Pd-catalyzed synthesis of 3-(diarylmethylene)-2-oxindoles and 3-(arylmethylene)-2-oxindoles

Article abstract of DOI:10.1016/j.tet.2011.09.089

An efficient method for the stereoselective synthesis of 3-(diarylmethylene)-2-oxindoles and 3-(arylmethylene)-2-oxindoles via carbopalladation is described. In this approach, an Ugi-4-component reaction (4-CR) adduct was used as the starting material. A

Full text of DOI:10.1016/j.tet.2011.09.089

Tetrahedron 67 (2011) 9134e9141
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journal homepage: www.elsevier.com/locate/tet
Pd-catalyzed synthesis of 3-(diarylmethylene)-2-oxindoles and
3-(arylmethylene)-2-oxindoles
,
a
a
b,
*
Saeed Balalaie a , Hassan Motaghedi , Morteza Bararjanian , Daryoush Tahmassebi
,
*
Hamid Reza Bijanzadeh c
a Peptide Chemistry Research Center, K. N. Tossi University of Technology, PO Box 15875-4416, Tehran, Iran
b Chemistry Department, Indiana University-Purdue University Fort Wayne, Fort Wayne, IN 46805, USA
c Department of Chemistry, Tarbiat Modares University, PO Box 14115-175, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 May 2011
Received in revised form 25 August 2011
Accepted 20 September 2011
Available online 25 September 2011
An efficient method for the stereoselective synthesis of 3-(diarylmethylene)-2-oxindoles and 3-(aryl-
methylene)-2-oxindoles via carbopalladation is described. In this approach, an Ugi-4-component re-
action (4-CR) adduct was used as the starting material. A one-pot sequence involving intermolecular
carbopalladation CeH activation/CeC bond formation efficiently afforded the oxindole derivatives.
Ó 2011 Elsevier Ltd. All rights reserved.
Dedicated to Professor M. M. Hashemi on
the occasion of his 60th birthday
Keywords:
3-(Diarylmethylene)-2-oxindoles
3-(Arylmethylene)-2-oxindoles
Modified Heck reaction
Palladium catalyst
1. Introduction
Theexistenceof tri-ortetra-substitutedolefininthe3-alkylidene-
2-oxindole scaffold is important for their biological activitiy.3,11
A
3-Alkylideneoxindoles are well known to be versatile com-
pounds in synthesis and biology.1 Some of the E- and Z-alkylidene-
2-oxindoles were found to be promising inhibitors of tyrosine-ki-
nase, such as SU4984,1a,2 cyclic-dependent protein kinase in-
hibitors,3 and antirheumatic agents.4 Compound B (SU11248) is the
orally active receptor tyrosine kinase (RTK) inhibitor marketed by
Pfizer as SutentÒ.5 Semaxanib (SU5416, C) is a related anticancer
compound, which passed to phase III clinical trials for use in the
treatment of colo-rectal cancer. Meanwhile, E-alkylideneoxindoles
are important synthetic intermediates to TMC-95A.6 The cone
structure of some 3-methylidene-2-oxinoles is shown in Fig. 1.
Also, some 3-alkenyl-2-oxindole derivatives were separated
from natural sources (Fig. 2), which possess different biological
activities, such as antipyretic (E),7 antiviral, detoxifying (G),8 anti-
inflammatory, analgesic properties (H),9 and some of them are
self-germination inhibitors (F).10
number of related compounds are given in a review article.12
Consequently, the synthesis of 2-oxindoles with a tri- or tetra-
substituted exocyclic double-bond at the C-3 position is an in-
teresting goal.13 There are several approaches for the synthesis of 3-
arylidene and diarylidene-2-oxindoles, which are summarized in
Scheme 1.
The metal-catalyzed domino cyclization of a suitable starting
material is an efficient method to construct the oxindole skeleton.
In this way, the suitable materials are: amidophosphonates (route
a),13 2-alkynyl anilines (route b),14 2-iodoarylpropynamides (route
c),15 2-carboamidoaryl triflate (route d).16 N-Substituted-2-
alkynamides are both common and suitable starting material for
the synthesis of 3-arylidene-2-oxindoles.15d,17 It was shown that
a transition-metal could catalytically activate sp2 CeH bonds of
arenes to form new CeC bonds.18 Zhu and co-workers have re-
ported an interesting palladium-catalyzed domino N-arylation/
carbopalladation/CeH functionalization reaction of arylalkynes
with electrophilic aryl iodides to afford five-membered heterocy-
cles.19 There are two different strategies for the synthesis of 3-
alkylidene-2-oxindoles using N-substituted-2-alkynamides via
areneealkyne-cyclization, as summarized in Scheme 2.19e
* Corresponding authors. E-mail addresses: balalaie@kntu.ac.ir (S. Balalaie),
tahmassd@ipfw.edu (D. Tahmassebi).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.089

S. Balalaie et al. / Tetrahedron 67 (2011) 9134e9141
9135
Fig. 1. Representative 3-alkenyl-oxindoles.
OMe
HO
MeO
Me
O
O
O
O
N
H
N
H
N
H
N
H
MeO
Mixture of
Mixture of
E- form
(G)
Soulieotine
(H)
E-& Z- forms
E- & Z-forms
(F)
(E)
Fig. 2. The structures of some natural 3-arylidene-2-oxindoles.
In continuation of our research work toward the synthesis of
functionalized 2-oxindoles,21 we wish to report an efficient protocol
for the stereoselective synthesis of 3-alkyliden-2-oxindoles. In our
retrosynthetic analysis, the formation of the exocyclic double bond
in 3-(diarylmethylene)-2-oxindoles was investigated by a ring-
closure procedure of N-substituted-2-alkynamides I that resulted
from the Ugi 4-CR (Ugi 4-component reaction) of benzaldehyde 1,
aniline 2, phenylpropiolic acid 3, and isocyanides 4 (Scheme 3).
