Synthesis of (E)-3-(isobenzofuran-3(1H)-ylidene)- indolin-2-ones by the palladium-catalyzed intramolecular C-H functionalization process

Article abstract of DOI:10.1021/jo900437p

A novel and selective protocol has been developed for the synthesis of (E)-3-(isobenzofuran-3(1H)-ylidene)indolin-2-ones by Pd-catalyzed oxidative intramolecular C-H functionalization reactions of various 3-(2-(hydroxymethyl) aryl)-N-methyl-N-arylpropiola

Full text of DOI:10.1021/jo900437p

catalyzed transformations.3-5 Despite the high selectivity and
efficiency of these transition metal-catalyzed methods, many
require the use of expensive 2-haloanilides or 2-(alkynyl)phe-
nylisocyanates as the starting materials.3 Direct C-H function-
alization has emerged as a promising and economically attractive
alternative for the direct cyclization of N-arylpropiolamides with
an electrophile4 or a nucleophile.5 Zhu and co-workers have
first reported a Pd(0)-catalyzed intermolecular domino carbo-
palladation/C-H activation/C-C bond-forming reaction that
employs both an anilide sp2 C-H bond and an electrophilic
reagent (aryl iodide) as the coupling partners.4 However, only
carbon atoms were introduced to the triple bond to form
carbon-carbon bonds. Many bioactive 3-methyleneindolin-2-
ones include the carbon-heteroatom bonds at the terminal of
the 3-methylene group. Recently, we described several protocols
for constructing carbon-carbon bonds or carbon-heteroatom
bonds at the terminal of the 3-methylene group by the Pd(II)/
Pd(IV)-catalyzed intermolecular C-H functionalization of N-
arylpropiolamides with a nucleophilic reagent (phthalimide, an
acid, or an aryliodonium salt). However, these oxidative
approaches suffer the limitation of requiring noneasily accessible
iodine(III) salts as the oxidants.5 Therefore, a novel strategy,
involving the use of inexpensive and environmentally benign
oxidants, able to carry out the C-H functionalization to
construct carbon-heteroatom bonds, would be highly desirable.6-9
Here, we report the first example of Pd(II)-catalyzed intramo-
lecular C-H activation reactions of 3-(2-(hydroxymethyl)aryl)-
N-phenylpropiolamides to prepare (E)-3-(isobenzofuran-3(1H)-
Synthesis of (E)-3-(Isobenzofuran-3(1H)-ylidene)-
indolin-2-ones by the Palladium-Catalyzed
Intramolecular C-H Functionalization Process
Peng Peng,† Bo-Xiao Tang,† Shao-Feng Pi,† Yun Liang,†
and Jin-Heng Li*,†,‡
Key Laboratory of Chemical Biology & Traditional Chinese
Medicine Research (Ministry of Education), Hunan Normal
UniVersity, Changsha 410081, China, and State Key
Laboratory of Chemo/Biosensing and Chemometrics, Hunan
UniVersity, Changsha 410082, China
jhli@hunnu.edu.cn
ReceiVed February 27, 2009
A novel and selective protocol has been developed for the
synthesis of (E)-3-(isobenzofuran-3(1H)-ylidene)indolin-2-
ones by Pd-catalyzed oxidative intramolecular C-H func-
tionalization reactions of various 3-(2-(hydroxymethyl)aryl)-
N-methyl-N-arylpropiolamides in moderate yields. Mechanisms
involving a C-H activation process were proposed for this
transformation on the basis of the observed values of kinetic
isotope effects.
(3) (a) Cheung, W. S.; Patch, R. J.; Player, M. R. J. Org. Chem. 2005, 70,
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Yamagami, T.; Hayashi, T. Org. Lett. 2006, 8, 4799. (f) Miura, T.; Takahashi,
Y.; Murakami, M. Org. Lett. 2007, 9, 5075. (g) Tang, S.; Yu, Q.-F.; Peng, P.;
Li, J.-H.; Zhong, P.; Tang, R.-Y. Org. Lett. 2007, 9, 3413. (h) Miura, T.;
Takahashi, Y.; Murakami, M. Org. Lett. 2008, 10, 1743. (i) Miura, T.; Toyoshima,
T.; Takahashi, Y.; Murakami, M. Org. Lett. 2008, 10, 4887. (j) Park, J. H.;
Kim, E.; Chung, Y. K. Org. Lett. 2008, 10, 4719.
