Synthesis of 3-(diarylmethylene)oxindoles via a palladium-catalyzed one-pot reaction: Sonogashira-heck-suzuki-miyaura combined reaction

Article abstract of DOI:10.1055/s-0033-1339690

A novel one-pot reaction for the synthesis of 3-(diarylmethylene)oxindoles is described. The reaction involves the successive combination of three palladium-catalyzed reactions (Sonogashira, Heck, and Suzuki-Miyaura reactions). This method enables the rapid synthesis of various 3-(diarylmethylene)oxindoles from simple propiolamides. The addition of silver salts dramatically enhanced the E/Z stereoselectivity of the reaction. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1339690

LETTER
▌1993
lSetyternthesis of 3-(Diarylmethylene)oxindoles via a Palladium-Catalyzed One-Pot
Reaction: Sonogashira–Heck–Suzuki–Miyaura Combined Reaction
Palladium-Catalyzed One-Pot Reaction
Guang Ri Dong, Sunhwa Park, Dahye Lee, Kye Jung Shin, Jae Hong Seo*
Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu,
Bucheon, Gyeonggi-do 420-743, Republic of Korea
Fax +82(2)21644059; E-mail: jaehongseo@catholic.ac.kr
Received: 26.05.2013; Accepted after revision: 27.06.2013
Dedicated with respect to Professor Deukjoon Kim on the occasion of his 65th birthday
R1
R2
R1
O
Abstract: A novel one-pot reaction for the synthesis of 3-(diaryl-
methylene)oxindoles is described. The reaction involves the succes-
sive combination of three palladium-catalyzed reactions
(Sonogashira, Heck, and Suzuki–Miyaura reactions). This method
enables the rapid synthesis of various 3-(diarylmethylene)oxindoles
from simple propiolamides. The addition of silver salts dramatically
enhanced the E/Z stereoselectivity of the reaction.
X = H
metal
catalyst
I
Zhu's work
X
X = Br
this work
N
N
O
N
R
O
R
R
1
2
3
Scheme 1 Synthetic approaches to 3-(diarylmethylene)oxindoles
Key words: palladium,
stereoselectivity,
Heck
reaction,
Sonogashira reaction, oxindole
The Sonogashira reaction6 has been used in various dom-
ino reactions coupled with other palladium-catalyzed re-
actions.7 To the best of our knowledge, however, a
Sonogashira–Heck–Suzuki–Miyaura combined reaction
has not been applied to the synthesis of 3-(diarylmeth-
ylene)oxindoles 2.8 This is likely because the electron-de-
ficient acetylene group of propiolamides 3 has low
reactivity toward Sonogashira reactions. Recently, several
modified Sonogashira reactions have been reported to
overcome the problem.9 These reports prompted us to ap-
ply the modified Sonogashira reaction conditions to
Heck–Suzuki–Miyaura reaction of phenylpropiolamide 4
(Table 1). The bromo substituent of an anilide ring was se-
lected instead of an iodo group because the bromo substit-
uent was expected to have lower reactivity toward
palladium catalysts and thus increase the preference for
the Sonogashira over the Heck reaction as the first step.
The traditional Sonogashira conditions6a were tested first.
As expected, the desired product was not observed (Table
1, entry 1). Elevating the reaction temperature to 70 °C
provided product 5 in 14% yield (Table 1, entry 2).
Changing the solvent from THF to EtOAc, which has
been reported as an effective method for the synthesis of
phenylpropiolamide derivatives,9a also did not give prod-
ucts at 25 °C but produced small amounts at 60 °C (Table
1, entries 3 and 4). When propiolamide 4 was exposed to
silver-mediated Sonogashira conditions,9c 3-(diphenyl-
methylene)oxindole (5) was obtained in 58% yield (Table
1, entry 5). Despite the promising result under these con-
ditions, the Sonogashira and Heck reactions might occur
simultaneously as the first step of a successive process.