Scheme 1. Some approaches for the synthesis of 3-arylidene-2-oxindoles.
Scheme 3. Retrosynthetic pathway for the synthesis of 3-arylidene-2-oxindoles using
Ugi-4MCR.
2. Results and discussions
Scheme 2. Two different strategies for the synthesis of 3-alkylidene-2-oxindoles.
N-Substituted-2-alkynamides have been widely used as an effi-
cient starting material for the synthesis of 2-oxindole derivatives.
Different methodologies have been reported for the synthesis of
N-substituted-2-alkynamides.22 The most common approach is the
conversion of a carboxylic acid moiety to a more reactive functional
group, such as an acyl chloride, and then reaction with amines or
acetylides in the presence of a suitable catalyst. They can also be
synthesized by other methods, such as: (a) reaction of carboxylic
acid containing an alkyne moiety with amines in the presence of
coupling reagents, such as DCC;23 (b) carbonylation of alkynes using
CO in the presence of a Pd catalyst and O2 in high temperature and
highpressure;24 (c) applying an enzymaticreaction;25 (d) reaction of
In these approaches two different three-component variants
were used for the stereoselective synthesis of unsymmetrically
substituted 3-diarylmethylene-2-oxindoles, derived from terminal
alkynes and two aryl iodides using an in situ Sonogashira cross-
coupling.19d
The number of aryl groups and their stereochemistry has a sig-
nificant role in their biological activities. However, the stereo-
selective synthesis of (E)- and (Z)-3-alkylidene-2-oxindoles is
challenging.20 Therefore, significant effort has been devoted to the
development of an efficient method for the stereoselective syn-
thesis of these (E)- or (Z)-disubstituted-3-alkylidene-2-oxindoles.

9136
S. Balalaie et al. / Tetrahedron 67 (2011) 9134e9141
isocyanates with Grignard reagent.26 Drawbacks to these methods
are the need for harsh thermal conditions, long reaction times,
modest yields, use of expensive reagents, and in some cases multi-
step reactions. In this report N-substituted-2-alkynamides were
synthesized from the reaction of benzaldehyde, aniline, phenyl-
propiolic acid and isocyanides by an Ugi 4-CR approach (Scheme 4).
Initially, we planned to synthesize the N-substituted-2-
alkynamides precursors (5aeh). They could be prepared via Ugi-
4CR using the benzaldehyde derivatives, aniline, phenylpropiolic
acid, and isocyanides in MeOH at room temperature. Several
benzaldehyde derivatives, which contained electron-donating or
electron-withdrawing groups were used. With alkyne precursors in
hand, we then turned our attention to the preparation of an oxin-
dole scaffold and examined the ability of acetylenic derivatives as
efficient substrates for the tandem carbopalladation.
Under the optimized conditions, reaction of N-substituted-2-
alkynamides, which contained electron-donating groups with
iodobenzene (1 equiv), Pd(OAc)2 (5 mol %), potassium carbonate
(1 equiv) refluxing in acetonitrile led to the desired diaryl-3-
methylidene-2-oxindoles 8aeh. All of the starting materials with
electron-donating groups gave the diarylmethyildene-2-oxindoles.
But application of the carbopalladation step to substrate (Ph) gave
the desired 2-oxindole in 60% yield as mixture of two tetra- and tri-
substituted alkenes in a ratio of 80:20, respectively.
NH2
MeOH, rt
O
H
N
R1 CHO
R2 NC
N
+
+
+
12 -24 h
85 - 95%
R1
R2
HO
O
O
1
2
3
4
5a-h
Scheme 4. Synthesis of N-substituted-2-alkynamides (5aeh) via Ugi 4-CR.
According to the known palladium chemistry, the proposed
mechanism was shown in Scheme 6 and the reaction procedure
could be categorized as follows:
Cyclization of N-substituted-2-alkylamides was investigated
under different conditions in the presence of Brønstead or Lewis
acids. Our main focus was on the overall efficiency of this cyclization
reaction instead of optimizing factors such as the Lewis acid catalyst
type, the catalyst loading, the solvent, and the temperature of re-
action media. The results are summarized in Table 1. Reaction of N-
substituted-2-alkynamide 5a with iodobenzene was selected as the
benchmark reaction. The best results were obtained when Pd(OAc)2
was used as the catalyst in acetonitrile at 60 ꢀC (Scheme 5).
Ph
N
R
O
HI / Base
PdII
PdII
Ph
O
Base
Reductive
elimination
Table 1
Ph
Optimization of reaction condition for the synthesis of 3-aryl-2-oxindole (7a)
N
R
O
H
PdIV
N
Catalyst loading (mol %)
Temperature
Solvent
Products
[O]
NHR
CF3SO3H (10%)
TFA (10%)
rt
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
[bmim][PF6]
DMF
Complex mixturea
d
I
Ar
8 a-h
I
rt and reflux
rt and reflux
rt and reflux
rt and reflux
rt and reflux
rt and reflux
rt
Reflux
rt
60 ꢀC
O
H
SSAb (10%)
d
Ph PdIV
CuI (10%)
d
PdIV
a
AuCl3 (20%)
Sc(OTf)3 (10%)
Sc(OTf)3 (10%)
Pd(OAc)2 (5%)
Pd(OAc)2 (5%)
Pd(OAc)2 (5%)
Pd(OAc)2 (5%)
d
d
N
R
O
N
R
O
d
d
d
H
PdIV
PhI
Insertion
DMF
MeCN
MeCN
7 (20%)
d
PdIV
7a (20%), 8a (80%)
C-H activation
a
A mixture of different products was obtained and the desired product was
N
R
O
N
R
b
O
only 3%.
b
Carbopalladation
SSA (Silica Sulfuric Acid).
c
Scheme 6. Proposed mechanism for the synthesis of 3-(diarylmethylene)-2-oxindoles
8aeh.
