Stereoselective synthesis of 3-alkylideneoxindoles using tandem in-mediated carbometalation and Pd-catalyzed cross-coupling reaction

Article abstract of DOI:10.1021/ol048866n

Efficient methods for stereoselective synthesis of various (E)-, (Z)-, and disubstituted 3-alkylideneoxindoles were investigated using tandem In-mediated carbometalation and ligandless Pd-catalyzed coupling reaction.

Full text of DOI:10.1021/ol048866n

ORGANIC
LETTERS
2004
Vol. 6, No. 16
2825-2828
Stereoselective Synthesis of
3-Alkylideneoxindoles Using Tandem
In-Mediated Carbometalation and
Pd-Catalyzed Cross-Coupling Reaction
,†
Reiko Yanada,† Shingo Obika,† Munetaka Oyama,‡ and Yoshiji Takemoto*
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity, Yoshida, Sakyo-ku,
Kyoto 606-8501, Japan, and DiVision of Research InitiatiVes, International InnoVation
Center, Kyoto UniVersity, Sakyo-ku, Kyoto 606-8501, Japan
takemoto@pharm.kyoto-u.ac.jp
Received June 16, 2004
ABSTRACT
Efficient methods for stereoselective synthesis of various (E)-, (Z)-, and disubstituted 3-alkylideneoxindoles were investigated using tandem
In-mediated carbometalation and ligandless Pd-catalyzed coupling reaction.
Oxindoles are important constituents of natural indole
alkaloids,1 drug candidates,2 and metabolic intermediates.
Among them, 3-alkylideneoxindoles are well-known to be
versatile compounds in terms of biological activity and
synthetic applicability. For example, (E)-alkylideneoxindoles
are important synthetic intermediates of TMC-95A3 as well
as drug candidates of tyrosine kinase inhibitors4 and anti-
rheumatic compounds.5 Similarly, much attention has been
directed to (Z)-alkylideneoxindoles as promising inhibitors
of tyrosin kinase4 and cyclin-dependent protein kinases.6
However, despite their importance, stereoselective synthesis
of these (E)- and (Z)-3-alkylideneoxindoles remains a dif-
ficult problem.3,7 In addition, stereoselective synthesis of
3-disubstituted 3-alkylideneoxindoles, which are expected to
have unique biological activity, has not been achieved.
(4) (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.; Tang, F.; App, H.; Hirth, P.; McMahon, G.; Tang, C. J.
Med. Chem. 1998, 41, 2588. (c) Vieth, M.; Commins, D. J. J. Med. Chem.
2000, 43, 3020. (d) Bramson, H. N.; Corona, J.; Davis, S. T.; Dickerson,
S. H.; Ederstein, 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.; Schewchuk, L.; Veal, J. M.;
Walker, D. H.; Kuyper, L. F. J. Med. Chem. 2001, 44, 4339. (e) 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.
† Graduate School of Pharmaceutical Sciences.
‡ International Innovation Center.
(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.;
Carreira, E. M. Eur. J. Org. Chem. 2003, 2209. (e) Akai, S.; Tsujino, T.;
Akiyama, E.; Tanimoto, K.; Naka, T.; Kita, Y. J. Org. Chem. 2004, 69,
2478.
(2) Zhang, T. Y.; Zhang, H. Tetrahedron Lett. 2002, 43, 193 and
references therein.
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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.
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Sanchez, M.-L.; Kyle, D. E.; Bhattacharjee, A. K.; Nichols, D. A.; Ellis,
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Danishefsky, S. J. Angew. Chem., Int. Ed. 2001, 40, 1967. (c) Inoue, M.;
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Chem. Soc. 2004, 126, 6347.
10.1021/ol048866n CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/16/2004

