Stereoselective synthesis of 3-alkylideneoxindoles via palladium-catalyzed domino reactions

Article abstract of DOI:10.1021/jo0508604

We have developed efficient catalytic methods for the stereoselective and diversity synthesis of various (E)-, (Z)-, and disubstituted 3-alkylideneoxindoles and 3-alkylidene-benzofuran-2-ones via palladium-catalyzed Heck/Suzuki-Miyaura, Heck/Heck, and Hec

Full text of DOI:10.1021/jo0508604

antirheumatic compounds,6 and analogues of the anti-
breast cancer drug tamoxifen. However, despite their
importance, stereoselective synthesis of these 3-alkyli-
deneoxindoles had remained a difficult problem.3,7 Re-
cently, we have reported the first efficient method for
stereoselective synthesis of (E)-, (Z)-, and disubstituted-
3-alkylideneoxindoles A using reductive radical cycliza-
tion reactions of compound B with a typical metal indium
(path a). The key step of this reaction is the strong
coordination of the indium cation to the amide carbonyl
oxygen (Scheme 1).8 However, different starting materi-
als should be prepared to synthesize both (E)- and (Z)-
isomers. On the other hand, domino reactions initiated
by intramolecular Heck reactions9 have been developed
and advanced to prepare polycyclic compounds in a single
operation.10 In contrast to these facts, oxindole synthesis
via a domino Pd-catalyzed reaction has seldom been
examined until now. Recently, Cossy reported an elegant
synthesis of (E)-3-alkylideneoxyisoindoles via a Heck/
Suzuki-Miyaura domino reaction,11 and very recently,
Mu¨ller applied a Heck/Sonogashira domino reaction to
synthesize 3-alkylideneoxindole derivatives.12 The key
step of these reactions is the syn addition of arylpalla-
dium halide to the triple bond. If the same palladium-
Stereoselective Synthesis of
3-Alkylideneoxindoles via
Palladium-Catalyzed Domino Reactions†
Reiko Yanada,‡ Shingo Obika,‡ Tsubasa Inokuma,‡
Kazuo Yanada,§ Masayuki Yamashita,
Shunsaku Ohta, and Yoshiji Takemoto*,‡
Graduate School of Pharmaceutical Sciences, Kyoto
University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan,
Faculty of Pharmaceutical Sciences, Setsunan University,
Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan, and
Kyoto Pharmaceutical University, Misasagi-Nakauchicho 5,
Yamashinaku, Kyoto 607-8414, Japan
takemoto@pharm.kyoto-u.ac.jp
Received April 28, 2005
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W.; Prigge, S. T.; Geyer, J. A.; Waters, N. C. J. Med. Chem. 2003, 46,
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C. F. J. Med. Chem. 1996, 39, 10.
(7) E:Z ) 5:1-1:5, for example: (a) Mori, M.; Ban, Y. Tetrahedron
Lett. 1979, 20, 1133. (b) Fielding, M. R.; Grigg, R.; Urch, C. J. Chem.
Commun. 2000, 2239. (c) Teichert, A.; Jantos, K.; Harms, K.; Studer,
A. Org. Lett. 2004, 6, 3477.
We have developed efficient catalytic methods for the
stereoselective and diversity synthesis of various (E)-, (Z)-,
and disubstituted 3-alkylideneoxindoles and 3-alkylidene-
benzofuran-2-ones via palladium-catalyzed Heck/Suzuki-
Miyaura, Heck/Heck, and Heck/carbonylation/Suzuki-
Miyaura domino reactions.
Oxindoles are important compounds of natural indole
alkaloids,1 drug candidates,2 and metabolic intermedi-
ates. Among them, 3-alkylideneoxindoles are well-known
to be versatile compounds in terms of biological activity
and synthetic applicability. For example, the (E)-3-
alkylideneoxindoles are important synthetic intermedi-
ates of TMC-95A,3 and the (E)- and (Z)-3-alkylideneox-
indoles are involved in drug candidates of tyrosine kinase
inhibitors,4 cyclin-dependent protein kinase inhibitors,5
† This paper is dedicated to the memory of the late Professor Kiyoshi
Tanaka.