R3
Ph
O
Pd(OAc)2 (0.05 mol)
K2CO3
The proposed reaction sequences for the synthesis of 3-(diaryl
methylene)-2-oxindoles 8aeh are as follows:
H
N
,
(a) Oxidative-addition of PdII to PdIV and complexation of PdIV
with nitrogen and alkyne (structure a).
MeCN
R2
N
I
R1
7a-i
8 a-h
O
N
(b) C(sp3)eH activation (structure b).
6
O
R3 = H
R3 =Ph
H
N
If R1 = EWG-Ar, rt
If R1 = EDG-Ar, reflux
R1
R2
(c) Insertion of palladium to alkyne moiety and formation of in-
termediate (Carbopalladation, structure c).
(d) Insertion of iodobenzene (structure d).
O
(e) Reductive elimination and finally formation of 8aeh.
5a-h
Scheme 5. Pd-catalyzed synthesis of 3-(diarylmethylene) and 3-(arylmethylene)2-
oxindoles.
The structures of the products were characterized by spectro-
scopic data (see Experimental section).
To further probe the scope and limitations of this process, we
also examined the reaction of benzaldehydes derivatives possess-
ing electron-withdrawing groups. The results were surprising and
the (Z)-3-arylidene-2-oxindoles were obtained as the sole stereo-
isomeric product (Scheme 7). This reaction was carried out at room
To probe the scope and limitation of this reaction a range of
substituted benzaldehydes and isocyanides were examined and
finally the cyclization was conducted using catalytic palladium
acetate and aryl iodide, which could react via carbopalladation.

S. Balalaie et al. / Tetrahedron 67 (2011) 9134e9141
9137
temperature and the existence of iodobenzene does not affect the
reaction process. In this case, the reaction was tested in the pres-
ence or absence iodobenzene. In two cases, the product was the
same and aryl iodide does not insert in the structure of oxindole.
The results are presented in Table 2.
The proposed mechanism for the synthesis of Z-3-(aryl-
methylene)-2-oxindoles is shown in Scheme 8 (Table 3).
In summary, we have developed an efficient approach to the
synthesis of substituted 3-(diarylmethylene)-2-oxindole and Z-3-
(arylmethylene)-2-oxindole derivatives. The overall reaction in-
volves a sequence of carbopalladation/CeH activation, and CeC
bond forming steps and is catalyzed by a palladium catalyst system.
The readily accessibility of functionalized starting materials and the
generality of this process make it highly valuable in view of the
synthetic and medicinal importance of 2-oxindole derivatives.
H
Ph
Pd(OAc)2 (0.05% mol)
K2CO3, PhI
O
N
H
N
R2
MeCN, rt
O
H
N
R1
N
3. Experimental section
3.1. General
O
R1
R2
R1 = EWG-Ar
Z isomer
O
5 i-p
7 b-i
Commercially available materials were used without further
Scheme 7. Pd-catalyzed synthesis of 3-(arylmethylene)2-oxindoles.
purification. Melting points were determined on an Electrothermal
Table 2
Synthesis of diarylmethylidene-2-oxindoles
N-substituted-2-
N-substituted-2-
Products
Products
alkynamide
alkynamide
H
H
O
O
O
H
N
O
H
N
H
N
N
N
H
N
N
N
O
O
N
N
O
H
N
H
N
O
O
O
O
O
7a
(4:1)
8a
7e (trace)
8e (54%)
5a
5e
(60%) / 18h
22h
O
O
H
N
N
H
N
N
O
O
N
N
H
N
H
N
O
O
O
O
Me
Me
N
Me
N
Me
5b
8b (64%) / 24h
5f
8f (65%) / 17h
O
O
H
N
N
H
N
O
N
O
N
O
H
N
N
H
N
MeO
MeO
MeO
MeO
O
O
O
Me
Me
OMe
OMe
5g
8g (64%) / 17h
8c (54%) / 26h
5c
O
O
O
N
H
N
N
H
N
N
H
N
O
N
H
N
O
O
Me
O
N
O
Me
Me
N
Me
5h
8h (63%) / 17h
8d (56%) / 26h
5d

9138
S. Balalaie et al. / Tetrahedron 67 (2011) 9134e9141
9100 apparatus and were uncorrected. IR spectra were obtained on
an ABB FT-IR FTLA 2000 spectrometer. 1H NMR and 13C NMR
spectra were run on Bruker DRX-500 AVANCE spectrometers at
500 MHz for 1H NMR, and 125 MHz for 13C NMR. CDCl3 was used as
solvents. High resolution mass spectra were recorded on HR-MS
was recorded on Mass-ESI-POS (Apex Qe-FT-ICR instrument)
spectrometer.
3.2. General procedure for the synthesis of N-substituted-2-
alkynamides: (5aep)
To a solution of aldehyde 1 (1 mmol) in MeOH (5 mL) was added
aniline as a primary amine 2 (1 mmol), and the reaction mixture
was stirred at room temperature (25 ꢀC) for 1 h. Then, phenyl-
acetylenecarboxylic acid 3 (1 mmol) was added and stirring was
continued for 15 min, followed by addition of isocyanide 4
(1 mmol). The mixture was stirred for 24 h. The progress of the
reaction was monitored using TLC (petroleum ether/EtOAc 3:1).
After completion of reaction, petroleum ether was added and the
solid was filtered and dried.
Scheme 8. Proposed mechanism for the synthesis of Z-3-(aryl methylene)-2-oxindoles
7aei.