Therefore, development of a stereoselective and diversity-
oriented approach for synthesis of such 3-alkylideneoxindoles
(AfC) are in high demand (Scheme 1). We have already
Table 1. Reductive Radical Cyclization Reaction
Scheme 1
yield (%)
3a (E:Z)
run
condition
1a
1
2
3a
4
5
6
In (2 equiv) + I2 (1 equiv)
40 (E)
81 (E)
80 (E)
0
45
0
0
80
0
50
In (2 equiv) + Br2 (1 equiv)
In (2 equiv) + Py‚HBr3 (1 equiv)
In (2 equiv) + NBS (1 equiv)
Bu3SnH (1.2 equiv) + Et3B (1.2 equiv) 59 (2:1)
InCl3 (0.1 equiv) + NaBH4 (2.0 equiv) 19 (1.1:1)
a Reaction mixture of compound 1 (1 mmol), In (2 mmol), Py‚HBr3, or
Br2 (1 mmol) in DMF (2 mL) was stirred for 12 h at room temperature
under an argon atmosphere.
potentiality of other reagents, 1a was treated with Bu3SnH11
and InCl3-NaBH4,12 affording the mixture of (E)- and (Z)-
alkenes 3a in a ratio of 1/1 to 2/1 (runs 5 and 6). These
results suggests that the (E)-selective production in the In-
mediated reaction was due to strong coordination of the
indium atom to the amidecarbonyl group of the intermediate
2a. It has been reported that the coordination of indium
reagents to a hydroxy group of the substrate can be used to
control stereogenic centers.13
Having established the optimized reaction conditions for
3a, we next applied these conditions to synthesize various
(E)-3-alkylideneoxindoles 3b-g. Representative results are
shown in Table 2. Except for 1f and 1g, the In-mediated
reported reductive cyclization of D with In and iodine to
prepare 3-alkylidenehexahydrofuro[2,3-b]pyrans F.8 The
intramolecular carboindation of D occurred via vinylindium
intermediate E to give a mixture of (E)- and (Z)-isomers F
in good yield with moderate stereoselectivity (1/1-8/1) of
E/Z (eq 1). We expected that in the case of iodo-ynamide
A, stereochemically defined alkene C would be obtained
predominantly if the indium atom coordinates to the amide-
carbonyl group in B. Here we report the first stereoselective
synthesis of (E)-, (Z)-, and disubstituted 3-alkylideneoxin-
doles C using tandem indium-mediated carbometalation and
palladium-catalyzed cross-coupling reaction.
We initially examined the cyclization of 1a under the
reaction conditions developed previously (In and I2 in DMF,
Table 1).8a,c Although the cyclization product 3a was obtained
exclusively, the chemical yield of 3a was only 40% due to
recovery of the starting material 1a in 45% yield (run 1).
After optimization of the reaction conditions, we found that
additives had a dramatic effect on the reaction rate. When
Br2 was added to the reaction mixture instead of I2, 5-exo
cyclization proceeded smoothly to give (E)-3a in 81% yield
as a single isomer (run 2).9,10 Furthermore, it was revealed
that pyridinium tribromide (Py‚HBr3) could be used for this
reaction instead of Br2, but the combination of In and NBS
provided no desired product (runs 3 and 4). We preferred to
use Py‚HBr3 due to its easy handling. To investigate the
Table 2. Reductive Radical Cyclization Reaction for Synthesis
of (E)-Alkenes
yield (%)
run
1
R
reaction time (h)
3
(E:Z)
1
1b
1c
1d
1e
1f
Et
24
24
18
24
18
18
3b
3c
3d
3e7a
3f
75 (E)
70 (E)
75 (E)
80 (E)
84 (19:1)
80 (10:1)
2a
CH2OBn
p-CF3-Ph
Ph
p-CH3-Ph
p-MeO-Ph
3
4
5
6
(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.
1g
3g
a Two folds of In and Py‚HBr3 was used.
(8) (a) Yanada, R.; Nishimori, N.; Matsumura, A.; Fujii, N.; Takemoto,
Y. Tetrahedron Lett. 2002, 43, 4585. (b) Ueda, M.; Miyabe, H.; Nishimura,
A.; Miyata, O.; Takemoto, Y.; Naito, T. Org. Lett. 2003, 5, 3835. (c) Yanada,
R.; Koh, Y.; Nishimori, N.; Matsumura, A.; Obika, S.; Mitsuya, H.; Fujii,
N.; Takemoto, Y. J. Org. Chem. 2004, 69, 2417. (d) Yanada, R.; Obika,
S.; Nishimori, N.; Yamauchi, M.; Takemoto, Y. Tetrahedron Lett. 2004,
45, 2331.
cyclizations of 1b-e under the same conditions gave the
desired products 3b-e as single isomers in good yields (runs
1-4). In contrast, treatment of 1f and 1g, each bearing an
2826
Org. Lett., Vol. 6, No. 16, 2004

