On the other hand for antifungal activity, com-
pound 9f, 9r, and 9t showed better activity against C.
albicans and A. niger with reference sample greseofulvin
than other synthesized compounds. Comparative activity of
some selected compounds with standard drugs against have
been shown in Fig. 2
1
photometer. The H NMR spectra were recorded in CDCl3
and dimethyl sulfoxide (DMSO)-d6 solution on a Jeol JNM-
ECX400P at 400 MHz. The 13C NMR spectra were recorded
in CDCl3 and DMSO-d6 solution on Jeol JNM-ECX400P at
100 MHz. Chemical shifts for carbons are reported in ppm
from tetramethylsilane and are referenced to the carbon
resonance of the solvent. Data were reported as follows:
chemical shift, multiplicity (s = singlet, d = doublet, t = tri-
plet, q = quartet, m = multiplet, dd = doublet of doublet, br s
= broad singlet), coupling constants in Hertz, and integra-
tion. All purchased chemicals were used as received. All
melting points are uncorrected. Indole-2,3-dione, phenyl
hydrazine hydrochloride, and DAST were procured from
Sigma Aldrich or Alfa aesar. DMF-DMA and sodium
hydride were procured from spectrochem. All solvents were
purified and dried by standard methods. DMF was distilled
over calcium hydride under reduced pressure and stored
under nitrogen. DCM was distilled over calcium hydride.
Experimental section
Materials and methods
All the reactions were performed in an oven-dried Schlenk
flask under an nitrogen atmosphere. Column chromato-
graphy was performed using silica gel (mesh 100–200).
Table 2 In vitro antimicrobial
activity expressed by MICs in
µg/ml of all compounds (9a–t)
Compound
R
R′
Antibacterial activity
Antifungal activity
S.aureus B.subtilis E.coli S.typhi C. albicans A. niger
9a
H
H
250
200
250
200
200
250
200
200
250
200
250
250
250
500
125
250
200
150
125
200
125
250
—
250
250
200
250
200
150
250
200
250
200
250
200
500
250
200
150
150
80
250
250
200
200
250
125
250
250
250
250
250
150
250
200
150
200
125
100
250
200
100
—
>1000
1000
500
1000
>500
1000
1000
500
9b
H
4-CH3 200
9c
H
4-CN
H
200
150
9d
4-OCH3
4-OCH3
4-OCH3
4-Cl
1000
500
9e
4-CH3 200
9f
4-CN
H
150
250
250
500
9g
500
>500
<500
500
9h
4-Cl
4-CH3 250
1000
500
9i
4-Cl
4-CN
H
200
250
9j
4-CH3
4-CH3
4-CH3
4-Br
>500
1000
500
1000
1000
500
9k
4-CH3 250
9l
4-CN
H
200
250
9m
>1000
1000
500
1000
>1000
1000
500
9n
4-Br
4-CH3 250
9o
4-Br
4-CN
H
200
150
9p
4-F
1000
500
9q
4-F
4-CH3 125
500
9r
4-F
4-CN
H
100
200
200
250
—
250
500
9s
2-Cl,4-Cl
250
150
100
—
500
1000
250
9t
2-Cl,4-Cl 4-CN
500
Ampicilin
Greseofulvin
—
—
—
—
—
—
500
—
MIC minimum inhibition concentration in µg/ml

Med Chem Res
Fig. 2 Comparison of MICs of
some selected compounds with
ampicilin and greseofulvin
against bacterial strains S.
aureus, E. Coli, C. Albicans, and
A. niger employes broth dilution
method
Procedure for the synthesis of compounds
Synthesis of 2-bromo-1-phenyl-ethanone 3a–g
Procedure for the synthesis of spiro-[[1, 3]-dioxolane-2, 3′-
indolin]-2′-one (1)
N-bromosuccinimide (0.37 mmol) was added to the stirred
solution of acetophenone (2) (0.37 mol, 1 equiv) in acet-
onitrile (40 mL). The resulting reaction mixture was stirred
for 10–15 min. After that p-TsOH (0.74 mmol, 2 equiv) was
added to the reaction mixture and refluxed for 4–5 h and
monitored by TLC. After completion of reaction, reaction
content was brought to room temperature and washed with
saturated solution of sodium bicarbonate and extracted with
ethyl acetate (3 × 20 mL), organic layer was dried over
sodium sulphate and concentrated under reduced pressure.
The obtained residues were purified by column chromato-
graphy using silica 100–200 mesh size by ethyl acetate:
hexane (4:96) mixture and pure compound was identified as
2-bromo-1-phenyl-ethanone 3a–g.
A mixture of indole-2,3-dione (33.9 mmol, 1 equiv), ethy-
lene glycol (10 equiv), and the catalytic amount of
p-toluenesulfonic acid (5–10 %) were taken in toluene
(40 mL). The resulting reaction mixture was refluxed using
Dean-Stark apparatus for 12–15 h and monitored by TLC.
After completion of reaction, solid Na2CO3 and water were
added into the reaction content for removal of excess of
diol. The aqueous layer was extracted twice with dichlor-
omethane. The collected organic layers were dried over
Na2SO4, filtered, and concentrated under reduced pressure.
The yellowish solid was washed with diethyl ether to give
the desired compound.
2-Bromo-1-phenyl-ethanone (3a) The compound was
obtained as a white solid; yield: 0.15 g (94 %); m.p.:
49–52 °C; IR (KBr) ʋmax: 2944, 1692, 1605, 1543, 1185,
1029, 856 cm−1; 1H-NMR (CDCl3, 400 MHz): δ = 7.97
(2H, d, J = 8.05 Hz, H-1, H-5), 7.60 (1H, t, J = 6.59 Hz, H-
2), 7.47 (2H, t, J = 7.32 Hz, H-3, H-4), 4.44 (2H, s, –CH2);
13C-NMR (CDCl3, 100 MHz): δ = 188.24 (C=O), 165.42,
132.03, 127.40, 115.62, 114.68, 30.46 (CH2); ESI-MS
(m/z): 199.01 [M + 1].
Following the general procedure above, the reaction
was carried out with a solution of isatin (10 g, 67 mmol),
ethylene glycol (35 mL, 670 mmol), and toluene (225 mL).
The expected compound was isolated as a pale yellow
solid (8.5 g).
Spiro-[[1, 3]-dioxolane-2, 3′-indolin]-2′-one (1) The com-
pound was obtained as a light yellow solid; yield: 8.5 g (78
%); m.p.: 133–135 °C; IR (KBr) ʋmax: 3261, 1733, 1624,
1200, 1083, 755 cm−1; 1H-NMR (DMSO-d6, 400 MHz):
δ = 7.86 (1H, s), 7.33 (1H, d, J = 7.32 Hz, H-1), 7.27 (1H, t,
J = 7.32 Hz, H-2), 7.03 (1H, t, J = 7.32 Hz, H-3), 6.79
(1H, d, J = 8.05 Hz, H-4), 4.55 (2H, t, J = 7.32 Hz,
–OCH2), 4.31 (2H, t, J = 7.32 Hz, –OCH2); 13C-NMR
(DMSO-d6, 100 MHz): δ = 175.55 (C=O), 141.80, 131.61,
125.08, 124.33, 123.28, 110.72, 65.79 (–CH2); ESI-MS
(m/z): 192.10 [M + 1].
2-Bromo-1-(4-methoxy-phenyl)-ethanone (3b) The com-
pound was obtained as a pale yellow solid; yield: 0.13 g (90
%); m.p.:70–72 °C; IR (KBr) ʋmax: 2942, 1687, 1601, 1511,
1
1261, 1173, 1023, 834, 582 cm−1. H-NMR (CDCl3, 400
MHz): δ = 7.95 (2H, d, J = 9.52 Hz, H-1, H-5), 6.93 (2H, d,
J = 8.79 Hz, H-2, H-4), 4.37 (2H, s, –CH2), 3.86 (3H, s,
–OCH3); 13C-NMR (CDCl3, 100 MHz): δ = 190.02 (C=O),
164.08, 131.30, 126.84, 114.02, 113.78, 55.52 (OCH3),
30.70 (CH2); ESI-MS (m/z): 227.99 [M + 1].

Med Chem Res
2-Bromo-1-(4-chloro-phenyl)-ethanone (3c) The com-
pound was obtained as a light brown solid; yield: 0.13 g (90
%); m.p.:98–100 °C; IR (KBr) ʋmax: 2954, 1693, 1402,
and monitored by TLC. After completion of reaction, it was
quenched by cold water. On cooling the reaction mixture
precipitate was formed which was filtered and washed with
cold water, solid was dried and washed with ether and again
dried and identified as 1′-(2-oxo-2-phenylethyl) spiro [[1,3]
dioxolane-2,3′-indolin]-2′-one (4a–g).
1
1200, 1093, 812 cm−1. H-NMR (CDCl3, 400 MHz): δ =
7.91 (2H, d, J = 8.79 Hz, H-1, H-5), 7.45 (2H, d, J = 8.05
Hz, H-2, H-4), 4.38 (2H, s, –CH2); 13C-NMR (CDCl3, 100
MHz): δ = 190.18 (C=O), 140.50, 132.19, 130.33, 129.20,
30.36 (CH2); ESI-MS (m/z): 232.91 [M + 1].