Table 3
Synthesis of 3-(arylmethylene)-2-oxindoles
Phenylprppiolamide
Products
Phenylprppiolamide
Products
H
H
O
H
N
O
N
H
N
O
N
N
H
N
O
N
O
H
N
O
N
O
O
N
NO
NO
7f (68%) / 12h
7b (70%) / 12h
5m
5i
H
H
O
O
H
N
N
H
N
N
O
O
N
N
O
H
N
H
N
O
O
N
O
N
F C
F C
7c (71%) / 13h
7g (68%) / 14h
5j
5n
H
H
O
O
H
N
N
H
N
N
O
N
O
N
H
N
H
N
O
O
S
O
F C
S
O
F C
7h (67%) / 13h
7d (80%) / 11h
5o
5k
H
H
O
H
O
O
N
H
N
H
N
N
N
N
O
N
O
N
O
H
N
H
N
O
O
Cl
O
O
Cl
NC
NC
Cl
7i
(1:4)
8i
7e (77%) / 12h
5l
5p
60% / 16h

S. Balalaie et al. / Tetrahedron 67 (2011) 9134e9141
9139
R3
7.9 Hz, HeAr), 7.26e7.45 (10H, m, HeAr); dC (125 MHz, CDCl3): 28.6,
52.0, 56.3, 59.0, 60.8, 105.7, 111.6, 121.6, 123.0, 123.2, 123.5, 127.8,
128.5,129.0,129.2,129.3,130.1,130.2,138.0,140.0,141.2,141.4,153.4,
155.3,167.2; HR-MS (ESI) MHþ found 577.2697, C36H37N2O5 requires
577.2698; MNaþ found 599.2518, C36H36N2NaO5 requires 599.2516;
[MþK]þ found 615.2256, C36H36KN2O5 requires 615.2258.
Ph
O
Pd(OAc)2 (0.05% mol)
K2CO3, PhI
H
N
N
R1
O
H
N
R2
N
O
MeCN, reflux
R1 = EDG-Ar
8 a-h
R1
R2
O
3.3.5. N-Cyclohexyl-2-(4-(dimethylamino)phenyl)-2-(2-oxo-3-(di-
phenylmethylene)indolin-1-yl)acetamide
(300 mg, 54%); mp: 204e206 ꢀC; Rf (25% EtOAc/hexane) 0.55; nmax
(KBr): 1675, 1742, 3328 cmꢂ1
dH (500 MHz, CDCl3): 1.09e2.00 (10H,
(8d). Orange
powder
3.3. General procedure for the synthesis of
diarylmethylidene-2-oxindoles (8aeh)
;
m, Hecyclohexyl), 2.92 (6H, s, N(CH3)2) 3.87 (1H, m, CHecyclohexyl),
5.89 (1H, d, J 7.8 Hz, NH), 6.14 (1H, s, CH), 6.40 (1H, d, J 7.7 Hz, HeAr),
6.60 (1H, t, J 7.6 Hz, HeAr), 6.67 (2H, d, J 8.7 Hz, HeAr), 6.84 (1H, d, J
7.9 Hz, HeAr), 6.99 (1H, t, J 7.8 Hz, HeAr), 7.27 (2H, d, J 8.8 Hz, HeAr),
7.26e7.45 (7H, m, HeAr); dC (125 MHz, CDCl3): 24.8, 25.5, 32.8, 33.0,
40.4, 48.7, 58.0,111.6,112.4,121.3,121.8,122.9,123.3,123.9,127.8,128.4,
128.9, 129.1, 129.2, 129.3, 129.4, 130.2, 140.1, 141.4, 141.7, 150.2, 154.7,
167.0, 167.5; HR-MS (ESI) MHþ found, 556.2958 C37H38N3O2 requires
556.2959; MNaþ found,578.2778 C37H 37N3NaO2 requires 578.2779;
MKþ found 594.2517, C37H37KN3O2 [MþK]þ requires 594.2518.
The Ugi adduct (5aeh) (1 mmol) was added to a round bottom
flask, which contain acetonitrile (20 mL), Pd(OAc)2 (11 mg,
0.05 equiv), potassium carbonate (414 mg, 3 mmol), and iodo-
benzene (245 mg, 1.2 mmol). The mixture was heated under reflux
for 18e24 h. Reaction progress was monitored using TLC (hexane/
EtOAc 3:1). After cooling to room temperature, the reaction mixture
was diluted with brine (2ꢁ30 mL). The aqueous phase was extracted
with EtOAc (2ꢁ30 mL). The combined organic phase was separated,
dried over sodium sulfate, filtered, and concentrated to dryness in
vacuo, and finally purified by column chromatography on silica gel
(hexane/ethyl acetate 3:1) to give 8aei in yields of 54e65%.
3.3.6. N-Cyclohexyl-2-(2-oxo-3-(diphenylmethylene)indolin-1-yl)-2-
phenylacetamide (8e). Orange powder (333 mg, 65%); mp:
202e204 ꢀC; Rf (25% EtOAc/hexane) 0.40; nmax (KBr): 1655, 1700,
3.3.1. N-tert-Butyl-2-(2-oxo-3-(diphenylmethylene)indolin-1-yl)-2-
phenylacetamide (8a). Orange powder (389 mg, 80%); mp:
226e227 ꢀC; Rf (25% EtOAc/hexane) 0.45; nmax (KBr): 1672, 1749,
3308 cmꢂ1
; dH (500 MHz, CDCl3): 1.11e1.89 (10H, m, Hecyclohexyl),
3.84e3.88 (1H, m, CH- cyclohexyl), 5.97 (1H, d, J 7.8 Hz, NH), 6.20 (1H,
s, CH), 6.43 (1H, d, J 7.5 Hz, HeAr), 6.63 (1H, td, J 7.5, 0.6 Hz, HeAr),
6.79 (1H, d, J 7.9 Hz, HeAr), 6.98 (1H, td, J 7.0, 0.99 Hz, HeAr),
7.26e7.46 (14H, m, HeAr); dC (125 MHz, CDCl3): 24.7, 25.4, 32.7, 32.8,
48.7, 58.2, 111.6, 121.6, 123.0, 123.2, 123.5, 127.8, 128.0, 128.5, 128.6,
128.9, 129.2, 130.2, 134.4, 140.0, 141.1, 141.2, 155.4, 166.9, 167.1; HR-
MS (ESI) MHþ found 513.2536, C35H33N2O2 requires 513.2537;
MNaþ found 535.2356, C35H32N2NaO2 requires 535.2357.