electron-donating group on the aromatic ring in the R group,
with In and Py‚HBr3 provided the corresponding (E)-isomers
3f-g along with (Z)-isomers as minor products (runs 5 and
6). The ratio of Z/E was dependent on the substituents on
the aromatic ring in the R group. Substrates bearing a more
electron-donating group in the R group tended to provide a
(Z)-isomer with a higher Z/E ratio.
To confirm the existence of the vinylindium intermediate
2a, the reaction mixture of 1a was quenched with 1N-DCl,
resulting in the production of the deuterated product (E)-
3a-D (75% D) (eq 2). Since this observation confirmed the
could not be identified in the reaction mixture, the (Z)-
selectivity was revealed to be very high. To improve the
chemical yield, we examined cross-coupling reactions with
various palladium catalysts other than Pd(PPh3)4. Although
the reaction of 2h with Pd(acac)2 gave a mixture of (Z)-
alkene 3f and 3h, we found that the addition of LiBr (3
equiv),8c,13 together with Pd(acac)2, accelerated the coupling
reaction, giving the expected (Z)-alkene 3f as a single isomer
in 60% yield (runs 2 and 3). The same subjection of
vinylindium 2h to the coupling reaction with several aryl
iodides produced the corresponding (Z)-alkenes 3e, 3d, and
3i exclusively (runs 4-6). In this way, we accomplished a
novel stereoselective synthesis of several (Z)-3-alkylidene-
oxindoles 3 from 1h by a tandem intramolecular carbo-
indation and ligandless Pd-catalyzed cross-coupling reaction15
via 2h, though the chemical yields of (Z)-3 need to be
improved. This ligandless process should be a useful method
from the viewpoint of cost, purification of the reaction
mixture, and atom economy.
involvement of 2a, we next examined the reaction of
vinylindium intermediate 2h and aryl halides in the presence
of a palladium catalyst to give (Z)-alkenes 3 stereoselectively
(Table 3). Pd-catalyzed cross-coupling reactions of vinyl-
Having succeeded in the synthesis of (E)- and (Z)-3-
alkylideneoxindoles, we finally undertook the stereoselective
synthesis of disubstituted 3-alkylideneoxindoles 4. Tandem
cross-coupling reactions of 1e with several aryl iodides via
vinylindium 2e were carried out under the conditions in the
presence of Pd(acac)2 and LiBr. In all cases, the correspond-
ing disubstituted 3-alkylideneoxindoles 4 were obtained in
good yields with no contamination of other stereoisomers.
Since stereoisomer 4a (E) of 4a (Z) could be prepared starting
from 1f and iodobenzene by the same procedure, the
stereoselectivity was unambiguously determined by a com-
Table 3. Tandem Carboindation and Cross-Coupling Reaction
for (Z)-Alkenes
1
parison of their H NMR spectra. In addition, it is notable
that a p-methoxyphenyl group could be introduced with
perfect retention of the configuration in the synthesis of 4c,
in sharp contrast to the synthesis of 3g. Generally, the
coupling reaction into disubstituted 3-alkylideneoxindoles 4
proceeded not only with perfect stereoselectivity but also in
better yield than that of the corresponding (Z)-adducts.
Consequently, this method provides an efficient route to
disubstituted 3-alkylideneoxindoles, which can be regarded
as oxindole analogues of the anti-breast cancer drug tamox-
ifen.16 In summary, we have developed the first efficient
methods for stereoselective and diversity-oriented synthesis
indiums and aryl halides have already been reported by
Sarandeses, Yamamoto, Araki, Oshima, and our group.8a,8c,14
Treatment of the vinylindium intermediate 2h prepared from
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14b
1h with 4-iodotoluene and 0.05 equiv of 6Pd(PPh3)4
afforded the coupling product (Z)-3f in 30% yield along with
the protonated product 3h (run 1). Since the (E)-isomer 3f
(9) We tried to observe the cyclic voltammograms of In with I2 and In
with Br2 in DMF to consider the differences in the reactions, referring to
the previous results of SmI2 and SmBr2, which showed remarkable potential
differences.10 However, no clear redox responses involving In ions were
observed. This is presumably due to the less electroactive nature of In.
Actually, the electrochemical data of In have been scarcely available up to
now.
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Kuhlman, M. L.; Flowers, R. A., II. Tetrahedron Lett. 2000, 41, 8049. (d)
Knettle, B. W.; Flowers, R. A., II. Org. Lett. 2001, 3, 2321.
Org. Lett., Vol. 6, No. 16, 2004
2827

provides a versatile tool for the total synthesis of natural
products and for random screening to find drug candidates.
Table 4. Tandem Carboindation and Cross-Coupling Reaction
for Disubstituted 3-Alkylideneoxindoles
Acknowledgment. This work was supported in part by
a Grant-in-Aid for Scientific Research (C) from the Ministry
of Education, Science, Sports, and Culture, Japan, and by
the 21st Century COE Program “Knowledge Information
Infrastructure for Genome Science”.
Supporting Information Available: Information on
general experimental procedures and on characteristics of
synthetic compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL048866N
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of various (E)-, (Z)-, and disubstituted 3-alkylideneoxindoles
using tandem In-mediated carbometalation and ligandless Pd-
catalyzed coupling reaction. The key step is the first
stereoselective carboindation reaction of 1a-g using the
strong coordination ability of an indium atom. Our method
2828
Org. Lett., Vol. 6, No. 16, 2004