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4927. (b) Pinto, A.; Neuville, L.; Zhu, J. Angew. Chem., Int. Ed. 2007, 46, 3291.
(5) (a) Tang, S.; Peng, P.; Pi, S.-F.; Liang, Y.; Wang, N.-X.; Li, J.-H. Org.
Lett. 2008, 10, 1179. (b) Tang, S.; Peng, P.; Wang, Z.-Q.; Tang, B.-X.; Deng,
C.-L.; Li, J.-H.; Zhong, P.; Wang, N.-X. Org. Lett. 2008, 10, 1875. (c) Tang,
S.; Peng, P.; Zhong, P.; Li, J.-H. J. Org. Chem. 2008, 73, 5476.
(6) For selected papers on the kinetic isotope effect studies, see: (a) Shue,
R. S. J. Am. Chem. Soc. 1971, 93, 7116. (b) Boele, M. D. K.; van Strijdonck,
G. P. F.; de Vries, A. H. M.; Kamer, P. C. J.; de Vries, J. G.; van Leeuwen,
P. W. N. M. J. Am. Chem. Soc. 2002, 124, 1586. (c) Hennessy, E. J.; Buchwald,
S. L. J. Am. Chem. Soc. 2003, 125, 12084. (d) Tunge, A. A.; Foresee, L. N.
Organometallics 2005, 24, 6640. (e) Campeau, L.-C.; Parisien, M.; Jean, A.;
Fagnou, K. J. Am. Chem. Soc. 2006, 128, 581. (f) Garcıa-Cuadrado, D.; de
Mendoza, P.; Braga, A. A. C.; Maseras, F.; Echavarren, A. M. J. Am. Chem.
Soc. 2007, 129, 6880.
(7) For selected reviews on the aloxypalladation reactions, see: (a) Stahl, S. S.
Angew. Chem., Int. Ed. 2004, 43, 3400. (b) Hosokawa, T.; Murahash, S.-I. In
Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi, E.,
Ed.; J. Wiley & Sons: New York, 2002; p 2186. (c) Cacchi, S.; Arcadi, A. In
Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi, E.,
Ed.; J. Wiley & Sons: New York, 2002; p 2193. (d) Henry, P. M. Palladium-
Catalyzed Oxidation of Hydrocarbons; D. Reidel: Dordrecht, Holland, 1980.
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The indolin-2-one skeleton is a prevalent motif found in many
naturally occurring products and biologically active compounds.1
Two 3-methyleneindolin-2-ones, SU11248 and tenidap, were
commercialized as medicines by Pfizer Inc. The traditional
method for synthesizing these compounds is the Knoevenagel
reaction,butitissometimeslimitedduetoitslowstereoselectivity.1,2
Recently, much attention has been paid on transition metal-
† Hunan Normal University.
‡ Hunan University.
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10.1021/jo900437p CCC: $40.75
Published on Web 03/27/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 3569–3572 3569

TABLE 1. Screening Optimal Conditionsa
amounts of the target (E)-3-(isobenzofuran-3(1H)-ylidene)-
1-methylindolin-2-one (2a)10 were determined by GC-MS
analysis with either air or Cu(OAc)2 as the oxidant alone
(entries 2 and 3), Cu(OAc)2 combined with air increased the
yield of 2a sharply to 68% (entry 4). The yield was reduced
slightly with oxygen instead of air (entry 5). We found that
the other oxidant systems, such as Cu(OTf)2/air, CuCl2/air,
PhI(OAc)2/air, oxone/air, and Cu(OAc)2/PhI(OAc)2/air, were
less effective (entries 6-10). The amount of Cu(OAc)2 was
also evaluated, and 1 equiv of Cu(OAc)2 decreased the yield
to some extent (entry 11). Subsequently, the effect of solvent
was examined, and it turned out that MeCN was the most
effective solvent in terms of yield (entries 4 and 12-15).
Finally, a number of other Pd catalytic systems, including
PdCl2/PPh3, Pd(OAc)2/PPh3, PdCl2/PCy3, PdCl2/P(o-tol)3,
PdCl2/Imes, PdCl2/bipyridinyl, and PdCl2, were investigated,
and they were less efficient than PdCl2(PPh3)2 (entries
16-22). It is noted that the reaction does not take place
without Pd (entry 23).