3316 cmꢂ1
; dH (500 MHz, CDCl3): 1.38 (9H, s, t-Bu), 5.89 (1H, s, NH),
6.15 (1H, s, CH), 6.43 (1H, d, J 7.0 Hz, HeAr), 6.63 (1H, t, J 8.0 Hz,
HeAr), 6.80 (1H, d, J 7.2 Hz, HeAr), 6.99 (1H, t, J 7.0 Hz, HeAr),
7.26e7.45 (14H, m, HeAr); dC (125 MHz, CDCl3): 28.6, 52.0, 59.0,
112.0, 121.5, 123.0, 123.2, 123.6, 127.8, 128.0, 128.1, 128.5, 128.7, 19.0,
129.2,129.3,129.3,130.2,134.7,140.0,141.3,141.3,155.3,167.1,167.2;
HR-MS (ESI): MHþ found 487.2380, C33H31N2O2 requires 487.2380.
MNaþ found 509.2199, C33H30N2NaO2 requires 509.2200.
3.3.7. N-tert-Butyl-2-(biphenyl)-2-(2-oxo-3-(diphenylmethylene)in-
dolin-1-yl)acetamide (8f). Red powder (360 mg, 64%); mp:
173e175 ꢀC; Rf (25% EtOAc/hexane) 0.47; nmax (KBr): 1667,
3.3.2. N-tert-Butyl-2-((Z)-3-benzylidene-2-oxoindolin-1-yl)-2-
phenylacetamide (7a). White powder (263 mg, 64%); mp:
172e173 ꢀC; Rf (25% EtOAc/hexane) 0.41; nmax (KBr): 1670, 1749,
3317 cmꢂ1
; dH (500 MHz, CDCl3): 1.40 (9H, s, t-Bu), 5.97 (1H, s, NH),
3343 cmꢂ1
;
dH (500 MHz, CDCl3): 1.22 (9H, s, t-Bu), 6.09 (1H, s, NH),
6.20 (1H, s, CH), 6.46 (1H, d, J 7.7 Hz, HeAr), 6.63 (1H, t, J 7.6 Hz,
HeAr), 6.80 (1H, d, J 7.9 Hz, HeAr), 6.99 (1H, t, J 7.5 Hz, HeAr),
7.26e7.59 (22H, m, HeAr); dC (125 MHz, CDCl3): 28.7, 52.0, 58.5,
111.7, 121.6, 123.0, 123.3, 123.6, 127.1, 127.4, 127.5, 127.9, 128.6, 128.8,
129.3, 129.3, 130.2, 133.7, 140.0, 140.4, 140.9, 141.3, 155.4, 167.2; HR-
MS (ESI) MHþ found 563.2693, C39H35N2O2 requires 563.2694;
MNaþ found, 585.2512 C39H34N2NaO2 requires 585.2514.
7.04 (1H, t, J 7.9 Hz, HeAr), 7.21e7.37 (11H, m, HeAr, CH, C]CH),
7.51 (2H, dd, J 8.7, 1 Hz, HeAr), 7.62 (2H, dd, J 8.4, 1 Hz, HeAr); dC
(125 MHz, CDCl3): 28.3, 52.0, 76.6, 118.4, 124.5, 126.5, 128.3, 128.7,
128.9, 129.1, 130.2, 130.6, 131.9, 134.9, 136.7, 141.1, 163.1, 166.2; HR-
MS (ESI): MHþ found 411.2067, C27H27N2O2 requires 411.2067;
MNaþ found 433.1886, C27H26N2NaO2 requires 433.1887.
3.3.3. N-tert-Butyl-2-(4-(dimethylamino)phenyl)-2-(2-oxo-3-(di-
3.3.8. N-tert-Butyl-2-(2-oxo-3-(diphenylmethylene)indolin-1-yl)-2-
p-tolylacetamide (8g). Orange powder (315 mg, 63%); mp:
259e261 ꢀC; Rf (25% EtOAc/hexane) 0.51; nmax (KBr): 1673,
phenylmethylene)indolin-1-yl)acetamide
(286 mg, 54%); mp: 272e274 ꢀC; Rf (25% EtOAc/hexane) 0.50; nmax
(KBr): 1670, 3318; cmꢂ1
dH (500 MHz, CDCl3): 1.36 (9H, s, t-Bu),
(8b). Orange powder
;
3414 cmꢂ1
; dH (500 MHz, CDCl3): 1.37 (9H, s, t-Bu), 2.33 (3H, s, CH3),
6.07 (1H, s, NH), 5.82 (1H, s, CH), 6.38 (1H, d, J 8.3 Hz, HeAr), 6.59
(1H, t, J 7.7 Hz, HeAr), 6.67 (2H, d, J 7.1 Hz, HeAr) 6.84 (1H, d, J
8.1 Hz, HeAr), 6.98 (1H, t, J 7.8 Hz, HeAr), 7.27 (2H, d, J 7.1 Hz,
HeAr), 7.26e7.45 (10H, m, HeAr); dC (125 MHz, CDCl3): 28.7, 40.3,
51.8, 58.5, 111.7, 112.4, 121.2, 122.0, 122.1, 123.2, 124.0, 127.8, 128.4,
128.9,129.0, 129.1,129.3,130.1,140.2, 141.5, 141.8,150.2,154.5, 167.0,
167.9; HR-MS(ESI) MHþ found 530.2802, C35H36N3O2 requires
530.2802; MNaþ found 552.2621, requires 552.2622.
5.87 (1H, s, NH), 6.11 (1H, s, CH), 6.42 (1H, d, J 9.9 Hz, HeAr), 6.62
(1H, t, J 8.2 Hz, HeAr), 6.81 (1H, d, J 8.3 Hz, HeAr), 6.99 (1H, t, J
8.3 Hz, HeAr), 7.14 (2H, d, J 8.0 Hz, HeAr), 7.28 (2H, d, J 8.0 Hz,
HeAr), 7.26e7.45 (10H, m, HeAr); dC (125 MHz, CDCl3): 21.1, 28.6,
51.9, 58.6, 111.7, 121.5, 122.9, 123.2, 123.7, 127.8, 128.1, 128.4, 128.9,
129.1, 129.2, 129.3, 129.4, 130.1, 131.7, 137.8, 140.0, 141.3, 141.4, 155.1,
167.1, 167.3. HR-MS (ESI) MHþ found 501.2536, C34H33N2O2 requires
501.2536; MNaþ found 523.2356, C34H32N2NaO2 requires
523.2356; MKþ found 539.2095, C34H32KN2O2 requires 539.2096.
3.3.4. N-tert-Butyl-2-(3,4,5-trimethoxyphenyl)-2-(2-oxo-3-(diphe-
nylmethylene)indolin-1-yl)acetamide (8c). Orange powder (323 mg,
56%); mp: 218e220 ꢀC; Rf (25% EtOAc/hexane) 0.52; nmax (KBr): 1673,
3.3.9. N-tert-Butyl-2-(4-isopropylphenyl)-2-(2-oxo-3-(diphenyl-
methylene)indolin-1-yl)acetamide (8h). Orange powder (105 mg,
20%); mp: 262e264 ꢀC; Rf (25% EtOAc/hexane) 0.50; nmax (KBr):
1755 cmꢂ1
; dH (500 MHz, CDCl3): 1.39 (9H, s, t-Bu), 3.79e3.83 (9H, m,
OCH3), 5.92 (1H, s, NH), 6.08 (1H, s, CH), 6.43 (1H, d, J 8.8 Hz, HeAr),
6.63e6.65 (3H, m, HeAr), 6.86 (2H, d, J 7.9 Hz, HeAr), 7.01 (1H, t, J
1675, 3328 cmꢂ1
;
dH (500 MHz, CDCl3): 1.24 (6H, dd, J 6.9,1.2 Hz, 2ꢁ
CH3), 1.38 (9H, s, t-Bu), 2.89 (1H, m, CH(Me)2), 5.89 (1H, s, NH), 6.14

9140
S. Balalaie et al. / Tetrahedron 67 (2011) 9134e9141
(1H, s, CH), 6.42 (1H, d, J 7.7 Hz, HeAr), 6.63 (1H, t, J 7.6 Hz, HeAr),
6.83 (1H, d, J 7.9 Hz, HeAr), 7.00 (1H, t, J 8.1 Hz, HeAr), 7.20 (2H, d, J
8.2 Hz, HeAr), 7.32 (2H, d, J 8.2 Hz, HeAr), 7.35e7.45 (10H, m,
HeAr); dC (125 MHz, CDCl3): 21.8, 23.8, 23.9, 28.6, 33.8, 51.9, 58.7,
111.7, 121.4, 122.9, 123.2, 123.7, 126.8, 127.8, 128.2, 128.4, 128.9,
129.2, 129.2, 129.3, 130.2, 132.0, 140.0, 141.3, 141.5, 148.7, 155.1, 167.1,
167.4; HR-MS (ESI) MHþ found 529.2849, C36H37N2O2 requires
529.2850; MNaþ found 551.2669, C36H36N2NaO2 requires 551.2669;
MKþ found 567.2408 C36H36KN2O2 requires 567.2409,.
129.2, 130.6, 130.7, 130.7, 131.4, 136.2, 138.6, 140.1, 162.7, 165.7; HR-
MS (ESI) MHþ found 479.1941, C28H26 F3N2O2 479.1942; MNaþ
C28H25F3N2NaO2 found, 501.1760 requires 501.1761.
3.4.4. N-tert-Butyl-2-((Z)-3-benzylidene-2-oxoindolin-1-yl)-2-(4-
cyanophenyl)acetamide (7e). White powder (348 mg, 80%); mp:
182e184 ꢀC; Rf (25% EtOAc/hexane) 0.55; nmax (KBr): 1670, 1751,
3349 cmꢂ1
; dH (500 MHz, CDCl3): 1.27 (9H, s, t-Bu), 6.21 (1H, s, NH),
7.08 (1H, t, J 7.9 Hz, HeAr), 7.25e7.44 (10H, m, HeAr, CH, C]CH),
7.60 (2H, d, J 8.4 Hz, HeAr), 7.62 (2H, d, J 8.4 Hz, HeAr); dC
(125 MHz, CDCl3): 28.3, 52.4, 75.0, 112.9, 118.0, 118.1, 125.1, 127.9,
128.8, 129.3, 130.7, 130.8, 131.2, 132.4, 136.1, 139.8, 162.5, 165.5; HR-
MS (ESI) MHþ found 436.2019, C28H26N3O2 requires 436.2020;
MNaþ found 458.1839, C28H25N3NaO2 requires 458.1840.
R3
Ph
Pd(OAc)2 (0.05% mol)
O
H
N
K2CO3 (1.5 equiv), PhI
N
R2
O
H
N
R1
N
MeCN, reflux
O
R1 = EWG-Ar
R1
R2
3.4.5. N-tert-Butyl-2-((Z)-3-benzylidene-2-oxoindolin-1-yl)-2-(pyr-
idin-2-yl)acetamide (7f). White powder (317 mg, 77%); mp:
159e161 ꢀC; Rf (25% EtOAc/hexane) 0.49; nmax (KBr): 1673, 1755, 3214,
O
7b-7i
3429 cmꢂ1
; dH (500 MHz, CDCl3): 1.34 (9H, s, t-Bu), 7.01 (1H, t, J 7.7 Hz,
3.4. General procedure for the synthesis of arylmethylidene-
2-oxindoles (7bei)
HeAr), 7.14 (1H, s, NH), 7.22e7.67 (12H, m, HeAr, C]CH), 8.63 (1H, d, J
5.7 Hz, HeAr), 9.61 (1H, s, CH); dC (125 MHz, CDCl3): 28.5, 51.8, 117.4,
123.4, 123.5, 125.6, 128.4, 129.0, 129.8, 130.3, 132.2, 137.0, 138.1, 142.1,
147.7,156.2,162.7,165.0; HR-MS (ESI) MHþ found 412.2019 C26H26N3O2
requires 412.2019. MNaþ found 434.1839, C26H25N3NaO2 requires
434.1839; MKþ found 450.1578, C26H25KN3O2 requires 450.1579.
The Ugi adduct (5iep) (1 mmol) was added to a round bottom
flask, which contain acetonitrile (20 mL), Pd(OAc)2 (11 mg,
0.05 equiv), potassium carbonate (414 mg, 3 mmol), and iodo-
benzene (245 mg, 1.2 mmol). The mixture was heated under reflux
condition for 18e24 h. Progress of reaction was monitored by TLC
(hexane/EtOAc 3:1). After cooling to room temperature, the reaction
mixture was diluted with brine (2ꢁ30 mL). The aqueous phase was
extracted with EtOAc (2ꢁ30 mL). The combined organic phase was
separated, dried over sodium sulfate, filtered, and concentrated to
dryness in vacuo, and finally purified by column chromatography on
silica gel (hexane/ethyl acetate 3:1) to give 7aei in yields of 60e80%.
3.4.6. 2-((Z)-3-Benzylidene-2-oxoindolin-1-yl)-N-cyclohexyl-2-(4-
(trifluoromethyl)phenyl)acetamide (7g). White powder (343 mg,
68%); mp: 166e168 ꢀC; Rf (25% EtOAc/hexane) 0.54; nmax (KBr):
1668, 1750, 3342 cmꢂ1
; dH (500 MHz, CDCl3): 1.00e1.87 (10H, m,
Hecyclohexyl), 3.87e3.92 (1H, m, CHecyclohexyl), 6.31 (1H, d, J 7.8,
NH), 7.01 (1H, t, J 7.4 Hz, HeAr), 7.25e7.46 (10H, m, HeAr, CH, C]
CH), 7.58 (1H, d, J 8.4 Hz, HeAr), 7.83 (1H, d, J 8.4 Hz, HeAr); dC
(125 MHz, CDCl3): 24.4, 24.5, 25.2, 32.4, 32.6, 48.9, 75.0,118.0,122.6,
124.8,124.9, 125.7,125.7,127.9,128.7,128.9, 129.3, 130.7,130.9, 131.1,
131.2, 136.1, 138.3, 139.7, 162.7, 165.6; HR-MS (ESI) MHþ found
505.2097, C30H28F3N2O2 requires 505.2098; MNaþ found 527.1917,
C30H27F3N2NaO2 requires 527.19168; MKþ found 543.1656,
C30H27F3KN2O2 requires 543.1657.
3.4.1. N-tert-Butyl-2-((Z)-3-benzylidene-2-oxoindolin-1-yl)-2-(3-
nitrophenyl)acetamide (7b). White powder (91 mg, 20%); mp:
182e184 ꢀC; Rf (25% EtOAc/hexane) 0.47; nmax (KBr): 1673, 1740,
3383 cmꢂ1
; dH (500 MHz, CDCl3): 1.29 (9H, s, t-Bu), 6.29 (1H, s, NH),
7.08 (1H, t, J¼7.3 Hz, HeAr), 7.26e7.51 (11H, m, HeAr, CH, C]CH),
7.96 (1H, d, J 8.0 Hz, HeAr), 8.15 (1H, d, J 8.0 Hz, HeAr), 8.60 (1H, t, J
2.1 Hz, HeAr); dC (125 MHz, CDCl3): 28.3, 52.5, 74.7, 118.0, 123.8,
123.9, 125.1, 128.1, 128.9, 129.4, 129.7, 130.7, 130.8, 131.2, 134.3,
136.0, 136.6, 139.7, 148.3, 162.5, 165.5; HR-MS (ESI) MHþ found
456.1918, C27H26N3O4 requires 456.1918; MNaþ found 478.1737,
C27H25N3NaO4 requires 478.1738.
3.4.7. N-tert-Butyl-2-((Z)-3-benzylidene-2-oxoindolin-1-yl)-2-(thio-
phen-2-yl)acetamide (7h). Yellow powder (283 mg, 68%); mp:
174e176 ꢀC; Rf (25% EtOAc/hexane) 0.43; nmax (KBr): 1670, 1749,
3338 cmꢂ1
; dH (500 MHz, CDCl3): 1.24 (9H, s, t-Bu), 6.19 (1H, s, NH),
6.92 (1H, dd, J 4.9, 3.9 Hz, Hethionyl), 7.07 (1H, t, J 8.2 Hz, HeAr),
7.18 (1H, s, CH), 7.26e7.52 (9H, m, HeAr, C]CH); dC (125 MHz,
CDCl3): 28.3, 52.2, 72.3, 117.9, 124.7, 126.6, 126.7, 128.2, 128.7, 128.8,
129.12, 130.4, 130.9, 131.6, 136.2, 136.4, 141.4, 162.6, 166.1; HR-MS
3.4.2. N-tert-Butyl-2-((Z)-3-benzylidene-2-oxoindolin-1-yl)-2-(pyr-
idin-3-yl)acetamide (7c). White powder (288 mg, 70%); mp:
161e162 ꢀC; Rf (25% EtOAc/hexane) 0.43; nmax (KBr): 1675, 1744,
H
(ESI) MHþ found 417.1631, C25 25N2O2S; requires 417.1631; MNaþ
3339 cmꢂ1
;
dH (500 MHz, CDCl3): 1.27 (9H, s, t-Bu), 6.25 (1H, s, NH),
found 439.1451, C25H24N2NaO2S requires 439.1451.
7.07 (1H, t, J¼7.4 Hz, HeAr), 7.21e7.37 (7H, m, HeAr, CH, C]CH), 7.44
(2H, d, J 6.5 Hz, HeAr), 7.47 (2H, d, J 8.2 Hz, HeAr), 7.95 (1H, d, J 9.3 Hz,
HeAr), 8.53 (1H, d, J 4.7 Hz, HeAr), 8.93 (1H, s, HeAr); dC (125 MHz,
CDCl3): 28.3, 52.3, 74.3, 118.1, 123.3, 125.0, 127.8, 128.8, 129.2, 130.4,
130.6, 130.7, 131.3, 136.1, 136.2, 139.6, 149.9, 150.0, 162.6, 165.6; HR-
MS (ESI) MHþ found 412.2019, C26H26N3O2 requires 412.2019;
MNaþ found, 434.1839 C26H25N3NaO2 requires 434.1839.
3.4.8. N-tert-Butyl-2-((Z)-3-benzylidene-2-oxoindolin-1-yl)-2-(4-
chlorophenyl)acetamide (7i). White powder (298 mg, 67%); mp:
184e185 ꢀC; Rf (25% EtOAc/hexane) 0.58; nmax (KBr): 1671, 1747,
3341,3341 cmꢂ1
; dH (500 MHz, CDCl3): 1.24 (9H, s, t-Bu), 6.15 (1H, s,
NH), 7.06 (1H, t, J 8.5 Hz, HeAr), 7.23e7.32 (7H, m, HeAr, CH, C]
CH), 7.41 (2H, d, J 7.1 Hz, HeAr), 7.48 (2H, d, J 8.0 Hz, HeAr), 7.61
(2H, d, J 8.5 Hz, HeAr); dC (125 MHz, CDCl3): 28.3, 52.2, 75.6, 118.3,
124.7, 127.1, 128.7, 129.0, 129.1, 129.9, 130.4, 130.7, 131.6, 133.2, 135.0,
136.4, 140.5, 162.8, 165.9; HR-MS (ESI) MHþ found 445.1677,
3.4.3. N-tert-Butyl-2-((Z)-3-benzylidene-2-oxoindolin-1-yl)-2-(4-
(trifluoromethyl)phenyl)acetamide (7d). White powder (340 mg,
71%); mp: 182e184 ꢀC; Rf (25% EtOAc/hexane) 0.51; nmax (KBr):
C27H26ClN2O2 requires 445.1678; MNaþ found 467.1497, C27
25ClN2NaO2 requires 467.1498,.
H
1670, 1751, 3349 cmꢂ1
; dH (500 MHz, CDCl3): 1.26 (9H, s, t-Bu), 6.21
(1H, s, NH), 7.08 (1H, t, J 7.3 Hz, HeAr), 7.25e7.34 (6H, m, HeAr, CH,
C]CH),7.41 (2H, d, J 7.1 Hz, HeAr), 7.47 (2H, d, J 7.9 Hz, HeAr), 7.59
(2H, d, J 8.1 Hz, HeAr), 7.80 (2H, d, J 8.1 Hz, HeAr); dC (125 MHz,
CDCl3): 28.3, 52.3, 75.4, 118.1, 122.7, 124.9, 125.7, 127.5, 128.8, 128.9,
3.4.9. N-tert-Butyl-2-(4-chlorophenyl)-2-(2-oxo-3-(diphenyl-
methylene)indolin-1-yl)acetamide (8i). Orange powder (416 mg,
80%); mp: 250e252 ꢀC; Rf (25% EtOAc/hexane) 0.41; nmax (KBr):

S. Balalaie et al. / Tetrahedron 67 (2011) 9134e9141
9141
1663, 3311 cmꢂ1
; dH (500 MHz, CDCl3): 1.36 (9H, s, t-Bu), 5.91 (1H, s,
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HeAr), 6.79 (1H, d, J 8.0 Hz, HeAr), 7.01 (1H, t, J 7.9 Hz, HeAr),
7.26e7.46(13H, m, HeAr); dC (125 MHz, CDCl3): 28.6, 52.0, 58.0,
111.4, 121.8, 123.1, 123.3, 123.3, 127.8, 128.5, 128.8, 129.0, 129.3,
129.4, 129.5, 130.1, 133.1, 134.0, 139.9, 140.8, 141.1, 155.8, 166.7, 167.1;
HR-MS (ESI) MHþ found 521.1988, C33H30ClN2O2 requires 521.1988;
MHþ found 543.1810, C33H29ClN2NaO2 requires 543.1810.
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Acknowledgements
We gratefully acknowledge the Ministry of Science, Research
and Technology of Iran for the financial support. We are also
grateful to Prof. R. Gleiter for fruitful and helpful discussions. We
express our gratitude to Mr. M. Jalilevand, managing director of
Kimia Exir Company for the donation of chemicals/reagents and
financial support.
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Supplementary data
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2011.09.089.
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