1′-(2-Oxo-2-phenylethyl)-spiro-[[1, 3]-dioxolane-2, 3′-indo-
lin]-2′-one (4a) The compound was obtained as a yel-
lowish brown solid; yield: 0.14 g (90 %); IR (KBr) ʋmax:
2-Bromo-1-p-tolyl-ethanone (3d) The compound was
obtained as a white solid; yield: 0.14 g (94 %); m.p.:
66–68 °C; IR (KBr) ʋmax: 2952, 1695, 1611, 1392, 1197,
1183, 800 cm−1; 1H-NMR (CDCl3, 400 MHz): δ = 7.86
(2H, d, J = 8.78 Hz, H-1, H-5), 7.26 (2H, d, J = 8.78 Hz, H-
2, H-4), 4.41 (2H, s, –CH2), 2.41 (3H, s, –CH3); 13C-NMR
(CDCl3, 100 MHz): δ = 190.92 (C=O), 144.99, 131.42,
129.52, 30.93 (CH2), 21.72 (CH3); ESI-MS (m/z): 213.02
[M + 1].
2923, 1651, 1225, 1181, 1131, 753 cm−1; 1H NMR (CDCl3,
400 MHz): δ = 7.99 (2H, d, J = 8.05 Hz), 7.61 (1H, t, J =
7.32 Hz), 7.49 (2H, t, J = 7.32 Hz), 7.38 (1H, d, J = 7.32
Hz), 7.27 (1H, t, J = 7.32 Hz), 7.06 (1H, t, J = 8.05 Hz),
6.60 (1H, d, J = 8.05 Hz), 5.01 (2H, s, –CH2), 4.57 (2H, t, J
= 7.32 Hz, –OCH2), 4.32 (2H, t, J = 8.05 Hz, –OCH2); 13C
NMR (CDCl3, 100 MHz): δ = 191.61 (C=O), 173.48
(C=O), 162.63, 143.75, 134.40, 131.54, 128.89, 124.87,
123.77, 123.47, 109.04, 102.12, 65.80 (CH2), 45.90 (CH2);
ESI-MS (m/z) :310.02 [M + 1].
2-Bromo-1-(4-bromo-phenyl)-ethanone (3e) The com-
pound was obtained as a white solid; yield: 0.12 g (93 %);
m.p.:72–74 °C; IR (KBr) ʋmax: 2953, 1694, 1397, 807 cm−1;
1H-NMR (CDCl3, 400 MHz): δ = 7.82 (2H, d, J = 8.79 Hz,
H-1, H-5), 7.61 (2H, d, J = 8.79 Hz, H-2, H-4), 4.37 (2H, s,
–CH2); 13C-NMR (CDCl3, 100 MHz): δ = 190.37 (C=O),
132.56, 131.93, 129.25, 129.04, 30.36 (CH2); ESI-MS
(m/z): 276.90 [M + 1].
1′-(2-(4-Methoxyphenyl)-2-oxoethyl)spiro-[[1,3]-dioxo-
lane-2,3′-indolin]-2′-one (4b) The compound was
obtained as a yellow solid; yield: 0.17 g (87 %); IR (KBr)
ʋ
max: 2922, 1732, 1686, 1469, 1236, 1173, 1026, 754
cm−1;1H NMR (CDCl3, 400 MHz): δ = 7.97 (2H, d, J =
8.79 Hz), 7.44 (1H, d, J = 7.32 Hz), 7.37 (1H, d, J = 7.32
Hz), 7.28 (1H, t, J = 8.05 Hz), 7.05 (1H, t, J = 9.52 Hz),
6.94 (2H, d, J = 8.05 Hz), 6.63 (1H, d, J = 8.05 Hz), 4.95
(2H, s, –CH2), 4.57 (2H, t, J = 7.32 Hz, –OCH2), 4.31 (2H,
t, J = 6.59 Hz, –OCH2), 3.86 (3H, s, –OCH3); 13C NMR
(CDCl3, 100 MHz): δ = 190.80 (C=O), 173.43 (C=O),
143.58, 140.62, 132.68, 131.59, 129.56, 123.77, 109.02,
102.08, 65.84 (CH2), 45.89 (CH3); ESI-MS (m/z): 340.19
[M + 1].
2-Bromo-1-(4-fluoro-phenyl)-ethanone (3f) The com-
pound was obtained as a white solid; yield: 0.14 g (90 %);
m.p.:49–52 °C; IR (KBr) ʋmax: 2953, 1392, 1201, 824 cm−1;
1H-NMR (CDCl3, 400 MHz): δ = 8.00 (2H, dd, J = 8.79
Hz, J = 5.96 Hz, H-1, H-5), 7.41 (2H, dd, J = 8.05 Hz, H-2,
H-4), 4.39 (2H, s, –CH2); 13C-NMR (CDCl3, 100 MHz): δ
= 189.78 (C=O), 167.35, 131.71, 130.26, 116.13, 30.47
(CH2); ESI-MS (m/z): 216.94 [M + 1].
1′-(2-(4-Chlorophenyl)-2-oxoethyl)spiro-[[1,3]-dioxolane-
2,3′-indolin]-2′-one (4c) The compound was obtained as a
brownish solid; yield: 0.17 g (85 %); IR (KBr) ʋmax: 2921,
1735, 1698, 1618, 1224, 1091, 754 cm−1; 1H NMR (CDCl3,
400 MHz): δ = 7.92 (2H, d, J = 8.79 Hz), 7.45 (2H, d, J =
8.79 Hz), 7.37 (1H, d, J = 7.32 Hz), 7.26 (1H, t, J = 7.32
Hz), 7.06 (1H, t, J = 8.05 Hz), 6.61 (1H, d, J = 8.05 Hz),
4.95 (2H, s, –CH2), 4.56 (2H, t, J = 7.32 Hz, –OCH2), 4.32
(2H, t, J = 6.59 Hz, –OCH2); 13C NMR (CDCl3, 100 MHz):
δ = 190.80 (C=O), 173.43 (C=O), 143.58, 140.62, 132.68,
131.59, 129.56, 129.26, 124.94, 123.60, 109.02, 102.08,
65.84 (CH2), 45.89 (CH2); ESI-MS (m/z): 343.92 [M + 1].
2-Bromo-1-(2,4-dichloro-phenyl)-ethanone (3g) The com-
pound was obtained as a transparent liquid; yield: 0.12 g
(88 %); m.p.:48–50 °C; IR (KBr) ʋmax: 2921, 1696, 1583,
1084, 819 cm−1; 1H-NMR (CDCl3, 400 MHz): δ = 7.53
(1H, t, J = 8.05 Hz, H-1), 7.44 (1H, d, J = 11.72 Hz, H-3),
7.34–7.28 (1H, m, H-2), 4.46 (2H, s, –CH2); 13C-NMR
(CDCl3, 100 MHz): δ = 192.89 (C=O), 138.58, 132.51,
130.51, 127.59, 34.13 (CH2); ESI-MS (m/z): 266.88 [M + 1].
Synthesis of 1′-(2-oxo-2-phenylethyl)-spiro-[[1, 3]
–dioxolane-2,3′-indolin]-2′-ones (4a–g)
Under nitrogen atmosphere sodium hydride (4.1 mmol) was
added to the stirred solution of compound 1 in DMF
(10 mL). After addition, reaction mixture was stirred for
10 min then the solution of 2 in DMF was added drop wise
into the stirred reaction mixture. The resulting reaction
mixture was brought to room temperature and kept for 2 h
1′-(2-Oxo-2-(p-tolyl)-ethyl)-spiro-[[1,3]-dioxolane-2,3′-
indolin]-2′-one (4d) The compound was obtained as a
yellow solid; yield: 0.16 g (82 %); IR (KBr) ʋmax: 2920,
1733, 1620, 1469, 1182, 1055, 754 cm−1; 1H NMR (CDCl3,
400 MHz): δ = 7.88 (2H, d, J = 8.05 Hz), 7.44 (1H, d,
J = 6.59 Hz), 7.37 (1H, d, J = 8.05 Hz), 7.27 (3H, t,

Med Chem Res
J = 8.05 Hz), 7.05 (1H, t, J = 8.05 Hz), 6.60 (1H, d, J =
8.05 Hz), 4.98 (2H, s, –CH2), 4.57 (2H, t, J = 7.32 Hz,
–OCH2), 4.32 (2H, t, J = 7.32 Hz, –OCH2), 2.41 (3H, s,
–CH3); 13C NMR (CDCl3, 100 MHz): δ = 191.23 (C=O),
173.47 (C=O), 145.06, 143.84, 131.96, 129.57, 128.23,
124.84, 123.76, 123.43, 109.10, 102.14, 65.80 (CH2), 45.83
(CH2), 21.73 (CH3); ESI-MS (m/z): 324.24 [M + 1].
