Scandium(III)-catalyzed enantioselective allylation of isatins using allylsilanes

Article abstract of DOI:10.1021/ol300496v

The scandium(III)-catalyzed enantioselective Hosomi-Sakurai allylation of isatins with various substituted allylic silanes is described. A catalyst loading as low as 0.05 mol % is utilized at room temperature to afford the 3-allyl-3-hydroxy-2-oxindoles in

Full text of DOI:10.1021/ol300496v

ORGANIC
LETTERS
2012
Vol. 14, No. 9
2218–2221
Scandium(III)-Catalyzed Enantioselective
Allylation of Isatins Using Allylsilanes
Nadine V. Hanhan, Yng C. Tang, Ngon T. Tran, and Annaliese K. Franz*
Department of Chemistry, University of California, One Shields Avenue, Davis,
California 95616, United States
akfranz@ucdavis.edu
Received February 27, 2012
ABSTRACT
The scandium(III)-catalyzed enantioselective HosomiꢀSakurai allylation of isatins with various substituted allylic silanes is described. A catalyst
loading as low as 0.05 mol % is utilized at room temperature to afford the 3-allyl-3-hydroxy-2-oxindoles in excellent yields and enantioselectivity up
to 99% ee, including a demonstration of a gram-scale reaction. The effects of additives and varying silyl groups were explored to demonstrate the
scope and application.
The synthesis of oxindoles continues to be an exciting
challenge due to their importance as core structures in
natural products and pharmaceutical lead compounds.1
Enantioenriched 3-hydroxy-2-oxindole structures are key
intermediates reported in the synthesis of several natural
products and biologically relevant small molecules.2 In
particular, the 3-allyl-3-hydroxy-oxindole is a useful inter-
mediate for synthesis because the alkene provides a func-
tional handle for further transformations.3,4
Using chiral Lewis acids with good chelating potential,
our research has focused on developing a broadly applic-
able methodology for the enantioselective addition of
π-nucleophiles to isatins.5 We have previously described the
addition of allylstannanes to isatins, which afforded 3-allyl-
3-hydroxy-oxindoles with 80% ee (at ꢀ40 °C).5a Allylation
reactions with allylic silanes, known as the Hosomiꢀ
Sakurai reaction,6 provide an attractive alternative to
allylstannanes because allylsilanes are less toxic and have
a reactivity that can be tailored by varying the steric and
electronic properties.7 Allylsilanes have been successfully
utilized for the enantioselective allylation of various reac-
tive electrophiles, such as aldehydes and imines;8 yet, there
is only one current example for the enantioselective allyla-
tion of isatins using allylsilanes, which proceeds with
modest enantioselectivity.9 Here we report an efficient
(1) For reviews on the synthesis of oxindoles in natural products and
drug discovery, see: (a) Badillo, J. J.; Hanhan, N. V.; Franz, A. K. Curr.
Opin. Drug Discovery Dev. 2010, 13, 758–776. (b) Zhou, F.; Liu, Y. L.;
Zhou, J. A. Adv. Synth. Catal. 2010, 352, 1381–1407. (c) Trost, B. M.;
Brennan, M. K. Synthesis 2009, 3003–3025. (d) Galliford, C. V.; Scheidt,
K. A. Angew. Chem., Int. Ed. 2007, 46, 8748–8758.
(2) Peddibhotla, S. Curr. Bioact. Compd. 2009, 5, 20–38.
(3) (a) Kawasaki, T.; Nagaoka, M.; Satoh, T.; Okamoto, A.; Ukon,
R.; Ogawa, A. Tetrahedron 2004, 60, 3493–3503. (b) Kawasaki, T.;
Takamiya, W.; Okamoto, N.; Nagaoka, M.; Hirayama, T. Tetrahedron
Lett. 2006, 47, 5379–5382. (c) Kitajima, M.; Mori, I.; Arai, K.; Kogure,
N.; Takayama, H. Tetrahedron Lett. 2006, 47, 3199–3202.
(4) For syntheses of 3-allyl-3-hydroxy-oxindoles from isatin, see: (a)
Alcaide, B.; Almendros, P.; Rodriguez-Acebes, R. J. Org. Chem. 2005,
70, 3198–3204. (b) Nair, V.; Ros, S.; Jayan, C. N.; Viji, S. Synthesis 2003,
2542–2546. (c) Vyas, D. J.; Frohlich, R.; Oestreich, M. J. Org. Chem.
2010, 75, 6720–6723. For catalytic asymmetric allylations of isatin, see:
(d) Qiao, X. C.; Zhu, S. F.; Zhou, Q. L. Tetrahedron: Asymmetry 2009,
20, 1254–1261. (e) Itoh, J.; Han, S. B.; Krische, M. J. Angew. Chem., Int.
Ed. 2009, 48, 6313–6316. (f) Grant, C. D.; Krische, M. J. Org. Lett. 2009,
11, 4485–4487. For an example of a catalytic asymmetric hydroxylation
of 3-allyl-oxindoles, see: (g) Sano, D.; Nagata, K.; Itoh, T. Org. Lett.
2008, 10, 1593–1595.
(5) (a) Hanhan, N. V.; Sahin, A. H.; Chang, T. W.; Fettinger, J. C.;
Franz, A. K. Angew. Chem., Int. Ed. 2010, 49, 744–747. (b) Gutierrez,
E. G.; Wong, C. J.; Sahin, A. H.; Franz, A. K. Org. Lett. 2011, 13, 5754–
5757.
(6) (a) Hosomi, A.; Sakurai, H. J. Am. Chem. Soc. 1977, 99, 1673–
1675. (b) Hosomi, A. Acc. Chem. Res. 1988, 21, 200–206.
(7) For reviews on allylsilane reactivity, see: (a) Chabaud, L.; James,
P.; Landais, Y. Eur. J. Org. Chem. 2004, 3173–3199. (b) Masse, C. E.;
Panek, J. S. Chem. Rev. 1995, 95, 1293–1316. For a comparison of
allylsilane nucleophilicity, see: (c) Mayr, H.; Kempf, B.; Ofial, A. R. Acc.
Chem. Res. 2003, 36, 66–77. (d) Mayr, H.; Patz, M. Angew. Chem., Int.
Ed. Engl. 1994, 33, 938–957.
r
10.1021/ol300496v
Published on Web 04/16/2012
2012 American Chemical Society