Next, we examined Zhu’s conditions,5d although C–H ac-
tivation might occur yielding the corresponding C–H ac-
tivated product as a by-product. Under the standard Zhu’s
Sonogashira conditions, the desired product 5 was formed
as the sole product in 31% yield (Table 1, entry 6). Ex-
tending the reaction time increased the product yield to
The 3-alkylideneoxindole skeleton is one of the sub-
groups of the oxindole family1 and has been found in nat-
ural products,2 drugs, and synthetic intermediates.3 The
unique structure and various biological activities of 3-al-
kylideneoxindoles have attracted the attention of synthet-
ic chemists and numerous synthetic methods have been
reported.4 However, attemps to synthesize 3-(diarylmeth-
ylene)oxindoles 2 are relatively new and rare.5 One ap-
proach to synthesize this skeleton is to react iodoanilines
1 via metal-catalyzed domino reactions using metals such
as palladium,5b indium/palladium,5a and rhodium5c as cat-
alyst (Scheme 1). In this case, one of the two aryl groups
has already been installed in substrates 1. Recently, Zhu
and co-workers reported an elegant palladium-catalyzed
one-pot reaction (Sonogashira–carbopalladation–C–H ac-
tivation–C–C bond-forming sequence) of simple propiol-
amides 3, which introduced two aryl groups in one
process with good stereoselectivities.5d Although Zhu’s
method showed good electronic compatibility and regio-
selective annulations of anilide substrates, a need still ex-
ists to develop an efficient methodology to expand the
potential substrates. To this end, we combined the
Sonogashira reaction and the well-known Heck–Suzuki–
Miyaura domino reaction into a one-pot reaction. The
Heck–Suzuki–Miyaura reaction is electronically compat-
ible with substituents on the anilide ring and mechanisti-
cally proceeds via regiospecific ring formation. Here,
we describe our new one-pot reaction for the synthesis of
3-(diarylmethylene)oxindoles and discuss the potential
substrates and applications.
SYNLETT 21709013, 2415, 1993–1997
Advanced online publication: 13.08.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339690; Art ID: ST-2013-U0486-L
© Georg Thieme Verlag Stuttgart · New York

1994
G. R. Dong et al.
LETTER
Table 1 Heck–Suzuki–Miyaura Reaction of 4 under Sonogashira Reaction Conditions
Ph
Ph
Sonogashira
reaction
conditions
Ph
O
Br
PhB(OH)2
(1.2 equiv)
N
N
O
Me
Me
4
5
Entry
Conditions
Temp (°C)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
PdCl2(PPh3)2 (5 mol%), CuI (10 mol%), Et3N–THF (1:1)
PdCl2(PPh3)2 (5 mol%), CuI (10 mol%), Et3N–THF (1:1)
PdCl2(PPh3)2 (5 mol%), CuI (15 mol%), Et3N (3 equiv), EtOAc
PdCl2(PPh3)2 (5 mol%), CuI (15 mol%), Et3N (3 equiv), EtOAc
Pd(OAc)2 (10 mol%), Ag2O (1.5 equiv), K2CO3 (3 equiv), MeCN
Pd(PPh3)4 (10 mol%), CuI (5 mol%), NaOAc (3 equiv), DMF
Pd(PPh3)4 (10 mol%), CuI (5 mol%), NaOAc (3 equiv), DMF
Pd(PPh3)4 (10 mol%), CuI (5 mol%), NaOAc (3 equiv), DMF
25
70
25
60
70
60
60
90
24
12
24
24
16
1
n.r.a
14
n.r.a
8
58
31
71
98
24
24
a No reaction.
71% (Table 1, entry 7). Finally, propiolamide 4 was ex- reaction of 6e, which bears an electron-donating methoxy
posed to Zhu’s conditions at a higher temperature (90 °C) group at the 5-position of the anilide yielded the desired
to provide 5 in excellent yield (98%, Table 1, entry 8). product 7g in 52% yield along with the C–H activated by-
These results implied that Zhu’s conditions would be fea- product (7g-1) in 10% yield (Table 2, entry 7). This result
sible not only for combining all three palladium-catalyzed implied that electron-rich anilides are prone to react with
reactions in one-pot, but also for differentiating the remaining aryl iodides according to the mechanisms of
Sonogashira and Heck–Suzuki–Miyaura reactions in fa- Zhu’s domino reaction (Scheme 2).
vor of the Sonogashira reaction. We selected one-pot re-
action conditions based on the above results. First, the
Sonogashira reaction was performed at 60 °C for one hour
as Zhu’s conditions. After addition of the corresponding
aryl boronic acid to the reaction mixture, the reaction tem-
perature was increased to 90 °C to initiate the Heck–
Suzuki–Miyaura reaction.