* Corresponding author. Tel: +81 75 753 4528. Fax: +81 75 753
4569.
‡ Kyoto University.
§ Setsunan University.
Kyoto Pharmaceutical University.
(8) Yanada, R.; Obika, S.; Oyama, M.; Takemoto, Y. Org. Lett. 2004,
6, 2825.
(9) Lautens, M.; Tayama, E.; Herse, C. J. Am. Chem. Soc. 2005, 127,
72.
(10) For an excellent review on cyclic carbopalladations: Negishi,
E.-I.; Co¨peret, C.; Ma, S.; Liou, S.-Y.; Liu, F. Chem. Rev. 1996, 96,
365.
(11) Couty, S.; Lie´gault, B.; Meyer, C.; Cossy, J. Org. Lett. 2004, 6,
2511.
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Int. Ed. 2005, 44, 153.
(1) (a) Kam, T.-S.; Choo, Y.-M. Tetrahedron 2000, 56, 6143. (b) Cane,
A.; Tournaire, M.-C.; Barritault, D.; Crumeyrolle-Arias, M. Biochem.
Biophys. Res. Commun. 2000, 276, 379. (c) Tsuda, M.; Mugishima, T.;
Komatsu, K.; Sone, T.; Tanaka, M.; Mikami, Y.; Shiro, M.; Hirai, M.;
Ohizumi, Y.; Kobayashi, J. Tetrahedron 2003, 59, 3227. (d) Marti, C.;
E. Carreira, M. Eur. J. Org. Chem. 2003, 2209. (e) Akai, S.; Tsujino,
T.; Akiyama, E.; Tanimoto, K.; Naka, T.; Kita, Y. J. Org. Chem. 2004,
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(2) Zhang, T. Y.; Zhang, H. Tetrahedron Lett. 2002, 43, 193 and
references therein.
10.1021/jo0508604 CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/26/2005
6972
J. Org. Chem. 2005, 70, 6972-6975

SCHEME 1
SCHEME 2
TABLE 2. Synthesis of Disubstituted
3-Alkylideneoxindoles
TABLE 1. Synthesis of (E)-3-Alkylideneoxindoles
a Reaction time was 10 h, and starting material (18%) was
recovered.
run
R1
additive
(E)-3
yield (%)
some aryl- and alkylboronic acids in the presence of
cesium fluoride. The cascade reaction proceeded to comple-
tion to produce (E)-alkenes 3a-d exclusively in high
yields (runs 2-5). The vinylic protons of (E)-isomers 3
1
2
3
4
5
Ph
Ph
NaOH (aq)
CsF
a
a
b
c
88:4 (E:Z)
95
77
78
70
p-MeO-Ph
p-CF3-Ph
Bu
CsF
CsF
1
appeared at a lower field in the H NMR spectra than
CsF
d
the corresponding signals of the (Z)-isomers due to the
effect of the amide carbonyl oxygen. As we envisaged, the
(E)-alkenes 3 might be produced via (E)-vinylpalladium
intermediate 2. This feature is in contrast to the pos-
sibility that the vinylindium intermediate might be a (Z)-
vinylindium intermediate due to the strong coordination
of the indium atom to the amide carbonyl group.8
Having succeeded in the synthesis of (E)-3-alkyli-
deneoxindoles, we next applied this method to the ste-
reoselective synthesis of disubstituted 3-alkylideneoxin-
doles 4 using aryl- and alkyl-boronic acids. While this
paper was in preparation, Player et al. published a
complementary stereoselective synthesis of disubstituted
3-alkylideneoxindoles with N-containing heterocycles.13
They found that copper(I) thiophen-2-carboxylate (CuTC)
was an appropriate additive for obtaining high stereo-
selectivity. Table 2 shows our results. In most cases, the
corresponding disubstituted 3-alkylideneoxindoles 4a-h
were obtained in high yields with no contamination of
other stereoisomers (runs 1-10). Only when aliphatic
boronic acid was used was the product yield low (run 11),
as usually seen in the Suzuki-Miyaura reaction. The
catalyzed Heck/Suzuki-Miyaura domino reaction was
carried out with starting material B, the other stereo-
isomer C of A should be obtained stereoselectively via
path b. Herein we report the palladium-catalyzed domino
reaction of compound B to yield (E)-, (Z)-, and disubsti-
tuted-3-alkylideneoxindoles as single stereoisomers. We
applied this procedure to the palladium-catalyzed Heck/
Heck domino reaction and to the Heck/carbonylation/
Suzuki-Miyaura domino reaction (Scheme 2).