We next explored the scope of the reaction under the standard
conditions, and the results are summarized in Table 2.10 The
results demonstrated that various 3-(2-(hydroxymethyl)aryl)-
N-phenylpropiolamides 1b-r were suitable to afford the cor-
responding (E)-3-(isobenzofuran-3(1H)-ylidene)indolin-2-ones
in moderate yields under the standard conditions. Gratifyingly,
the N-methyl group can be replaced for a benzyl group without
affecting the yield in the presence of PdCl2(PPh3)2, Cu(OAc)2,
and air (entry 1).
Subsequently, substitutents on the N-aryl rings were tested
(entries 2-11). We found that both electron-withdrawing and
electron-donating substitutents, such as methyl, butyl, methoxy,
fluoro, chloro, bromo, ester, and trifluoromethyl, were tolerated
well (entries 2-11). It is noteworthy that the reaction of the
amide 1k bearing a m-methyl group gives the corresponding
6-aryl C-H activated product 2k regiospecifically in 40% yield
(entry 10). Gratifying, the reaction conditions are compatible
with ether, halide, and ester functional group (entries 4-9). The
substitution in the alkynylarene moiety was investigated under
the standard conditions (entries 12-17). We found that 3-(4,6-
disubstituted aryl)propiolamides 1m and 1n could also undergo
the reaction with PdCl2(PPh3)2, Cu(OAc)2, and air smoothly in
moderate yields (entries 12 and 13). It was interesting to diclose
that heteroarylpropiolamides 1o-q were also suitable substrates
(entries 14-16). 3-(3-(Hydroxymethyl)thiophen-2-yl)-N-methyl-
N-phenylpropiolamide (1o), for instance, was treated with
PdCl2(PPh3)2, Cu(OAc)2, and air to gave the target product in
73% yield (entry 14). Notably, 17% yield was still achieved
from a tertiary benzyl alcohol after 22 h (entry 17).
entry
catalyst
[O]
solvent
MeCN
MeCN
MeCN
t (h) yield (%)d
10
10 trace
25 trace
10 68
1c
2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
0
air
Cu(OAc)2
Cu(OAc)2/air MeCN
Cu(OAc)2/O2 MeCN
Cu(OTf)2/air MeCN
3c
4
5d
6
25 65
10 mixture
10 mixture
10 25
10 mixture
10 39
10 60
10 48
10 42
10 61
7
CuCl2/air
MeCN
MeCN
MeCN
8e
9f
air
air
10e PdCl2(PPh3)2
Cu(OAc)2/air MeCN
Cu(OAc)2/air MeCN
Cu(OAc)2/air THF
Cu(OAc)2/air dioxane
Cu(OAc)2/air DMF
11g PdCl2(PPh3)2
12
13
14
15
16
17
18
19
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2/PPh3
Pd(OAc)2/PPh3
PdCl2/PCy3
PdCl2/P(o-tol)3
Cu(OAc)2/air CH2ClCH2Cl 10 41
Cu(OAc)2/air MeCN
Cu(OAc)2/air MeCN
Cu(OAc)2/air MeCN
Cu(OAc)2/air MeCN
Cu(OAc)2/air MeCN
10 56
10 44
10 40
10 10
10 51
10 35
20h PdCl2/IMes
21
22
23
PdCl2/bipyridinyl Cu(OAc)2/air MeCN
PdCl2
Cu(OAc)2/air MeCN
Cu(OAc)2/air MeCN
10
10
8
0
a Reaction conditions: 1a (0.2 mmol), [Pd] (5 mol %), [Cu] (10 mol
%), solvent (2 mL) at 80 °C under air atmosphere. b Isolated yield.
c Under argon atmosphere. d Under oxygen atmosphere. e PhI(OAc)2 (1.5
equiv) was added. f Oxone (1.5 equiv) was added. g Cu(OAc)2 (1 equiv).
h IMes ) 1,3-dimesitylimidazol-2-ylidene.