Table 2 Synthesis of Symmetrically Substituted 3-(Diarylmeth-
ylene)oxindoles 5 and 7a
Ar
a) ArI, Pd(PPh3)4
CuI, NaOAc
Ar
Br
DMF, 60 °C, 1 h
O
R
N
O
b) ArB(OH)2
90 °C, 24 h
N
R
Me
Me
We first applied the selected reaction conditions to the
synthesis of symmetrically substituted 3-(diarylmethyl-
ene)oxindoles 5/7 (Table 2). Under our conditions propiol-
amide 6a readily transformed to 3-(diphenyl-
methylene)oxindole (5) in good yield (81%, Table 2, entry
1). Next, the influence of substituents on the aryl boronic
acids was investigated. Reactions with both 4-methoxy
and 4-chloro benzene boronic acid occurred readily to
provide the desired products 7a and 7b in 85% and 80%
yield, respectively (Table 2, entries 2 and 3). 4-Nitroben-
zene boronic acid required an elevated reaction tempera-
ture for the Heck–Suzuki–Miyaura process to complete
the reaction. The product 7c was obtained in 67% yield,
likely due to the low reactivity of 4-nitrobenzene boronic
acid toward transmetalation (Table 2, entry 4). Next, the
substituent effect of the anilide ring was examined. Under
standard conditions propiolamides 6b–d with electron-
withdrawing groups (Cl, CF3, and NO2) at the 5-position
of the anilide were efficiently transformed to oxindoles
7d–f in good yields (Table 2, entries 5–7). However, the
6
5,7
Entry
6
R
Ar
Ph
5/7
Yield (%)
1
2
3
4
5
6
7
8
6a
6a
6a
6a
6b
6c
6d
6e
H
5
81
85
80
67b
65
76
73
52c
H
4-MeOC6H4
7a
7b
7c
7d
7e
7f
7g
H
4-ClC6H4
H
4-O2NC6H4
Cl
Ph
Ph
Ph
Ph
CF3
NO2
OMe
a Reaction conditions: 6 (0.1 mmol), ArI (1.1 euiv), Pd(PPh3)4 (10
mol%), CuI (5 mol%), NaOAc (3.0 equiv), DMF, 60 °C, 1 h; then
ArB(OH)2 (1.2 equiv), 90 °C, 24 h.
b Heck–Suzuki–Miyaura reaction was conducted at 110 °C.
c C–H activated by-product 7g′ was isolated in 10% yield.
Synlett 2013, 24, 1993–1997
© Georg Thieme Verlag Stuttgart · New York

LETTER
Palladium-Catalyzed One-Pot Reaction
1995
E/Z-Isomerization of the product itself under the tested re-
action conditions could be a reason for the resulting ste-
reochemistry. However, when we re-exposed pure E- and
Z-isomers of 8a and 8b to the reaction conditions, isomer-
ized products were obtained in less than 20% yield.10
Thus, the stereochemical outcomes of our reactions are
mainly decided at Suzuki–Miyaura reaction step rather
than E/Z-isomerization after product formation. Similar
E/Z-isomerization of transition-metal-catalyzed reactions
has been explained by isomerization of vinyl metal inter-
mediates through zwitterionic metal carbene11 or η2-vi-
nyl–metal complexes.12 Here, we propose a plausible
mechanism for E/Z mixture formation based on the zwit-
terionic metal carbene route, which could explain the ste-
reochemistry results under our reaction conditions
(Scheme 3). During the Heck–Suzuki–Miyaura reaction,
an alkyne of propiolamide inserts into the palladium–car-
bon bond via syn addition to give the vinyl–palladium in-
termediate (E)-9. Direct isomerization of (E)-9 to (Z)-9
seems unlikely because rotation around the 3-methylenyl
double bond is not feasible. However, zwitterion 10a, a
resonance structure of (E)-9, has an s-trans single bond at
the 3-methylenyl double bond. Rotation around the single
bond of 10a would produce s-cis 10b, which is a reso-
nance structure of (Z)-9.This mechanism explains the ste-
reoselectivity of the Heck–Suzuki–Miyaura reaction,
which was significantly affected by the substituents of the
aryl iodides. When 4-methoxyphenyl iodide was used
(Ar1 = 4-MeOC6H4), the corresponding vinyl–palladium
intermediate had an additional resonance structure 11,
which increases the single bond character of the 3-meth-
lylenyl double bond and thus facilitated interconversion
between (E)-9 and (Z)-9. In the case of aryl iodides bear-
ing electron-withdrawing groups (Cl, NO2, Ac), the corre-
sponding resonance structure of 10a would be less likely
to form due to inductive destabilization by substituents.
