Synthesis of (E)-3-Alkylideneindolin-2-ones by an Iron-Catalyzed Aerobic Oxidative Condensation of Csp3–H Bonds of Oxindoles and Benzylamines

Article abstract of DOI:10.1002/ejoc.202001300

A novel synthetic route for the construction of (E)-3-alkylideneindolin-2-ones through iron-catalyzed aerobic oxidative condensation of oxindoles with benzylamines has been developed. This oxidative reaction involves a sequence of C–H activation, amine self-condensation, nucleophilic addition, and C–C double bond formation. The synthetic importance of this protocol has been demonstrated by preparing tyrosine kinase inhibitors, anticonvulsant and antitumor agents, and other valuable 3-alkylideneindolin-2-one derivatives. Key intermediates are isolated and a plausible mechanistic pathway for the reaction has been discussed.

Full text of DOI:10.1002/ejoc.202001300

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Synthesis of (E)-3-Alkylideneindolin-2-ones by an Iron-Catalyzed
Aerobic Oxidative Condensation of Csp3–H Bonds of Oxindoles
and Benzylamines
Authors: Kovuru Gopalaiah and Ankit Tiwari
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202001300
Link to VoR: https://doi.org/10.1002/ejoc.202001300
01/2020

10.1002/ejoc.202001300
European Journal of Organic Chemistry
Synthesis of (E)-3-Alkylideneindolin-2-ones by an Iron-Catalyzed Aerobic
Oxidative Condensation of Csp3–H Bonds of Oxindoles and Benzylamines
Kovuru Gopalaiah*[a] and Ankit Tiwari[a]
Dedicated to Prof. Sambasivarao Kotha for his outstanding contribution to the transition metal
mediated organic synthesis.
[a] Prof. Dr. K. Gopalaiah, A. Tiwari
Department of Chemistry
University of Delhi
Delhi 110007, India
E-mail: gopal@chemistry.du.ac.in
http://www.du.ac.in/du/uploads/Faculty%20Profiles/Chemistry/Chem_Gopalaiah_Kovuru.pdf
Abstract
A novel synthetic route for the construction of (E)-3-alkylideneindolin-2-ones via iron-catalyzed
aerobic oxidative condensation of oxindoles with benzylamines has been developed. This
oxidative reaction involves a sequence of C-H activation, amine self-condensation, nucleophilic
addition, and C-C double bond formation. The synthetic importance of this protocol has been
demonstrated by preparing tyrosine kinase inhibitors, anticonvulsant and antitumor agents, and
other valuable 3-alkylideneindolin-2-one derivatives. Key intermediates are isolated and a
plausible mechanistic pathway for the reaction has been discussed.
Keywords: oxidative condensation, 3-alkylideneindolin-2-ones, iron catalyst, C-H activation,
oxindoles
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001300
European Journal of Organic Chemistry
Introduction
The 3-alkylideneindolin-2-one scaffold is a prevalent motif found in many biologically active
compounds (Figure 1).1 In addition, 3-alkylideneindolin-2-ones serve as useful precursors for the
synthesis of naturally occurring alkaloids2 and drug candidates.3 The traditional method for
preparing these compounds is the Knoevenagel reaction between oxindole and carbonyl
compounds, but it is limited due to its low stereoselectivity (eq. 1 in Scheme 1).4 In the past few
years, tremendous efforts have been made toward the stereoselective synthesis of these important
molecules via the transition-metal-catalyzed intramolecular hydroarylation and sequential
reactions. For instance, Taylor and co-workers reported a tandem Horner-Wadsworth-Emmons
olefination/Pd-catalyzed intramolecular Heck reaction of ortho-halo-anilides with aldehydes (eq.
2 in Scheme 1).5 Yamamoto et al. and Murakami et al. independently demonstrated the
palladium or rhodium-catalyzed cyclization reactions of 2-(alkynyl)aryl isocyanates with
terminal alkynes and organoboronic acids, respectively to construct 3-alkylideneindolin-2-one
derivatives (eq. 3 in Scheme 1).6 Ma and other research groups reported the formation of 3-
alkylideneindolin-2-ones through the cyclization of 2-alkynylanilines in the presence of carbon
dioxide/carbon monoxide using palladium, rhodium and nickel catalysts (eq. 4 in Scheme 1).7
Zhu et al.8 and Li et al.9 independently developed palladium-catalyzed domino
carbopalladation/C-H activation/C-C bond-forming reactions that employs an anilide sp2 C-H
bond and either an electrophilic reagent (Ar-I) or a nucleophilic reagent (Ar-H, R-OH, R-CO2H,
ArI(OAc)2, and phthalimide) as the coupling partners to give 3-alkylideneindolin-2-ones (eq. 5 in
Scheme 1). Nagasawa’s group demonstrated the formation of 3-alkylideneindolin-2-ones from
N-cinnamoylanilines via palladium-catalyzed aromatic C-H activation and intramolecular
alkenylation (eq. 6 in Scheme 1).10 Despite their usefulness, many of these precious metal
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001300
European Journal of Organic Chemistry
catalyzed processes are not applicable in biotechnological or pharmaceutical applications due to
the toxicity concerns, and the requirement of specially functionalized starting materials,
expensive catalysts, and large amount of oxidants and bases. Therefore, the more
straightforward, stereospecific, cost-effective, and environmentally benign routes to construct 3-
alkylideneindolin-2-ones are highly needed.
Figure 1. Representative 3-Alkylideneindolin-2-one Based Biologically Active Compounds
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001300
European Journal of Organic Chemistry
In recent years, researchers have made impressive developments in the iron-catalyzed C-H
bond oxidative transformations owing to their low-cost, availability, and environmentally
friendly features.11 For these oxidative reactions, oxygen or air are ideal oxidants because they
are cheap, renewable, and generates at best water as the by-product. Our group and others
successfully employed the Fe(II or III)/O2 (air) catalytic system for oxidative transformation of
C-H bonds and X-H (X is a heteroatom) bonds to construct carbon-carbon and carbon-
heteroatom bonds.12,13 Inspired by these studies, we expected that 3-alkylideneindolin-2-ones
could be furnished from oxindoles and benzylamines when iron salts are employed as catalysts.
Herein we describe an iron(II)-catalyzed oxidative condensation of Csp3–H bonds of oxindoles
and benzylamines for the synthesis of (E)-3-alkylideneindolin-2-one scaffolds under aerobic
conditions (eq. 7 in Scheme 1).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001300
European Journal of Organic Chemistry
Scheme 1. Strategies for the Synthesis of 3-Alkylideneindolin-2-ones
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001300
European Journal of Organic Chemistry
Results and Discussion
The reaction of oxindole (1a) and benzylamine (2a) was chosen as a model system to investigate
the optimal reaction conditions (Table 1). After screening of several iron(II) and iron(III)
o
catalysts in toluene at 100 C for 8 h under the atmosphere of molecular oxygen (entries 1-8),
FeBr2 turned out to be the most effective catalyst, and afforded ((E)-3-benzylideneindolin-2-one
1
(3a) in 68% yield as a single stereoisomer (E/Z = >25:1 by H NMR) (entry 6). The E-
configuration of the trisubstituted double bond was unambiguously assigned by X-ray analysis.14
We next surveyed the effect of various solvents. The reactions proceeded with low yields in
DME (1,2-dimethoxyethane), 1,4-dioxane, and DMSO (entries 9-11). To our delight, in the
absence of solvent, the reaction efficiency was enhanced and yield of the product 3a was
increased to 81% (entry 12). The effect of air or molecular oxygen as oxidant in the reaction was
also examined. A lower yield of 3a was observed when the reaction carried out under air
atmosphere, and only trace amount of product was formed in the absence of oxygen (entries 13
and 14). Subsequently, other conditions, such as temperature and reaction time, were evaluated
using FeBr2/O2 system. No substantial improvement in the yield was observed when elevating
o
o
the reaction temperature to 120 C, while low yield of the product was noticed at 80 C (entries
15 and 16). Interestingly, when the reaction time was extended from 8 to 16 h, the yield of 3a
was further improved to 90% (entry 17). Furthermore, we carried out the reaction with iron(III)
bromide under solvent-free conditions, which gave the product 3a in 65% yield (entry 18). This
oxidative reaction did not proceed in the absence of iron catalyst (entry 19).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001300
European Journal of Organic Chemistry
Table 1. Screening of Reaction Parametersa
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001300
European Journal of Organic Chemistry
With the established reaction conditions in hand (Table 1, entry 17), we first studied the
scope of oxindoles bearing different substituents on the arene periphery (Scheme 2). As
illustrated, the oxindoles possessing electron-donating groups such as methyl, iso-propyl, or
methoxy at the 5 position of the aryl ring were efficiently reacted with benzylamine, producing
the desired products with high yields (3b, 3c, 3d). Electron-releasing disubstituted oxindole also
furnished excellent yield of the product (3e). Oxindoles bearing electron-withdrawing
substituents such as fluoro, chloro, bromo, or iodo groups at the 5 position also smoothly
underwent the reaction to furnish the corresponding alkenylated products in good to high yields
(3f, 3h, 3k, 3l). In addition, oxindole derivatives with chloro substituent in the 4, 6, or 7 position
performed well, giving the desired products in high yields (3g, 3i, 3j). Notably, even when a
strong electron-withdrawing group such as NO2 substituted oxindole was employed as substrate,
the reaction proceeded to give the desired alkenylated product 3m in synthetically useful yield.