Preparation of the starting materials 1 was easily
achieved according to our recently reported method.8 We
initially examined the reaction of 1 in the presence of a
catalytic amount of Pd(OAc)2, PPh3, and 1.1 equiv of aryl-
and alkylboronic acids (Table 1). When sodium hydroxide
was used as a base, a mixture of (E)- and (Z)-3-alkyli-
deneoxindoles 3a (E:Z ) 22:1) was obtained (run 1). After
some trials, we found that cesium fluoride was an
appropriate additive as an activator for boronic acids of
this Heck/Suzuki-Miyaura domino coupling reaction.
Then, we examined the reaction of alkyneamide 1a and
J. Org. Chem, Vol. 70, No. 17, 2005 6973

TABLE 3. Synthesis of Disubstituted 3-Alkylideneoxindoles and 3-Alkylidenebenzofuran-2-ones
TABLE 4. Synthesis of (Z)-3-Alkylideneoxindoles
reaction of compounds 1 bearing an electron-donating or
electron-withdrawing group on the aromatic ring also
gave stereoselectively the desired cyclized products 4i-k
in good yields (runs 12-14). By our previous method,8 it
was not possible to obtain compounds (E)-4f or 4g-k
containing alkyl groups as R1 substituents. The Heck/
Suzuki-Miyaura domino reaction mentioned here can
achieve the synthesis of these compounds exclusively.
The stereoselectivity of compounds 4 was unambiguously
confirmed using the authentic samples or by comparison
1
with the tendencies of their H NMR spectra.8
run
1
X
R1
base
(Z)-7
yield (%)
Encouraged by these results, we applied these opti-
mized conditions to N-free alkyneamide 1 and alkynester
1. Our radical cyclization method with indium was not a
suitable method for N-free alkyneamides 1, but the
palladium-catalyzed cyclization reactions mentioned here
fortunately proceeded smoothly and stereoselectively to
yield disubstituted 3-alkylideneoxindoles 5a-e (X ) NH,
Table 3, runs 1-5) and 3-alkylidenebenzofuran-2-ones
known as topoisomerase inhibitors and angiogenesis14
5f15-j (X ) O, runs 6-10) in high yields.
1
2
3
4
5
b
c
d
f
NBn
NBn
NBn
NBn
O
Ph
CsF
CsF
CsF
CsF
CsF
a
b
c
d
e
80
70
70
0
Tol
p-CF3-Ph
Bu
Ph
o
65
SCHEME 3. Heck Carbonylation/Suzuki-Miyaura
Domino Reaction
To obtain (Z)-3-alkylideneoxindoles and benzofuran-
2-one, compound 1 was treated with a catalytic amount
of Pd(OAc)2 and PPh3 in the presence of cesium fluoride
in THF. In the presence of ammonium formate, the
reaction proceeded smoothly to regenerate the Pd(0)
catalyst from the intermediate σ-vinylpalladium com-
plexes 6. Under these conditions, the desired (Z)-7a-7c
and 7e15 were cleanly obtained in good yields (Table 4,
runs 1-3, 5). Unfortunately, our attempted synthesis of
compound 7d bearing an aliphatic substituent was
unsuccessful (R1 ) Bu, run 4).