This is the reason for the high stereoselectivity of aryl io-
dides with electron-withdrawing groups.
Ph
Ph
OMe
Br
MeO
Ph
O
H
PhI
6e
carbopalla-
dation, C–H
activation
Sonogashira
reaction
N
N
O
Me
Me
Br
7g'
Scheme 2 Formation of the C–H activated by-product 7g′
Based on these results, we expanded the application of our
reaction to the synthesis of unsymmetrically substituted
3-(diarylmethylene)oxindoles 8 expecting stereoselective
formation of the desired products (Table 3). Unexpected-
ly, all reactions with phenyl iodide and three different aryl
boronic acids afforded the oxindoles 8a–c as 1:1 mixtures
of E/Z stereoisomers in moderate yields (Table 3, entries
1–3). In addition, the treatment with 4-methoxyphenyl io-
dide followed by phenyl boronic acid gave the E-isomer
as a major component of product 8a (E/Z = 1.6:1; Table 3,
entry 4). The resulting stereochemistry was completely
opposite to our expectation of the Z preference, based on
the generally accepted mechanism that migratory inser-
tion in Heck reaction proceeds via syn addition. Note that
when the substituent of aryl iodide was changed to an
electron-withdrawing group, the stereoselectivity was re-
versed to give Z-isomers as the major products, consistent
with the expected results (Table 3, entries 5–7).
Table 3 Synthesis of Unsymmetrically Substituted 3-(Diarylmeth-
ylene)oxindoles 8a
a) Ar1I, Pd(PPh3)4
Ar2
Ar1
CuI, NaOAc
DMF, 60 °C, 1 h
Br
O
b) Ar2B(OH)2
90 °C, 24 h
N
N
O
Me
Me
6a
8
Entry Ar1
Ar2
8
Yield Ratioc
Based on our proposed mechanism, we considered op-
tions for increasing the stereoselectivity of our reactions.
In a cationic pathway, one of the mechanisms for the Heck
reaction, the vinyl–palladium species possesses a positive
charge at the palladium atom, as shown in structure 12;
thus, the corresponding resonance structure 10a is unlike-
ly to form. We explored the effects of silver additives
known for changing palladium catalytic cycles from a
neutral to a cationic pathway (Table 4).13 As expected, ad-
dition of AgOAc and Ag2CO3 to the second step of the re-
action dramatically changed the stereoselectivities from
1.6:1 (E/Z, Table 3, entry 4) to 1:2 and 1:3, respectively
(Table 4, entries 1 and 2). However, yields were very low
due to incomplete reactions. The use of AgBF4 as an ad-
ditive increased the yield to 52%, but showed almost no
effect on the stereoselectivity (E/Z = 1.4:1; Table 4, entry
3). AgOTf was the most promising silver additive, afford-
ing the product 8a in 68% yield with enhanced stereose-
lectivity (E/Z = 1:1.2, Table 4, entry 4). We applied these
reaction conditions and AgOTf to other substrates, which
(%)b
(E:Z)
1
2
3
4
5
6
7
Ph
Ph
Ph
4-MeOC6H4
8a
8b
8c
8a
8b
8c
8d
52
57
52
70
77
73d
82d
1:1
4-ClC6H4
1:1
4-O2NC6H4
1:1
4-MeOC6H4
4-ClC6H4
Ph
Ph
Ph
Ph
1.6:1
1:3.4
1:10
1:4.5
4-O2NC6H4
4-AcC6H4
a Reaction conditions: 6a (0.1 mmol), Ar1I (1.1 equiv), Pd(PPh3)4 (10
mol%), CuI (5 mol%), NaOAc (3.0 equiv), DMF, 60 °C, 1 h; then
Ar2B(OH)2 (1.2 equiv), 90 °C, 24 h.