Next, we examined the reactions of oxindoles bearing different substituents on the
nitrogen with benzylamine. The N-alkyl oxindoles viz., N-methyloxindole, N-benzyloxindole,
and N-hexyloxindole were compatible under the reaction conditions, affording the desired
products in high yields (3n, 3o, 3p). N-Phenyloxindole also smoothly participated in the reaction
to obtain the alkenylated product in 87 % yield (3q). Unfortunately, N-acyl substrates such as N-
acetyloxindole and N-benzoyloxindole failed to give the desired products.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001300
European Journal of Organic Chemistry
Scheme 2. Substrate Scope of Oxindoles in Fe-Catalyzed Oxidative Condensation
Reactiona,b
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001300
European Journal of Organic Chemistry
To further test the generality of the oxidative condensation, a series of benzylamines were
investigated under the optimized catalytic conditions (Scheme 3). Electron-donating
benzylamines underwent the oxidative condensation with oxindole to give the corresponding
products in good to excellent yields (4a-4g). The structure of compound 4a was confirmed by its
single-crystal X-ray diffraction analysis.15 Piperonylamine and 1-(1-naphthyl)methanamine were
tolerated well in this transformation, thus providing 4h and 4i in 83% and 86% yields,
respectively. It is noteworthy that the halo-substituted benzylamines reacted smoothly with
oxindole, leading to halo-substituted 3-alkylideneindolin-2-ones (4j-4m), which could be further
utilized in conventional Pd-catalyzed cross-coupling transformations. In addition, trifluoromethyl
groups containing benzylamine, 3,5-bis(trifluoromethyl)benzylamine was also tolerated under
the reaction conditions, affording 4n in 80% yield. Heteroarylmethanamines such as
furfurylamine and 2-thiophenemethylamine were also served as suitable substrates in this
oxidative condensation reaction (4o, 4p). 2-Thiophenemethylamine was observed to produce a
1
mixture of E and Z alkenylated products ((E)-4p:(Z)-4p = 1:1.2 ratio by H NMR). It is known
that the 3-[(substituted furanyl)methylidenyl]indolin-2-ones favors the E isomer form due to the
electrostatic repulsion between the C-2 carbonyl oxygen atom of the indolin-2-one and the O-1′
of furan in their Z isomer form.1b On the other hand, the 3-[(substituted thienyl)methylidenyl]-
indolin-2-ones favors the Z isomer form due to the electrostatic interaction between the C-2
carbonyl oxygen and partial positively charged S-1′ of thiophene in their Z isomeric form.1b
However, an alkyl amine namely n-octylamine did not afford the desired product.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001300
European Journal of Organic Chemistry
Scheme 3. Substrate Scope of Benzylamines in Fe-Catalyzed Oxidative Condensation
Reactiona,b
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001300
European Journal of Organic Chemistry
To demonstrate the utility of this synthetic approach, several pharmaceutically relevant
(E)-3-alkylideneindolin-2-one molecules have been prepared. For example, (E)-3-benzylidene-6-
chloroindolin-2-one (3i), (E)-3-(4-isopropylbenzylidene)indolin-2-one (4b) and (E)-3-[4-(1-
formylpiperazin-4-yl)benzylidenyl]indolin-2-one (6) are reported as excellent inhibitors of
tyrosine kinase activities.1b,1f,16 Compound 6 could be prepared by a three-step procedure
involving the oxidative condensation of oxindole (1a) with 4-bromobenzylamine (2j) to give (E)-
3-(4-bromobenzylidene)indolin-2-one (4j) in 93% yield under the optimized reaction conditions,
followed by Buchwald–Hartwig amination, and N-formylation reaction as shown in Scheme 4a.
In addition, (E)-3-(benzo[d][1,3]dioxol-5-ylmethylene)indolin-2-one (4h) and (E)-3-(3,4,5-
trimethoxybenzylidene)-5-methoxyindolin-2-one (9) are identified as potent anticonvulsant agent
and antitumor agent, respectively.1c,17 Compound 9 could be synthesized by oxidative reaction of
5-methoxyoxindole (7) with 3,4,5-trimethoxybenzylamine (8) under the standard conditions
(Scheme 4b). Besides, many of the synthesized 3-alkylideneindolin-2-one compounds, namely
(E)-3-benzylidene-7-chloroindolin-2-one (3j), (E)-3-benzylidene-5-bromoindolin-2-one (3k) and
(E)-3-(4-methylbenzylidene)indolin-2-one (4a) are used as key precursors for the synthesis of
bioactive molecules;1a,18 and (E)-3-(3,4,5-trimethoxybenzylidene)indolin-2-one (4g) is employed
as precursor for the preparation of cyanide-scavenging material.19
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001300
European Journal of Organic Chemistry
Scheme 4. Synthesis of Pharmaceutically Relevant (E)-3-Alkylideneindolin-2-one Products
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001300
European Journal of Organic Chemistry
In order to understand the reaction mechanism, we carried out some control experiments
(Scheme 5). Initially, benzylamine (2a) was treated with FeBr2 and molecular oxygen at 100 °C
for 5 h, which resulted the formation of self-condensation product N-benzylidenebenzylamine
(10) in 96% isolated yield (Scheme 5a). Subsequently, the isolated imine 10 was allowed to react
with oxindole (1a) under the standard reaction conditions, leading to the desired product (E)-3-
benzylideneindolin-2-one (3a) in 92% yield (Scheme 5b). In another experiment, the imine 10
o
was treated with oxindole (1a) in the presence of FeBr2 and molecular oxygen at 70 C for 6 h,
fortunately, an intermediate, 3-[(benzylamino)(phenyl)methyl]indolin-2-one (11) was isolated
along with the desired product 3a in 43% and 10% yields, respectively (Scheme 5c), and the
unreacted starting materials were also recovered. Although there is a possibility of the formation
of a mixture of diastereomers, we able to isolate one of the diastereomers, because the
diastereomeric intermediates are unstable under the reaction conditions as they undergo
dehydrogenation to form the thermodynamically stable product E-3a. The intermediate 11
successfully produced the desired product 3a in 93% yield under the standard conditions
(Scheme 5d).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001300
European Journal of Organic Chemistry
Scheme 5. Control Experiments
On the basis of above experimental results and earlier reports,4a,12f a plausible mechanism
is outlined in Scheme 6. Initially, the enol form of oxindole reacts with iron(II) bromide in the
presence of oxygen to give an iron(III) enolate 12. Concomitantly, benzylamine is participated in
the oxidative self-condensation to form N-benzylidenebenzylamine (10) in the presence of
iron(II) bromide and molecular oxygen. Subsequently, the nucleophilic attack of 12 takes place
on the imine 10 to generate 3-alkylated oxindole 14 via a six-membered transition state 13.
Finally, the intermediate 14 breaks down to the thermodynamically driven stable product (E)-3-
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001300
European Journal of Organic Chemistry
benzylideneindolin-2-one (3a), and generating the benzylamine (2a) and iron(II) bromide in the
process.