catalytic enantioselective allylation and crotylation of
isatins with allylsilanes using a Sc(III)-indapybox complex
with a TMSCl activator.10,11
and up to 94% ee (entries 4ꢀ6).15 While, the addition of
NaSbF6 is not essential for rate or enantioselectivity, it
provides deprotection (in situ or upon workup) of any
resulting TMS-ether side product.
We first investigated the allylation of isatin 1a using a
Sc(OTf)3 complex with (S,R)-indapybox, which had been
identified as the optimal catalyst complex for the addition
of indoles and allylstannane.5a This complex afforded
hydroxy-oxindole 2a with 71% ee at rt, albeit with ex-
tremely low catalytic activity (Table 1, entry 1). We envi-
sioned that additives such as NaSbF6 could be used to
enhance the rate of reaction, by either creating a more
reactive cationic complex12 or providing a counterion to
stabilize formation of the β-silyl carbocation intermediate.13
However, the NaSbF6 addition did not improve catalytic
activity (entry 2). We then investigated the addition of
TMSCl to promote the reaction,11,14 and a dramatic effect
on both the yield and enantioselectivity was observed:
hydroxy-oxindole 2a was isolated with 91% yield and
88% ee (entry 3). Under these reaction conditions, the
silylated 2a (i.e., TMS-ether) product was often isolated in
11ꢀ20%. The addition of NaSbF6 (10ꢀ30 mol %) with
TMSCl afforded hydroxy-oxindole 2a with 92ꢀ99% yield
Table 1. Optimization for Asymmetric Allylsilane Allylationa
(8) For reviews and selected recent examples of enantioselective
allylations using allylsilanes, see: (a) Yus, M.; Gonzalez-Gomez, J. C.;
Foubelo, F. Chem. Rev. 2011, 111, 7774–7854. (b) Denmark, S. E.; Fu,
J. P. Chem. Rev. 2003, 103, 2763–2793. (c) Momiyama, N.; Nishimoto,
H.; Terada, M. Org. Lett. 2011, 13, 2126–2129. (d) Ong, W. W.; Beeler,
A. B.; Kesavan, S.; Panek, J. S.; Porco, J. A. Angew. Chem., Int. Ed. 2007,
46, 7470–7472. (e) Evans, D. A.; Aye, Y.; Wu, J. Org. Lett. 2006, 8, 2071–
2073. (f) Kim, H.; Ho, S.; Leighton, J. L. J. Am. Chem. Soc. 2011, 133,
6517–6520.
(9) (a) Hg(ClO4)2 3H2O has recently been shown to catalyze the
3
addition of allylsilanes to isatins, where the use of (S)-BINOL affords
55ꢀ63% ee; see: Cao, Z. Y.; Zhang, Y.; Ji, C. B.; Zhou, J. Org. Lett.
2011, 13, 6398–6401. (b) A racemic Bi(OTf)3-catalyzed addition of
allylsilanes to isatins has recently been reported; see: Meshram, H. M.;
Ramesh, P.; Reddy, B. C.; Kumar, G. S. Chem. Lett. 2011, 40, 357–359.
(10) Sc(III)-pybox complexes are effective chiral Lewis acid catalysts
with good chelating potential; for example, see: (a) Evans, D. A.;
Sweeney, Z. K.; Rovis, T.; Tedrow, J. S. J. Am. Chem. Soc. 2001, 123,
12095–12096. (b) Evans, D. A.; Fandrick, K. R.; Song, H. J.; Scheidt,
K. A.; Xu, R. S. J. Am. Chem. Soc. 2007, 129, 10029–10041. (c)