b Combined yield of E- and Z-products.
c Ratio between isolated yield of E- and Z-products.
d Heck–Suzuki–Miyaura reaction was conducted at 110 °C.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1993–1997

1996
G. R. Dong et al.
LETTER
BrL2Pd
Table 4 Effects of Silver Additives on E/Z Stereoselectivitya
Ar1
Ar1
O
PdL2Br
O
a) Ar1I, Pd(PPh3)4
CuI, NaOAc
Ar2
Ar1
O
DMF, 60 °C, 1 h
Br
N
N
Me
Me
(E)-9
(Z)-9
b) Ar2B(OH)2
N
N
O
Ag additive (1.1 equiv)
90 °C, 24 h
Me
Me
6a
8
Ar1
Entry Ar1
Ar2
Silver
additive
8
Yield Ratioc
PdL2Br
O
BrL2Pd
Ar1
(%)b (E/Z)
O
N
1
2
3
4
5
6
7
8
4-MeOC6H4 Ph
4-MeOC6H4 Ph
4-MeOC6H4 Ph
4-MeOC6H4 Ph
AgOAc 8a 25
Ag2CO3 8a 25
1:2
N
Me
10b
10a
1:3
Me
Ar1 = 4-MeOC6H4
AgBF4
AgOTf
AgOTf
8a 52
8a 68
8b 71
8a 70
8b 45
8c 56d
1.4:1
1:1.2
1:8
L2Pd
OMe
Ar1
O
BrL2Pd
4-ClC6H4
Ph
O
N
Ph
Ph
Ph
4-MeOC6H4 AgOTf
4-ClC6H4 AgOTf
4-O2NC6H4 AgOTf
2.5:1
7:1
N
Me
Me
12
11
5.2:1
Scheme 3 Plausible mechanism for E/Z-interconversion of vinyl–
palladium intermediates
a Reaction conditions: 6a (0.1 mmol), Ar1I (1.1 equiv), Pd(PPh3)4 (10
mol%), CuI (5 mol%), NaOAc (3.0 equiv), DMF, 60 °C, 1 h; then
Ar2B(OH)2 (1.2 equiv), silver additive (1.1 equiv), 90 °C, 24 h.
b Combined yield of E- and Z-products.
showed low stereoselectivity without silver addition.
When AgOTf was added to the reaction with 4-chlorophe-
nyl iodide and phenyl boronic acid, enhanced stereoselec-
tivity (E/Z = 1:3.4 to 1:8) was achieved in similar yield
(Table 4, entry 5). Reaction with phenyl iodide under pre-
vious conditions showed no stereoselectivity regardless of
three different aryl boronic acid partners (E/Z = 1:1; Table
3, entries 1–3). However, with AgOTf addition, all three
reactions showed good stereoselectivity with E preference
(E/Z = 2.5–7:1; Table 4, entries 6–8). Thus, AgOTf
proved to be a good additive for our one-pot reaction for
stereoselective approach to unsymmetrically substituted
3-(diarylmethylene)oxindoles.
c Ratio between isolated E- and Z-products.
d Heck–Suzuki–Miyaura reaction was conducted at 110 °C.
hexane–EtOAc) to yield 3-(diarylmethylene)oxindoles 5, 7a–h, 8a–
d). In the case of using silver additives, it was added with aryl bo-
ronic acid at the second step.