Scheme 6. Plausible Reaction Mechanism
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001300
European Journal of Organic Chemistry
Conclusions
In summary, we have developed a novel reaction protocol for the synthesis of (E)-3-
alkylideneindolin-2-ones via iron-catalyzed aerobic oxidative condensation of oxindoles with
benzylamines. This approach exhibited a broad substrate scope relating to both the reaction
partners and allowed the synthesis of many biologically active molecules. The mechanistic
investigations disclosed that this oxidative reaction proceeded through C-H activation, amine
self-condensation, nucleophilic addition, and C-C double bond formation. Cheap iron salt as the
catalyst and molecular oxygen as the oxidant were used in this one-pot procedure, which makes
the transformation very economical and practical.
Experimental Section
General Information. All chemicals were purchased from commercial suppliers and used as
received. The reactions were performed in oven-dried glassware under appropriate atmosphere.
The reactions were monitored by Thin-layer chromatography (TLC) on 0.25 mm Merck Silica
gel 60 F254 plates using UV light for visualization. The column chromatography was performed
with 100−200 mesh silica gel using hexane and ethylacetate as eluents. NMR spectra were
13
recorded on a Jeol ECZ-400S spectrometer (1H at 400 MHz, C at 100 MHz), using DMSO-d6
or CDCl3 or acetone-d6 as the solvent with TMS as the internal standard. The abbreviations for
multiplicity are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m= multiplet, dd =
doublet of doublet, td = triplet of doublet, br s = broad singlet. Chemical shifts (δ) are reported
relative to residual solvent signals (Chloroform-d, 7.26 ppm for 1H NMR and triplet centered at
77.00 ppm for 13C NMR; DMSO-d6, 2.50 ppm for 1H NMR and septet centered at 39.50 ppm for
1
13
13C NMR; Acetone-d6, 2.05 ppm for H NMR and septet centered at 29.84 ppm for C NMR).
Melting points were determined using Büchi melting point apparatus and are uncorrected. High-
resolution mass spectra (HRMS) were recorded using an electrospray quadrupole time-of-flight
(ESI-Q-TOF) mass spectrometer. The X-ray data for compounds 3a and 4a were collected at 298
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001300
European Journal of Organic Chemistry
K with an Oxford XCalibur CCD diffractometer equipped with graphite monochromatic Mo Kα
radiation (λ = 0.71073 Å).
General procedure for the synthesis of skeletons 3 and 4: Oxindole 1 (1 mmol), benzylamine
2 (1.2 mmol) and iron(II) bromide (5 mol %) were added into an oven-dried 10 mL Schlenk tube
equipped with oxygen balloon. The tube was immersed in silicon oil bath placed over magnetic
stirrer and heated at 100 °C with constant stirring for 16 h. The reaction mixture was cooled to
room temperature, diluted with ethyl acetate and washed with water (2 x 20 ml). The organic
layer was dried over anhydrous Na2SO4, filtered and the solvent was evaporated under reduced
pressure. The residue was purified by column chromatography using hexane and ethyl acetate as
eluents to afford the compounds 3a-q and 4a-p.
(E)-3-Benzylideneindolin-2-one (3a). Yellow solid; yield: 90%; mp 178-180 °C (lit.10 mp 178-
1
179 °C); H NMR (400 MHz, CDCl3): δ 9.35 (br s, 1H), 7.86 (s, 1H), 7.69-7.63 (m, 3H), 7.50-
13
7.42 (m, 3H), 7.24-7.19 (m, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.89-6.85 (m, 1H); C NMR (100
MHz, CDCl3): δ 170.7, 141.8, 137.5, 134.8, 129.9, 129.6, 129.3, 128.6, 127.7, 122.9, 121.8,
121.6, 110.4; HRMS (ESI) m/z calcd for C15H11NO [M + H]+: 222.0913, found 222.0916.
(E)-3-Benzylidene-5-methylindolin-2-one (3b). Red solid; yield: 92%; mp 178-180 °C (lit.10
mp 178-180 °C); 1H NMR (400 MHz, CDCl3): δ 9.02 (br s, 1H), 7.82 (s, 1H), 7.67 (d, J = 6.4
13
Hz, 2H), 7.50-7.44 (m, 4H), 7.03 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 2.22 (s, 3H); C
NMR (100 MHz, CDCl3): δ 170.5, 139.5, 137.1, 134.9, 131.1, 130.4, 129.6, 129.3, 128.6, 127.8,
123.6, 121.7, 110.0, 21.2; HRMS (ESI) m/z calcd for C16H13NO [M + H]+: 236.1070, found
236.1073.
(E)-3-Benzylidene-5-isopropylindolin-2-one (3c). Brown solid; yield: 90%; mp 191-192 °C; 1H
NMR (400 MHz, CDCl3): δ 9.45 (br s, 1H), 7.83 (s, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.54 (s, 1H),
7.51-7.44 (m, 3H), 7.09 (dd, J = 8.0, 1.6 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 2.82-2.72 (m, 1H),
1.16 (d, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 170.9, 142.3, 139.8, 136.9, 134.9,
129.6, 129.3, 128.5, 128.1, 127.9, 121.6, 120.9, 110.1, 33.7, 24.1; HRMS (ESI) m/z calcd for
C18H17NO [M + H]+: 264.1383, found 264.1388.
(E)-3-Benzylidene-5-methoxyindolin-2-one (3d). Orange solid; yield: 89%; mp 180-181 °C; 1H
NMR (400 MHz, CDCl3): δ 9.59 (br s, 1H), 7.84 (s, 1H), 7.65 (d, J = 7.6 Hz, 2H), 7.49-7.42 (m,
13
3H), 7.21 (d, J = 2.0 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.76 (m, 1H), 3.65 (s, 3H); C NMR
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001300
European Journal of Organic Chemistry
(100 MHz, CDCl3): δ 170.9, 154.8, 137.6, 135.7, 134.6, 129.7, 129.2, 128.6, 128.2, 122.4, 114.9,
110.7, 109.6, 55.6; HRMS (ESI) m/z calcd for C16H13NO2 [M + H]+: 252.1019, found 252.1025.
(E)-3-Benzylidene-5,7-dimethylindolin-2-one (3e). Orange-yellow solid; yield: 94%; mp 216-
1
217 °C; H NMR (400 MHz, CDCl3): δ 9.14 (br s, 1H), 7.81 (s, 1H), 7.67 (d, J = 8.4 Hz, 2H),
13
7.49-7.41 (m, 3H), 7.31 (s, 1H), 6.88 (s, 1H), 2.29 (s, 3H), 2.19 (s, 3H); C NMR (100 MHz,
CDCl3): δ 170.8, 138.3, 137.1, 134.9, 131.9, 130.9, 129.5, 129.4, 128.6, 128.3, 121.3, 121.1,
119.1, 21.1, 16.3; HRMS (ESI) m/z calcd for C17H15NO [M + H]+: 250.1226, found 250.1236.
(E)-3-Benzylidene-5-fluoroindolin-2-one (3f). Brown solid; yield: 85%; mp 196-197 °C (lit.10
mp 196-197 °C); 1H NMR (400 MHz, CDCl3): δ 9.13 (br s, 1H), 7.89 (s, 1H), 7.65-7.62 (m, 2H),
7.52-7.44 (m, 3H), 7.35 (dd, J = 9.2, 2.4 Hz, 1H), 6.93 (td, J = 8.8, 2.4 Hz, 1H), 6.87-6.83 (m,
13
1
1H); C NMR (100 MHz, CDCl3): δ 170.5, 158.3 (d, JCF = 237.7 Hz), 139.1, 137.7, 134.3,
130.1, 129.2, 128.8, 127.4, 122.6 (d, 3JCF = 8.6 Hz), 116.2 (d, 2JCF = 24.0 Hz), 110.7 (d, 3JCF
=
7.7 Hz), 110.4 (d, 2JCF = 26.8 Hz); HRMS (ESI) m/z calcd for C15H10FNO [M + H]+: 240.0819,
found 240.0792.
1
(E)-3-Benzylidene-4-chloroindolin-2-one (3g). Yellow solid; yield: 86%; mp 187-188 °C; H
NMR (400 MHz, DMSO-d6): δ 10.71 (br s, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.62 (d, J = 6.4 Hz,
1H), 7.58 (s, 1H), 7.52-7.46 (m, 2H), 7.25-7.21 (m, 1H), 7.13 (d, J = 7.6 Hz, 1H), 6.88 (d, J = 7.6
Hz, 1H), 6.79 (t, J = 7.6 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ 168.3, 143.2, 133.0, 131.7,
131.5, 130.8, 130.5, 129.9, 129.7, 127.6, 122.7, 121.5, 120.6, 110.5; HRMS (ESI) m/z calcd for
C15H10ClNO [M + H]+: 256.0524, found 256.0528.