DMF-DMA (3.3 mmol, 3 equiv) were heated at 110 °C for
15 h. After that a solution of phenylhydrazine hydrochloride
6a–c (1.2 equiv) in 10 mL solution of ethanol and water
(9:1) was added to the stirred reaction mixture and again
refluxed for additional 3–4 h and monitored by TLC. After
completion of reaction, the reaction content was con-
centrated under reduced pressure, washed with water, and
extracted with ethyl acetate (3 × 20 mL), organic layer was
dried over sodium sulphate and concentrated under reduced
pressure. The obtained residues were purified by column
chromatography using silica 100–200 mesh size by ethyl
acetate: hexane (25:75) as eluent and pure compound was
identified as 1′-(1,3-diphenyl-1H –pyrazol-4-yl)-spiro-
[[1,3]-dioxolane-2,3′indolin]-2′-ones 7a–t.
1′-(2-(4-Bromophenyl)-2-oxoethyl)-spiro[[1,3]-dioxolane-
2,3′-indolin]-2′-one (4e) The compound was obtained as a
yellowish brown solid; yield: 0.20 g (92 %); IR (KBr) ʋmax
:
2919, 1733, 1619, 1469, 1223, 1181, 1055, 754 cm−1; H
NMR (CDCl3, 400 MHz): δ = 7.85 (2H, d, J = 8.79 Hz),
7.63 (2H, d, J = 8.05 Hz), 7.37 (1H, d, J = 6.59 Hz), 7.27
(1H, t, J = 8.05 Hz), 7.07 (1H, t, J = 7.32 Hz), 6.61 (1H, d,
J = 8.05 Hz), 4.95 (2H, s, –CH2), 4.56 (2H, t, J = 7.32 Hz,
–OCH2), 4.32 (2H, t, J = 6.59 Hz, –OCH2); 13C NMR
(CDCl3, 100 MHz): δ = 191.02 (C=O), 173.43 (C=O),
143.57, 133.07, 132.26, 131.59, 129.62, 124.94, 123.77,
109.01, 102.08, 65.84 (CH2), 45.87 (CH2); ESI-MS (m/z):
388.02 [M + 1].
1
1′-(1,3-Diphenyl-1H-pyrazol-4-yl)spiro-[[1,3]-dioxolane-
2,3′-indolin]-2′-one (7a) The compound was obtained as a
yellowish brown solid; yield: 0.10 g (78 %); IR (KBr) ʋmax
:
2919, 1744, 1609, 1589, 1318, 1184, 1120, 754 cm−1; H
NMR (CDCl3, 400 MHz): δ = 7.55 (1H, s), 7.42–7.24 (11H,
m), 7.10–7.00 (2H, m), 6.63 (1H, d, J = 8.05 Hz), 4.57–4.50
(2H, m, –OCH2), 4.30–4.25 (2H, m, –OCH2); 13C NMR
(CDCl3, 100 MHz): δ = 172.21 (C=O), 145.20, 139.85,
138.33, 131.68, 130.26, 129.78, 128.91, 127.64, 124.97,
123.42, 117.00, 113.50, 109.93, 65.82 (CH2); ESI-MS
(m/z): 410.15 [M + 1].
1
1′-(2-(4-Fluorophenyl)-2-oxoethyl)-spiro[[1,3]-dioxolane-
2,3′-indolin]-2′-one (4f) The compound was obtained as a
yellowish brown solid; yield: 0.17 g (88 %); IR (KBr) ʋmax
:
2918, 1733, 1621, 1469, 1226, 1136, 1055, 754 cm−1; H
NMR (CDCl3, 400 MHz): δ = 8.04–8.00 (2H, m), 7.37 (1H,
d, J = 7.32 Hz), 7.26 (1H, t, J = 7.32 Hz), 7.15 (2H, t, J =
8.05 Hz), 7.05 (1H, t, J = 7.32 Hz), 6.61 (1H, d, J = 8.05
Hz), 4.496 (2H, s, –CH2), 4.56 (2H, t, J = 7.32 Hz, –OCH2),
4.32 (2H, t, J = 7.32 Hz, –OCH2); 13C NMR (CDCl3, 100
MHz): δ = 190.33 (C=O), 173.45 (C=O), 167.50, 143.53,
131.58, 130.97, 124.92, 123.76, 116.25, 109.04, 102.10,
65.83 (CH2), 45.84 (CH2); ESI-MS (m/z): 328.06 [M + 1].
1
1′-(3-Phenyl-1-(p-tolyl)-1H-pyrazol-4-yl)spiro-[[1,3]-diox-
olane-2,3′-indolin]-2′-one (7b) The compound was
obtained as a dark brown solid; yield: 0.10 g (80) %; IR
(KBr) ʋmax: 2919, 1736, 1644, 1588, 1395, 1304, 1198,
1122, 758 cm−1; 1H NMR (CDCl3, 400 MHz): δ = 7.53
(1H, s), 7.41 (3H, d, J = 8.05 Hz), 7.32 (2H, d, J = 8.05 Hz),
7.26 (3H, t, J = 8.79 Hz), 7.08 (3H, d, J = 8.05 Hz), 7.01
(1H, t, J = 7.32 Hz), 6.65 (1H, d, J = 7.32 Hz), 4.56 (2H, m,
–OCH2), 4.28 (2H, m, –OCH2), 2.29 (3H, s, –CH3); 13C
NMR (CDCl3, 100 MHz): δ = 174.23 (C=O), 152.25,
145.83, 140.31, 136.29, 132.16, 128.09, 123.29, 110.72,
102.01, 65.86 (CH2), 21.46 (CH3); ESI-MS (m/z): 424.14
[M + 1].
1′-(2-(2,4-Dichlorophenyl)-2-oxoethyl)-spiro-[[1,3]-dioxo-
lane-2,3′-indolin]-2′-one (4g) The compound was
obtained as a brown yellow solid; yield: 0.19 g (85 %); IR
(KBr) ʋmax: 2903, 1735, 1618, 1469, 1181, 1051, 755 cm−1;
1H NMR (CDCl3, 400 MHz): δ = 7.59 (2H, d, J = 8.79 Hz),
7.46 (1H, s), 7.37 (1H, d, J = 7.32 Hz), 7.34–7.28 (2H, m),
7.07 (1H, t, J = 7.32 Hz), 7.64 (1H, d, J = 8.05 Hz), 4.93
(2H, s, –CH2), 4.54 (2H, t, J = 7.32 Hz, –OCH2), 4.31 (2H,
t, J = 7.32 Hz, –OCH2); 13C NMR (CDCl3, 100 MHz): δ =
193.50 (C=O), 173.38 (C=O), 143.37, 138.79, 131.63,
130.72, 127.66, 125.04, 123.77, 123.69, 108.91, 102.03,
65.83 (CH2), 48.85 (CH2); ESI-MS (m/z): 378.08 [M + 1].
4-(4-(2′-Oxospiro-[[1,3]-dioxolane-2,3′-indolin]-1′-yl)-3-
phenyl-1H-pyrazol-1-yl-benzonitrile (7c) The compound
was obtained as a yellowish brown solid; yield: 0.10 (77 %);
IR (KBr) ʋmax: 2923, 2228, 1741, 1605, 1466, 1301, 1121,
1083, 757 cm−1; 1H NMR (CDCl3, 400 MHz): δ = 7.88
(1H, s), 7.62 (2H, d, J = 8.70 Hz), 7.43 (2H, d, J = 9.16 Hz),
7.37 (1H, d, J = 8.24 Hz), 7.31–7.21 (4H, m), 7.16 (2H, d,
J = 7.33 Hz), 7.06 (1H, t, J = 7.32 Hz), 6.56 (1H, d, J =
7.79 Hz), 4.54 (2H, t, –OCH2), 4.33 (2H, t, –OCH2); 13C
NMR (CDCl3, 100 MHz): δ = 173.47 (C=O), 169.68,
144.79, 142.96, 140.75, 139.63, 132.96, 131.69, 129.71,
129.15, 128.92, 127.13, 125.01, 124.80, 123.87, 118.08,
116.17, 65.86 (CH2); ESI-MS (m/z): 435.19 [M + 1].
Synthesis of 1′-(1, 3-diphenyl-1H-pyrazol-4-yl)–spiro-[[1,
3]-dioxolane-2, 3′ indolin]-2′-ones (7a-t) via in situ
cyclization of (4a–g)
A mixture of 1′-(2-oxo-2-phenylethyl)-spiro-[[1,3]–dioxolane-
2, 3′-indolin]-2′-ones 4a–g (1.1 mmol, 1 equiv) and

Med Chem Res
1′-(3-(4-Methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)-spiro-
[[1,3]-dioxolane-2,3′-indolin]-2′-one (7d) The compound
was obtained as a yellowish solid; yield: 0.10 g (78 %); IR
(KBr) ʋmax: 2923, 1738, 1599, 1466, 1254, 1173, 1027,
123.55, 110.15, 101.93, 65.96 (CH2); ESI-MS (m/z): 444.08
[M + 1].
1′-(3-(4-Chlorophenyl)-1-(p-tolyl)-1H-pyrazol-4-yl)-spiro-
[[1,3]-dioxolane-2,3′-indolin]-2′-one (7h) The compound
was obtained as a yellow solid; yield: 0.10 g (80 %); IR
(KBr) ʋmax: 2921, 1734, 1618, 1591, 1398, 1323, 1119,
1
758 cm−1; H NMR (CDCl3, 400 MHz): δ = 7.78 (1H, s),
7.56-7.49 (1H, m), 7.36–7.19 (7H, m), 7.02 (2H, d, J =
8.70 Hz), 6.72 (2H, d, J = 7.79 Hz), 6.56 (1H, d, J = 7.32
Hz), 4.56 (2H, t, –OCH2), 4.30 (2H, t, –OCH2), 3.70 (3H, s,
–CH3); 13C NMR (CDCl3, 100 MHz): δ = 173.82 (C=O),
159.96, 138.04, 130.27, 128.92, 124.98, 124.82, 123.65,
114.23, 109.94, 65.83 (CH2), 55.10 (OCH3); ESI-MS (m/z):
440.09 [M + 1].
1
757 cm−1; H NMR (CDCl3, 400 MHz): δ = 7.80 (1H, s),
7.37 (2H, d, J = 8.05 Hz), 7.32 (1H, d, J = 6.59 Hz),
7.27–7.19 (6H, m), 6.92 (2H, t, J = 8.79 Hz), 6.68 (1H, d, J
= 8.05 Hz), 4.54 (2H, m, –OCH2), 4.30 (2H, m, –OCH2),
2.34 (3H, s, –CH3); 13C NMR (CDCl3, 100 MHz): δ =
174.29 (C=O), 152.07, 145.58, 137.87, 136.20, 131.74,
129.06, 128.21, 124.86, 123.67, 110.12, 101.91, 65.95
(CH2), 21.19 (CH3); ESI-MS (m/z): 458.09 [M + 1].
1′-(3-(4-Methoxyphenyl)-1-(p-tolyl)-1H-pyrazol-4-yl)-spiro-
[[1,3]-dioxolane-2,3′-indolin]-2′-one (7e) The compound
was obtained as a yellowish brown solid; yield: 0.10 g (82
%); IR (KBr) ʋmax: 2921, 1735, 1602, 1301, 1253, 1172,
4-(3-(4-Chlorophenyl)-4-(2′-oxospiro-[[1,3]-dioxolane-
2,3′-indolin]-1′-yl)-1H-pyrazol-1-yl)-benzonitrile (7i) The
compound was obtained as a yellowish sticky solid; yield:
0.11 g (84 %); IR (KBr) ʋmax: 2921, 1742, 1618, 1514,
1
757 cm−1; H NMR (CDCl3, 400 MHz): δ = 7.56 (1H, s),
7.52 (1H, d, J = 8.05 Hz), 7.33 (1H, d, J = 7.32 Hz), 7.26
(2H, m), 7.14 (1H, d, J = 8.79 Hz), 7.04–6.99 (2H, m), 6.88
(1H, d), 6.80 (2H, d, J = 8.05 Hz), 6.73 (1H, d, J = 8.79
Hz), 6.65 (1H, t, J = 8.05 Hz), 4.63–4.52 (2H, m, –OCH2),
4.34–4.25 (2H, m, –OCH2), 3.78 (3H, s, –OCH3), 2.30 (3H,
s, –CH3); 13C NMR (CDCl3, 100 MHz): δ = 171.32(C=O),
152.17, 147.12, 145.60, 136.47, 131.94, 130.24, 129.93,
128.83, 124.74, 123.56, 116.95, 113.43, 110.25, 65.93
(CH2), 55.18 (OCH3), 20.71 (CH3); ESI-MS (m/z): 454.15
[M + 1].
1
1301, 1192, 1119, 755 cm−1; H NMR (CDCl3, 400 MHz):
δ = 7.80 (1H, s), 7.36 (1H, d, J = 8.05 Hz), 7.26 (1H, t, J =
8.05 Hz), 7.17–7.04 (7H, m), 6.93 (2H, t, J = 8.79 Hz), 6.59
(1H, d, J = 8.05 Hz), 4.54 (2H, t, J = 6.59 Hz, –OCH2), 4.30
(2H, t, J = 6.59 Hz, –OCH2); 13C NMR (CDCl3, 100 MHz):
δ = 173.26 (C=O), 145.06, 139.02, 138.04, 137.03, 131.38,
129.06, 125.47, 124.29, 123.19, 116.34, 115.47, 114.66,
110.42, 109.13, 101.67, 65.54 (CH2); ESI-MS (m/z): 469.11
[M + 1].
4-(3-(4-Methoxyphenyl)-4-(2′-oxospiro-[[1,3]-dioxolane-
2,3′-indolin]-1′-yl)-1H-pyrazol-1-yl)-benzonitrile (7f) The
compound was obtained as a brown solid; yield: 0.11 g (84
%); IR (KBr) ʋmax: 2922, 1742, 1606, 1510, 1465, 1254,
1′-(1-Phenyl-3-(p-tolyl)-1H-pyrazol-4-yl)spiro[[1,3]dioxo-
lane-2,3′-indolin]-2′-one (7j) The compound was
obtained as a light yellow solid; yield: 0.10 g (78 %); IR
(KBr) ʋmax: 2920, 1734, 1645, 1589, 1397, 1321, 1197,
1
756 cm−1; H NMR (CDCl3, 400 MHz): δ = 7.85 (1H, s),
1
756 cm−1; H NMR (CDCl3, 400 MHz): δ = 7.53 (1H, s),
7.62 (2H, d, J = 8.79 Hz), 7.44 (2H, d, J = 8.05 Hz), 7.37
(1H, d, J = 7.32 Hz), 7.23 (1H, t, J = 6.59 Hz), 7.08–7.05
(3H, m), 6.80 (2H, d, J = 8.79 Hz), 6.56 (1H, d, J = 8.05
Hz), 4.57 (2H, t, J = 6.59 Hz, –OCH2), 4.32 (2H, t, J = 6.59
Hz, –OCH2), 3.75 (3H, s, –OCH3); 13C NMR (CDCl3, 100
MHz): δ = 173.48 (C=O), 160.37, 144.82, 142.98, 140.67,
139.55, 132.91, 131.68, 130.25, 124.93, 123.79, 119.90,
114.61, 110.09, 101.85, 65.83 (CH2), 55.16 (OCH3); ESI-
MS (m/z): 465.18 [M + 1].
7.41 (3H, d), 7.32 (2H, d), 7.26 (3H, t), 7.08 (3H, d), 7.01
(1H, t), 6.65 (1H, d), 4.53 (2H, m, –OCH2), 4.30 (2H, m,
–OCH2), 2.21 (3H, s, –CH3); 13C NMR (CDCl3, 100 MHz):
δ = 174.23 (C=O), 152.29, 145.88, 140.56, 136.74, 132.00,
131.23, 129.18, 127.88, 125.04, 123.64, 110.84, 102.42,
66.40 (CH2), 21.42 (CH3); ESI-MS (m/z): 424.18 [M + 1].
1′-(1,3-Di-p-tolyl-1H-pyrazol-4-yl)-spiro-[[1,3]-dioxolane-
2,3′-indolin]-2′-one (7k) The compound was obtained as a
yellowish brown solid; yield: 0.11 g (84 %); IR (KBr) ʋmax
:
1′-(3-(4-Chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)-spiro-
[[1,3]-dioxolane-2,3′-indolin]-2′-one (7g) The compound
was obtained as a yellowish brown solid; yield: 0.10 g
(80 %); IR (KBr) ʋmax: 2921, 1735, 1617, 1590, 1322,
2920, 1735, 1642, 1587, 1397, 1301, 1197, 1119, 754 cm−1;
1H NMR (CDCl3, 400 MHz): δ = 7.52 (1H, s), 7.41 (3H, d,
J = 8.05 Hz), 7.32 (1H, d, J = 7.32 Hz), 7.24 (2H, t, J =
7.32 Hz), 7.09 (3H, d, J = 8.05 Hz), 7.02 (2H, t, J = 6.59
Hz), 6.65 (1H, d, J = 8.05 Hz), 4.55 (2H, m, –OCH2), 4.28
(2H, m, –OCH2), 2.29 (6H, s, –2CH3); 13C NMR (CDCl3,
100 MHz): δ = 174.20 (C=O), 152.48, 145.79, 140.43,
136.72, 131.67, 128.59, 127.97, 124.66, 123.40, 116.99,
110.23, 102.32, 65.93 (CH2), 21.33 (CH3); ESI-MS (m/z):
438.19 [M + 1].
1
1197, 1119, 756 cm−1; H NMR (CDCl3, 400 MHz): δ =
7.59 (1H, s), 7.42 (3H, d, J = 8.05 Hz), 7.33–7.24 (8H, m),
7.03 (1H, t, J = 7.32 Hz), 6.64 (1H, d, J = 7.32 Hz),
4.60–4.51 (2H, m, –OCH2), 4.33–4.29 (2H, m, –OCH2);
13C NMR (CDCl3, 100 MHz): δ = 174.29 (C=O), 152.28,
145.63, 137.92, 136.21, 131.75, 129.08, 128.21, 124.88,

Med Chem Res
4-(4-(2′-Oxospiro-[[1,3]-dioxolane-2,3′-indolin]-1′-yl)-3-
(p-tolyl)-1H-pyrazol-1-yl)benzonitrile (7l) The compound
was obtained as a yellow solid; yield: 0.11 g (82 %); IR
(4H, m), 6.75 (1H, d, J = 8.05 Hz), 6.38 (1H, d, J = 8.05
Hz), 4.53 (2H, m, –OCH2), 4.28 (2H, m, –OCH2); 13C
NMR (CDCl3, 100 MHz) δ: 174.26 (C=O), 165.01, 152.36,
145.57, 131.69, 129.89, 124.79, 123.60, 115.07, 113.34,
110.10, 101.89, 65.92 (CH2); ESI-MS (m/z): 428.16 [M +
1].
1
(KBr) ʋmax: 2923, 1731, 1635, 1583, 1289, 754 cm−1; H
NMR (CDCl3, 400 MHz): δ = 7.58 (1H, s), 7.42 (3H, d, J =
8.05 Hz), 7.33 (1H, d, J = 7.32 Hz), 7.30–7.20 (5H, m),
7.04 (2H, t, J = 7.32 Hz), 6.64 (1H, d, J = 7.32 Hz), 4.55
(2H, m, –OCH2), 4.29 (2H, m, –OCH2), 2.37 (3H, s, –CH3);
13C NMR (CDCl3, 100 MHz): δ = 174.53 (C=O), 152.70,
145.65, 138.14, 136.14, 133.25, 129.28, 128.27, 124.98,
123.70, 110.08, 101.92, 65.98 (CH2), 21.63 (CH3); ESI-MS
(m/z): 449.112 [M + 1].
1′-(3-(4-Fluorophenyl)-1-(p-tolyl)-1H-pyrazol-4-yl)-spiro-
[[1,3]-dioxolane-2,3′-indolin]-2′-one (7q) The compound
was obtained as a yellowish brown solid; yield: 0.113 g
(84 %); IR (KBr) ʋmax: 2922, 1736, 1593, 1466, 1398,
1
1323, 1120, 1085, 758 cm−1; H NMR (CDCl3, 400 MHz):
δ = 7.55 (1H, s), 7.41 (3H, d, J = 8.05 Hz), 7.33 (2H, d, J =
8.05 Hz), 7.31–7.24 (4H, m), 7.02 (2H, t, J = 8.05 Hz), 6.63
(1H, d, J = 8.05 Hz), 4.53 (2H, m, –OCH2), 4.28 (2H, m,
–OCH2), 2.14 (3H, s, –CH3); 13C NMR (CDCl3, 100 MHz):
δ = 174.31 (C=O), 152.70, 145.54, 137.83, 136.31, 133.25,
131.76, 129.52, 128.27, 124.90, 123.70, 110.08, 101.92,
65.98 (CH2), 21.10 (CH3); ESI-MS (m/z): 442.12 [M + 1].
1′-(3-(4-Bromophenyl)-1-phenyl-1H-pyrazol-4-yl)-spiro-[[1,3]
-dioxolane-2,3′-indolin]-2′-one (7m) The compound was
obtained as a yellowish brown solid; yield: 0.10 g (80 %);
IR (KBr) ʋmax: 2918, 1735, 1645, 1617, 1586, 1398, 1323,
1
1197, 1009, 756 cm−1; H NMR (CDCl3, 400 MHz): δ =
7.56 (1H, s), 7.41–7.24 (11H, m), 7.02 (1H, t, J = 8.05 Hz),
6.62 (1H, d, J = 8.05 Hz), 4.58 (2H, m, –OCH2), 4.23 (2H,
m, –OCH2); 13C NMR (CDCl3, 100 MHz): δ = 174.29
(C=O), 152.37, 145.62, 138.37, 131.75, 131.16, 129.26,
124.87, 123.67, 110.13, 101.93, 65.95 (CH2); ESI-MS
(m/z): 488.01 [M + 1].
4-(3-(4-Fluorophenyl)-4-(2′-oxospiro-[[1,3]-dioxolane-
2,3′-indolin]-1′-yl)-1H-pyrazol-1-yl)-benzonitrile (7r) The
compound was obtained as a yellowish brown solid; yield:
0.118 g (86 %); IR (KBr) ʋmax: 2921, 1742, 1606, 1509,
1
1466, 1416, 1301, 1120, 843, 756 cm−1; H NMR (CDCl3,
1′-(3-(4-Bromophenyl)-1-(p-tolyl)-1H-pyrazol-4-yl)-spiro-
[[1,3]-dioxolane-2,3′-indolin]-2′-one (7n) The compound
was obtained as a yellowish brown solid; yield: 0.10 g (84
%); IR (KBr) ʋmax: 2923, 1736, 1586, 1397, 1323, 1119,
400 MHz): δ = 7.87 (1H, s), 7.64 (2H, d, J = 8.79 Hz), 7.42
(2H, d, J = 8.79 Hz), 7.38 (1H, d, J = 7.32 Hz), 7.25 (1H, t,
J = 8.05 Hz), 7.15–7.12 (2H, m), 7.08 (1H, t, J = 7.32 Hz),
6.98 (2H, t, J = 8.79 Hz), 6.57 (1H, d, J = 7.32 Hz), 4.53
(2H, m, –OCH2), 4.33 (2H, m, –OCH2); 13C NMR (CDCl3,
100 MHz): δ = 173.41 (C=O), 164.28, 139.55, 133.04,
131.73, 130.99, 125.10, 125.78, 123.47, 116.63, 111.30,
109.66, 101.87, 65.98 (CH2); ESI-MS (m/z): 453.11;
[M + 1].
1
756 cm−1; H NMR (CDCl3, 400 MHz): δ = 7.59 (1H, s),
7.43–7.22 (10H, m), 7.04 (1H, t, J = 7.32 Hz), 6.65 (1H, d,
J = 7.32 Hz), 4.58 (2H, m, –OCH2), 4.28 (2H, m, –OCH2),
2.31 (3H, s, –CH3); 13C NMR (CDCl3, 100 MHz): δ =
174.35 (C=O), 152.12, 145.63, 139.54, 138.22, 131.74,
129.53, 124.87, 123.66, 110.13, 101.93, 65.95 (CH2), 21.04
(CH3); ESI-MS (m/z): 501.99 [M + 1].
1′-(3-(2,4-Dichlorophenyl)-1-phenyl-1H-pyrazol-4-yl)-spiro-
[[1,3]-dioxolane-2,3′-indolin]-2′-one (7s) The compound
was obtained as a brown solid; yield: 0.102 g (79 %); IR
(KBr) ʋmax: 2922, 1740, 1597, 1466, 1322, 1194, 1120,
4-(3-(4-Bromophenyl)-4-(2′-oxospiro-[[1,3]-dioxolane-2,3′-
indolin]-1′-yl)-1H-pyrazol-1-yl)-benzonitrile
(7o) The
1
compound was obtained as a yellowish brown solid; yield:
0.11 g (85 %); IR (KBr) ʋmax: 2921, 1736, 1605, 1466,
1400, 1301, 1120, 756 cm−1; 1H NMR (CDCl3, 400 MHz): δ
= 7.87 (1H, s), 7.64 (2H, d, J = 8.79 Hz), 7.46–7.34 (6H, m),
7.11–7.00 (3H, m), 6.58 (1H, d, J = 8.05 Hz), 4.54 (2H, m,
–OCH2), 4.28 (2H, m, –OCH2); 13C NMR (CDCl3, 100
MHz): δ = 173.46(C=O), 139.61, 138.12, 133.08, 132.47,
131.24, 130.35, 129.34, 125.12, 124.93, 117.94, 116.07,
109.58, 101.81, 65.98 (CH2); ESI-MS (m/z): 513.11 [M + 1].
757 cm−1; H NMR (CDCl3, 400 MHz): δ = 7.85 (1H, s),
7.40–7.20 (7H, m), 7.15 (2H, t, J = 7.32 Hz), 7.05 (2H, t, J
= 8.05 Hz), 6.69 (1H, d, J = 8.05 Hz), 4.54 (2H, m,
–OCH2), 4.32 (2H, m, –OCH2); 13C NMR (CDCl3, 100
MHz): δ = 173.13 (C=O), 144.70, 139.53, 132.28, 131.70,
129.90, 127.78, 124.87, 123.83, 117.24, 109.79, 65.81
(CH2); ESI-MS (m/z): 492.04 [M + 1].
4-(3-(2,4-Dichlorophenyl)-4-(2′-oxospiro-[[1,3]-dioxolane-
2,3′-indolin]-1′-yl)-1H-pyrazol-1-yl)-benzonitrile (7t) The
compound was obtained as a yellowish brown solid; yield:
0.101 g (76 %); IR (KBr) ʋmax: 2020, 1737, 1467, 1401,
1′-(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-spiro-
[[1,3]-dioxolane-2,3′-indolin]-2′-one (7p) The compound
was obtained as a yellowish brown solid; yield: 0.104 g
(80 %); IR (KBr) ʋmax: 2921, 1735, 1599, 1399, 1223,
1
1123, 1084, 758 cm−1; H NMR (CDCl3, 400 MHz): δ =
7.85 (1H, s), 7.62–7.01 (9H, m), 6.85–6.75 (2H, dd), 4.46
(2H, m, –OCH2), 4.26 (2H, m, –OCH2); 13C NMR (CDCl3,
100 MHz): δ = 174.09 (C=O), 148.75, 144.66, 137.07,
1
1084, 757 cm−1; H NMR (CDCl3, 400 MHz) δ: 7.58 (1H,
s), 7.47 (3H, t, J = 5.86 Hz), 7.32–7.24 (4H, m), 7.04–6.92

Med Chem Res
133.72, 131.91, 129.86, 127.77, 125.51, 124.36, 123.86,
119.21, 112.60, 109.75, 65.93 (CH2); ESI-MS (m/z): 503.11
[M + 1].