(E)-3-[(4-Chlorophenyl)(phenyl)methylene]-1-methylindolin-2-
one [(E)-8b]14
Yellow solid; mp 54.8 °C; Rf = 0.35 (silica gel; hexanes–EtOAc,
4:1). 1H NMR (500 MHz, CDCl3): δ = 7.41–7.18 (m, 9 H), 7.19 (td,
J = 7.5, 1.0 Hz, 1 H), 6.78 (d, J = 7.5 Hz, 1 H), 6.73 (td, J = 7.5, 1.0
Hz, 1 H), 6.53 (dd, J = 7.5, 0.5 Hz, 1 H), 3.20 (s, 3H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 166.8, 153.0, 143.6, 139.8, 139.7, 135.5,
131.1, 130.2, 129.4, 129.4, 129.2, 128.1, 124.7, 123.2, 123.0, 121.6,
108.0, 26.0 ppm. HRMS (EI): m/z calcd for C22H16ClNO [M+]:
345.0920; found: 345.0919.
In conclusion, a novel and effective palladium-catalyzed
one-pot reaction for the synthesis of 3-(diarylmeth-
ylene)oxindoles was developed. The reaction enables the
rapid synthesis of various 3-(diarylmethylene)oxindoles
from simple propiolamides. Stereoselective synthesis of
unsymmetrically substituted 3-(diarylmethylene)oxin-
doles was also achieved using AgOTf as an additive.
(Z)-3-[(4-Chlorophenyl)(phenyl)methylene]-1-methylindolin-2-
one [(Z)-8b]14
Yellow solid; mp 59.0 °C; Rf = 0.37 (silica gel; hexanes–EtOAc,
4:1). IR (film): 3054, 1698, 1606, 1486, 1335, 1090 cm–1. 1H NMR
(500 MHz, CDCl3): δ = 7.48–7.43 (m, 3 H), 7.35–7.27 (m, 6 H),
7.17 (td, J = 7.5, 1.0 Hz, 1 H), 6.77 (d, J = 8.0 Hz, 1 H), 6.68 (td,
J = 7.5, 1.0 Hz, 1 H), 6.42 (dd, J = 7.5, 0.5 Hz, 1 H), 3.20 (s, 3 H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 166.9, 153.0, 143.5, 141.0,
138.4, 135.3, 131.6, 129.5, 129.5, 129.2, 129.1, 128.2, 124.7, 123.4,
123.2, 121.6, 107.9, 26.0 ppm. HRMS (EI): m/z calcd for
C22H16ClNO [M+]: 345.0920; found: 345.0916.
General Procedure for the Palladium-Catalyzed One-Pot Reac-
tion
To a stirred solution of N-methylpropiolamide 6a–e (0.5 mmol, 1.0
equiv) in DMF (5 mL) were added the corresponding aryl iodide
(0.55 mmol, 1.1 equiv), CuI (0.025 mmol, 5 mol%), NaOAc (1.5
mmol, 3.0 equiv), and Pd(PPh3)4 (0.05 mmol, 10 mol%) at 25 °C.
The reaction mixture was stirred at 60 °C for 1 h. Then, the corre-
sponding aryl boronic acid (0.6 mmol, 1.2 equiv) was added to the
mixture. The reaction temperature was raised to 90 °C or 110 °C.
After 24 h stirring at the indicated temperature, the mixture was
cooled to 25 °C and diluted with EtOAc (200 mL). The organic lay-
er was washed with H2O (3 × 30 mL) and brine (30 mL), then dried
(Na2SO4), filtered, and concentrated under reduced pressure. The
crude residue was purified by column chromatography (silica gel,
Acknowledgment
This work was supported by Research Fund 2011 of The Catholic
University of Korea.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
Synlett 2013, 24, 1993–1997
© Georg Thieme Verlag Stuttgart · New York

LETTER
Palladium-Catalyzed One-Pot Reaction
1997
(5) For selective examples for the synthesis of 3-(diaryl-
methylene)oxindoles, see: (a) Yanada, R.; Obika, S.;
Oyama, M.; Takemoto, Y. Org. Lett. 2004, 6, 2825.
(b) Yanada, R.; Obika, S.; Inokuma, T.; Yanada, K.;
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