Synthesis of 3-(aminomethylene)-2-oxoindolines by palladium-catalyzed annulation of 3-chloro-2-iodo-N-arylacrylamides with amides or amines

Article abstract of DOI:10.1039/c1cc11602a

A new palladium-catalyzed C-H bond activation-annulation-amination tandem method was presented for selectively synthesizing 3-(aminomethylene)-2- oxoindolines. In the presence of Pd(dba)₂, xantphos (L8), AgOAc and Na₂CO₃,

Full text of DOI:10.1039/c1cc11602a

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COMMUNICATION
Synthesis of 3-(aminomethylene)-2-oxoindolines by palladium-catalyzed
annulation of 3-chloro-2-iodo-N-arylacrylamides with amides or aminesw
Guo-Bo Deng,a Zhi-Qiang Wang,a Ren-Jie Song,a Ming-Bo Zhou,a Wen-Ting Wei,a
Peng Xiea and Jin-Heng Li*b
Received 20th March 2011, Accepted 23rd May 2011
DOI: 10.1039/c1cc11602a
A new palladium-catalyzed C–H bond activation–annulation–
amination tandem method was presented for selectively
synthesizing 3-(aminomethylene)-2-oxoindolines. In the presence
of Pd(dba)2, xantphos (L8), AgOAc and Na2CO3, a variety of
3-chloro-2-iodo-N-arylacrylamides underwent the reaction with
Scheme 1 A new route to 3-(aminomethylene)-2-oxoindolines.
amides or amines to afford the corresponding 3-(aminomethylene)-
importance of 3-(aminomethylene)-2-oxoindolines,2 the develop-
2-oxoindolines in moderate to good yields.
ment of new methods involving the C–H bond activation
strategy for their preparation is desirable.5a,6j Here, we report
a novel route to (Z)-3-(aminomethylene)-2-oxoindolines by
palladium-catalyzed C–H bond activation–annulation–amination
of 3-chloro-2-iodo-N-arylacrylamides with amides or amines
(Scheme 1).8,9
3-Methyleneindolin-2-ones,1–7 particularly 3-(aminomethylene)-
2-oxoindolines,2 are pharmacologically important components
of numerous biologically active natural products and medicinally
significant compounds.1 The common classical methods used
for the construction of the 3-methyleneindolin-2-one framework
are the intermolecular condensation of oxindoles with diaryl
ketones, and often they are limited due to nonavailability of
suitably substituted starting precursors and unsatisfactory
selectivity.3 Therefore, considerable effort has been made on
the development of efficient metal-catalyzed methods for
selectively synthesizing 3-methyleneindolin-2-ones.4–6 Among
these methods, palladium-catalyzed reactions that involve
the arene C–H bond functionalization are particularly
attractive4,5 because they can avoid the use of expensive
2-haloanilide or 2-(alkynyl)phenylisocyanate reagents.6 Zhu
and co-workers have disclosed Pd(0)-catalyzed arene C–H
bond activation domino reactions of N-arylpropiolamides
with aryl halide electrophilic reagents leading to the corres-
ponding 3-(diarylmethylenyl)oxindoles under basic conditions.4
Our group also found that N-arylpropiolamides could
react with a wide range of nucleophilic reagents, such as
phthalimide, acids, ArI(OAc)2 and alcohols, through a Pd(II)-
catalyzed oxidative C–H bond functionalization process
with the aid of oxidants.5 However, only an amide, phthalimide,
was employed to react with N-arylpropiolamides leading
to (E)-(2-oxindolin-3-ylidene)phthalimides.5a In view of the
Our investigation began with the reaction of 3-chloro-2-
iodo-N-methyl-N-phenylacrylamide (1a) with benzamide (2a)
to determine the optimal reaction conditions (Table 1).10
Initially, a series of ligands L1–L10 were examined, and
xantphos (L8) gave the best results (entries 1–12). While the
reaction of substrate 1a with 2a, Pd(OAc)2, AgOAc and
Cs2CO3 afforded a trace of the desired product 3 without
ligands (entry 1), the yield of 3 was increased to 20% in the
presence of PPh3 (L1) (entry 2). Gratifyingly, the yield was
enhanced to 45% using xantphos (L8) (entry 10). Notably,
Na2CO3 was more effective than Cs2CO3 (entries 8 and 9).
Subsequently, a number of other Pd catalysts, such as PdCl2,
Pd(PPh3)2Cl2, Pd(PPh3)4 and Pd(dba)2, were tested, and they
were more efficient than Pd(OAc)2 (entries 13–16). The results
showed that the Ag effect affected the reaction (entries 16–22).
The activities of other Ag salts, such as CF3CO2Ag, Ag2O or
Ag2CO3, were lowered slightly in terms of yields (entries 16–19).
We found that the amount of AgOAc has a fundamental
influence on the reaction (entries 20–22): the best results were
obtained at 2 equiv. AgOAc. From the reaction temperature
examination, it turned out that the reaction at 50 1C gave the
highest yield after prolonging the reaction time (entries 23 and 24).
However, the yield of 3 was reduced to 58% in the presence of
5 mol% Pd(dba)2 (entry 25).
a Key Laboratory of Chemical Biology & Traditional Chinese
Medicine Research (Ministry of Education),
Hunan Normal University, Changsha 410081, China
b State Key Laboratory of Chemo/Biosensing and Chemometrics,
College of Chemistry and Chemical Engineering, Hunan University,
Changsha 410082, China. E-mail: jhli@hunnu.edu.cn;
Fax: +86731 8887 2531; Tel: +86731 8887 2576
As shown in Table 2, the scope of both 3-chloro-2-iodo-N-
arylacrylamides 1 with amides 2 was explored under the
optimal conditions. The results demonstrated that substrate
1b with a N-Bn group was reacted with amide 2a, Pd(dba)2,
L8, AgOAc and Na2CO3 smoothly to afford the target
product 4 in 60% yield (entry 1), which was less active than
w Electronic supplementary information (ESI) available. CCDC
822997. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c1cc11602a
c
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Chem. Commun., 2011, 47, 8151–8153 8151