(E)-3-Benzylidene-5-chloroindolin-2-one (3h). Yellow solid; yield: 90%; mp 219-220 °C (lit.10
mp 219-220 °C); 1H NMR (400 MHz, CDCl3): δ 8.82 (br s, 1H), 7.89 (s, 1H), 7.66-7.61 (m, 3H),
13
7.54-7.46 (m, 3H), 7.19 (dd, J = 8.4, 2.0 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H); C NMR (100
MHz, CDCl3): δ 169.9, 139.9, 139.3, 135.3, 134.2, 130.2, 129.6, 129.3, 128.9, 127.1, 126.7,
123.0, 111.1; HRMS (ESI) m/z calcd for C15H10ClNO [M + H]+: 256.0524, found 256.0533.
1
(E)-3-Benzylidene-6-chloroindolin-2-one (3i). Orange solid; yield: 87%; mp 176-177 °C; H
NMR (400 MHz, CDCl3): δ 8.39 (br s, 1H), 7.84 (s, 1H), 7.65-7.63 (m, 2H), 7.55 (d, J = 8.0 Hz,
1H), 7.51-7.45 (m, 3H), 6.91 (d, J = 2.0 Hz, 1H), 6.85 (dd, J = 8.0, 2.0 Hz, 1H); 13C NMR (100
MHz, CDCl3): δ 170.4, 142.6, 138.1, 135.4, 134.5, 129.9, 129.3, 128.8, 126.5, 123.8, 121.9,
120.1, 110.8; HRMS (ESI) m/z calcd for C15H10ClNO [M + H]+: 256.0524, found 256.0529.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001300
European Journal of Organic Chemistry
1
(E)-3-Benzylidene-7-chloroindolin-2-one (3j). Yellow solid; yield: 88%; mp 202-203 °C; H
NMR (400 MHz, CDCl3): δ 8.30 (br s, 1H), 7.90 (s, 1H), 7.66-7.63 (m, 2H), 7.54-7.43 (m, 4H),
7.21 (d, J = 8.4 Hz, 1H), 6.84-6.80 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 168.8, 139.4,
139.0, 134.4, 130.0, 129.4, 129.3, 128.8, 127.3, 123.1, 122.6, 121.2, 115.4; HRMS (ESI) m/z
calcd for C15H10ClNO [M + H]+: 256.0524, found 256.0531.
1
(E)-3-Benzylidene-5-bromoindolin-2-one (3k). Yellow solid; yield: 83%; mp 200-201 °C; H
NMR (400 MHz, CDCl3): δ 8.92 (br s, 1H), 7.87 (s, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.65-7.63 (m,
2H), 7.54-7.44 (m, 3H), 7.35-7.32 (m, 1H), 6.80 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3): δ 169.9, 140.4, 139.3, 139.2, 134.2, 132.4, 132.2, 130.3, 129.3, 128.9, 125.8, 123.5,
111.6; HRMS (ESI) m/z calcd for C15H10BrNO [M + H]+: 300.0019, found 300.0018.
1
(E)-3-Benzylidene-5-iodoindolin-2-one (3l). Yellow solid; yield: 81%; mp 184-185 °C; H
NMR (400 MHz, CDCl3): δ 8.62 (br s, 1H), 7.94 (d, J = 1.2 Hz, 1H), 7.86 (s, 1H), 7.65-7.63 (m,
2H), 7.54-7.45 (m, 4H), 6.70 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 169.4, 140.9,
139.3, 138.3, 134.2, 132.2, 131.5, 130.3, 129.3, 128.8, 126.2, 124.0, 112.1; HRMS (ESI) m/z
calcd for C15H10INO [M + H]+: 347.9880, found 347.9881.
(E)-3-Benzylidene-5-nitroindolin-2-one (3m). Pale yellow solid; yield: 76%; mp 184-185 °C;
1H NMR (400 MHz, DMSO-d6): δ 10.80 (br s, 1H), 7.73-7.67 (m, 3H), 7.54-7.45 (m, 4H), 6.91-
6.88 (m, 2H);13C NMR (100 MHz, DMSO-d6): δ 168.7, 144.4, 136.9, 134.3, 132.1, 130.1, 129.5,
129.0, 128.4, 126.6, 123.7, 121.1, 110.3; HRMS (ESI) m/z calcd for C15H10N2O3 [M + H]+:
267.0764, found 267.0769.
1
(E)-3-Benzylidene-1-methylindolin-2-one (3n). Orange oil; yield: 89%; H NMR (400 MHz,
CDCl3): δ 7.84 (s, 1H), 7.63-7.60 (m, 3H), 7.49-7.39 (m, 3H), 7.25-7.22 (m, 1H), 6.87-6.83 (m,
1H), 6.79 (d, J = 8.0 Hz, 1H), 3.25 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 168.3, 144.1, 136.9,
134.8, 129.7, 129.4, 129.2, 128.5, 127.1, 122.6, 121.6, 120.9, 108.0, 26.0; HRMS (ESI) m/z
calcd for C16H13NO [M + H]+: 236.1070, found 236.1078.
1
(E)-1-Benzyl-3-benzylideneindolin-2-one (3o). Orange viscous oil; yield: 91%; H NMR (400
MHz, CDCl3): δ 7.93 (s, 1H), 7.66-7.62 (m, 3H), 7.48-7.41 (m, 3H), 7.35-7.29 (m, 4H), 7.27-
13
7.23 (m, 1H), 7.16-7.11 (m, 1H), 6.85-6.81 (m, 1H), 6.71 (d, J = 8.0 Hz, 1H), 4.99 (s, 2H); C
NMR (100 MHz, CDCl3): δ 168.5, 143.3, 137.5, 135.9, 134.9, 131.9, 129.7, 129.5, 129.2, 128.7,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001300
European Journal of Organic Chemistry
128.6, 127.5, 127.2, 126.9, 122.7, 121.8, 121.2, 109.1, 43.7; HRMS (ESI) m/z calcd for
C22H17NO [M + H]+: 312.1383, found 312.1387.
1
(E)-3-Benzylidene-1-hexylindolin-2-one (3p). Red viscous oil; yield: 90%; H NMR (400
MHz, CDCl3): δ 7.85 (s, 1H), 7.62 (d, J = 7.6 Hz, 3H), 7.46-7.37 (m, 3H), 7.24-7.20 (m, 1H),
6.86-6.81 (m, 2H), 3.77-3.74 (m, 2H), 1.73-1.66 (m, 2H), 1.39-1.31 (m, 6H), 0.91-0.87 (m, 3H);
13C NMR (100 MHz, CDCl3): δ 168.1, 143.5, 136.8, 134.8, 129.5, 129.3, 129.0, 128.4, 127.0,
122.6, 121.3, 121.0, 108.2, 39.8, 31.3, 27.4, 26.5, 22.4, 13.9; HRMS (ESI) m/z calcd for
C21H23NO [M + H]+: 306.1852, found 306.1857.
1
(E)-3-Benzylidene-1-phenylindolin-2-one (3q). Orange solid; yield: 87%; mp 50-52 °C; H
NMR (400 MHz, CDCl3): δ 7.95 (s, 1H), 7.68-7.65 (m, 3H), 7.49-7.43 (m, 3H), 7.37-7.25 (m,
5H), 7.17-7.13 (m, 1H), 6.87-6.83 (m, 1H), 6.73 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3): δ 168.6, 143.4, 137.5, 135.9, 134.9, 129.7, 129.5, 129.2, 128.7, 128.6, 127.5, 127.2,
126.9, 122.7, 121.8, 121.2, 109.2; HRMS (ESI) m/z calcd for C21H15NO [M + H]+: 298.1226,
found 298.1234.
(E)-3-(4-Methylbenzylidene)indolin-2-one (4a). Orange solid; yield: 93%; mp 197-198 °C
(lit.20 mp 199-200 °C); 1H NMR (400 MHz, CDCl3): δ 9.56 (br s, 1H), 7.82 (s, 1H), 7.70 (d, J =
7.6 Hz, 1H), 7.58 (d, J = 7.6 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.21-7.17 (m, 1H), 6.94 (d, J =
8.0 Hz, 1H), 6.88-6.84 (m, 1H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 170.7, 141.5,
140.1, 137.9, 131.9, 129.6, 129.5, 129.3, 126.8, 122.9, 121.8, 121.7, 110.2, 21.6; HRMS (ESI)
m/z calcd for C16H13NO [M + H]+: 236.1070, found 236.1072.
(E)-3-(4-Isopropylbenzylidene)indolin-2-one (4b). Yellow solid; yield: 92%; mp 144-145 °C
(lit.10 mp 144-146 °C); 1H NMR (400 MHz, CDCl3): δ 9.06 (br s, 1H), 7.83 (s, 1H), 7.75 (d, J =
8.0 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.24-7.19 (m, 1H), 6.95-6.91 (m,
1H), 6.89 (d, J = 7.6 Hz, 1H), 3.04-2.93 (m, 1H), 1.31 (d, J = 6.8 Hz, 6H); 13C NMR (100 MHz,
CDCl3): δ 170.7, 151.1, 141.6, 137.9, 132.2, 129.7, 126.7, 122.9, 121.8, 121.7, 110.2, 34.2, 23.8;
HRMS (ESI) m/z calcd for C18H17NO [M + H]+: 264.1383, found 264.1388.
(E)-3-(2-Methoxybenzylidene)indolin-2-one (4c). Mustard yellow solid; yield: 89%; mp 221-
224 °C (lit.21 mp 221-222 °C); 1H NMR (400 MHz, CDCl3): δ 8.49 (br s, 1H), 7.98 (s, 1H), 7.73
(d, J = 7.6 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.45-7.41 (m, 1H), 7.21-7.17 (m, 1H), 7.05-6.98
13
(m, 2H), 6.90-6.83 (m, 2H), 3.88 (s, 3H); C NMR (100 MHz, CDCl3): δ 170.1, 158.2, 141.3,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001300
European Journal of Organic Chemistry
134.1, 131.5, 129.9, 129.5, 127.1, 123.7, 122.9, 122.0, 121.7, 120.1, 110.9, 109.9, 55.5; HRMS
(ESI) m/z calcd for C16H13NO2 [M + H]+: 252.1019, found 252.1023.
(E)-3-(3-Methoxybenzylidene)indolin-2-one (4d). Pale-yellow solid; yield: 93%; mp 151-152
°C (lit.21 mp 150-152 °C); 1H NMR (400 MHz, CDCl3): δ 9.14 (br s, 1H), 7.82 (s, 1H), 7.68 (d, J
= 7.6 Hz, 1H), 7.41-7.37 (m, 1H), 7.27-7.19 (m, 3H), 6.98 (dd, J = 8.4, 2.4Hz, 1H), 6.93 (d, J =
7.6 Hz, 1H), 6.89-6.86 (m, 1H), 3.85 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 170.7, 159.6,
141.8, 137.3, 136.1, 129.9, 129.7, 127.8, 123.2, 121.8, 121.7, 121.6, 115.6, 114.2, 110.4, 55.3;
HRMS (ESI) m/z calcd for C16H13NO2 [M + H]+: 252.1019, found 252.1019.
(E)-3-(4-Methoxybenzylidene)indolin-2-one (4e). Reddish yellow solid; yield: 88%; mp 203-
204 °C (lit.10 mp 203-204 °C); 1H NMR (400 MHz, CDCl3): δ 8.75 (br s, 1H), 7.79 (s, 1H), 7.75
(d, J = 7.6 Hz, 1H), 7.67 (d, J = 8.8 Hz, 2H), 7.23-7.19 (m, 1H), 6.99 (d, J = 8.8 Hz, 2H), 6.93-
6.88 (m, 2H), 3.89 (s, 3H); 13C NMR (100 MHz, CDCl3):δ 170.6, 160.9, 141.3, 137.8, 131.5,
129.4, 127.1, 125.6, 122.7, 121.9, 121.7, 114.1, 110.1, 55.4; HRMS (ESI) m/z calcd for
C16H13NO2 [M + H]+: 252.1019, found 252.1025.
(E)-3-([1,1'-Biphenyl]-4-ylmethylene)indolin-2-one (4f). Orange solid; yield: 91%; mp 144-
145 °C; 1H NMR (400 MHz, DMSO-d6): δ 10.53 (br s, 1H), 8.36 (d, J = 8.0 Hz, 2H), 7.69-7.58
(m, 6H), 7.37-7.24 (m, 3H), 7.08 (t, J = 7.6 Hz, 1H), 6.86 (t, J = 8.0 Hz, 1H), 6.70 (d, J = 7.6 Hz,
13
1H); C NMR (100 MHz, DMSO-d6): δ 167.3, 141.8, 140.8, 139.3, 136.3, 133.3, 132.8, 130.3,
129.2, 128.1, 126.9, 126.8, 126.4, 125.1, 121.2, 119.9, 109.5; HRMS (ESI) m/z calcd for
C21H15NO [M + H]+: 298.1226, found 298.1229.
(E)-3-(3,4,5-Trimethoxybenzylidene)indolin-2-one (4g). Yellow solid; yield: 85%; mp 204-
205 °C (lit.20 mp 205-207 °C); 1H NMR (400 MHz, CDCl3): δ 8.25 (br s, 1H), 7.82 (s, 2H), 7.53
(d, J = 7.6 Hz, 1H), 7.48 (s, 1H), 7.25-7.21 (m, 1H), 7.07-7.03 (m, 1H), 6.84 (d, J = 7.6 Hz, 1H),
3.97 (s, 6H), 3.94 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 168.3, 152.6, 140.4, 139.3, 138.0,
129.3, 128.6, 125.5, 125.2, 121.8, 119.0, 109.8, 109.4, 60.9, 56.2; HRMS (ESI) m/z calcd for
C18H17NO4 [M + H]+: 312.1230, found 312.1034.
(E)-3-(Benzo[d][1,3]dioxol-5-ylmethylene)indolin-2-one (4h). Yellow solid; yield: 83%; mp
208-209 °C (lit.22 mp 210 °C); 1H NMR (400 MHz, DMSO-d6): δ 10.57 (br s, 1H), 7.63 (d, J =
7.2 Hz, 1H), 7.53 (s, 1H), 7.29-7.19 (m, 3H), 7.05 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 6.8 Hz, 2H),
6.12 (s, 2H); 13C NMR (100 MHz, DMSO-d6): δ 168.9, 148.7, 147.7, 142.8, 136.1, 129.9, 128.3,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001300
European Journal of Organic Chemistry
126.2, 124.7, 122.3, 121.2, 121.1, 110.2, 109.4, 108.7, 101.7; HRMS (ESI) m/z calcd for
C16H11NO3 [M + H]+: 266.0812, found 266.0817.
(E)-3-(Naphthalen-1-ylmethylene)indolin-2-one (4i). Yellow solid; yield: 86%; mp 190-191
°C (lit.20 mp 198-199 °C); 1H NMR (400 MHz, CDCl3): δ 9.15 (br s, 1H), 8.37 (s, 1H), 8.06-8.03
(m, 1H), 7.98-7.93 (m, 2H), 7.85 (d, J = 7.6 Hz, 1H), 7.59-7.53 (m, 3H), 7.20-7.17 (m, 2H), 6.95
(d, J = 7.6 Hz, 1H), 6.74 (t, J = 7.6 Hz, 1H);13C NMR (100 MHz, CDCl3): δ 170.2, 141.7,
135.5, 133.6, 132.1, 131.3, 130.0, 129.9, 129.4, 128.6, 126.9, 126.7, 126.5, 125.1, 124.8, 123.3,
121.8, 110.2; HRMS (ESI) m/z calcd for C19H13NO [M + H]+: 272.1070, found 272.1081.