Desimoni, G.; Faita, G.; Mella, M.; Piccinini, F.; Toscanini, M. Eur.
J. Org. Chem. 2007, 1529–1534.
(11) We recently reported a Sc(III)-catalyzed enantioselective [3 þ 2]
allylsilane annulation reaction with isatins using the cationic ScCl2-
(SbF6)-pybox complex; see: Hanhan, N. V.; Ball-Jones, N. R.; Tran,
N. T.; Franz, A. K. Angew. Chem., Int. Ed. 2012, 51, 989–992.
(12) The use of AgSbF6 has been reported previously to access
cationic metal chloride complexes with scandium, copper, and indium.
For examples, see: (a) Evans, D. A.; Kozlowski, M. C.; Murry, J. A.;
Burgey, C. S.; Campos, K. R.; Connell, B. T.; Staples, R. J. J. Am. Chem.
Soc. 1999, 121, 669–685. (b) Evans, D. A.; Willis, M. C.; Johnston, J. N.
Org. Lett. 1999, 1, 865–868. (c) Evans, D. A.; Wu, J.; Masse, C. E.;
MacMillan, D. W. C. Org. Lett. 2002, 4, 3379–3382. (d) Zhao, J. F.;
Tjan, T. B. W.; Loh, T. P. Tetrahedron Lett. 2010, 51, 5649–5652. (e)
Zhao, J.-F.; Tan, B.-H.; Loh, T.-P. Chem. Sci 2011, 2, 349.
(13) For descriptions of β-silyl carbocations, see refs 6a, 7, and 8, and
also: (a) Lambert, J. B.; Zhao, Y. J. Am. Chem. Soc. 1996, 118, 7867–
7868. (b) Lambert, J. B. Tetrahedron 1990, 46, 2677–2689.
a All reactions performed under Ar using 3 equiv of allylsilane. b Isolated
yield. c Determined by HPLC analysis with chiral AD-H stationary phase.
d Yield and enantioselectivity reflect an average of two replicates. Under these
reactions conditions, the yield varies from 80 to 99% because up to 20% of
TMS-ether product is also isolated. e Reaction run with CH2Cl2, and 14% of
the [3 þ 2]-annulation product was isolated; see Supporting Information and
ref 11. f Reaction run with ScCl3(THF)3. TMS = trimethylsilyl.
Investigating other additives and reaction conditions
showed that the Sc(III)-catalyzed allylation maintains a
high yield and enantioselectivity under various conditions
(Table 1). Reactions with alternate counterion sources
(17) Lee, P. H.; Seomoon, D.; Kim, S.; Nagaiah, K.; Damle, S. V.;
Lee, K. Synthesis 2003, 2189–2193.
(18) (a) Knolker, H. J.; Foitzik, N.; Goesmann, H.; Graf, R. Angew.
Chem., Int. Ed. 1993, 32, 1081–1083. (b) Organ, M. G.; Dragan, V.;
Miller, M.; Froese, R. D. J.; Goddard, J. D. J. Org. Chem. 2000, 65,
3666–3678.
(19) We have previously noted that selection of the scandium salt
(OTf vs Cl) and solvent (MeCN vs CH2Cl2) is important to control the
allylation vs annulation pathway. The allylation pathway is dominant
when using the Sc(OTf)3 complex with MeCN solvent. See ref 11.
(20) For a review and pioneering examples of allyltrichlorosilane
activation, see: (a) Kobayashi, S.; Nishio, K. Tetrahedron Lett. 1993, 34,
3453–3456. (b) Kobayashi, S.; Sugiura, M.; Ogawa, C. Adv. Synth.
Catal. 2004, 346, 1023–1034. (c) Denmark, S. E.; