Synthesis of (2-oxoindolin-3-ylidene)methyl acetates involving a C-H functionalization process

Article abstract of DOI:10.1021/ol8006315

A novel palladium-catalyzed oxidative C-H functionalization protocol for the synthesis of (2-oxoindolin-3-ylidene)methyl acetates has been developed. In the presence of Pd(OAc)₂ and Phl(OAc)₂, a variety of N-arylpropiolamides underwent the C-H functionalization reaction with acids to afford the corresponding (E)-(2-oxoindolin-3-ylidene)methyl acetates selectively In moderate to excellent yields.

Full text of DOI:10.1021/ol8006315

ORGANIC
LETTERS
2008
Vol. 10, No. 9
1875-1878
Synthesis of
(2-Oxoindolin-3-ylidene)methyl Acetates
Involving a C-H Functionalization
Process
Shi Tang,†,‡ Peng Peng,† Zhi-Qiang Wang,† Bo-Xiao Tang,† Chen-Liang Deng,†
Jin-Heng Li,*,†,§ Ping Zhong,§ and Nai-Xing Wang*,‡
College of Chemistry and Materials Science, Wenzhou UniVersity, Wenzhou, 325035,
China, Key Laboratory of Chemical Biology & Traditional Chinese Medicine
Research, Hunan Normal UniVersity, Changsha 410081, China, and Technical Institute
of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100080, China
jhli@hunnu.edu.cn
Received March 19, 2008
ABSTRACT
A novel palladium-catalyzed oxidative C-H functionalization protocol for the synthesis of (2-oxoindolin-3-ylidene)methyl acetates has been
developed. In the presence of Pd(OAc)2 and PhI(OAc)2, a variety of N-arylpropiolamides underwent the C-H functionalization reaction with
acids to afford the corresponding (E)-(2-oxoindolin-3-ylidene)methyl acetates selectively in moderate to excellent yields.
3-Methyleneindolin-2-ones are pharmacologically important
compounds that display great potential utilizations in many
major therapeutic areas, such as oncology, inflammation,
CNS, immunology, and endocrinology.1 For example,
SU11248 was commercialized by Pfizer, Inc. in 2006 to treat
renal cell carcinoma and gastrointestinal stromal tumors
(Figure 1). The traditionally synthetic method for these
† Hunan Normal University.
‡ Technical Institute of Physics and Chemistry.
§ Wenzhou University.
(1) (a) Mohammadi, M.; McMahon, G.; Sun, L.; Tang, C.; Hirth, P.;
Yeh, B. K.; Hubbard, S. R.; Schlessinger, J. Science 1997, 276, 955. (b)
Sun, L.; Tran, N.; Liang, C.; Tang, F.; Rice, A.; Schreck, R.; Waltz, K.;
Shawver, L. K.; McMahon, G.; Tang, C. J. Med. Chem. 1999, 42, 5120.
(c) Hare, B. J.; Walters, W. P.; Caron, P. R.; Bemis, G. W. J. Med. Chem.
2004, 47, 4731. (d) Noble, M. E. M.; Endicott, J. A.; Johnson, L. N. Science
2004, 203, 1800. (e) Liao, J. J.-L. J. Med. Chem. 2007, 50, 409. (f) Drugs
Future 1990, 15898. (g) Robinson, R. P.; Reiter, L. A.; Barth, W. E.;
Campeta, A. M.; Cooper, K.; Cronin, B. J.; Destito, R.; Donahue, K. M.;
Falkner, F. C.; Fiese, E. F.; Johnson, D. L.; Kuperman, A. V.; Liston, T. E.;
Malloy, D.; Martin, J. J.; Mitchell, D. Y.; Rusek, F. W.; Shamblin, S. L.;
Wright, C. F. J. Med. Chem. 1996, 39, 10. (h) Bramson, H. N.; Corona, J.;
Davis, S. T.; Dickerson, S. H.; Edelstein, M.; Frye, S. V.; Gampe, R. T.,
Jr.; Harris, P. A.; Hassell, A.; Holmes, W. D.; Hunter, R. N.; Lackey, K. E.;
Lovejoy, B.; Luzzio, M. J.; Montana, V.; Rocque, W. J.; Rusnak, D.;
Shewchuk, L.; Veal, J. M.; Walker, D. H.; Kuyper, L. F. J. Med. Chem.