(E)-3-(4-Bromobenzylidene)indolin-2-one (4j). Orange solid; yield: 93%; mp 162-163 °C (lit.23
mp 191-192 °C); 1H NMR (400 MHz, CDCl3): δ 8.91 (br s, 1H), 7.78 (s, 1H), 7.69-7.65 (m, 2H),
7.60 (d, J = 8.0 Hz, 1H), 7.25-7.21 (m, 1H), 7.17 (t, J = 8.8 Hz, 2H), 6.93 (d, J = 8.0 Hz, 1H),
6.91-6.87 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 170.0, 140.4, 139.3, 134.2, 132.4, 132.2,
130.3, 129.3, 128.9, 125.8, 123.5, 114.5, 111.6; HRMS (ESI) m/z calcd for C15H10BrNO [M +
H]+: 300.0019, found 300.0022.
(E)-3-(4-Chlorobenzylidene)indolin-2-one (4k). Yellow solid; yield: 95%; mp 178-181 °C
(lit.21 mp 178-181 °C); 1H NMR (400 MHz, CDCl3): δ 8.50 (br s, 1H), 7.75 (s, 1H), 7.62-7.57
(m, 3H), 7.46-7.44 (m, 2H), 7.25-7.21 (m, 1H), 6.92-6.87 (m, 2H); 13C NMR (100 MHz, CDCl3):
δ 170.4, 141.9, 135.8, 135.5, 133.2, 130.6, 130.2, 128.9, 128.1, 122.9, 121.9, 121.3, 110.5;
HRMS (ESI) m/z calcd for C15H10ClNO [M + H]+: 256.0524, found 256.0526.
(E)-3-(2-Chlorobenzylidene)indolin-2-one (4l). Yellow solid; yield: 87%; mp 176-177 °C (lit.22
mp 178 °C); 1H NMR (400 MHz, CDCl3): δ 9.09 (br s, 1H), 7.88 (s, 1H), 7.74-7.72 (m, 1H),
7.53-7.50 (m, 1H), 7.41-7.32 (m, 3H), 7.24-7.19 (m, 1H), 6.93 (d, J = 7.6 Hz, 1H), 6.85-6.81
(m, 1H); 13C NMR (100 MHz, CDCl3): δ 169.9, 141.9, 134.4, 133.8, 133.5, 130.7, 130.3, 130.2,
129.9, 129.2, 126.6, 123.1, 121.8, 121.3, 110.4; HRMS (ESI) m/z calcd for C15H10ClNO [M +
H]+: 256.0524, found 256.0532.
(E)-3-(3,4-Dichlorobenzylidene)indolin-2-one (4m). Orange solid; yield: 88%; mp 195-197 °C
(lit.23 mp 195-197 °C); 1H NMR (400 MHz, DMSO-d6): δ 10.68 (br s, 1H), 7.93 (s, 1H), 7.76 (d,
J = 8.0 Hz, 1H), 7.73-7.67 (m, 1H), 7.54 (s, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.26-7.23 (m, 1H),
6.89-6.82 (m, 2H); 13C NMR (100 MHz, DMSO-d6): δ 168.4, 143.3, 135.4, 132.9, 132.0, 131.7,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001300
European Journal of Organic Chemistry
131.2, 131.1, 130.9, 129.3, 129.2, 122.7, 121.5, 120.5, 110.5; HRMS (ESI) m/z calcd for
C15H9Cl2NO [M + H]+: 290.0134, found 290.0138.
(E)-3-(3,5-Bis(trifluoromethyl)benzylidene)indolin-2-one (4n). Yellow solid; yield: 80%; mp
1
180-181 °C; H NMR (400 MHz, CDCl3): δ 9.11 (br s, 1H), 7.78 (s, 1H), 7.68-7.65 (m, 2H),
13
7.59 (d, J = 8.0 Hz, 1H), 7.25-7.14 (m, 2H), 6.93 (d, J = 8.0 Hz, 1H), 6.90-6.86 (m, 1H); C
NMR (100 MHz, CDCl3): δ 170.3, 141.7, 136.3, 131.4 (d, 1JCF = 8.6 Hz), 130.8 (2JCF = 3.8 Hz),
130.0, 127.5, 122.8, 121.9, 121.5, 115.9, 115.8, 110.4; HRMS (ESI) m/z calcd for C17H9F6NO
[M + H]+: 358.0661, found 358.0678.
(E)-3-(Furan-2-ylmethylene)indolin-2-one (4o). Brown-yellow solid; yield: 79%; mp 181-182
°C (lit.22 mp 183 °C); 1H NMR (400 MHz, CDCl3): δ 9.07 (br s, 1H), 8.45 (d, J = 8.0 Hz, 1H),
7.77 (d, J = 2.0 Hz, 1H), 7.49-7.45 (m, 1H), 7.27-7.19 (m, 1H), 7.09-7.01 (m, 1H), 6.93-6.90
13
(m, 2H), 6.64-6.62 (m, 1H); C NMR (100 MHz, CDCl3): δ 177.9, 151.3, 127.8, 125.3, 125.1,
124.9, 124.6, 122.3, 122.1, 121.9, 120.8, 109.8, 109.7; HRMS (ESI) m/z calcd for C13H9NO2 [M
+ H]+: 212.0706, found 212.0739.
(E)-3-(Thiophen-2-ylmethylene)indolin-2-one ((E)-4p). Yellow solid; yield: 36%; mp 210-211
°C (lit.22 mp 210 °C); 1H NMR (400 MHz, CDCl3): δ 9.19 (br s, 1H), 8.23 (d, J = 8.0 Hz, 1H),
13
7.93 (s, 1H), 7.65-7.61 (m, 1H), 7.27-7.16 (m, 3H), 7.06-7.01 (m, 1H), 6.97-6.91 (m, 1H); C
NMR (100 MHz, CDCl3): δ 171.1, 141.4, 137.8, 137.1, 134.7, 130.7, 129.6, 128.7, 128.5, 128.1,
123.6, 121.9, 110.3; HRMS (ESI) m/z calcd for C13H9NOS [M + H]+: 228.0478, found
228.0471.
(Z)-3-(Thiophen-2-ylmethylene)indolin-2-one ((Z)-4p). Yellow solid; yield: 45%; mp 221 °C;
1H NMR (400 MHz, DMSO-d6): δ 10.58 (br s, 1H), 8.06 (s, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.84
(d, J = 5.2 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.19-7.14 (m, 2H), 6.97-6.93 (m, 1H), 6.82 (d, J =
7.6 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ 167.4, 140.5, 137.6, 137.4, 134.3, 128.5, 128.2,
127.5, 124.4, 121.7, 121.1, 119.5, 109.5; HRMS (ESI) m/z calcd for C13H9NOS [M + H]+:
228.0478, found 228.0485.
Preparation of (E)-3-(4-(piperazin-1-yl)benzylidene)indolin-2-one (5). To an oven-dried 10
mL Schlenk tube, (E)-3-(4-bromobenzylidene)indolin-2-one (4j, 1.0 mmol), palladium(II)
acetate (2 mol %), BINAP (4 mol %), cesium carbonate (2 mmol), and toluene (1 mL) were
added under N2 atmosphere. Afterwards, piperazine hydrochloride (1.2 mmol) was added to the
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001300
European Journal of Organic Chemistry
reaction mixture in small portions over a period of 30 minutes with constant stirring. The tube
was immersed in silicon oil bath placed over magnetic stirrer and heated at 110 °C for 10 h. The
reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with
brine. The organic layer was dried over anhydrous Na2SO4, filtered and the solvent was
evaporated under reduced pressure. The residue was purified on silica gel column using
dichloromethane and methanol (CH2Cl2:MeOH = 8:2) as eluents to afford the compound 5 as
1
yellow solid. Yield: 60%; mp 188-189 °C; H NMR (400 MHz, Acetone-d6): δ 7.63-7.57 (m,
1H), 7.54-7.47 (m, 1H), 7.21-7.12 (m, 2H), 7.06-6.93 (m, 2H), 6.86-6.74 (m, 1H), 6.65 (d, J =
8.0 Hz, 1H), 6.58 (d, J = 8.0 Hz, 1H), 2.67-2.64 (m, 4H), 2.16 (br s, 2H), 1.99-1.94 (m, 4H); 13C
NMR (100 MHz, Acetone-d6): δ 178.3, 140.6, 131.5, 131.2, 128.9, 128.5, 125.2, 122.2, 122.0,
120.9, 120.8, 110.1, 109.9, 46.8, 46.1; HRMS (ESI) m/z calcd for C19H19N3O [M + H]+:
306.1601, found 306.1605.