monoxide atmosphere to produce compound 8 in 70%
yield. The (E)-configuration of the double bond is unam-
biguously supported by the NOESY spectrum for the
interaction between the aromatic proton of anisole and
the aromatic proton in the 4-position of the indolone
moiety. We also applied our method to the synthesis of
compound 9. As shown in Table 5, Heck/Heck domino
reactions proceeded to give compounds 9 as a single
isomer in high yields (runs 1-3). The stereostructure of
the newly introduced olefins was found to be of trans
geometry and confirmed by the large olefinic coupling
constant of their 1H NMR. Only when we used allyl
acetate as an olefin did we obtain the unusual product
9d in 80% yield (run 4). This product would be produced
by intramolecular Heck cyclization, followed by intermo-
lecular Heck reaction, and then maybe a palladium-â-
alkoxy elimination. Lautens reported Pd-catalyzed in-
tramolecular coupling reaction between aryl iodide and
allyl moieties.9 He wrote that the amine base should be
the reductant of Pd(II) to Pd(0) after the catalytic cycle,
and inorganic bases instead of the amine base gave very
Next, we applied these methods to the synthesis of
compound 8 known as a a CDK inhibitor14 via a Heck/
carbonylation/Suzuki-Miyaura domino reaction (Scheme
3). This reaction proceeded smoothly under a carbon
(13) Cheung, W. S.; Patch, R. J.; Player, M. R. J. Org. Chem. 2005,
70, 3741.
(14) (a) Woodard, C. L.; Li, Z.; Kathcart, A. K.; Terrell, J.; Gerena,
L.; L.-Sanchez, M.; Kyle, D. E.; Bhattacharjee, A. K.; Nichols, D. A.;
Ellis, W.; Prigge, S. T.; Geyer, J. A.; Waters, N. C. J. Med. Chem. 2003,
46, 3877. (b) Adams, C.; Aldous, D. J.; Amendola, S.; Bamborough, P.;
Bright, C.; Crowe, S.; Eastwood, P.; Fenton, G.; Foster, M.; Harrison,
T. K. P.; King, S.; Lai, J.; Lawrence, C.; Letallec, J.-P.; McCarthy, C.;
Moorcroft, N.; Page, K.; Rao, S.; Redford, J.; Sadiq, S.; Smith, K.;
Souness, J. E.; Thurairatnam, S.; Vine, M.; Wyman, B. Bioorg. Med.
Chem. Lett. 2003, 13, 3105.
(15) Msaddek, M.; Rammah, M.; Ciamala, K.; Vebrel, J.; Laude, B.
Synthesis 1997, 1495.
6974 J. Org. Chem., Vol. 70, No. 17, 2005

TABLE 5. Heck/Heck Domino Reaction
column chromatography on silica gel (hexane/AcOEt ) 5/1) to
give 8 (31.2 mg, 70%).
(E)-1-Benzyl-3-(2-(4-methoxyphenyl)-2-oxo-1-phenyleth-
1
ylidene)indolin-2-one (8): H NMR (500 MHz, CDCl3) δ 7.80
(d, J ) 7.9 Hz, 2H), 7.44-7.24 (m, 8H), 7.05 (t, J ) 7.6 Hz, 1H),
6.97-6.88 (m, 4H), 6.68-6.66 (m, 3H), 4.92 (s, 2H), 3.87 (s, 3H);
13C NMR (126 MHz, CDCl3) δ 168.8, 163.3, 160.8, 155.4, 140.4,
140.3, 137.5, 165.6, 133.6, 131.7, 130.7, 129.3, 128.5, 127.8, 124.5,
123.8, 123.0, 121.2, 114.2, 113.5, 109.5, 55.3; IR (CHCl3) ν 2980,
1602 cm-1; MS (FAB) m/z 446 (MH+); HRMS (FAB) calcd for
C30H24NO3 (MH+) 446.1756, found 446.1758.
Heck/Heck Domino Reaction: Synthesis of Compound
9. To a solution of iodoalkyne 1b (36.1 mg, 0.10 mmol) in DMF
were added palladium(II) acetate (1.12 mg, 5 × 10-3 mmol),
triphenylphosphine (2.62 mg, 0.01 mmol), tert-butyl acrylate
(25.6 mg, 0.20 mmol), and potassium carbonate (27.6 mg, 0.20
mmol), and the mixture was stirred for 6 h at 60 °C under an
argon atmosphere. After being quenched with water, the mixture
was extracted with AcOEt and dried over MgSO4. The residue
was purified by column chromatography on silica gel (hexane/
AcOEt ) 5/1) to give 9 (39.3 mg, 90%).