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Table 1 Screening optimal conditionsa
Table 2 Palladium-catalyzed tandem reactions of 3-chloro-2-iodo-N-
arylacrylamides (1) with amides (2)a
Entry R/R1 in substrate 1 R2 in amide 2
T/1C Yieldb (%)
1
H/Bn (1b)
C6H5 (2a)
C6H5 (2a)
C6H5 (2a)
C6H5 (2a)
C6H5 (2a)
p-MeC6H4 (2b)
m-MeC6H4 (2c)
p-MeOC6H4 (2d)
o-MeOC6H4 (2e)
p-ClC6H4 (2f)
o-BrC6H4 (2g)
5-Mepyridin-2-yl (2h) 50
Vinyl (2i)
Me (2j)
OMe (2k)
OBn (2l)
50
50
80
50
50
50
50
80
50
50
50
60 (4)
74 (5)
60 (6)
73 (7)
79 (8)
74 (9)
60 (10)
68 (11)
73 (12)
93 (13)
78 (14)
61 (15)
51 (16)
65 (17)
75 (18)
80 (19)
2
p-MeO/Me (1c)
o-Me/Me (1d)
p-Cl/Me (1e)
p-CF3/Me (1f)
H/Me (1a)
H/Me (1a)
H/Me (1a)
H/Me (1a)
H/Me (1a)
H/Me (1a)
H/Me (1a)
H/Me (1a)
H/Me (1a)
H/Me (1a)
H/Me (1a)
3c
4
Entry [Pd] (mol%) Ligand [Ag] (equiv.)
Base
Yieldb (%)
5
6
7
8
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
—
AgOAc (1)
AgOAc (1)
AgOAc (1)
AgOAc (1)
AgOAc (1)
AgOAc (1)
AgOAc (1)
AgOAc (1)
AgOAc (1)
AgOAc (1)
AgOAc (1)
AgOAc (1)
AgOAc (1)
AgOAc (1)
AgOAc (1)
AgOAc (1)
Cs2CO3 Trace
Cs2CO3 20
Cs2CO3 Trace
Cs2CO3 30
Cs2CO3 21
Cs2CO3 Trace
Cs2CO3 Trace
Cs2CO3 30
Na2CO3 35
Na2CO3 45
Na2CO3 25
Na2CO3 Trace
Na2CO3 67
Na2CO3 65
Na2CO3 66
Na2CO3 68
L1
L2
L3
L4
L5
L6
L7
L7
L8
L9
L10
L8
9
10
11
12
13
14
15
16
80
50
50
50
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23c
24d
a
Reaction conditions:
(10 mol%), L8 (10 mol%), AgOAc (2 equiv.) and Na2CO3 (2 equiv.)
1
(0.3 mmol), 2 (0.45 mmol), Pd(dba)2
Pd(PPh3)2Cl2 L8
b
in toluene (2 mL) for 13 h. Isolated yield. For 24 h.
c
Pd(PPh3)4
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
L8
L8
L8
L8
L8
L8
L8
L8
L8
L8
L8
CF3CO2Ag (1) Na2CO3 46
Ag2O (1)
Na2CO3 56
Na2CO3 50
Na2CO3 79
Na2CO3 85
Na2CO3 80
Na2CO3 86
Na2CO3 72
Na2CO3 58
with substrate 1a leading to the corresponding products 16
and 17 in moderate yields (entries 13 and 14). It is noteworthy
that annulation of substrate 1a with carbamates 2k or 2l is
successful under the same conditions (entries 15 and 16).
In light of the above results, a variety of amines were
employed for the annulation reaction with 3-chloro-2-iodo-
N-methyl-N-arylacrylamide (1a) under the optimal conditions
(Scheme 2). However, the reaction between substrate 1a and
aniline gave a mixture of Z/E-isomers 20 in a low total yield.
To our delight, amines with a para-substituent on the aryl
ring were selectively treated with substrate 1a, providing
the corresponding products 21 and 22 in moderate yields.
Cyclohexanamine reacted with substrate 1a, Pd(dba)2, L8,
AgOAc and Na2CO3 in 32% yield.
Ag2CO3 (1)
AgOAc (1.5)
AgOAc (2)
AgOAc (3)
AgOAc (1)
AgOAc (1)
AgOAc (1)
25c,e Pd(dba)2
a
Reaction conditions: 1a (0.3 mmol), 2a (0.45 mmol), [Pd] (10 mol%),
ligand (10 mol%), [Ag] (1 equiv.) and base (2 equiv.) in the solvent
b
c