ylidene)indolin-2-ones using
a
catalytic amount of
Cu(OAc)2combined with air as the oxidant (eq 1). (E)-3-
(Isobenzofuran-3(1H)-ylidene)indolin-2-ones have also been
proven to display high bioactivity as potential tyrosine kinase
inhibitors.1g
As shown in Table 1, 3-(2-(hydroxymethyl)phenyl)-N-
methyl-N-phenylpropiolamide (1a) was selected as the model
substrate to screen the optimal reaction conditions. Initially,
we sought effective oxidants. We found that Cu(OAc)2
combined with air provided the best results. No reaction was
observed in the absence of oxidants (entry 1). While trace
As shown in Scheme 1, a mixture of products including
1-methyleneisobenzofuran (3s) was isolated from the reaction
of substrate 1s with PdCl2(PPh3)2, Cu(OAc)2, and air. However,
both amine 1t and ester 1u were unsuitable for the reaction with
a mixture of products being formed.
To elucidate this transformation further, kinetic isotope effect
studies as outlined in Scheme 2 were conducted. The results
demonstrated that this reaction exhibited significant intermo-
lecular (kH/kD ) 2.2) and intramolecular (kH/kD ) 4.3) hydrogen/
deuterium kinetic isotope effects. These data are in a range of
(8) For selected papers on the aloxypalladation reactions of alkynes, see: (a)
Utimoto, K. Pure Appl. Chem. 1983, 55, 1845. (b) Gabriele, B.; Salerno, G.;
Fazio, A.; Pittelli, R. Tetrahedron 2003, 59, 6251. (c) Kadota, I.; Lutete, L. M.;
Shibuya, A.; Yamamoto, Y. Tetrahedron Lett. 2001, 42, 6207. (d) Cacchi, S. J.
Organomet. Chem. 1999, 576, 42. (e) Wei, W.-G.; Zhang, Y.-X.; Yao, Z.-J.
Tetrahedron 2005, 61, 11882. (f) Bacchi, A.; Costa, M.; Ca`, N. D.; Fabbricatore,
M.; Fazio, A.; Gabriele, B.; Nasi, C.; Salerno, G. Eur. J. Org. Chem. 2004, 574.
(9) (a) Kotov, V.; Scarborough, C. C.; Stahl, S. S. Inorg. Chem. 2007, 46,
1910. (b) Popp, B. V.; Stahl, S. S. In Organometallic Oxidation Catalysis; Meyer,
F., Limberg, C., Eds.; Springer: New York, 2007; Vol. 22, p 149. (c) Konnick,
M. M.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 5753. (d) Mueller, J. A.; Goller,
C. P.; Sigman, M. S. J. Am. Chem. Soc. 2004, 126, 9724. (e) Steinhoff, B. A.;
Guzei, I. A.; Stahl, S. S. J. Am. Chem. Soc. 2004, 126, 11268.
(10) The structure and the E-configuration of the products 2 were unambigu-
ously assigned by X-ray analysis of the product 2c (Figure 1), see the Supporting
Information for details.
(11) In Zhu’s and our reported results, the intermolecular kH/kD value is 1,
and the intramolecular kH/kD value is about 2.8 to 3.4, see refs 4 and 5.
3570 J. Org. Chem. Vol. 74, No. 9, 2009

TABLE 2. Palladium-Catalyzed Intramolecular Cyclization of
Amides 1 in the Presence of PdCl2(PPh3)2, Cu(OAc)2, and Aira
FIGURE 1. X-ray structure of 2c.
SCHEME 1. The Reactions of Other Substrates
SCHEME 2. Kinetic Isotope Effect Experiments
SCHEME 3. A Working Mechanism
that these kinetic isotope effects are different from those of Zhu’s
and our reported intermolecular C-H activation reactions.4,5,11
Accordingly, a possible mechanisms as shown in Scheme 3
is proposed on the basis of the reported and present results.4-10
Complexation of the triple bond with the active Pd(II) species
readily occurs to afford intermediate A.6-9 Intermediate A
undergoes the intramolecular cis-addition of Pd and -OH to
the triple bond to give intermediate B.6-9 Oxidative C-H
activation/reductive elimination of intermediate B affords 2 and
a Pd(0) species. The active Pd(II) species are regenerated from
oxidation of the Pd(0) species by Cu(OAc)2 and air to start a
new catalytic cycle. In the process, the propiolamido group may
facilitate the activation of the o-arene C-H bond.6b,12
a Reaction conditions:
1 (0.2 mmol), PdCl2(PPh3)2 (5 mol %),
Cu(OAc)2 (10 mol %), and MeCN (2 mL) at 80 °C under air
atmosphere for 10 h. b Isolated yield. The substrate 1 was consumed
completely, and some decomposed products by the cleavage of two
C-N bons were determined by GC-MS analysis. c For 22 h.