(2E,4Z)-tert-Butyl 4-(1-Benzyl-2-oxindolin-3-ylidene)-4-
phenylbut-2-enoate (9a): 1H NMR (500 MHz, CDCl3) δ 9.50
(d, J ) 15.5 Hz, 1H), 7.52-7.50 (m, 4H), 7.33-7.22 (m, 6H),
7.05-7.03 (m, 1H), 6.63 (d, J ) 7.9 Hz, 1H), 6.56 (m, 1H), 5.77
(d, J ) 7.6 Hz, 1H), 5.67 (d, J ) 15.5 Hz, 1H), 4.98 (s, 2H), 1.50
(s, 9H); 13C NMR (126 MHz, CDCl3) δ 165.9, 147.8, 143.1, 140.4,
136.1, 131.4, 129.7, 129.5, 129.3, 128.8, 128.3, 127.6, 127.4, 127.0,
124.7, 122.6, 121.8, 108.7, 80.8, 43.3, 28.0; IR (CHCl3) ν 2950,
1640 cm-1; MS (FAB) m/z 438 (MH+); HRMS (FAB) calcd for
C29H28NO3 (MH+) 438.2069, found 438.2070.
(2E,4Z)-4-(1-Benzyl-2-oxindolin-3-ylidene)-4-phenylbut-
2-enenitrile (9b): 1H NMR (500 MHz, CDCl3) δ 9.48 (d, J )
16.2 Hz, 1H), 7.59-7.54 (m, 3H), 7.34-7.20 (m, 8H), 7.07 (t, J
) 6.4 Hz, 1H), 6.59 (t, J ) 7.7 Hz, 1H), 5.79 (d, J ) 8.0 Hz, 1H),
5.21 (d, J ) 16.2 Hz, 1H), 4.96 (s, 2H); 13C NMR (126 MHz,
CDCl3) δ 166.9, 147.2, 145.4, 143.6, 135.7, 134.9, 130.6, 129.8,
129.4, 128.9, 128.4, 127.8, 127.8, 127.4, 125.2, 122.2, 122.0, 118.0,
109.0, 106.3, 43.5; IR (CHCl3) ν 2960, 1605 cm-1; MS (FAB) m/z
363 (MH+); HRMS (FAB) calcd for C25H19N2O (MH+) 363.1497,
found 363.1495.
low product yields. In our experiment, when we used
potassium carbonate as a base, compound 9 was obtained
exclusively. This is an interesting result, and we are
currently investigating the same type of reaction.
Conclusion
We have developed efficient catalytic methods for the
stereoselective and diversity-generating synthesis of
various (E)-, (Z)-, and disubstituted 3-alkylideneoxindoles
and 3-alkylidenebenzofuran-2-ones via palladium-cata-
lyzed Heck/Suzuki-Miyaura, Heck/Heck, and Heck/car-
bonylation/Suzuki-Miyaura domino reactions. Our method
provides a versatile tool for further expansion of the
synthetic utility such as the total synthesis of natural
products and random screening in the search for drug
candidates.
(3Z)-1-Benzyl-3-((E)-1,3-diphenylallylidene)indolin-2-
one (9c): 1H NMR (500 MHz, CDCl3) δ 9.42 (d, J ) 12.2 Hz,
1H), 7.58-7.53 (m, 5H), 7.37-7.24 (m, 10H), 7.00 (t, J ) 7.6
Hz, 1H), 6.67 (d, J ) 6.3 Hz, 1H), 6.57 (t, J ) 7.6 Hz, 1H), 6.50
(d, J ) 12.2 Hz, 1H), 5.75-5.72 (m, 1H), 5.02 (s, 2H); 13C NMR
(126 MHz, CDCl3) δ 168.1, 151.6, 141.8, 137.6, 136.4, 129.3,
129.1, 128.8, 128.7, 128.6, 128.5, 128.2, 128.0, 127.7, 127.5, 127.3,
123.7, 123.4, 121.6, 108.4, 96.9, 43.3; IR (CHCl3) ν 3002, 1640
Experimental Section
General Procedure for the Synthesis of (E)- and Disub-
stituted Compounds (3-5). To a solution of iodoalkyne 1a
(36.1 mg, 0.10 mmol) in THF were added palladium(II) acetate
(1.12 mg, 5 × 10-3 mmol), triphenylphosphine (2.62 mg, 0.01
mmol), phenylboronic acid (13.3 mg, 0.11 mmol), and cesium
fluoride (45.3 mg, 0.30 mmol), and the solution was stirred for
1 h at 60 °C under an argon atmosphere. After being quenched
with water, the mixture was extracted with AcOEt and dried
over MgSO4. The residue was purified by column chromatogra-
phy on silica gel (hexane/AcOEt ) 5/1) to give (E)-3a (29.5 mg,
95%).