2001, 44, 4339. (i) Graczyk, P. P. J. Med. Chem. 2007, 50, 5773.
Figure 1. Two commercial medicines.
compounds is via the intermolecular condensation of an
oxindole with a diaryl ketone.1,2 However, the method is
10.1021/ol8006315 CCC: $40.75
Published on Web 04/08/2008
2008 American Chemical Society

limited due to its low selectivity and tedium. Recently,
considerable effort has been devoted to develop transition
metals, in particular, palladium-catalyzed domino reactions
for the synthesis of 3-methyleneindolin-2-ones to solve these
drawbacks (Scheme 1).3,5 However, most of these reactions
is of considerable importance. Very recently, we developed
a novel protocol for constructing two bonds, a C-C bond
and a C-N bond, via a sequential intermolecular aminopal-
ladation/ortho-arene C-H activation process (eq 3 in Scheme
1).4 As a continuing interest in constructing the oxindole
skeleton, we report herein that (2-oxoindolin-3-ylidene)-
methyl acetates could be prepared successfully by the
acetoxypalladation/C-H functionalization of anilides in the
presence of PhI(OAc)2.
Scheme 1. Three Protocols for the Synthesis of Oxindoles
Table 1. Screening Conditionsa
entry
PhI(OAc)2 (equiv)
solvent
time (h)
yield (%)b
1c
2d
3e
4
5
6
2.0
2.0
2.0
2.0
2.0
1.2
1.2
1.2
1.2
1.2
MeCN
MeCN
MeCN
MeCN
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
10
10
10
10
2
2
5
5
2
trace
56
80
89
91
90
89
0
require the use of 2-haloanilides or 2-(alkynyl)phenylisocy-
anates as the starting materials (eq 1 in Scheme 1). An
interesting approach is the palladium-catalyzed domino
carbopalladation/C-H activation/C-C bond-forming reac-
tion that uses an anilide sp2 C-H bond as one of the coupling
partners (eq 2).3c,d Although all the reported palladium-
catalyzed transformations provided an efficient and selective
route to the synthesis of methylenyloxindoles, only carbon
atoms were introduced to the triple bonds to form two
carbon-carbon bonds in all cases.3
7f
8g
9h
10i
38
88
2
a Reaction conditions: 1 (0.2 mmol), Pd(OAc)2 (10 mol %), PhI(OAc)2
and HOAc (10 equiv) in solvent (3 mL) at 80 °C. b Isolated yield. c Without
HOAc, a 17% yield of 1-methyl-3-(diphenylmethylene)indolin-2-one (4)
was isolated. d HOAc (2 equiv). A 6% yield of 4 was isolated. e HOAc (5
equiv). f Pd(OAc)2 (5 mol %). g Without Pd(OAc)2. h At room temperature.
i At 100 °C.
Many bioactive 3-methyleneindolin-2-ones include the
carbon-heteroatom bonds at the terminal of the 3-methylene
group.1f–h Tenidap (commercialized in 1993; Pfizer, Inc.),
for instance, is an anti-inflammatory medicine for the therapy
of arthritis, etc. (Figure 1).1f Thus, the development of new
palladium-catalyzed routes to synthesize these indolin-2-ones
As demonstrated in Table 1, N-methyl-N,3-diphenylpro-
piolamide (1) was employed as the starting substrate to
explore the optimal conditions.5 Initially, the amount of
HOAc was examined, and the results showed that the amount
of HOAc has a fundamental influence on the reaction in