(CDCl3, 100 MHz): δ = 163.50(C=O), 139.21, 137.45,
134.44, 133.46, 130.89, 130.35, 129.08, 128.20, 125.94,
125.46, 124.79, 124.18, 117.59, 114.05, 109.87, 22.68; 19F
NMR (CDCl3, 376 MHz): δ = −110.02 (2F, s, CF2); ESI-
MS (m/z): 402.42 [M + 1].
Synthesis of target compound 1-(1,3-diphenyl-1H –pyrazol-
4-yl)-3,3di-fluoroindolin-2-ones (9a–t)
4-(4-(3,3-Difluoro-2-oxoindolin-1-yl)-3-phenyl-1H-pyrazol-
1-yl)benzonitrile (9c) The compound was obtained as a
yellow solid; yield: 0.081 g (86 %); IR (KBr) ʋmax: 2922,
1764, 1621, 1467, 1199, 1084, 767 cm−1; 1H NMR (CDCl3,
400 MHz): δ = 7.90 (1H, s), 7.61 (2H, d, J = 8.05 Hz), 7.54
(1H, d, J = 8.79 Hz), 7.42 (2H, d, J = 8.79 Hz), 7.38–7.27
(3H, m), 7.15–7.10 (4H, m), 6.67 (1H, d, J = 8.05 Hz); 13C
NMR (CDCl3, 100 MHz): δ = 165.61(C=O), 144.47,
141.08, 139.27, 133.68, 130.03, 129.32, 129.01, 128.83,
128.20, 126.75, 124.91, 124.77, 117.92, 115.85, 114.11,
111.43, 110.48; 19F NMR (CDCl3, 376 MHz): δ = −109.98
(2F, s, CF2); ESI-MS (m/z): 413.10 [M + 1].
Deprotection of compound (7a–t) A mixture of 1′-(1, 3-
diphenyl-1H-pyrazol-4-yl) spiro [[1,3]-dioxolane-2,3′-
indolin]-2′-one 7a–t and HCl/Acetic acid (3:1) was heated
at 90 °C for 1 h and monitored by TLC. After completion of
reaction, the reaction content was concentrated under
reduced pressure, washed with saturated sodium bicarbo-
nate solution at pH 10, then extracted with ethyl acetate
(3 × 20 mL), organic layer was dried over sodium sulphate
and concentrated under reduced pressure. Crude compound
8a–t was brought forward for fluorination reaction.
3,3-Difluoro-1-(3-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-
4-yl)-indolin-2-one (9d) The compound was obtained as a
Synthesis of 1-(1, 3-diphenyl-1H-pyrazol-4-yl)-3, 3-di-
fluoroindolin-2-ones (9a–t) by the fluorination reaction
of (8a–t)
light yellow solid; yield: 0.079 g (84 %); IR (KBr) ʋmax
:
2924, 1769, 1617, 1462, 1259, 1084, 766 cm−1; H NMR
(CDCl3, 400 MHz): δ = 7.80 (1H, s), 7.55–7.45 (1H, m),
7.34–7.22 (7H, m), 6.98 (2H, d, J = 8.79 Hz), 6.68 (2H, d,
J = 7.79 Hz), 6.52 (1H, d, J = 7.32 Hz), 3.72 (3H, s,
–OCH3); 13C NMR (CDCl3, 100 MHz): δ = 163.97(C=O),
161.54, 140.54, 139.05, 134.70, 131.85, 128.43, 127.11,
1
DAST (0.26 mmol, 2 equiv) was added to the stirred solu-
tion of compound (8a–t) (0.13 mmol, 1 equiv) and DCM at
0 °C. After addition, the resulting reaction mixture was
stirred for additional 2 h at room temperature and monitored
by TLC. After completion of reaction, the reaction content
was quenched with cold water and extracted with ethyl
acetate (3 × 10 mL), organic layer was dried over sodium
sulphate and concentrated under reduced pressure. The
obtained residues were purified by column chromatography
using silica 100–200 mesh size by ethyl acetate:hexane
(30:70) and pure compound was identified as 1-(1,3-diphe-
nyl-1H-pyrazol-4-yl)-3,3-difluoro indolin-2-ones (9a–t).
125.79, 123.51, 118.99, 114.41, 111.82, 55.60 (OCH3); 19
F
NMR (CDCl3, 376 MHz): δ = −110.00 (2F, s, CF2); ESI-
MS (m/z): 418.13 [M + 1].
3,3-Difluoro-1-(3-(4-methoxyphenyl)-1-(p-tolyl)-1H-pyr-
azol-4-yl)indolin-2-one (9e) The compound was obtained
as a brownish yellow solid; yield: 0.081 g (86 %); IR (KBr)
1
ʋ
max: 2922, 1765, 1612, 1469, 1254, 1085, 763 cm−1; H
NMR (CDCl3, 400 MHz): δ = 7.68 (1H, s), 7.58 (1H, d, J =
8.05 Hz), 7.42 (1H, d, J = 7.32 Hz), 7.32 (2H, m), 7.24 (1H,
d, J = 8.79 Hz), 7.10–6.94 (2H, m), 6.82 (1H, d), 6.76 (2H,
d, J = 8.05 Hz), 6.68 (1H, d, J = 8.79 Hz), 6.62 (1H, t, J =
8.05 Hz), 3.79 (3H, s, –OCH3), 2.32 (3H, s, –CH3); 13C
NMR (δppm, CDCl3, 100 MHz): δ = 164.16(C=O), 161.44,
140.95, 138.82, 135.18, 132.99, 129.02, 127.43, 126.16,
124.87, 119.01, 114.52, 112.64, 56.63 (OCH3), 22.00
(CH3); 19F NMR (CDCl3, 376 MHz): δ = −110.32 (2F, s,
CF2); ESI-MS (m/z): 432.16 [M + 1].
1-(1,3-Diphenyl-1H-pyrazol-4-yl)-3,3-difluoroindolin-2-one
(9a) The compound was obtained as a yellowish sticky
solid; yield: 0.077 g (82 %); IR (KBr) ʋmax: 2924, 1737,
1
1698, 1621, 1470, 1301, 1229, 1083, 755 cm−1; H NMR
(CDCl3, 400 MHz): δ = 7.80 (1H, s), 7.48 (1H, d, J = 7.32
Hz), 7.32–7.15 (9H, m), 7.10–7.04 (3H, m), 6.64 (1H, d, J
= 8.05 Hz); 13C NMR (CDCl3, 100 MHz): δ = 163.29
(C=O), 140.47, 139.37, 138.04, 128.99, 128.84, 127.96,
124.89, 124.72, 110.63; 19F NMR (CDCl3, 376 MHz): δ =
−110.12 (2F, s, CF2); ESI-MS (m/z): 388.09 [M + 1].
4-(4-(3,3-Difluoro-2-oxoindolin-1-yl)-3-(4-methoxyphenyl)-
1H-pyrazol-1-yl)-benzonitrile (9f) The compound was
obtained as a yellowish brown solid; yield: 0.074 g (78 %);
IR (KBr) ʋmax: 2923, 1763, 1607, 1463, 1253, 1084, 767
3,3-Difluoro-1-(3-phenyl-1-(p-tolyl)-1H-pyrazol-4-yl)indo-
lin-2-one (9b) The compound was obtained as a yellow
solid; yield: 0.080 g (85 %); IR (KBr) ʋmax: 2924, 1760,
1
1
1623, 1465, 1288, 1084, 766 cm−1; H NMR (CDCl3, 400
cm−1; H NMR (CDCl3, 400 MHz): δ = 8.01 (1H, d, J =
MHz): δ = 7.91 (1H, s), 7.62 (2H, d, J = 8.05 Hz), 7.54 (1H,
d, J = 7.32 Hz), 7.43 (2H, d, J = 8.05 Hz), 7.38–7.27
(3H, m), 7.17–7.11 (5H, m), 2.33 (3H, s, –CH3); 13C NMR
8.79 Hz), 7.86 (1H, s), 7.54 (2H, d, J = 6.69 Hz), 7.42–7.36
(2H, m), 7.15 (2H, d, J = 7.32 Hz), 7.05-6.98 (2H, m), 6.79
(1H, d, J = 8.79 Hz), 6.68 (1H, d, J = 7.32 Hz), 6.58 (1H, d,

Med Chem Res
J = 8.79 Hz), 3.74 (3H, s, –OCH3); 13C NMR (CDCl3, 100
MHz): δ = 163.91(C=O), 161.54, 143.21, 141.32, 133.41,
129.29, 127.11, 126.16, 124.70, 123.46, 117.91, 115.69,
111.61, 107.79, 102.59, 55.81 (OCH3); 19F NMR (CDCl3,
376 MHz): δ = −109.94 (2F, s, CF2); ESI-MS (m/z): 443.14
[M + 1].