Preparation of (E)-3-[4-(1-formylpiperazin-4-yl)benzylidenyl]indolin-2-one (6).
To a solution of 15 mL dimethylformamide in 10 mL of anhydrous 1,2-dichloroethane was
added dropwise 15 mL of phosphorusoxychloride at 0 °C under N2 atmosphere. The reaction
mixture was stirred at room temperature for 30 minutes and then cooled in an ice bath. (E)-3-(4-
(Piperazin-1-yl)benzylidene)indolin-2-one (5, 1 mmol) was added to the above solution
portionwise over a period of 15 minutes, and the reaction mixture was stirred at 30 °C for 3h.
The reaction mixture was poured into ice-cold 1N NaOH solution and stirred for 1 h. The
organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The
combined organic layer was washed with brine until pH = 7, dried over anhydrous sodium
sulfate, and evaporated under reduced pressure. The residue was purified on a silica gel column
eluting with a mixture of hexane and ethyl acetate (hexane:EtOAc = 8:2) to afford the product 6
1
as yellow solid. Yield: 52%; mp 176-177 °C; H NMR (400 MHz, CDCl3): δ 7.99 (s, 1H), 7.80
(s, 1H), 7.64-7.59 (m, 2H), 7.46-7.39 (m, 3H), 7.18-7.14 (m, 1H), 6.90 (d, J = 7.6 Hz, 1H), 6.82
(t, J = 7.6 Hz, 1H), 2.98-2.89 (m, 4H), 2.45 (br s, 1H), 2.27-2.26 (m, 4H); 13C NMR (100 MHz,
CDCl3): δ 170.7, 162.6, 142.0, 137.2, 134.7, 129.8, 129.5, 129.3, 129.2, 128.5, 127.8, 122.8,
121.6, 110.4, 46.2, 44.8; HRMS (ESI) m/z calcd for C20H19N3O2 [M + H]+: 334.1550, found
334.1556.
(E)-3-(3,4,5-Trimethoxybenzylidene)-5-methoxyindolin-2-one (9). Following the general
procedure reported above for the synthesis of compounds 3 and 4, 5-methoxyindolin-2-one (7, 1
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001300
European Journal of Organic Chemistry
mmol), 3,4,5-trimethoxybenzylamine (8, 1.2 mmol) and iron(II) bromide (5 mol %) were
employed in the reaction to furnish the title compound 9 as orangish-red solid. Yield: 84%; mp
210-211 °C; 1H NMR (400 MHz, DMSO-d6): 10.43 (br s, 1H), 7.57 (s, 1H), 7.25 (d, J = 2.4 Hz,
1H), 7.05 (s, 2H), 6.86 (dd, J = 8.4, 2.4 Hz, 1H) 6.80 (d, J = 8.4 Hz, 1H), 3.81 (s, 6H), 3.74 (s,
13
3H), 3.63 (s, 3H); C NMR (100 MHz, DMSO-d6): δ 168.9, 154.2, 152.9, 138.8, 136.8, 136.6,
129.8, 127.4, 121.9, 115.2, 110.6, 109.3, 107.0, 60.3, 56.1, 55.5; HRMS (ESI) m/z calcd for
C19H19NO5 [M + H]+: 342.1336, found 342.1339.
Preparation of N-benzylidenebenzylamine (10). Benzylamine (2a, 1.2 mmol) and iron(II)
bromide (5 mol %) were added into an oven-dried 10 mL Schlenk tube equipped with oxygen
balloon. The tube was immersed in silicon oil bath placed over magnetic stirrer and heated at 100
°C with constant stirring for 5h. The reaction mixture cooled to room temperature, adsorbed on
basic alumina and purified by column chromatography (basic alumina, hexane–EtOAc) to afford
1
the compound 10 (96% yield) as pale yellow oil. Yield: 96%; H NMR (400 MHz, CDCl3): δ
8.42 (s, 1H), 7.83-7.81 (m, 2H), 7.45-7.44 (m, 3H), 7.39-7.37 (m, 4H), 7.32-7.28 (m, 1H), 4.86
13
(s, 2H); C NMR (100 MHz, CDCl3): δ 161.9, 139.2, 136.1, 130.7, 128.5, 128.4, 128.2, 127.9,
126.9, 64.9; HRMS (ESI) m/z calcd for C14H13N [M + H]+: 196.1126, found 196.1123.
Preparation of 3-[(benzylamino)(phenyl)methyl]indolin-2-one (11). Oxindole (1a, 1 mmol),
N-benzylidenebenzylamine (10, 1.2 mmol) and iron(II) bromide (5 mol %) were added into an
oven-dried 10 mL Schlenk tube equipped with oxygen balloon. The tube was immersed in
silicon oil bath placed over magnetic stirrer and heated at 70 °C with constant stirring for 6
hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and
washed with water. The organic layer was dried over anhydrous Na2SO4, filtered and the solvent
was evaporated under reduced pressure. The residue was purified by column chromatography
using hexane and ethyl acetate (hexane:EtOAc = 3:1) eluents to afford the compound 11 as
creamy colour solid. Yield: 43%; mp 211-212 °C; 1H NMR (400 MHz, DMSO-d6): δ 10.22 (br
s, 1H), 6.96-6.77 (m, 8H), 6.64 (d, J = 7.6 Hz, 2H), 6.55 (dd, J = 7.6, 2.8 Hz, 2H), 6.46-6.38 (m,
2H), 4.57 (d, J = 11.2 Hz, 1H), 4.28 (d, J= 8.4 Hz, 2H), 3.42-3.38 (m, 1H), 3.13 (t, J = 8.4 Hz,
13
1H); C NMR (100 MHz, DMSO-d6): δ 177.8, 142.9, 129.5, 129.4, 128.6, 128.3, 128.1, 128.0,
127.9, 127.6, 127.5, 127.4, 125.6, 121.2, 109.5, 55.0, 48.0, 46.7; HRMS (ESI) m/z calcd for
C22H20N2O [M + H]+: 329.1648, found 329.1650.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001300
European Journal of Organic Chemistry
Acknowledgments
The authors sincerely thank Council of Scientific & Industrial Research (CSIR), New Delhi
(Grant 02(0332)/18/EMR-II) for the financial support. The authors are also grateful to CIF,
University of Delhi, for providing NMR, HRMS, and Single Crystal X-ray data. One of the
authors (AT) thanks UGC, New Delhi, for a research fellowship. The authors thank Dr. K.
Mahiya for providing assistance in solving the X-ray structures.
References
[1] a) A. Nagarsenkar, S. K. Prajapti, S. D. Guggilapu, S. Birineni, S. S. Kotapalli, R. Ummanni,
B. N. Babu, Med. Chem. Commun. 2016, 7, 646–653; b) L. Sun, N. Tran, F. Tang, H. App,
P. Hirth, G. McMahon, C. Tang, J. Med. Chem. 1998, 41, 2588-2603; c) A. Andreani, S.
Burnelli, M. Granaiola, A. Leoni, A. Locatelli, R. Morigi, M. Rambaldi, L. Varoli, M. W.
Kunkel, J. Med. Chem. 2006, 49, 6922-6924; d) A. Khan, A. Khan, U. Farooq, M. Taha, S.
A. A. Shah, S. A. Halim, A. Akram, M. Z. Khan, A. K. Jan, A. Al-Harrasi, Med. Chem. Res.
2019, 28, 900–906; e) E. Rizzi, G. Cassinelli, S. Dallavalle, C. Lanzi, R. Cincinelli, R.
Nannei, G. Cuccuru, F. Zunino, Bioorg. Med. Chem. Lett. 2007, 17, 3962–3968; f) C. L.
Sun, J. G. Christensen, G. McMahon, Kinase Inhibitor Drugs; R. Li, J. A. Stafford, Eds.;
John Wiley & Sons: New Jersey, 2009, pp.1-39; g) M. Vieth, D. J. Cummins, J. Med. Chem.
2000, 43, 3020-3032.
[2] a) B. M. Trost, N. Cramer, H. Bernsmann, J. Am. Chem. Soc. 2007, 129, 3086-3087; b) S.
Lin, Z.-Q. Yang, B. H. B. Kwok, M. Koldoskiy, C. M. Crews, S. J. Danishefsky, J. Am.
