Synthesis of (E)-oxindolylidene acetate using tandem palladium-catalyzed Heck and alkoxycarbonylation reactions

Article abstract of DOI:10.1039/c5ob01863c

Tandem reactions use consecutive reaction steps to efficiently synthesize compounds of high molecular complexity. This paper presents a tandem Pd-catalyzed Heck and alkoxycarbonylation reaction for the stereoselective synthesis of (E)-oxindolylidene acetates. The mechanism underlying the Pd-catalyzed tandem reaction involves the syn-carbopalladation of ynamides followed by alkoxycarbonylation with CO and alcohol. This method makes it possible to obtain the desired (E)-configuration of oxindolylidene acetates exclusively. We evaluated the scope of the reaction by applying optimal reaction conditions to the facile synthesis of a library of (E)-oxindolylidene acetates. The resulting (E)-oxindolylidene acetates exhibited potent anticancer activities against a variety of human cancer cell lines. The anticancer activities of some (E)-oxindolylidene acetates were even superior to those of known CDK inhibitors indirubin-3′-oxime and roscovitine.

Full text of DOI:10.1039/c5ob01863c

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Organic & Biomolecular Chemistry
Synthesis of (E)-Oxindolylidene Acetate using One-pot Tandem Palladium-Catalyzed
Heck and Alkoxycarbonylation Reactions
th
Dear Editor,
September 7 , 2015
We are pleased to submit our manuscript entitled “Synthesis of
(E)-Oxindolylidene Acetate using One-pot Tandem Palladium-Catalyzed Heck and
Alkoxycarbonylation Reactions” as an original article for publication. The content of
this manuscript has not been published and is not currently submitted for publication
elsewhere. This manuscript described the development of one-pot tandem
Pd-catalyzed Heck and alkoxycarbonylation reactions for the production of the new
anticancer agents based on (E)-oxindolylidene acetates. The optimal reaction
conditions and scope of the reactions were also established. These (E)-oxindolylidene
acetates exhibit potent anticancer activities against human cancer cells. We believe
this work will provide the valuable synthetic methods, structure-activity relationships,
and bioactivity results to discover potential anticancer agents. Your kind
consideration for publication would be greatly appreciated.
Sincerely,
Wen-Tai Li, Ph.D.
National Research Institute of Chinese Medicine
Ministry of Health and Welfare
1
55-1, Sec. 2, Linong St., Beitou Distrct,
Taipei 11221, Taiwan, ROC
Phone: +886 2 2820 1999 ext. 8261
Fax: +886 2 2825 0743
E-mail: wtli@nricm.edu.tw

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Organic & Biomolecular Chemistry
Synthesis of (E)-Oxindolylidene Acetate using Tandem Palladium-Catalyzed Heck and
Alkoxycarbonylation Reactions
th
Dear Editor:
October 28 , 2015
Thank you very much for giving us the opportunity to revise our paper, entitled “Synthesis of
E)-Oxindolylidene Acetate using Tandem Palladium-Catalyzed Heck and Alkoxycarbonylation
(
Reactions”, which was initially submitted for publication in the journal Organic & Biomolecular
th
Chemistry on September 7 , 2015.
We have completed the required revisions, closely following the suggestions of the editor and
reviewers. The attached files describe these revisions in detail. We believe that we have fulfilled all
of the requirements for re-submission of our manuscript; however, if you find that any details have
been overlooked, or if you need any further information, please do not hesitate to contact us.
We look forward to your positive response.
Yours sincerely,
Sincerely,
Wen-Tai Li, Ph.D.
National Research Institute of Chinese Medicine
Ministry of Health and Welfare
1
55-1, Sec. 2, Linong St., Beitou Distrct,
Taipei 11221, Taiwan, ROC
Phone: +886 2 2820 1999 ext. 8261
Fax: +886 2 2825 0743
E-mail: wtli@nricm.edu.tw

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Organic & Biomolecular Chemistry
Synthesis of (E)-Oxindolylidene Acetate using Tandem Palladium-Catalyzed Heck and
Alkoxycarbonylation Reactions
Thank you for your useful comments regarding our manuscript. We have revised the manuscript
according to your suggestions, and detailed corrections are listed below point by point:
Referee: #1:
(1) The authors used “one-pot” reaction in the manuscript, but this reviewer does not think it is
appropriate here.
ꢀ
In accordance with your suggestion, we have deleted the term “one-pot” in the revised
manuscript.
(
2) Can this reaction be scale up to gram scale?
We did not scale the reaction up to grams, but we believe that it would be possible to do so.
ꢀ
(3) It better to put the H NMR and C13 NMR of each compound together.
1
13
ꢀ
In accordance with this suggestion, we have reported the H NMR and C NMR of each
compound together in the Supporting Information.
(4) The following references about palladium-catalyzed Heck-type alkoxycarbonylation reaction
should be cited.
1
2
3
)Tetrahedron Letters, 1992, 33, 7789-7792.
)JACS, 1985, 107, 8289.
)JACS, 1996, 118, 5919.
ꢀ
We have added the above references to the revised manuscript in accordance with the
reviewer’s suggestion.
Referee: #2:
(
1) The yield of the optimized reaction is 71% yield (table 1), which still leaves room for
improvement. Have you tried using CsF as the base? CsF was identified as the optimal base for
a similar process in the report by Takemoto and coworkers (J. Org. Chem. 2005, 70, 6972).

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ꢀ
We did try using CsF as the base when carrying out the reactions. The resulting yield was
4%, similar to KF. This result has been added to Table 1.
6
(2) Also, have you tried other monodendate phosphine ligands? PCy , P(p-FC H ) etc.
3 6 4
ꢀ
We did try reacting other monodendate phosphine ligands of PCy ; however, the reaction
3
yield was poor.
(
3) How many equivalent of PPh was employed in the optimization table? This information seems
3
to be lost in the paper.
ꢀ
The reaction was performed using the equivalent of 0.2 PPh . We have added this
3
information to the revised manuscript.
(
4) There are limited examples of various R3 substituents in the substrate table. Please explore the
effect of the substitution R3 in the aryl ring, which would affect the oxidative addition of Pd(0)
to the aryl-iodide; both electronic and steric effects should be considered.
ꢀ
For the revised manuscript, we investigated an additional electron withdrawing substituent
of CF in the aryl ring, which resulted in a yield of 45%.
3
(
5) Does this reaction tolerate di-substituted alkynes besides terminal alkynes? It would give rise to
tetrasubstituted oxindolylidene products, which will provide more varieties in the product
library.
ꢀ
We attempted to use a phenyl substituent as the terminal alkynyl, but the reaction provided
better results when an H substituent was used as the terminal alkynyl. We found a lot of
starting materials recovered under the same reaction condition of ynamide with phenyl
substituent at terminal alkynyl.
Other comments:
(
6) Table 2, missing PPh in the reaction conditions. Please also indicate the equivalent of PPh .
3
3
ꢀ
The reaction was performed using the equivalent of 0.2 PPh . This information has been
3
added to Table 2 in the revised manuscript.
(
7) Also, there is no description of PPh in the general procedures of preparing 3a in the SI.
3

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ꢀ
This information is now included in the revised manuscript.
(
8) Misspelling: “…as the core structure of a biologically active compound include sunitinib and
hesperidin…” "hesperidin" should be "hesperadin". Hesperidin and hesperadin are two different
compounds and only hesperadin has the ylideneoxindole moiety (see J Cell Biol 2003;161:281.).
ꢀ
We have corrected the spelling of hesperadin in the revised manuscript.
(9) In the SI, please report all the characterization date of N-substituted propiolamides starting
materials those are not reported in the literature.
ꢀ
We have reported the N-substituted propiolamides starting materials in the SI.
10) Also, compound 1a is missing HRMS.
We have added HRMS information for compound 1a in the spectra data.
Referee: #3:
(
ꢀ
(1) All reactions presented were performed with substrates having terminal alkynyl moieties. Would
not the method work with substituted alkynyl groups?
ꢀ
We attempted to use a phenyl substituent as the terminal alkynyl, but the reaction provided
better results when an H substituent was used as the terminal alkynyl. We found a lot of
starting materials recovered under the same reaction condition of ynamide with phenyl
substituent at terminal alkynyl.
(2) The solvent volume and concentration of methanol should be added to the Table 1.
ꢀ
In accordance with the reviewer’s suggestion, we have described reaction conditions such
as solvent volume and methanol concentration in Table 1 of the revised manuscript.
(3) The article needs a careful edition for typos and grammatical errors.
ꢀ
We have carefully revised the entire manuscript, ensuring that there are no grammar or
syntax errors. We believe that the language is now acceptable for publication in an English
language journal.

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Synthesis
of
(E)-Oxindolylidene
Acetate
using
Tandem
Palladium-Catalyzed Heck and Alkoxycarbonylation Reactions
a
Wei-Jen Lin, Kak-Shan Shia, Jen-Shin Song, Ming-Hsien Wu and Wen-Tai Li*
b
b
b
a
a
National Research Institute of Chinese Medicine, Ministry of Health and Welfare
Taipei 11221, Taiwan
b
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes
Miaoli 35053, Taiwan
*
Correspondence to:
Wen-Tai Li, Ph.D.
National Research Institute of Chinese Medicine, Ministry of Health and Welfare
1
55-1, Sec. 2, Linong St., Beitou Distrct,
Taipei 11221, Taiwan, ROC
Tel: +886 2 2820 1999 ext. 8261;
Fax: +886 2 2825 0743;
E-mail: wtli@nricm.edu.tw

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Abstract
Tandem reactions use consecutive reaction steps to efficiently synthesize compounds of high
molecular complexity. This paper presents a tandem Pd-catalyzed Heck and alkoxycarbonylation
reaction for the stereoselective synthesis of (E)-oxindolylidene acetates. The mechanism underlying
the Pd-catalyzed tandem reaction involves the syn-carbopalladation of ynamides followed by
alkoxycarbonylation with CO and alcohol. This method makes it possible to obtain the desired
(E)-configuration of oxindolylidene acetates exclusively. We evaluated the scope of the reaction by
applying optimal reaction conditions to the facile synthesis of a library of (E)-oxindolylidene acetates.
The resulting (E)-oxindolylidene acetates exhibited potent anticancer activities against a variety of
human cancer cell lines. The anticancer activities of some (E)-oxindolylidene acetates were even
superior to those of known CDK inhibitors indirubin-3’-oxime and roscovitine.
Keywords: (E)-oxindolylidene acetate, Heck and alkoxycarbonylation reactions, anticancer activity.

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Introduction
The 3-ylideneoxindole moiety presents a skeleton of pharmacologically important compounds,
1
which appear as the core structure in a variety of bioactive molecules exhibiting potent antifungal,
2
3
anticancer, and antiviral activities. For example, 3-ylideneoxindole is the core structure in
biologically active compounds such as sunitinib and hesperadin, which possess the capacity to bind
4
-6
receptor tyrosine kinase (RTK) and Aurora B with high affinity. 3-Ylideneoxindole also exists in a
7
number of natural indole alkaloids (including neolaugerine, costinone A, and costinine B ) which
8
possess a variety of biological properties.
Tandem reactions are a series of consecutive reactions that provide a highly efficient means of
9
assembling compounds. The molecular complexity and diversity that can be created using this facile
approach is suitable for combinatorial library synthesis as it is able to produce a large number of
10
compounds using a minimum number of steps.
The synthesis of 3-ylideneoxindole moiety has attracted considerable interest among researchers,
and impressive advances have already been made in which 3-alkylideneoxindole was used as an
1
1
important intermediate such as TMC-95A. The stereoselective synthesis of various substituted
3
-alkylideneoxindoles from a series of ynamides and boronic acids by way of palladium-catalyzed
12
Heck-Suzuki-Miyaura domino reactions has also been reported. The domino reaction, which further
expands the utility of ynamides, has been applied in the preparation of natural, biologically active
products.
Oxindolylidene acetate is commonly used as a synthetic target due to its interesting biological
13
activity. Previous successes involving the use of metal-catalyzed tandem reactions led us to
consider whether Pd-catalyzed tandem Heck and alkoxycarbonylation reactions of ynamides with
carbon monoxide (CO) and alcohols in a single pot could be used to produce oxindolylidene acetate.
In the following, we report a concise method for the stereoselective synthesis of (E)-oxindolylidene
acetates using the tandem Pd-catalyzed Heck and alkoxycarbonylation reactions of N-substituted

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propiolamides. The resulting (E)-oxindolylidene acetates exhibited potent anticancer activities
against a variety of human cancer cell lines.
Results and Discussion
Tandem Pd-catalyzed Heck and alkoxycarbonylation reactions were combined to develop an
efficient stereocontrolled method for the synthesis of (E)-oxindolylidene acetates using CO and
alcohols in one pot (Chart 1). Tandem Pd-catalyzed Heck-Suzuki-Miyaura domino reactions have
12
previously been used to synthesize 3-alkylideneoxindoles; however, this is the first study to report
on the use of tandem metal-catalyzed reactions in the synthesis of oxindolylidene acetates from
ynamides. At the outset of our investigation, N-(2-iodophenyl)-N-(4-nitrobenzyl)propiolamide (1a)
was selected as the model compound for the evaluation of tandem reactions. We initially evaluated
the reaction of N-(2-iodophenyl)-N-(4-nitrobenzyl)propiolamide (1a) and methanol (3 equiv.) under
CO at atmospheric pressure at elevated temperatures. The reaction was conducted in the presence of
14
triphenylphosphine (0.5 equiv.) in THF, and Pd(OAc)
E)-oxindolylidene acetate (3a) was obtained at a yield of 23% wherein only the (E)-configuration
was found (Table 1, entry 1).
2
was used as a catalyst. The desired
(
Notably, additives and phosphine ligands were shown to play important roles in the
Pd-catalyzed tandem reaction. In fact, the addition of KF increased the yield from 23% to 66%
(Table 1, entry 4); therefore, we subsequently turned our attention to the evaluation of various
additives with the aim of further improving reaction yields (Table 1, entries 2-6). A number of
carbonates, such as potassium carbonate and cesium carbonate, were used as additives; however, the
resulting yields were lower than the yield achieved using KF (Table 1, entries 2-4). Conversely, using
potassium fluoride, cesium fluoride, or potassium iodide as additives resulted in better yields of
(E)-oxindolylidene acetate (Table 1, entries 4-6). Phosphine ligands were also shown to exert a
strong effect on the yield of the Pd-catalyzed tandem reaction, as the reaction without the phosphine
ligand resulted in poor yield (Table 1, entry 7), and reactions with bulky bidentate ligands (dppp and

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dppe) or monodentate phosphine ligands (PPh
2 3
Me and PCy ), provided only slightly better yields
than reactions without the addition of ligands (Table 1, entries 8-12). As shown in Table 1, PPh
3
proved to be a more effective ligand for this reaction and others. A variety of palladium catalysts
were subsequently used to evaluate the stereoselective synthesis of (E)-oxindolylidene acetate under
CO at atmospheric pressure at elevated temperatures. The palladium catalysts Pd(OAc) and
2
2
Pd(dppf)Cl proved efficient for this tandem reaction; however, other palladium catalysts produced
lower yields (Table 1, entries 4, 13-16).
We further evaluated how a variety of solvents affected this Pd-catalyzed tandem reaction.
Among these, methanol and THF provided the best results. In addition, trace quantities of
N-substituted dimethyl 2-(2-oxoindolin-3-ylidene)malonate was also observed in this reactions,
perhaps due to the presence of trace quantities of oxygen, which may have caused the oxidative
15
alkoxycarbonylation of the terminal alkyne in the first step.
After establishing the optimal reaction conditions, we investigated a series of N-substituted
propiolamides 1 with various primary, secondary, and aryl alcohols in order to determine the scope of
the reaction (Table 2). Alkoxycarbonylation is sensitive to the steric features of alcohols, and we
observed that when N-substituted propiolamides 1 and various primary aliphatic alcohols, such as
methanol, ethanol, and n-butanol underwent Pd-catalyzed tandem Heck and alkoxycarbonylation
reactions the yield was good. Conversely, isopropanol, phenol, and benzyl alcohols were unreactive
(Table 2, entries 34-36). In addition, The Pd-catalyzed tandem Heck-alkoxycarbonylation reactions
1
revealed excellent functional group tolerance with benzyl substituents at R bearing electron
withdrawing groups at the phenyl ring, such as nitro, methyl ester, trifluoromethyl and cyano
resulting in a smooth reaction, resulting in corresponding oxindolylidene acetates 3a, 3f, 3g, 3h in
1
good yields. Benzyl and p-methoxybenzyl in R position were also well tolerated in the reaction,
thereby producing corresponding oxindolylidene acetates 3m and 3b in yields of 64% and 67%,
1
respectively. In addition, substitution at R position with isoxazolylmethyl ring, methyl and H, the

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products 3n, 3t and 3u were obtained exclusively in fair yield. Finally, the reaction conditions were
found to be favorable when functional groups 5-methyl, 5-methoxyl, and 5-chloride were substituted
3
at R (Table 2, entries 17, 18, 27, and 28), such that the resulting reactions respectively produced
corresponding oxindolylidene acetates 3q, 3r, 4e and 4f in good yields.
One plausible mechanism for the formation of compounds 3-5 is presented in Scheme 1. The
formation of the products may initially have followed the Heck reaction mechanism, which involves
the syn-carbopalladation of ynamide with a palladium catalyst to form the intermediate A. The
resulting products 3-5 were obtained following alkoxycarbonylation of intermediate A treated with
CO and alcohols. This mechanism involves a syn migratory insertion of the alkyne into the Ar–Pd
bond, followed by the alkoxycarbonylation of CO and alcohols, leading to the only (E)-configuration
of oxindolylidene acetate.
All of the synthesized (E)-oxindolylidene acetates 3-5 obtained via tandem Pd-catalyzed
reactions were evaluated for anticancer activities using human NCI-H460 lung cancer cells. We then
studied the structure-activity relationships (SARs) in compounds containing various substitutions in
the (E)-oxindolylidene acetate scaffold. Specifically, we examined the antiproliferative effects of
1
2
various R and R groups on oxindolylidene acetates. Compounds 3d, 3h, and 5b, containing
1
para-substituents on the phenyl ring of the R group, presented slightly better anticancer activity than
did compounds 3i, 3j, 3l, and 5a, which contained meta- and ortho-substituents on the phenyl ring of
oxindolylidene acetates. Interestingly, compound 3n, containing an isoxazolyl ring, was found to
1
decrease anticancer activity to below that of compounds with a phenyl ring at R . In our evaluation of
2
the anticancer activities of methyl, ethyl, and n-butyl groups at R , the activity of the methyl group
2
was found to be superior to that of ethyl and n-butyl groups, and the order of activity of R groups
against NCI-H460 cancer cells can be described as methyl > ethyl > n-butyl in most examples.
3
However, substitutions at R did not have significant effects on anticancer activity.

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Further evaluation of anticancer activities was conducted on selected active (E)-oxindolylidene
acetates using six different cancer cell lines: human lung adenocarcinoma cell CL 1-5, human
epidermoid carcinoma KB, human gastric cancer MKN-45, human breast adenocarcinoma MCF-7,
human pancreatic carcinoma MIA Paca-2, and human central nervous system cancer SF-268 (Table
4
). Most of the 3-ylideneoxindole acetamides exhibited a broad spectrum of anticancer activity
against human cancer cells, with effects even more pronounced than those associated with
well-known anticancer drug candidates indirubin-3’-oxime and roscovitine.
In summary, this study developed tandem Pd-catalyzed Heck and alkoxycarbonylation reactions
for the production of the new anticancer agents based on (E)-oxindolylidene acetates. This
stereoselective reaction proceeds through the key steps of syn-carbopalladation and
alkoxycarbonylation in the presence of CO and alcohols, resulting in only the (E)-configuration of
oxindolylidene acetates. We also established the optimal conditions and scope of the reactions. The
resulting (E)-oxindolylidene acetates exhibit potent anticancer activity against a variety of human
cancer cells.
Experimental section
General procedure for synthesis of N-(2-iodophenyl)-N-(4-nitrobenzyl) propiolamide (1a).
N-(2-Iodophenyl)propiolamide was synthesized with slightly modifications according to the
1
reported method. To a solution of N-(2-iodophenyl)propiolamide (400 mg, 1.48 mmol) in DMF (20
6
3
mL) was added NaHCO (248 mg, 2.95 mmol) portionwise. The mixture was stirred at 0 ℃ for 30
min and 4-nitrobenzyl chloride (329 mg, 1.92 mmol) was added dropwise. The reaction mixture was
heated to reflux for 6 h until complete by TLC. The reaction was quenched by addition of water and
extracted with ethyl acetate. The combined organic layers were washed with brine solution, dried

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4
over MgSO and concentrated in vacuo. The residue was purified by flash column chromatography
furnished the desired N-(2-iodophenyl)-N-(4-nitrobenzyl)propiolamide 1a (463 mg, 77 %) as a
yellow solid (two rotamers at a ratio of 7:1). Mp = 145-147 ℃. IR (KBr) νmax: 3210, 2106, 1646,
-
1 1
1
7
7
4
1
1
520, 1345, 1310 cm . H NMR (600 MHz, CDCl
3
) major/minor δ: 8.13/8.16 (d, J = 8.4 Hz, 2H),
.93/7.89 (dd, J = 7.9, 1.2 Hz, 1H), 7.40/7.42 (d, J = 8.4 Hz, 2H), 7.25/7.21 (dt, J = 7.8, 1.2 Hz, 1H),
.08/7.01 (dt, J = 7.8, 1.2 Hz, 1H), 6.81/6.71 (dd, J = 7.8, 1.2 Hz, 1H), 5.56/5.58 (d, J = 15.0, 1H),
13
.24/4.70 (d, J = 15.0 Hz, 1H), 2.78/3.35 (s, 1H). C NMR (150 MHz, CDCl
3
) major/minor δ:
53.3/152.6, 147.6/147.8, 143.0/142.7, 142.5/141.0, 140.3/140.3, 130.9/129.8, 130.7/129.6,
30.3/130.2, 129.2/129.3, 123.8/123.9, 100.0/98.1, 80.1/80.7, 75.6/75.8, 50.8/54.4. HRMS calcd for
+
(M+1) 406.9893, found 406.9894.
C
16
H12IN
2
O
3
General procedure for synthesis of (E)-methyl 2-(1-(4-nitrobenzyl)-2-oxoindolin-3
-ylidene)acetate (3a).
N-(2-Iodophenyl)-N-(4-nitrobenzyl)propiolamide 1a (200 mg, 0.49 mmol) in CH OH (10 mL)
3
was added Pd(OAc) (11 mg, 0.05 mmol), PPh (26 mg, 0.10 mmol) and potassium fluoride (85 mg,
2
3
1
.47 mmol) in a 25-mL round flask. The flask was evacuated under vacuum and back-filled with
carbon monoxide from a balloon. The cycle was repeated three times and vessel left open to a
dynamic atmosphere of CO. The mixture was then heated to 60 ℃ under vigorous stirring until
complete by TLC. Then the mixture was filtered and concentrated in vacuo. The residue dissolved in
EtOAc and then washed with water. The water phase was extracted with EtOAc (10 mL) twice. The
organic layers were combined, dried over MgSO and concentrated. The crude mixture was purified
4

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by flash column chromatography to afford the title compound 3a (118 mg, 71%) as a yellowish solid.
-1 1
Mp = 172-174 ℃. IR (KBr) νmax: 3415, 1700, 1602, 1515, 1468, 1342, 1214 cm . H NMR (600
MHz, CDCl
) δ: 8.58 (d, J = 7.8 Hz, 1H), 8.17 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.26 (t, J
7.2 Hz, 1H), 7.07 (t, J = 7.8 Hz, 1H), 6.98 (s, 1H), 6.59 (d, J = 8.4 Hz, 1H), 5.02 (s, 2H), 3.88 (s,
3
=
1
H). C NMR (150 MHz, CDCl
3
3
1
3
3
) δ: 167.7, 165.9, 147.6, 144.4, 142.8, 137.4, 132.6, 129.2, 128.0,
+
(M) 338.0882, found
24.2, 123.4, 122.9, 120.0, 108.7, 52.3, 43.3. HRMS calcd for C18
38.0892.
H
14
N
2
O
5
(E)-Methyl 2-(1-(4-methoxybenzyl)-2-oxoindolin-3-ylidene)acetate (3b). Yield: 67%. Orange
-1 1
solid. Mp = 94-96 ℃. IR (KBr) ν max: 2949, 2921, 1711, 1602, 1511, 1464, 1337, 1199 cm . H
NMR (500 MHz, CDCl
) δ: 8.53 (d, J = 8.0 Hz, 1H), 7.26-7.21 (m, 3H), 7.00 (dt, J = 8.0, 1.0 Hz,
H), 6.95 (s, 1H), 6.83-6.80 (m, 2H), 6.69 (d, J = 8.0, 1H), 4.85 (s, 2H), 3.86 (s, 3H), 3.75 (s, 3H).
3
1
1
3
C NMR (125 MHz, CDCl
3
) δ: 167.6, 166.1, 159.1, 145.2, 138.0, 132.4, 128.8, 128.6, 127.4, 122.8,
+
(M) 323.1151, found
1
22.1, 119.9, 114.2, 109.1, 55.2, 52.1, 43.3. HRMS calcd for C19
23.1154.
H
17NO
4
3
(E)-Methyl 2-(1-(4-fluorobenzyl)-2-oxoindolin-3-ylidene)acetate (3c). Yield: 60%. Yellow
-1 1
solid. Mp = 113-115 ℃. IR (KBr) νmax: 3411, 1704, 1606, 1504, 1464, 1344, 1214 cm . H NMR
(600 MHz, CDCl
3
) δ: 8.54 (d, J = 7.8 Hz, 1H), 7.26-7.23 (m, 3H), 7.01 (t, J = 7.8 Hz, 1H), 6.98-6.94
1
m, 3H), 6.65 (d, J = 7.8 Hz, 1H), 4.86 (s, 2H), 3.85 (s, 3H). C NMR (150 MHz, CDCl
3
(
3
) δ: 167.5,
1
65.9, 162.2 (d, JC-F = 245.0 Hz), 144.8, 137.7, 132.4, 131.1 (d, JC-F = 2.9 Hz), 128.9 (d, JC-F = 8.1
4
3
1

Organic & Biomolecular Chemistry
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2
Hz), 128.8, 122.9, 122.2, 120.0, 115.7 (d, JC-F = 21.3 Hz), 108.9, 52.1, 43.1. HRMS calcd for
+
(M) 311.0946, found 311.0952.
C
18
H14FNO
3
(E)-Methyl 2-(1-(4-chlorobenzyl)-2-oxoindolin-3-ylidene)acetate (3d). Yield: 68%. Yellow
-1 1
solid. Mp = 135-137 ℃. IR (KBr) νmax: 3415, 2957, 1700, 1606, 1464, 1344, 1217 cm . H NMR
(600 MHz, CDCl
3
) δ: 8.56 (d, J = 7.8 Hz, 1H), 7.28-7.23 (m, 3H), 7.21 (d, J = 8.4 Hz, 2H), 7.03 (dt,
13
J = 7.8, 1.2 Hz, 1H), 6.96 (s, 1H), 6.64 (d, J = 7.8 Hz, 1H), 4.88 (s, 2H), 3.87 (s, 3H). C NMR (150
MHz, CDCl
3
) δ: 167.6, 166.0, 144.8, 137.8, 133.9, 133.7, 132.5, 129.0, 129.0, 128.6, 123.1, 122.4,
+
(M) 327.0658, found 327.0660.
119.9, 108.9, 52.2, 43.2. HRMS calcd for C18
H14ClNO
3
(E)-Methyl 2-(1-(4-bromobenzyl)-2-oxoindolin-3-ylidene)acetate (3e). Yield: 64%. Brown
-1 1
solid. Mp = 133-135 ℃. IR (KBr) νmax: 2924, 2844, 1708, 1646, 1606, 1464, 1352, 1203 cm . H
NMR (600 MHz, CDCl
) δ: 8.57 (d, J = 6.0 Hz, 1H), 7.60 (d, J = 6.5 Hz, 2H), 7.38 (d, J = 6.5 Hz,
H), 7.26 (dt, J = 7.0, 1.0 Hz, 1H), 7.05 (dt, J = 6.5, 1.0 Hz, 1H), 6.97 (s, 1H), 6.58 (d, J = 6.5 Hz,
3
2
1
1
1
H), 4.97 (s, 2H), 3.87 (s, 3H). C NMR (CDCl
3
3
) δ: 167.7, 165.9, 144.4, 140.8, 137.4, 132.7, 132.5,
29.1, 127.8, 123.4, 122.8, 120.0, 118.4, 111.8, 108.7, 52.3, 43.5. HRMS calcd for C18H14BrNO
3
+
M) 371.0135, found 371.0146.
(
(E)-Methyl 4-((3-(2-methoxy-2-oxoethylidene)-2-oxoindolin-1-yl)methyl) benzoate (3f).
Yield: 74%. Yellow solid. Mp = 127-129 ℃. IR (KBr) νmax: 2861, 2224, 1712, 1607, 1469, 1367,
-
1 1
1
340, 1214 cm . H NMR (500 MHz, CDCl
3
) δ: 8.56 (d, J = 6.5 Hz, 1H), 7.96 (d, J = 6.5 Hz, 1H),
7
.33 (d, J = 6.5 Hz, 2H), 7.24 (m, 1H), 7.03 (dt, J = 6.0, 0.5 Hz, 1H), 6.97 (s, 1H), 6.61 (d, J = 6.0 Hz,

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1
3
1
1
H), 4.97 (s, 2H), 3.87 (s, 6H). C NMR (125 MHz, CDCl
3
) δ: 167.7, 166.6, 160.0, 144.7, 140.5,
37.7, 132.5, 130.2, 129.7, 128.9, 127.1, 123.1, 122.5, 119.9, 114.0, 109.0, 52.2, 43.6. HRMS calcd
+
(M) 351.1093, found 351.1100.
for C20
H
17NO
5
(E)-Methyl 2-(2-oxo-1-(4-(trifluoromethyl)benzyl)indolin-3-ylidene)acetate (3g). Yield: 70%.
Orange solid. Mp = 134-136 ℃. IR (KBr) νmax: 3415, 2917, 1715, 1606, 1352, 1326, 1203, 1119
-
1 1
cm . H NMR (500 MHz, CDCl
3
) δ: 8.57 (d, J = 6.5 Hz, 1H), 7.56 (d, J = 6.5 Hz, 2H), 7.38 (d, J =
7
6
1
.0 Hz, 2H), 7.26 (dt, J = 6.5, 1.0 Hz, 1H), 7.04 (dt, J = 6.5, 1.0 Hz, 1H), 6.97 (s, 1H), 6.62 (d, J =
1
3
.5 Hz, 1H), 4.97 (s, 2H), 3.87 (s, 3H). C NMR (125 MHz, CDCl
3
) δ: 167.7, 165.8, 144.6, 139.5,
2
37.6, 132.5, 130.1 (q, JC-F = 26.9 Hz), 129.0, 127.5, 125.8 (q, JC-F = 2.9 Hz), 123.9 (q, JC-F = 225.6
3
1
+
(M) 361.0939, found
Hz), 123.2, 122.6, 119.9, 108.9, 52.2, 43.4. HRMS calcd for C19
H
14
3
F NO
3
3
61.0932.
(E)-Methyl 2-(1-(4-cyanobenzyl)-2-oxoindolin-3-ylidene)acetate (3h). Yield: 66%. Orange
-1 1
solid. Mp = 192-194 ℃. IR (KBr) νmax: 3400, 2950, 2223, 1697, 1602, 1468, 1344, 1217 cm . H
NMR (500 MHz, CDCl
) δ: 8.57 (d, J = 6.0 Hz, 1H), 7.60 (d, J = 6.5 Hz, 2H), 7.38 (d, J = 6.5 Hz,
H), 7.26 (dt, J = 7.0, 1.0 Hz, 1H), 7.05 (dt, J = 6.5, 1.0 Hz, 1H), 6.97 (s, 1H), 6.58 (d, J = 6.5 Hz,
3
2
1
1
1
3
H), 4.97 (s, 2H), 3.87 (s, 3H). C NMR (125 MHz, CDCl
3
) δ: 167.7, 165.9, 144.4, 140.8, 137.4,
32.7, 132.5, 129.1, 127.8, 123.4, 122.8, 120.0, 118.4, 111.8, 108.7, 52.3, 43.5. HRMS calcd for
+
(M) 318.1024, found 318.1014.
C
19
H
14
N
2
O
3
(E)-Methyl 2-(1-(3-cyanobenzyl)-2-oxoindolin-3-ylidene)acetate (3i). Yield: 51%. Yellow

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-1 1
solid. Mp = 95-97 ℃. IR (KBr) νmax: 2861, 2224, 1712, 1607, 1469, 1367, 1340, 1214 cm . H
NMR (600 MHz, CDCl
) δ: 8.55 (d, J = 7.8 Hz, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.25 (dt, J = 7.8, 1.2
Hz, 1H), 7.24 (s, 1H), 7.15 (d, J = 9.0 Hz, 2H), 7.03 (dt, J = 7.8, 1.2 Hz, 1H), 6.96 (s, 1H), 6.63 (d, J
3
1
3
=
7.8 Hz, 1H), 4.86 (s, 2H), 3.87m (s, 3H). C NMR (150 MHz, CDCl
3
) δ: 167.6, 166.0, 144.8,
1
37.7, 134.4, 132.5, 132.0, 128.9, 123.1, 122.4, 121.7, 120.0, 109.0, 52.2, 43.3. HRMS calcd for
+
(M) 318.1018, found 318.1011.
C
19
H
14
N
2
O
3
(E)-Methyl 2-(1-(3-chlorobenzyl)-2-oxoindolin-3-ylidene)acetate (3j). Yield: 58%. Yellow
-1 1
solid. Mp = 84-86 ℃. IR (KBr) νmax: 2943, 1711, 1602, 1468, 1337, 1214 cm . H NMR (500
MHz, CDCl
3
) δ: 8.56 (d, J = 6.5 Hz, 1H), 7.27-7.24 (m, 3H), 7.15 (t, J = 3.5 Hz, 1H), 7.03 (dt, J =
1
3
6
.5, 0.5 Hz, 1H), 6.96 (s, 1H), 6.64 (d, J = 6.5 Hz, 1H), 4.87 (s, 2H), 3.86 (s, 3H). C NMR (125
MHz, CDCl
3
) δ: 167.5, 165.9, 144.7, 137.6, 137.4, 134.7, 132.5, 130.1, 128.9, 128.0, 127.2, 125.3,
+
(M) 327.0675, found
1
23.0, 122.4, 119.8, 108.9, 52.2, 43.2. HRMS calcd for C18
H
14ClNO
3
3
27.0669.
(E)-Methyl 2-(1-(naphthalen-2-ylmethyl)-2-oxoindolin-3-ylidene)acetate (3k). Yield: 59%.
-1
1
Orange solid. IR (KBr) νmax: 2943, 1711, 1602, 1468, 1337, 1214 cm . H NMR (500 MHz,
CDCl
) δ: 8.55 (d, J = 6.5 Hz, 1H), 7.79-7.75 (m, 3H), 7.71 (s, 1H), 7.47-7.42 (m, 3H), 7.38 (dd, J =
.5, 1.5 Hz), 7.20 (dt, J = 6.5, 1.0 Hz, 1H), 7.02-6.99 (m, 2H), 670 (d, J = 6.5 Hz, 1H), 5.08 (s, 2H),
3
6
3
1
1
.88 (s, 3H). C NMR (125 MHz, CDCl
3
3
) δ: 167.3, 166.1, 145.1, 138.0, 133.3, 132.8, 132.8, 132.5,
28.8, 128.8, 127.7, 127.7, 126.4, 126.1, 126.0, 125.1, 122.9, 122.3, 119.9, 113.9, 109.3, 52.2, 44.1.

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+
(M) 343.1208, found 343.1214
HRMS calcd for C22
H17NO
3
(E)-Methyl 2-(1-(2-chlorobenzyl)-2-oxoindolin-3-ylidene)acetate (3l). Yield: 57%. Yellow
-1 1
solid. Mp = 106-109 ℃. IR (KBr) νmax: 2371, 1715, 1599, 1472, 1348, 1196 cm . H NMR (500
MHz, CDCl
) δ: 8.57 (d, J = 7.0 Hz, 1H), 7.38 (dd, J = 8.1, 1.0 Hz, 1H), 7.25 (dt, J = 8.0, 1.0 Hz,
H), 7.20 (dt, J = 7.5, 1.0 Hz, 1H), 7.14 (dt, J = 8.0, 1.5 Hz, 1H), 7.08-7.03 (m, 2H), 6.98 (s, 1H),
3
1
6
1
1
3
.63 (d, J = 7.5Hz, 1H), 5.04 (s, 2H), 3.87 (3H). C NMR (125 MHz, CDCl
3
) δ: 167.8, 166.0, 144.8,
37.8, 132.8, 132.6, 132.6, 129.7, 128.9, 128.8, 127.8, 127.2, 123.1, 122.4, 119.9, 109.1, 52.2, 41.3.
+
Cl (M) 327.0664, found 327.0663.
HRMS calcd for C18
H14NO
3
(E)-Methyl 2-(1-benzyl-2-oxoindolin-3-ylidene)acetate (3m). Yield: 64%. Yellow solid. Mp =
-
1
1
1
18-120 ℃. IR (KBr) νmax: 2917, 1711, 1602, 1468, 1344, 1195 cm . H NMR (500 MHz,
CDCl
3
) δ: 8.54 (dt, J = 7.5, 0.5 Hz, 1H), 7.32-7.22 (m, 6H), 7.01 (dt, J = 8.0, 1.0 Hz, 1H), 6.96 (s,
1
3
1
1
H), 6.67 (d, J = 8.0 Hz, 1H). C NMR (125 MHz, CDCl
3
) δ: 167.6, 166.1, 145.1, 137.9, 135.4,
32.4, 128.8, 128.8, 127.7, 127.2, 122.9, 122.2, 119.9, 109.2, 52.2, 43.9. HRMS calcd for C18H15NO
3
+
M) 293.1048, found 293.1050.
(
(E)-Methyl 2-(1-((3-methylisoxazol-5-yl)methyl)-2-oxoindolin-3-ylidene)acetate (3n). Yield:
-
1 1
5
5%. Yellow solid. Mp = 131-134 ℃. IR (KBr) νmax: 2957, 1720, 1613, 1470, 1356, 1208 cm . H
NMR (600 MHz, CDCl
3
) δ: 8.55 (d, J = 7.8 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 7.07 (t, J = 7.8 Hz, 1H),
1
.92 (s, 1H), 6.85 (d, J = 7.8 Hz, 1H), 6.00 (s, 1H), 4.96 (s, 2H), 3.86 (s, 3H), 2.22 (s, 3H). C NMR
3
6
(150 MHz, CDCl
3
) δ: 167.2, 166.0, 165.8, 160.1, 144.1, 137.3, 132.7, 129.0, 123.4, 122.6, 119.8,

Organic & Biomolecular Chemistry
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DOI: 10.1039/C5OB01863C
+
(M) 298.0959, found 298.0956.
1
08.7, 103.6, 52.2, 35.6, 11.3. HRMS calcd for C16
H
14
N
2
O
4
(E)-Methyl 2-(1-(2,6-dichlorobenzyl)-2-oxoindolin-3-ylidene)acetate (3o). Yield: 59%.
Orange solid. Mp = 143-145 ℃. IR (KBr) νmax: 3077, 2943, 1711, 1602, 1472, 1435, 1348, 1199
-
1 1
cm . H NMR (500 MHz, CDCl
3
) δ: 8.52 (d, J = 6.5 Hz, 1H), 7.30 (d, J = 7.0 Hz, 2H), 7.27 (d, J =
7
5
1
.0 Hz, 1H), 7.19-7.13 (m, 3H), 6.97 (dt, J = 6.0, 1.0 Hz, 1H), 6.91 (s, 1H), 6.61 (d, J = 6.5 Hz, 1H),
1
.19 (s, 2H), 3.84 (s, 3H). C NMR (125 MHz, CDCl
3
3
) δ: 167.2, 166.0, 144.7, 137.6, 136.2, 132.4,
13 3
30.0, 129.8, 128.9, 128.7, 122.6, 122.1, 120.0, 109.1, 52.1, 40.1. HRMS calcd for C18H Cl2NO
+
M) 361.0254, found 361.0263.
(
(E)-Methyl 2-(2-oxo-1-(3,4,5-trimethoxybenzyl)indolin-3-ylidene)acetate (3p). Yield: 68%.
-1 1
Yellow solid. Mp = 145-148 ℃. IR (KBr) νmax: 2943, 2839, 1700, 1595, 1469, 1355, 1204 cm . H
NMR (600 MHz, CDCl
3
) δ: 8.55 (d, J = 7.8 Hz, 1H), 7.27 (t, J = 7.8 Hz, 1H), 7.03 (t, J = 7.8 Hz, 2H),
1
.60 (s, 1H), 6.71 (d, J = 7.8 Hz, 1H), 6.49 (s, 2H), 4.84 (s, 2H), 3.87 (s, 3H), 3.78 (s, 6H). C NMR
3
6
(
150 MHz, CDCl
3
) δ: 167.7, 166.0, 153.5, 145.2, 137.9, 137.5, 132.5, 131.1, 128.8, 123.0, 122.3,
+
(M) 383.1369, found
119.9, 109.2, 104.3, 60.8, 56.2, 52.2, 44.2. HRMS calcd for C21
H21NO
6
3
83.1375.
(E)-Methyl 2-(1-(4-chlorobenzyl)-5-methyl-2-oxoindolin-3-ylidene)acetate (3q). Yield: 67%.
-1 1
Yellow solid. Mp = 109-111 ℃. IR (KBr) νmax: 2917, 2845, 1712, 1487, 1352, 1205 cm . H NMR
(
600 MHz, CDCl
3
) δ: 8.342 (s, 1H), 7.25 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.05 (d, J =
1
.8 Hz, 1H), 6.93 (s, 1H), 6.51 (d, J = 7.8 Hz, 1H), 4.85 (s, 2H), 3.87 (s, 3H), 2.30 (s, 3H). C NMR
3
7

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(
150 MHz, CDCl
3
) δ: 167.6, 166.1, 142.6, 138.1, 134.1, 133.6, 132.9, 132.6, 129.5, 129.0, 128.6,
+
(M) 341.0798, found 341.0808.
1
22.0, 119.9, 108.7, 52.2, 43.2, 21.1. HRMS calcd for C19
H16ClNO
3
(E)-Methyl 2-(1-(4-chlorobenzyl)-5-methoxy-2-oxoindolin-3-ylidene)acetate (3r). Yield:
6
1
7
2
1
4%. Yellow solid. Mp = 169-171 ℃. IR (KBr) νmax: 2987, 2947, 1700, 1642, 1591, 1486, 1337,
-
1 1
239, 1199 cm . H NMR (500 MHz, CDCl
3
) δ: 8.27 (d, J = 2.5 Hz, 1H), 7.25 (d, J = 8.5 Hz, 2H),
.19 (d, J = 8.5 Hz, 2H), 6.95 (s, 1H), 6.80 (dd, J = 8.5, 3.0 Hz, 1H), 6.51 (d, J = 8.5 Hz, 1H), 4.84 (s,
1
3
H), 3.86 (s, 3H), 3.78 (s, 3H). C NMR (125 MHz, CDCl
3
) δ: 167.5, 165.9, 155.9, 138.6, 138.3,
34.0, 134.0, 129.0, 128.6, 122.5, 120.6, 118.4, 114.7, 109.4, 55.8, 52.2, 43.3. HRMS calcd for
+
(M) 357.0774, found 357.0771.
C
19
H16ClNO
4
(E)-Methyl 2-(1-((6-bromobenzo[d][1,3]dioxol-5-yl)methyl)-2-oxoindolin-3- ylidene)acetate
(3s). Yield: 54%. Orange solid. Mp = 203-205 ℃. IR (KBr) νmax: 3427, 2824, 1701, 1603, 1473,
-
1 1
1
353, 1201 cm . H NMR (600 MHz, CDCl
3
) δ: 8.56 (dd, J = 7.8, 0.6 Hz, 1H), 7.27 (dt, J = 7.8, 0.6
Hz, 1H), 7.05 (dt, J = 7.8, 0.6 Hz, 1H), 7.01 (s, 1H), 6.97 (s, 1H), 6.66 (d, J = 7.8 Hz, 1H), 6.55 (s,
1
3
1
1
H), 5.90 (s, 2H), 4.93 (s, 2H), 3.88 (s, 3H). C NMR (150 MHz, CDCl
3
) δ: 167.8, 166.0, 148.0,
44.7, 137.8, 132.7, 128.9, 127.3, 123.2, 122.5, 119.9, 113.1, 112.8, 109.3, 107.8, 101.9, 52.2, 43.7.
+
EIMS: 415.26 (M) .
(E)-Methyl 2-(1-methyl-2-oxoindolin-3-ylidene)acetate (3t). Yield: 61%. Yellow solid. Mp =
-
1 1
1
29-131 ℃. IR (KBr) νmax: 2947, 1711, 1602, 1464, 1435, 1344, 1206 cm . H NMR (600 MHz,
CDCl
3
) δ: 8.58 (d, J = 1.8 Hz, 1H), 7.34 (dt, J =7.8, 0.6 Hz, 1H), 7.04 (t, J = 1.2 Hz, 1H), 7.02 (d, J =

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1
3
0
1
.6 Hz, 1H), 6.82 (dd, J = 7.8, 1.2 Hz, 1H), 3.84 (s, 3H), 3.20 (s, 3H). C NMR (150 MHz, CDCl
3
) δ:
67.4, 166.1, 146.0, 138.1, 132.5, 128.7, 122.8, 121.8, 119.7, 108.1, 52.1, 26.2. HRMS calcd for
+
(M) 217.0722, found 217.0730.
C
12
H11NO
3
(E)-Methyl 2-(2-oxoindolin-3-ylidene)acetate (3u). Yield: 51%. Yellow solid. Mp = 171-173
-
1 1
℃
. IR (KBr) νmax: 3190, 2917, 1719, 1610, 1464, 1344, 1210 cm . H NMR (500 MHz, CDCl
3
) δ:
8
6
1
2
.51 (d, J = 7.5 Hz, 2H), 7.29 (dt, J = 8.1, 1.0 Hz, 1H), 7.02 (dt, J = 8.1, 1.0 Hz, 1H), 6.85 (s, 1H),
1
3
.84 (d, J = 9.0 Hz, 1H), 3.86 (s, 3H). C NMR (125 MHz, CDCl
3
) δ: 169.1, 166.0, 143.4, 138.4,
+
(M) 203.0601, found
32.6, 129.0, 122.9, 122.0, 120.3, 110.1, 52.2. HRMS calcd for C11
03.0592.
9
H NO
3
(E)-Methyl 2-(1-(4-nitrobenzyl)-2-oxo-5-(trifluoromethyl)indolin-3-ylidene) acetate (3v).
Yield: 45%. Orange solid. Mp = 178-180 ℃. IR (KBr) νmax: 3486, 1720, 1618, 1526, 1383, 1210,
-
1 1
1
108 cm . H NMR (600 MHz, CDCl
3
) δ: 8.94 (s, 1H), 8.18 (dd, J = 9.0, 1.8 Hz, 2H), 7.55 (d, J =
7
.8 Hz, 1H), 7.43 (d, J = 9.0 Hz, 2H), 7.07 (s, 1H), 6.70 (d, J = 8.4 Hz, 1H), 5.06 (s, 2H), 3.91 (s, 3H).
1
3
3
C NMR (150 MHz, CDCl
3
) δ: 167.5, 165.5, 147.8, 146.7, 142.1, 136.1, 129.7 (q, JC-F = 3.5 Hz),
3
2
28.0, 126.4 (q, JC-F = 3.9 Hz), 125.9 (q, JC-F = 32.9 Hz), 125.0, 124.3, 123.9 (q, JC-F = 270.2 Hz),
1
1
1
+
(M) 406.0777, found 406.0773.
20.2, 108.6, 52.6, 43.4. HRMS calcd for C19
H
13
F
3
N
O
2 5
(E)-Ethyl 2-(1-(4-nitrobenzyl)-2-oxoindolin-3-ylidene)acetate (4a). Yield: 62%. Orange solid.
-1 1
Mp = 149-152 ℃. IR (KBr) νmax: 3440, 2924, 2854, 1706, 1608, 1467, 1342, 1202 cm . H NMR
(600 MHz, CDCl
3
) δ: 8.58 (d, J = 7.8 Hz, 1H), 8.16 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H),

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7
5
1
1
.26 (dt, J = 7.8, 1.2 Hz, 1H), 7.05 (dt, J = 7.8, 1.2 Hz, 1H), 6.97 (s, 1H), 6.59 (d, J = 7.8 Hz, 1H),
1
.01 (s, 2H), 4.33 (q, J = 7.2 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H). C NMR (150 MHz, CDCl
3
3
) δ: 167.7,
65.4, 147.6, 144.3, 142.8, 137.1, 132.4, 129.1, 127.9, 124.1, 123.4, 123.6, 120.0, 108.6, 61.3, 43.2,
+
(M) 352.1060, found 352.1059.
4.2. HRMS calcd for C19
H
16
N
2
O
5
(E)-Ethyl 2-(1-(4-chlorobenzyl)-2-oxoindolin-3-ylidene)acetate (4b). Yield: 59%. Yellow
-1 1
solid. Mp = 75-77 ℃. IR (KBr) νmax: 2923, 1709, 1604, 1346, 1199 cm . H NMR (600 MHz,
CDCl
) δ: 8.55 (d, J = 7.8 Hz, 1H), 7.27 (d, J = 7.8 Hz, 2H), 7.27-7.23 (m, 1H), 7.21 (d, J = 7.8 Hz,
H), 7.02 (t, J = 7.8 Hz, 1H), 6.95 (s, 1H), 6.63 (d, J = 7.8 Hz, 1H), 4.88 (s, 2H), 4.32 (q, J = 7.2 Hz,
3
2
2
1
1
3
H), 1.36 (t, J = 7.2 Hz, 3H). C NMR (150 MHz, CDCl
3
) δ: 167.7, 165.6, 144.7, 137.4, 134.0,
33.6, 132.4, 129.0, 128.9, 128.6, 123.0, 120.0, 108.9, 61.3, 43.2, 14.2. HRMS calcd for
+
(M) 341.0803, found 341.0811.
C
19
H16ClNO
3
(E)-Ethyl 2-(1-(4-bromobenzyl)-2-oxoindolin-3-ylidene)acetate (4c). Yield: 57%. Brown
-1 1
solid. Mp = 107-110 ℃. IR (KBr) νmax: 2988, 1712, 1605, 1359, 1203 cm . H NMR (600 MHz,
CDCl
) δ: 8.55 (d, J = 7.8 Hz, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.25 (t, J = 7.8 Hz, 1H), 7.14 (d, J = 7.8
Hz, 1H), 7.03 (t, J = 7.8 Hz, 1H), 6.95 (s, H), 6.62 (d, J = 7.8 Hz, 1H), 4.86 (s, 2H), 4.32 (q, J = 7.2
3
1
3
Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H). C NMR (150 MHz, CDCl
3
) δ: 167.7, 165.6, 144.7, 137.4, 134.5,
1
32.4, 132.0, 128.9, 128.9, 123.1, 121.7, 120.0, 108.9, 61.3, 43.3, 14.2. HRMS calcd for
+
C
19 3
H16BrNO (M) 385.0314, found 385.0319.
(E)-Ethyl 2-(2-oxo-1-(3,4,5-trimethoxybenzyl)indolin-3-ylidene)acetate (4d). Yield: 64%.

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-1 1
Yellow solid. Mp = 168-173 ℃. IR (KBr) νmax: 2996, 1700, 1593, 1356, 1195 cm . H NMR (600
MHz, CDCl
) δ: 8.55 (d, J = 7.8 Hz, 1H), 7.27 (t, J = 7.8 Hz, 1H), 7.03 (t, J = 7.8 Hz, 1H), 6.96 (s,
H), 6.72 (d, J = 7.8 Hz, 1H), 6.47 (s, 2H), 4.84 (s, 2H), 4.32 (q, J = 7.2 Hz, 2H), 3.79 (s, 3H), 1.36 (t,
3
1
1
3
J = 7.2 Hz, 3H). C NMR (150 MHz, CDCl
3
) δ: 167.7, 165.6, 153.5, 145.1, 137.6, 137.5, 132.4,
1
31.2, 128.8, 123.0, 122.9, 120.0, 109.2, 104.3, 61.3, 60.8, 56.2, 44.2, 14.2. HRMS calcd for
+
C
22 6
H23NO (M) 397.1526, found 397.1533.
(E)-Ethyl 2-(5-chloro-1-(4-chlorobenzyl)-2-oxoindolin-3-ylidene)acetate (4e). Yield: 55%.
-1 1
Yellow solid. Mp = 136-139 ℃. IR (KBr) νmax: 2990, 1717, 1606, 1348, 1212 cm . H NMR (600
MHz, CDCl
) δ: 8.59 (d, J = 1.8 Hz, 1H), 7.26 (d, J = 8.4 Hz, 2H), 7.22 (dd, J = 8.4, 1.8 Hz, 1H),
.17 (d, J = 8.4 Hz, 1H), 6.99 (s, 1H), 6.55 (d, J = 8.4 Hz, 1H), 4.87 (s, 2H), 4.33 (q, J = 7.2 Hz, 2H),
3
7
1
1
1
3
.37 (t, J = 7.2 Hz, 3H). C NMR (150 MHz, CDCl
3
) δ: 167.2, 165.2, 143.1, 136.6, 133.8, 133.5,
2 3
32.0, 129.1, 129.0, 128.6, 124.5, 121.2, 109.8, 61.5, 43.3, 14.2. HRMS calcd for C19H15Cl NO
+
M) 376.0507, found 376.0480.
(
(E)-Ethyl 2-(1-(4-chlorobenzyl)-5-methoxy-2-oxoindolin-3-ylidene)acetate (4f). Yield: 61%.
-1 1
Yellow solid. Mp = 144-149 ℃. IR (KBr) νmax: 2982, 1704, 1652, 1488, 1196 cm . H NMR (600
MHz, CDCl
) δ: 8.26 (d, J = 2.4 Hz, 1H), 7.25 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 6.95 (s,
H), 6.79 (dd, J = 8.4, 2.4 Hz, 1H), 6.51 (d, J = 8.4 Hz, 1H), 4.85 (s, 2H), 4.32 (q, J = 7.2 Hz, 2H),
3
1
3
1
1
.78 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H). C NMR (150 MHz, CDCl
3
3
) δ: 167.6, 165.5, 155.9, 138.5,
38.0, 134.0, 133.6, 129.0, 128.6, 123.2, 120.7, 118.2, 114.7, 109.4, 61.3, 55.9, 43.3, 14.2. HRMS

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+
4
calcd for C20H18ClNO (M) 371.0925, found 371.0932.
(E)-Ethyl 2-(1-methyl-2-oxoindolin-3-ylidene)acetate (4g). Yield: 58%. Yellow solid. Mp =
-
1 1
7
8-81 ℃. IR (KBr) νmax: 2985, 1712, 1608, 1367, 1196 cm . H NMR (600 MHz, CDCl
3
) δ: 8.53
(d, J = 7.8 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.04 (dt, J = 7.8, 0.6 Hz, 1H), 6.89 (s, 1H), 6.77 (d, J =
1
3
7
.8 Hz, 1H), 4.30 (q, J = 7.2 Hz, 2H), 3.21 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H). C NMR (150 MHz,
CDCl
3
) δ: 167.6, 165.7, 145.9, 137.9, 132.4, 128.7, 122.8, 122.5, 119.8, 108.1, 61.2, 26.2, 14.2.
+
(M) 231.0896, found 231.0896.
HRMS calcd for C14
H11NO
3
(E)-Butyl 2-(1-(3-cyanobenzyl)-2-oxoindolin-3-ylidene)acetate (5a). Yield: 57%. Orange
-1 1
solid. Mp = 134-138 ℃. IR (KBr) νmax: 2957, 1717, 1606, 1468, 1344, 1207 cm . H NMR (600
MHz, CDCl
) δ: 8.58 (d, J = 7.8 Hz, 1H), 7.57-7.55 (m, 1H), 7.53-7.51 (m, 1H), 7.43 (t, J = 7.8 Hz,
H), 7.27 (t, J = 7.8 Hz, 1H), 7.06 (t, J = 7.8 Hz, 1H), 7.00 (s, 1H), 6.62 (d, J = 7.8 Hz, 1H), 4.94 (s,
3
1
1
3
2
H), 4.27 (t, J = 7.2 Hz, 2H), 1.73-1.69 (m, 2H), 1.45-1.41 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H). C
NMR (150 MHz, CDCl
3
) δ: 167.8, 165.6, 144.3, 137.2, 137.1, 132.4, 131.6, 131.6, 130.7, 129.8,
1
29.2, 123.5, 123.4, 120.0, 118.4, 113.1, 108.6, 65.2, 43.1, 30.6, 19.1, 13.7. HRMS calcd for
+
C
22 20 2 3
H N O (M) 360.1474, found 360.1472.
(E)-Butyl 2-(1-(4-cyanobenzyl)-2-oxoindolin-3-ylidene)acetate (5b). Yield: 53%. Orange
-1 1
solid. Mp = 129-134 ℃. IR (KBr) νmax: 2959, 1703, 1607, 1345, 1199 cm . H NMR (600 MHz,
CDCl
) δ: 8.58 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.26 (t, J = 7.8
Hz, 1H), 7.06 (t, J = 7.8 Hz, 1H), 6.97 (s, 1H), 6.58 (d, J = 7.8 Hz, 1H), 4.97 (s, 2H), 4.27 (t, J = 6.6
3

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13
Hz, 2H), 1.73-1.68 (m, 2H), 1.45-1.41 (m, 2H), 0.95 (t, J = 6.6 Hz, 3H). C NMR (150 MHz,
CDCl
3
) δ: 167.8, 165.6, 144.3, 140.9, 137.1, 132.7, 132.4, 129.1, 127.8, 123.4, 123.3, 120.0, 118.4,
+
(M) 360.1474, found
111.8, 108.7, 65.2, 43.4, 30.6, 19.1, 13.7. HRMS calcd for C22
H
20
2
N O
3
3
60.1478.
(E)-Butyl 2-(1-(4-nitrobenzyl)-2-oxoindolin-3-ylidene)acetate (5c). Yield: 55%. Orange solid.
-1
1
Mp = 110-115 ℃. IR (KBr) νmax: 2954, 1709, 1608, 1342, 1204 cm . H NMR (600 MHz,
CDCl
3
) δ: 8.56 (d, J = 8.4 Hz, 1H), 7.37 (dt, J =7.8, 7.2 Hz, 1H), 7.09 (t, J = 7.8 Hz,1 H), 7.00 (d, J =
1
3
7
.8 Hz, 1H), 6.90 (s, 1H), 4.51 (d, J = 1.8 Hz, 2H), 3.85 (s, 3H), 2.26 (s, J = 1.8 Hz, 1H). C NMR
(150 MHz, CDCl
3
) δ: 166.6, 165.9, 144.0, 137.6, 132.5, 128.9, 123.2, 122.4, 120.0, 109.1, 76.5, 72.5,
+
(M) 380.1372, found 380.1347.
5
2.2, 29.3. HRMS calcd for C21
H
20
N
2
O
5
(E)-Ethyl 2-(2-oxoindolin-3-ylidene)acetate (4h). Yield: 58%. Yellow solid. Mp = 260-264 ℃.
-
1 1
IR (KBr) νmax: 3188, 1718, 1612, 1463, 1323, 1200 cm . H NMR (600 MHz, CDCl
3
) δ: 8.52 (d, J
=
7.2 Hz, 1H), 8.36 (br, 1H), 7.30 (dt, J = 7.8, 1.2 Hz, 1H), 7.03 (dt, J = 7.8, 1.2 Hz, 1H), 6.86 (s, 1H),
1
.83 (d, J = 7.8 Hz, 1H), 4.32 (q, J = 7.2 Hz, 2H), 1.35 (t, J = 7.2 Hz, 3H). C NMR (150 MHz,
3
6
CDCl
3
) δ: 169.1, 165.6, 143.2, 138.0, 132.5, 129.1, 122.9, 122.7, 120.4, 110.1, 61.2, 14.2. EIMS:
+
+
2
3
17.0 (M) . HRMS calcd for C12H11NO (M) 217.0739, found 217.0749.
Cancer cell growth inhibition assay
Human cancer cell lines, included human lung adenocarcinoma cell CL 1-5, human epidermoid
carcinoma KB, human gastric cancer MKN-45, human breast adenocarcinoma MCF-7, Human

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pancreatic carcinoma MIA Paca-2 and human central nervous system cancer SF-268, were seeded in
9
2
6-well plates and incubated for 24 h at 37 ℃ in a 5% CO incubator. Test compounds were
dissolved in dimethylsulfoxide (DMSO) and diluted for cell treatment in culture medium containing
DMSO at the final concentration of 0.5%. Cells were treated with test compounds of various
concentrations in triplicates per concentration in the culture medium and incubated at 37 ℃ for 72 h.
Actinomycin D of 10 nM and 0.3% DMSO were used as the positive and vehicle controls,
respectively. A colorimetric assay using the MTS/PMS system was used to determine the cytotoxic
activity of the test compounds. The optical density (OD) values at 490 nm were measured with a
1
420-multilabel counter VICTOR from Wallac (Turku, Finland). The IC50, the concentration that
inhibited 50% of the cancer cell growth activity, was then determined. All experiments were repeated
17
three times.
Acknowledgements. We gratefully acknowledge the financial support of the National Science
Council (Grant NSC 102-2113-M-077-002-MY2).
1 13
Supporting Information Available: Compound characterization and spectral ( H and C NMR)
data. This material is available free of charge via the Internet at
Notes and references

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1
5. There is a byproduct, N-(2-iodophenyl)-3-methoxy-N-(4-nitrobenzyl)acrylamide, generated in
the other palladium catalysts. The byproduct was contributed from the addition of methanol to