19F NMR (CDCl3, 376 MHz): δ = −110.35 (2F, s, CF2);
ESI-MS (m/z): 402.11 [M + 1].
1-(1,3-Di-p-tolyl-1H-pyrazol-4-yl)-3,3-difluoroindolin-2-
one (9k) The compound was obtained as a yellow solid;
yield: 0.070 g (75 %); IR (KBr) ʋmax: 2924, 1759, 1624,
1
1465, 1188, 1085, 765 cm−1; H NMR (CDCl3, 400 MHz):
1-(3-(4-Chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)-3,3-
difluoroindolin-2-one (9g) The compound was obtained as
δ = 7.88 (3H, d, J = 8.79 Hz), 7.55 (2H, d, J = 8.05 Hz),
7.40 (2H, t, J = 8.05 Hz), 7.32 (3H, d, J = 8.05 Hz), 7.14
(2H, t, J = 7.32 Hz), 6.69 (1H, d, J = 7.32 Hz), 2.42 (6H, s,
–2CH3); 13C NMR (CDCl3, 100 MHz): δ = 164.08 (C=O),
134.97, 131.30, 129.00, 126.84, 125.34, 124.32, 122.97,
117.46, 111.40, 21.53 (CH3); 19F NMR (CDCl3, 376 MHz):
δ = −110.38 (2F, s, CF2); ESI-MS (m/z):416.13 [M + 1].
a yellowish brown solid; yield: 0.079 g (84 %); IR (KBr)
1
ʋ
max: 2923, 1756, 1624, 1463, 1085, 766 cm−1; H NMR
(CDCl3, 400 MHz): δ = 7.93 (3H, d, J = 8.79 Hz), 7.57 (1H,
d, J = 7.32 Hz), 7.49 (2H, d, J = 8.79 Hz), 7.40 (2H, t, J =
8.05 Hz), 7.19–71.4 (4H, m), 6.90 (1H, d, J = 7.32 Hz),
6.89 (1H, d, J = 7.32 Hz); 13C NMR (CDCl3, 100 MHz): δ
= 164.16 (C=O), 161.35, 143.96, 142.63, 141.12, 132.42,
129.79, 127.86, 126.75, 125.22, 120.73, 117.72; 19F NMR
(CDCl3, 376 MHz): δ = −110.00 (2F, s, CF2); ESI-MS
(m/z): 421.99 [M + 1].
4-(4-(3,3-Difluoro-2-oxoindolin-1-yl)-3-(p-tolyl)-1H-pyr-
azol-1-yl)-benzonitrile (9l) The compound was obtained as
a light yellow solid; yield: 0.074 g (79 %); IR (KBr) ʋmax
:
2923, 1765, 1628, 1462, 1984, 763 cm−1; 1H NMR (CDCl3,
400 MHz): δ = 7.88 (1H, d, J = 8.05 Hz), 7.52 (2H, d, J =
7.32 Hz), 7.43–7.36 (3H, m), 7.31 (2H, d, J = 8.05 Hz),
7.13 (2H, q, J = 8.05 Hz), 6.90 (2H, d, J = 7.32 Hz), 6.68
(1H, d, J = 8.05 Hz), 2.43 (3H, s, –CH3); 13C NMR (CDCl3,
100 MHz): δ = 165.67 (C=O), 143.72, 140.50, 135.77,
135.99, 132.19, 130.33, 129.20, 126.44, 123.03, 121.85,
118.61, 111.79, 21.55(CH3); 19F NMR (CDCl3, 376 MHz):
δ = −110.00 (2F, s, CF2); ESI-MS (m/z): 426.14 [M + 1].
1-(3-(4-Chlorophenyl)-1-(p-tolyl)-1H-pyrazol-4-yl)-3,3-
difluoroindolin-2-one (9h) The compound was obtained as
a light yellow solid; yield: 0.082 g (87 %); IR (KBr) ʋmax
:
1
2923, 1760, 1629, 1475, 1207, 1084, 769 cm−1; H NMR
(CDCl3, 400 MHz): δ = 7.84 (1H, s), 7.42 (2H, d, J = 8.05
Hz), 7.34 (1H, d, J = 6.59 Hz), 7.25–7.20 (6H, m), 6.94
(2H, t, J = 8.79 Hz), 6.64 (1H, d, J = 8.05 Hz), 2.36 (3H, s,
–CH3); 13C NMR (CDCl3, 100 MHz): δ = 163.61 (C=O),
143.00, 141.68, 140.75, 133.45, 132.48, 129.58, 125.04,
124.23, 22.67 (CH3); 19F NMR (CDCl3, 376 MHz): δ =
−110.42 (2F, s, CF2); ESI-MS (m/z): 436.11 [M + 1].
1-(3-(4-Bromophenyl)-1-phenyl-1H-pyrazol-4-yl)-3,3-
difluoroindolin-2-one (9m) The compound was obtained
as a brown yellow solid; yield: 0.076 g (80 %); IR (KBr)
1
ʋ
max: 2924, 1729, 1657, 1463, 1378, 1083, 754 cm−1; H
4-(3-(4-Chlorophenyl)-4-(3,3-difluoro-2-oxoindolin-1-yl)-
1H-pyrazol-1-yl)-benzonitrile (9i) The compound was
obtained as a yellow solid; yield: 0.078 g (82 %); IR (KBr)
NMR (CDCl3, 400 MHz): δ = 7.83 (1H, s), 7.73 (2H, d, J =
8.79 Hz), 7.63–7.57 (6H, m), 7.50 (1H, t, J = 8.05 Hz), 7.36
(2H, t, J = 8.05 Hz), 7.15 (1H, d, J = 7.32 Hz), 6.58 (1H, d,
J = 8.05 Hz); 13C NMR (CDCl3, 100 MHz): δ = 163.27
(C=O), 143.71, 142.77, 141.81, 131.99, 129.11, 127.91,
126.79, 120.22, 116.53, 112.04; 19F NMR (CDCl3, 376
MHz): δ = −110.62 (2F, s, CF2); ESI-MS (m/z): 465.98
[M + 1].
ʋ
max: 2924, 1737, 1613, 1466, 1231, 1085, 756 cm−1;1H
NMR (CDCl3, 400 MHz):δ = 7.83 (1H, s), 7.32 (1H, d, J =
8.05 Hz), 7.28 (1H, t, J = 8.05 Hz), 7.20–7.10 (7H, m), 6.96
(2H, t, J = 8.79 Hz), 6.64 (1H, d, J = 8.05 Hz); 13C NMR
(CDCl3, 100 MHz): δ = 165.24(C=O), 162.06, 142.64,
141.93, 132.57, 129.02, 127.64, 126.66, 125.10, 124.47,
117.03, 111.79; 19F NMR (CDCl3, 376 MHz): δ = −110.00
(2F, s, CF2); ESI-MS (m/z): 447.09 [M + 1].
1-(3-(4-Bromophenyl)-1-(p-tolyl)-1H-pyrazol-4-yl)-3,3-
difluoroindolin-2-one (9n) The compound was obtained as
a brownish light yellow solid; yield: 0.077 g (81 %); IR
1
3,3-Difluoro-1-(1-phenyl-3-(p-tolyl)-1H-pyrazol-4-yl)-indo-
lin-2-one (9j) The compound was obtained as a pale yel-
low solid; yield: 0.072 g (76 %); IR (KBr) ʋmax: 2923, 1761,
(KBr) ʋmax: 2923, 1758, 1625, 1463, 1084, 767 cm−1; H
NMR (CDCl3, 400 MHz): δ = 7.85 (2H, d, J = 8.79 Hz),
7.66 (2H, d, J = 8.79 Hz), 7.57 (2H, d, J = 7.32 Hz), 7.41
(2H, t, J = 8.05 Hz), 7.19–7.10 (3H, m), 6.90 (1H, d, J =
1
1695, 1473, 1084, 752 cm−1; H NMR (CDCl3, 400 MHz):
δ = 7.88 (3H, d, J = 8.05 Hz), 7.56 (2H, d, J = 7.32 Hz),
7.42 (2H, q, J = 8.05 Hz), 7.30 (2H, d, J = 8.05 Hz), 7.15
(3H, q, J = 7.32 Hz), 6.90 (1H, d, J = 7.32 Hz), 6.68 (1H, d,
J = 8.05 Hz), 2.42 (3H, s, –CH3); 13C NMR (CDCl3, 100
MHz): δ = 164.39(C=O), 143.38, 142.88, 131.15, 128.31,
126.84, 126.03, 121.05, 119.76, 114.77, 21.86 (CH3);
8.05 Hz), 6.68 (1H, d, J = 7.32 Hz), 2.33 (3H, s, –CH3); 13
C
NMR (CDCl3, 100 MHz): δ = 163.70 (C=O), 162.19,
142.00, 140.75, 133.45, 132.48, 129.64, 129.58, 125.04,
124.23, 117.73, 109.81, 22.67 (CH3); 19F NMR (CDCl3,
376 MHz): δ = −110.52 (2F, s, CF2); ESI-MS (m/z): 480.11
[M + 1].