terms of yield and rate (entries 1-5). Without HOAc, a trace
amount of the target acetoxypalladation product 3 was
detected by GC-MS analysis from the reaction of amide 1
with Pd(OAc)2 and PhI(OAc)2 in MeCN (entry 1), and the
product 3 was enhanced sharply to 56% in the presence of
2 equiv of HOAc (entry 2).6 In the presence of 5 equiv of
HOAc, the yield of 3 was increased to 80% (entry 3). To
our delight, substrate 1 was consumed completely in 2 h,
providing a 91% yield using HOAc as the medium (entry
5). We were happy to discover that a good yield of 3 was
still isolated even in the presence of 1.2 equiv of PhI(OAc)2
using HOAc as the medium (entry 6). Noteworthy is that
the reaction can be conducted in good yields even at a
loading of 5 mol % of Pd after prolonged reaction time (entry
(2) (a) Mori, M.; Ban, Y. Tetrahedron Lett. 1979, 20, 1133. (b) Sun,
L.; Liang, C.; Shirazian, S.; Zhou, Y.; Miller, T.; Cui, J.; Fukuda, J. Y.;
Chu, J.-Y.; Nematalla, A.; Wang, X.; Chen, H.; Sistla, A.; Luu, T. C.; Tang,
F.; Wei, J.; Tang, C. J. Med. Chem. 2003, 46, 1116. (c) Wang, L.; Zhang,
Y.; Hu, H.-Y.; Fun, H. K.; Xu, J.-H. J. Org. Chem. 2005, 70, 3805. (d)
Kalinski, C.; Umkehrer, M.; Schmidt, J.; Ross, G.; Kolb, J.; Burdack, C.;
Hiller, W.; Hoffmann, S. D. Tetrahedron Lett. 2006, 47, 4683. (e) Xing,
X.; Wu, J.; Luo, J.; Dai, W.-M. Synlett 2006, 2099. (f) Yang, T.-M.; Liu,
G. J. Comb. Chem. 2007, 9, 86
.
(3) Pd: (a) Cheung, W. S.; Patch, R. J.; Player, M. R. J. Org. Chem.
2005, 70, 3741. (b) Yanada, R.; Obika, S.; Inokuma, T.; Yanada, K.;
Yamashita, M.; Ohta, S.; Takemoto, Y. J. Org. Chem. 2005, 70, 6972. (c)
Pinto, A.; Neuville, L.; Retailleau, P.; Zhu, J. Org. Lett. 2006, 8, 4927. (d)
Pinto, A.; Neuville, L.; Zhu, J. Angew. Chem., Int. Ed. 2007, 46, 3291. (e)
Couty, S.; Lie´gault, B.; Meyer, C.; Cossy, J. Org. Lett. 2004, 6, 2511. (f)
D’Souza, D. M.; Rominger, F.; Mu¨ller, T. J. J. Angew. Chem., Int. Ed.
2005, 44, 153. (g) Tang, S.; Yu, Q.-F.; Peng, P.; Li, J.-H.; Zhong, P.; Tang,
R.-Y. Org. Lett. 2007, 9, 3413. In/Pd: (h) Yanada, R.; Obika, S.; Oyama,
M.; Takemoto, Y. Org. Lett. 2004, 6, 2825. Rh: (i) Shintani, R.; Yamagami,
T.; Hayashi, T. Org. Lett. 2006, 8, 4799. (j) Miura, T.; Takahashi, Y.;
Murakami, M. Org. Lett. 2007, 8, 5075
(4) Tang, S.; Peng, P.; Pi, S.-F.; Liang, Y.; Wang, N.-X.; Li, J.-H. Org.
Lett. 2008, 10, 1179
(5) The detailed experimental data are summarized in Table S1 in
.
(6) The structure of the products and the E-configuration of the
tetrasubstituted double bond were determined according to the COSY and
NOESY of the products 12 and 16 and were unambiguously assigned by
X-ray analysis of the products 9 and 14 (see Supporting Information).
.
Supporting Information
.
1876
Org. Lett., Vol. 10, No. 9, 2008

7). However, no reaction was observed without Pd(OAc)2
(entry 8). Finally, the temperature effect was investigated,
and a higher temperature favored the reaction (entries 9 and
10).
Subsequently, a variety of anilides were surveyed to
investigate the scope of the reaction with HOAc under the
standard reaction conditions (Table 2). In the presence of
yield (entry 1). However, both N-acetyl-N,3-diphenylpropi-
olamide and N,3-diphenylpropiolamide were unsuitable
substrates for the reaction (entries 2 and 3). We were
delighted to disclose that several functional groups, such as
the ester, nitro, chloro, bromo, and methoxy group, on the
N-phenyl group were tolerated well, but the yields were
reduced to some extent when the steric hindrance was
presented (entries 4-11). While N-(4-chlorophenyl)-N-
methyl-3-phenylpropiolamide, for instance, was treated with
Pd(OAc)2, PhI(OAc)2, and HOAc smoothly to afford the
corresponding (E)-10 in a 91% yield (entry 7), only a 28%
yield of (E)-13 was isolated from the reaction of the bulky
substrate, N-(2-methoxyphenyl)-N-methyl-3-phenylpropiol-
amide (entry 10). Gratifyingly, N-methyl-N-phenylpropiol-
amides bearing either electron-deficient or electron-rich aryl
groups at the terminal alkyne underwent the reaction suc-
cessfully in moderate to good yields under the standard
conditions (entries 11-13). We found that N-methyl-N-
phenylbut-2-ynamide, having a methyl group at the terminal
of alkyne, also gave the (E)-18 in a 93% yield (entry 14).
Unfortunately, attempts to cyclize N-methyl-N-phenylpro-
piolamide failed (entry 15). It is noteworthy that a tenidap
analogue 19 can be synthesized in one step (entry 16).
N-Methyl-3-phenyl-N-m-tolylpropiolamide (20) was cho-
sen to test the regioselectivity of the reaction. As shown in
Scheme 2, it was selectively para-cyclized to afford (E)-
Table 2. Pd(OAc)2-Catalyzed Cyclizations of Various Amides
a
with HOAc in the Presence of PhI(OAc)2
Scheme 2. Reaction of
N-Methyl-3-phenyl-N-m-tolylpropiolamide
(1,6-dimethyl-2-oxoindolin-3-ylidene)(phenyl)methyl acetate
(21) in 90% yield together with an ortho-cyclized product
(22) in <5% GC yield.
We then turned our attention to examine suitable acids
for the reaction. The results in Table 3 show that a variety
of acids 2b-i, either aryl or alkyl acids, all worked well
with amides in moderate to good yields. Moreover, the
reaction tolerated a series of functional groups including
nitro, bromo, fluoro, iodo, vinyl, or acetyl groups on the
aromatic ring of aryl acids. For example, treatment of amide
1 (0.2 mmol) with 4-nitrobenzoic acid (2b) (5 equiv),
Pd(OAc)2 (10 mol %), and PhI(OAc)2 (2 equiv) in MeCN
afforded the corresponding product 23 in 81% yield (entry
1). However, the yield of 23 was reduced to 47% in the
presence of 10 equiv of 4-nitrobenzoic acid (2b) (entry 2).
The other amide 26 with an acid 2e bearing an iodo group
was also reacted successfully to give the target product 28
in 55% yield (entry 5). Note that a bulky acid 2h can still
react with anilide 26 to give the target product 31 in 77%
yield under the standard conditions (entry 8).
a Reaction conditions: 1 (0.2 mmol), Pd(OAc)2 (10 mol %), PhI(OAc)2
(1.2 equiv), and HOAc (3 mL) at 80 °C for 2-5 h. b Isolated yield.
c HOAc/MeCN (1:4, 3 mL).
Pd(OAc)2 and PhI(OAc)2, N-benzyl-N,3-diphenylpropiola-
mide could also afford the target (E)-product (5) in a 69%
Org. Lett., Vol. 10, No. 9, 2008
1877

Table 3. Screening Suitable Acids (2)a
Scheme 3. Possible Mechanism
entry
R
R′
time (h) yield (%)b
1
2c
3
4
5
6
7
8
9
H (1)
H (1)
2-Cl (24)
4-Me (26) 4-BrC6H4 (2d)
4-Me (26) 2-IC6H4 (2e)
4-Me (26) 4-vinylC6H4 (2f)
4-Me (26) 2-CH3COC6H4 (2g)
4-Me (26) t-Bu (2 h)
4-NO2C6H4 (2b)
4-NO2C6H4 (2b)
2-Br-4-FC6H3 (2c)
2
2
3
3
4
5
2
6
3
81 (23)
47 (23)
57 (26)
77 (27)
52 (28)
52 (29)
75 (30)
77 (31)
75 (32)
dation of intermediate A with acid to afford intermediate B.
The PdII intermediate B is then oxidized by PhI(OAc)2 to
give a PdIV intermediate C. The PdIV intermediate D is
formed by activation of the ortho-C-H bond of intermediate
C. The reductive elimination of intermediate D occurs readily
to yield the target product and the active PdII species.