General Procedure for the Synthesis of (Z)-3-Alkyli-
deneoxindoles 7. To a solution of iodoalkyne 1b (43.7 mg, 0.10
mmol) in THF were added palladium(II) acetate (1.12 mg, 5 ×
10-3 mmol), triphenylphosphine (2.62 mg, 0.01 mmol), cesium
fluoride (45.3 mg, 0.30 mmol), and ammonium formate (12.6 mg,
0.20 mmol), and the solution was stirred for 6 h at 60 °C under
an argon atmosphere. After being quenched with water, the
mixture was extracted with AcOEt and dried over MgSO4. The
residue was purified by column chromatography on silica gel
(hexane/AcOEt ) 5/1) to give (Z)-7b (24.9 mg, 80%).
Heck/Carbonylation/Suzuki-Miyaura Domino Reac-
tion: Synthesis of Compound 8. To a solution of iodoalkyne
1b (36.1 mg, 0.10 mmol) in THF were added palladium(II)
acetate (1.12 mg, 5 × 10-3 mmol), triphenylphosphine (2.62 mg,
0.01 mmol), 4-methoxyphenylboronic acid (16.6 mg, 0.11 mmol),
and cesium fluoride (45.3 mg, 0.30 mmol), and the solution was
stirred for 3 h at 60 °C under a carbon monoxide atmosphere.
After being quenched with water, the mixture was extracted
with AcOEt and dried over MgSO4. The residue was purified by
cm-1; MS (FAB) m/z 414 (MH+); HRMS (FAB) calcd for C30H24
-
NO (MH+) 414.1858, found 414.1860.
(Z)-1-Benzyl-3-(1-phenylbut-3-enylidene)indolin-2-one
(9d). 1H NMR (500 MHz, CDCl3) δ 9.84 (d, J ) 8.0 Hz, 1H),
9.56 (d, J ) 15.8 Hz, 1H), 7.55-7.53 (m, 3H), 7.36-7.22 (m, 9H),
7.08 (t, J ) 5.6 Hz, 1H), 6.68 (d, J ) 7.7 Hz, 1H), 6.60 (t, J ) 7.7
Hz, 1H), 5.97 (q, J ) 8.0 Hz, 1H), 5.89 (d, J ) 8.0 Hz, 1H), 4.98
(s, 2H); 13C NMR (126 MHz, CDCl3) δ 166.9, 155.1, 142.5, 141.4,
139.9, 136.4, 132.2, 132.1, 130.2, 129.4, 129.2, 129.0, 128.8, 128.7,
128.6, 128.5, 127.8, 127.5, 127.3, 127.2, 124.0, 123.4, 123.2, 121.4,
108.7, 43.4; IR (CHCl3) ν 3002, 1652 cm-1; MS (FAB) m/z 352
(MH+); HRMS (FAB) calcd for C25H22NO (MH+) 352.1701, found
352.1703.
Acknowledgment. This work was supported in part
by a Grant-in-Aid for Scientific Research (B and C) from
the Ministry of Education, Science, Sports, and Culture,
Japan, and by the 21st Century COE Program “Knowl-
edge Information Infrastructure for Genome Science”.
Supporting Information Available: Characterization
data and 1H and 13C NMR spectra of synthetic new compounds
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO0508604
J. Org. Chem, Vol. 70, No. 17, 2005 6975