Med Chem Res
1
4-(3-(4-Bromophenyl)-4-(3,3-difluoro-2-oxoindolin-1-yl)-
1H-pyrazol-1-yl)-benzonitrile (9o) The compound was
obtained as a yellowish brown solid; yield: 0.081 g (85 %);
IR (KBr) ʋmax: 2923, 1738, 1626, 1463, 1378, 1288, 1189,
1983, 750 cm−1; 1H NMR (CDCl3, 400 MHz): δ = 7.85
(5H, d, J = 8.79 Hz), 7.67 (4H, d, J = 8.79 Hz), 7.57 (1H, d,
J = 8.05 Hz), 7.42 (1H, t, J = 8.79 Hz), 7.17 (1H, t, J = 7.32
Hz), 6.68 (1H, d, J = 7.32 Hz); 13C NMR (CDCl3, 100
MHz): δ = 164.83 (C=O), 162.96, 142.64, 141.93, 132.49,
129.02, 127.64, 126.66, 125.10, 120.38, 117.06, 111.79;
19F NMR (CDCl3, 376 MHz): δ = −110.02 (2F, s, CF2);
ESI-MS (m/z): 489.97 [M + 1].
1765, 1621, 1470, 1302, 1198, 1085, 766 cm−1; H NMR
(CDCl3, 400 MHz): δ = 7.90 (1H, s), 7.54 (1H, d, J = 7.32
Hz), 7.38 (1H, t, J = 6.59 Hz), 7.34–7.30 (3H, m),
7.29–7.22 (5H, m), 7.16 (1H, t, J = 7.32 Hz), 6.81 (1H, d, J
= 8.05 Hz); 13C NMR (CDCl3, 100 MHz): δ = 165.05
(C=O), 143.08, 139.40, 137.63, 136.89, 134.62, 133.67,
129.99, 128.17, 127.79, 125.56, 124.79, 123.94, 115.27,
110.60; 19F NMR (CDCl3, 376 MHz): δ = −110.00 (2F, s,
CF2); ESI-MS (m/z): 455.99 [M + 1].
4-(3-(2,4-Dichlorophenyl)-4-(3,3-difluoro-2-oxoindolin-1-
yl)-1H-pyrazol-1-yl)-benzonitrile (9t) The compound was
obtained as a pale yellow solid; yield: 0.072 g (76 %)s; IR
(KBr) ʋmax: 2922, 1765, 1621, 1469, 1414, 1302, 1197,
1085, 766 cm−1; 1H NMR (CDCl3, 400 MHz): δ = 7.93
(1H, s), 7.63 (2H, d, J = 8.79 Hz), 7.53 (1H, d, J = 8.05 Hz),
7.40–7.35 (4H, m), 7.30 (2H, t, J = 7.32 Hz), 7.15 (1H, t, J
= 8.05 Hz), 6.74 (1H, d, J = 8.05 Hz); 13C NMR (CDCl3,
100 MHz): δ = 164.84 (C=O), 144.03, 142.59, 139.94,
137.20, 132.91, 130.14, 128.40, 125.53, 123.63, 119.66,
117.38, 112.10, 110.39; 19F NMR (CDCl3, 376 MHz): δ =
−110.01 (2F, s, CF2); ESI-MS (m/z): 480.97 [M + 1].
3,3-Difluoro-1-(3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-
yl)-indolin-2-one (9p) The compound was obtained as a
light yellow solid; yield: 0.082 g (87 %); IR (KBr) ʋmax
:
2923, 1771, 1626, 1505, 1484, 762 cm−1; 1H NMR (CDCl3,
400 MHz) : δ = 7.85 (1H, s), 7.58–7.50 (3H, m), 7.41 (2H,
t, J = 8.05 Hz), 7.33 (1H, t, J = 8.05 Hz), 7.21–7.07 (3H,
m), 6.91 (3H, d, J = 8.05 Hz), 6.69 (1H, d, J = 7.32 Hz); 13
C
NMR (CDCl3, 100 MHz): δ = 164.88 (C=O), 162.23,
142.08, 133.60, 127.52, 126.59, 125.07, 123.94, 122.55,
116.36, 111.49; 19F NMR (CDCl3, 376 MHz): δ = −110.22
(2F, s, CF2), −112.64 (1F, s, CF); ESI-MS (m/z): 406.12
[M + 1].
Antimicrobial assays
Materials
3,3-Difluoro-1-(3-(4-fluorophenyl)-1-(p-tolyl)-1H-pyrazol-
4-yl)-indolin-2-one (9q) The compound was obtained as a
brown solid; yield: 0.080 g (85 %); IR (KBr) ʋmax: 2921,
1
1764, 1621, 1515, 1470, 1301, 1199, 1086, 767 cm−1; H
All clinically standard strains bacteria S. aureus (ATCC
25923), B. subtilis (MTCC 441), E. coli (ATCC 25922), S.
typhi (MTCC 98), and the fungi C. albicans (MTCC 227),
A. niger (MTCC 282) were used for screening of anti-
bacterial and antifungal activities were procured from
Institute of Microbial Technology, Chandigarh, India. All
necessary controls like: drug control, vehicle control, agar
control, organism control, known antibacterial drugs control
were used. Muller Hinton Broth was used as nutrient
medium to grow and dilute the drug suspension for the test
bacteria. Inoculum size for test strain was adjusted to 108
colony forming unit per milliliter by comparing the tur-
bidity. DMSO was used as diluents/vehicle to get desired
concentration of drugs to test upon standard bacterial
strains.
NMR (CDCl3, 400 MHz): δ = 7.82 (1H, s), 7.54 (1H, d),
7.38 (1H, t), 7.16–7.10 (5H, m), 7.08 (2H, t), 6.91 (2H, t),
6.70 (1H, d), 2.34 (3H, s, –CH3); 13C NMR (CDCl3, 100
MHz): δ = 164.24(C=O), 161.75, 144.55, 139.43, 137.80,
136.61, 133.69, 129.68, 116.29, 113.63, 110.59, 21.06
(CH3); 19F NMR (CDCl3, 376 MHz): δ = −110.12 (2F, s,
CF2), −112.58 (1F, s, CF); ESI-MS (m/z): 420.11 [M + 1].
4-(4-(3,3-Difluoro-2-oxoindolin-1-yl)-3-(4-fluorophenyl)-
1H-pyrazol-1-yl)-benzo-nitrile (9r) The compound was
obtained as a yellowish brown solid; yield: 0.081 g (86 %);
IR (KBr) ʋmax: 2922, 1764, 1621, 1464, 1386, 1084, 769;
1H NMR (CDCl3, 400 MHz): δ = 7.90 (1H, s), 7.64 (2H, d,
J = 8.79 Hz), 7.55 (1H, d, J = 7.32 Hz), 7.40 (2H, d, J =
8.79 Hz), 7.37 (1H, d, J = 7.32 Hz), 7.19 (1H, d, J = 7.32
Hz), 7.15–7.10 (2H, m), 7.08 (2H, t, J = 8.79 Hz), 6.68 (1H,
d, J = 8.05 Hz); 13C NMR (CDCl3, 100 MHz): δ = 163.97
(C=O), 162.58, 142.64, 140.12, 139.24, 133.13, 130.99,
125.04, 124.79, 122.83, 116.65, 111.65, 110.39; 19F NMR
(CDCl3, 376 MHz): δ = −110.12 (2F, s, CF2), −112.44 (1F,
s, CF); ESI-MS (m/z): 431.08 [M + 1].
Method
‘Broth dilution method’ was used for minimum inhibition
concentration (MIC) of synthesized compounds against
antibacterial and antifungal strains (Riesselman et al., 2000;
Chundawat et al., 2013). It is one of the nonautomated
in vitro bacterial susceptibility tests. This classic method
yields a quantitative result for the amount of antimicrobial
1-(3-(2,4-Dichlorophenyl)-1-phenyl-1H-pyrazol-4-yl)-3,3-
difluoroindolin-2-one (9s) The compound was obtained as
a yellow solid; yield: 0.068 g (74 %); IR (KBr) ʋmax: 2922,

Med Chem Res
Acknowledgments The authors are thankful to Department of Sci-
ence & Technology (SERB) and University Grants Commission
(UGC) for providing financial support and USIC, University of
Delhi for providing instrumentation facilities. TS, PK, and NS are
thankful to UGC for SPF, CSIR for JRF, and DST for INSPIRE
fellowship.
agents that is needed to inhibit growth of specific micro-
organisms. It is carried out in tubes.
●
●
Macrodillution method in tubes.
Microdillution format using plastic trays.
Serial dilutions of synthesized compounds in DMSO
Compliance with ethical standards
were prepared for primary and secondary screening. Each
synthesized drug was diluted obtaining 2000 µg/ml con-
centration, as a stock solution.
Conflict of interest The authors declare that they have no conflict of
interest.
Primary screen In primary screening 1000 µg/ml, 500
µg/ml, and 250 µg/ml concentrations of the synthesized
drugs were taken. The active synthesized drugs found in
this primary screening were further tested in a second set of
dilution against all microorganisms.
Secondary screen The drugs found active in primary
screening were similarly diluted to obtain 200 µg/ml
100 µg/ml, 50 µg/ml, 25 µg/ml, 12.5 µg/ml, 6.250 µg/ml
concentrations.
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