d
(2 mL) at 80 1C for 8 h. Isolated yield. At 50 1C for 13 h. At room
temperature for 96 h. 5 mol% of Pd(dba)2 was added.
e
N-Me-substituted substrate 1a (entry 23 in Table 1). Conse-
quently, a number of N-Me-substituted substrates 1c–1f were
tested (entries 2–5). To our delight, substrates 1c–1f, bearing
electron-donating or electron-deficient groups on the N-aryl
ring, were compatible under the optimal conditions. Substrate
1d with an o-Me group, for instance, underwent the reaction
with amide 2a in 60% yield (entry 3). Good yield was still
achieved from substrate 1f with a p-CF3 group (entry 5).
Subsequently, a variety of amides 2b–2l were evaluated under
the standard conditions (entries 6–16). Screening disclosed
that the annulation had a wide range of amides compatibility,
including arylamides, vinylamides, alkylamides and carba-
mates. Moreover, several functional groups, such as Me,
MeO, Cl or Br, on the aryl ring were tolerated well (entries
6–11). It was noted that amide 2g with an o-Br group was
successfully annulated with substrate 1a, Pd(dba)2, L8,
AgOAc and Na2CO3, furnishing the desired Br-containing
product 14 in 78% yield (entry 11), which provides a route
to introduction of a new group at the Br-substituted position.
Gratifyingly, heteroarylamide 2h was also suitable for the
reaction (entry 12). In the presence of Pd(dba)2, L8, AgOAc
and Na2CO3, acrylamide (2i) or acetamide (2j) could react
To our surprise, an acetoxypalladation product 24, not
(Z)-3-(chloromethylene)-1-methylindolin-2-one, was obtained
exclusively without amides 2. However, product 24 could not
be converted into product 3 under the present optimal conditions
(Scheme 3). Therefore, a possible mechanism as outlined in
Scheme 3 was proposed.2e,4,5,8,9 Oxidative addition of Pd(0) to
the C–X bond of substrate 1 yields intermediate A, followed
by arene C–H bond activation affording intermediate B.4,5,8
Sequential reductive elimination and oxidative addition of
intermediate B results in intermediate C, which is supported
Scheme 2 Annulation of substrate (1a) with amines (2).
c
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tandem protocol for the synthesis of (Z)-3-(aminomethylene)-
2-oxoindolines. This method allows two new bonds, a C–C
bond and a C–N bond, formation in one-step by a sequential
C–H bond activation/annulation/amination tandem process.
Importantly, this method displays high substrates compatibility,
which makes it more attractive for organic synthesis and
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This research was supported by the Scientific Research Fund
of Hunan Provincial Education Department (No. 08A037) and
NSFC (No. 20872112).
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c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 8151–8153 8153