However, we cannot rule out the possibility of a PdII/Pd0
mechanism because the target product could be obtained in
the presence of Cu(OAc)2, a traditional PdII/Pd0 oxidant.5,8
In summary, we describe here the first example of
constructing (1-substituted-2-oxoindolin-3-ylidene)methyl
acetates via a Pd(OAc)2-catalyzed C-H functionalization
reaction in the presence of PhI(OAc)2. Work to probe the
detailed mechanism and apply the reaction in organic
synthesis is currently underway.
4-Me (26) C6H5CH2CH2 (2i)
a Reaction conditions: 1 (0.2 mol), Pd(OAc)2 (10 mol %), PhI(OAc)2
(2 equiv), and R′COOH (5 equiv) in CH3CN (3 mL) at 80 °C. b Isolated
c
yield. R′COOH (10 equiv).
A working mechanism as outlined in Scheme 3 was
proposed on the basis of the previously proposed mecha-
nisms3,4,7,8 and the results of the kinetic isotope effect.9
Coordination of PdII with alkyne and nitrogen is readily
occurs to afford intermediate A, followed by acetoxypalla-
(7) For selected recent reviews and papers on the PdII/PdIV process, see:
(a) Yu, J.-Q.; Giri, R.; Chen, X. Org. Biomol. Chem. 2006, 4, 4042. (b)
Deprez, N. R.; Sanford, M. S. Inorg. Chem. 2007, 46, 1924. (c) Deprez,
N. R.; Kalyani, D.; Krause, A.; Sanford, M. S. J. Am. Chem. Soc. 2006,
128, 4972. (d) Hull, K. L.; Lanni, E. L.; Sanford, M. S. J. Am. Chem. Soc.
2006, 128, 14047. (e) Kalyani, D.; Dick, A. R.; Anani, W. Q.; Sanford,
M. S. Org. Lett. 2006, 8, 2523. (f) Thu, H.-Y.; Yu, W.-Y.; Che, C.-M.
J. Am. Chem. Soc. 2006, 128, 9048. (g) Liu, G.; Stahi, S. S. J. Am. Chem.
Soc. 2006, 128, 7179. (h) Tong, X.; Beller, M.; Tse, M. K. J. Am. Chem.
Soc. 2007, 129, 4906. (i) Welbes, L. L.; Lyons, T. W.; Cychosz, K. A.;
Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 5836. (j) Whitfield, S. R.;
Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 15142. (k) Muniz, K. J. Am.
Chem. Soc. 2007, 129, 14542. (l) Muniz, K.; Hovelmann, C. H.; Streuff, J.
Acknowledgment. We thank the Zhejiang Provincial
Natural Science Foundation of China (No. Y407116), the
Specialized Research Fund for the Doctoral Program of
Higher Education (No. 20060542007), the National Natural
Science Foundation of China (Nos. 20572020 and 20472090),
the New Century Excellent Talents in University (No. NCET-
06-0711) for financial support.
J. Am. Chem. Soc. 2008, 130, 763
.
(8) (a) The PdII/PdII-catalyzed hydroacetoxylation of 2-alkynoic amides
has also been reported using some specified additives such as LiX, LiOAc,
bipyridine, and Et3N. However, no desired product 3 was observed using
Pd(OAc)2 combined with the specified additives in the reaction of 1. Lu,
X.; Zhu, G.; Ma, S. Tetrahedron Lett. 1992, 33, 7205. (b) Wakabayashi,
T.; Ishii, Y.; Murata, T.; Mizobe, Y.; Hidai, M. Tetrahedron Lett. 1995,
36, 5585. (c) Han, X. L.; Liu, G. X.; Lu, X. Y. Chin. J. Org. Chem. 2005,
Supporting Information Available: Analytical data and
spectra (1H and 13C NMR) for all the products and typical
procedure for the acetoxypalladation/C-H functionalization
reaction. This material is available free of charge via the
Internet at http://pubs.acs.org.
25, 1182
.
(9) The results of the kinetic isotope effect are summarized in the
Supporting Information.
OL8006315
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Org. Lett., Vol. 10, No. 9, 2008