Chem. Soc. 2004, 126, 6347-6355; c) T. Fukuyama, G. Liu, J. Am. Chem. Soc. 1996, 118,
7426-7427.
[3] a) K. Ding, Y. Lu, Z. Nikolovska-Coleska, S. Qiu, Y. Ding, W. Gao, J. Stuckey, K.
Krajewski, P. P. Roller, Y. Tomita, D. A. Parrish, J. R. Deschamps, S. Wang, J. Am. Chem.
Soc. 2005, 127, 10130-10131; b) P. R. Sebahar, R. M. Williams, J. Am. Chem. Soc. 2000,
122, 5666-5667; c) D. Ma, Q. Wu, Tetrahedron Lett. 2000, 41, 9089-9092.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001300
European Journal of Organic Chemistry
[4] a) H. J. Lee, J. W. Lim, J. Yu, J. N. Kim, Tetrahedron Lett. 2014, 55, 1183–1187; b) T.-M.
Yang, G. Liu, J. Comb. Chem. 2007, 9, 86-95; c) H. Asahara, T. Kida, T. Hinoue, M.
Akashi, Tetrahedron 2013, 69, 9428-9433.
[5] J. Lubkoll, A. Millemaggi, A. Perry, R. J. K. Taylor, Tetrahedron 2010, 66, 6606-6612.
[6] For palladium-catalyzed cyclization reactions of 2-(alkynyl)aryl isocyanates with terminal
alkynes, see: a) S. Kamijo, Y. Sasaki, C. Kanazawa, T. Schüβeler, Y. Yamamoto, Angew.
Chem. Int. Ed. 2005, 44, 7718-7721; For palladium or rhodium-catalyzed cyclization
reactions of 2-(alkynyl)aryl isocyanates with organoboronic acids, see: b) T. Miura, T.
Toyoshima, Y. Takahashi, M. Murakami, Org. Lett. 2008, 10, 4887-4889; c) T. Miura, Y.
Takahashi, M. Murakami, Org. Lett. 2007, 9, 5075-5077.
[7] a) B. Miao, Y. Zheng, P. Wu, S. Li, S. Ma, Adv. Synth. Catal. 2017, 359, 1691-1707; b) J. H.
Park, E. Kim, Y. K. Chung, Org. Lett. 2008, 10, 4719-4721; c) S. Tang, Q.-F. Yu, P. Peng,
J.-H. Li, P. Zhong, R.-Y. Tang, Org. Lett. 2007, 9, 3413-3416.
[8] a) A. Pinto, L. Neuville, P. Retailleau, J. Zhu, Org. Lett. 2006, 8, 4927-4930; b) A. Pinto, L.
Neuville, J. Zhu, Angew. Chem. Int. Ed. 2007, 46, 3291-3295.
[9] a) S. Tang, P. Peng, Z.-Q. Wang, B.-X. Tang, C.-L. Deng, J.-H. Li, P. Zhong, N.-X. Wang,
Org. Lett. 2008, 10, 1875-1878; b) S. Tang, P. Peng, P. Zhong, J.-H. Li, J. Org. Chem. 2008,
73, 5476-5480; c) S. Tang, P. Peng, S.-F. Pi, Y. Liang, N.-X. Wang, J.-H. Li, Org. Lett.
2008, 10, 1179-1182; d) D.-J. Tang, B.-X. Tang, J.-H. Li, J. Org. Chem. 2009, 74, 6749-
6755; e) P. Peng, B.-X. Tang, S.-F. Pi, Y. Liang, J.-H. Li, J. Org. Chem. 2009, 74, 3569-
3572; f) T.-S. Jiang, R.-Y. Tang, X.-G. Zhang, X.-H. Li, J.-H. Li, J. Org. Chem. 2009, 74,
8834-8837; g) R.-J. Song, Y. Liu, R.-J. Li, J.-H. Li, Tetrahedron Lett. 2009, 50, 3912-3916.
[10] S. Ueda, T. Okada, H. Nagasawa, Chem. Commun. 2010, 46, 2462-2464.
[11] For recent reviews on iron-catalyzed/mediated C-H bond transformations, see: a) R. Shang,
L. Ilies, E. Nakamura, Chem. Rev. 2017, 117, 9086-9139; b) I. Bauer, H.-J. Knölker, Chem.
Rev. 2015, 115, 3170-3387; c) F. Jia, Z. Li, Org. Chem. Front. 2014, 1, 194-214; d) K.
Gopalaiah, Chem. Rev. 2013, 113, 3248-3296; For representative examples on iron-
catalyzed C-H bond oxidative functionalization, see: b) J. Lou, Q. Wang, K. Wu, P. Wu, Z.
Yu, Org. Lett. 2017, 19, 3287-3290; c) B. D. Barve, Y.-C. Wu, M. El-Shazly, M. Korinek,
Y.-B. Cheng, J.-J. Wang, F.-R. Chang, Org. Lett. 2014, 16, 1912-1915; d) K. Li, G. Tan, J.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001300
European Journal of Organic Chemistry
Huang, F. Song, J. You, Angew. Chem. Int. Ed. 2013, 52, 12942-12945; e) N. Takasu, K.
Oisaki, M. Kanai, Org. Lett. 2013, 15, 1918-1921.
[12] a) K. Gopalaiah, S. N. Chandrudu, A. Devi, Synthesis 2015, 47, 1766-1774; b) K.
Gopalaiah, A. Saini, A. Devi, Org. Biomol. Chem. 2017, 15, 5781-5789; c) K. Gopalaiah, D.
C. Rao, K. Mahiya, A. Tiwari, Asian J. Org. Chem. 2018, 7, 1872-1881; d) K. Gopalaiah, A.
Tiwari, R. Choudhary, K. Mahiya, ChemistrySelect 2019, 4, 5200-5205; e) K. Gopalaiah, S.
N. Chandrudu, RSC Adv. 2015, 5, 5015-5023; f) K. Gopalaiah, A. Saini, Catal. Lett. 2016,
146, 1648-1654.
[13] a) R. F. Fritsche, G. Theumer, O. Kataeva, H.-J. Knölker, Angew. Chem. Int. Ed. 2017, 56,
549-553; b) M. O. Ratnikov, X. Xu, M. P. Doyle, J. Am. Chem. Soc. 2013, 135, 9475-9479;
c) T. Shen, Y. Yuan, S. Song, N. Jiao, Chem. Commun. 2014, 50, 4115-4118; d) J. Y.
Hwang, A. Y. Ji, S. H. Lee, E. J. Kang, Org. Lett. 2020, 22, 16-21; e) N. Yoshikai, A.
Matsumoto, J. Norinder, E. Nakamura, Synlett 2010, 313-316; f) T. Jin, Z. Tang, J. Hu, H.
Yuan, Y. Chen, C. Li, X. Jia, J. Li, Org. Lett. 2018, 20, 413−416; g) P. Thapa, P. M.
Palacios, T. Tran, B. S. Pierce, F. W. Foss Jr, J. Org. Chem. 2020, 85, 1991-2009.
[14] Crystallographic data for compound 3a are available free of charge from the Cambridge
Crystallographic Data Centre, accession number CCDC 2026460.
[15] Crystallographic data for compound 4a are available free of charge from the Cambridge
Crystallographic Data Centre, accession number CCDC 2026477.
[16] M. L. Go, H. K. Ho, X. Chen, US Pat. Appl. US 20130035364 A1, 2013.
[17] S. Dong, T. Wang, C. Hu, X. Chen, Y. Jin, Z. Wang, Arch. Pharm. Chem. Life Sci. 2017,
349, e1600274.
[18] Â. Monteiro, L. M. Gonçalves, M. M. M. Santos, Eur. J. Med. Chem. 2014, 79, 266-272.
[19] P. Singh, H. Kaur, H. Singh, ACS Omega 2018, 3, 8003-8008.
[20] W. Zhang, M.-L. Go, Bioorg. Med. Chem. 2009, 17, 2077.
[21] P. Gholamzadeh, G. M. Ziarani, A. Badiei, Z. Bahrami, Eur. J. Chem. 2012, 3, 279.
[22] D. Villemin, B. Martin, Synth. Commun. 1998, 28, 3201.
[23] Y. Hu, H. Kang, B.-W. Zeng, H. Huang, P. Wei, Heterocycl. Commun. 2008, 14, 263.
This article is protected by copyright. All rights reserved.