the kinetic isotope effects observed for the reactions proceeding
via the Pd-catalyzed aromatic C-H functionalization pathways,
i.e., the C-H functionalization step is the rate-determining step
in the present reaction and the mechanism of C-H activation
is incompatible with the SEAr mechanism.7 It is noteworthy
(12) For selective papers, see: (a) Zaitsev, V. G.; Daugulis, O. J. Am. Chem.
Soc. 2005, 127, 4156. (b) Cai, Q.; Zou, B.; Ma, D. Angew. Chem., Int. Ed. 2006,
45, 1276. (c) Li, B.-J.; Yang, S.-D.; Shi, Z.-J. Synlett 2008, 949.
J. Org. Chem. Vol. 74, No. 9, 2009 3571

MHz, CD3Cl) δ 9.77 (d, J ) 8.0 Hz, 1H), 7.94 (d, J ) 7.5 Hz,
1H), 7.50-7.48 (m, 2H), 7.37 (d, J ) 8.5 Hz, 1H), 7.17 (t, J ) 7.5
Hz, 1H), 7.03 (t, J ) 7.5 Hz, 1H), 6.78 (d, J ) 8.0 Hz, 1H), 5.58
(s, 2H), 3.29 (s, 3H); 13C NMR (125 MHz, CD3Cl) δ 168.0, 167.6,
143.2, 140.4, 132.0, 131.6, 128.5, 128.4, 126.1, 123.7, 123.0, 121.4,
120.2, 106.9, 103.1, 75.6, 25.7; IR (KBr, cm-1) 1683; LRMS (EI,
70 eV) m/z (%) 263 (M+, 91), 234 (100); HRMS (EI) for C17H13NO2
(M+) calcd 263.0946, found 263.0946.
In summary, we have developed a new route to selectively
construct two heterocyclic rings in one step by an intramolecular
C-H functionalization protocol. This protocol allows selective
cyclization of various 3-(2-(hydroxymethyl)aryl)-N-methyl-N-
arylpropiolamides possessing electron-rich and electron-deficient
aryl rings into the corresponding (E)-3-(isobenzofuran-3(1H)-
ylidene)indolin-2-ones. Mechanisms involving the C-H activa-
tion process have been proposed for this transformation on the
basis of the observed values of kinetic isotope effects.
Acknowledgment. We thank the Specialized Research Fund
fortheDoctoralProgramofHigherEducation(No.20060542007),
New Century Excellent Talents in University (No. NCET-06-
0711), National Natural Science Foundation of China (No.
20572020), and State Key Laboratory of Chemo/Biosensing and
Chemometrics Foundation (No. 2006016) for financial support.
Experimental Section
Typical Experimental Procedure for the Palladium-Catalyzed
Intramolecular C-H Functionalization Process. A mixture of
N-arylpropiolamides 1 (0.2 mmol), PdCl2(PPh3)2 (5 mol %),
Cu(OAc)2 (10 mol %), and MeCN (2 mL) was stirred at 80 °C
under air atmosphere for 10 h until complete consumption of starting
material as monitored by TLC. Then the mixture was washed with
saturated NaS2O3 and extracted with diethyl ether. The organic
layers were dried with Na2SO3 and evaporated under vacuum, then
the residue was purified by flash column chromatography (hexane/
ethyl acetate) to afford the pure product 2.
Supporting Information Available: General experimental
procedures, characterization data for 2, copies of spectra, and a
CIF file of the product 2c. This material is available free of
charge via the Internet at http://pubs.acs.org.
(E)-3-(Isobenzofuran-1(3H)-ylidene)-1-methylindolin-2-one (2a):
1g yellow solid, mp 157.2-159.3 °C (uncorrected); 1H NMR (500
JO900437P
3572 J. Org. Chem. Vol. 74, No. 9, 2009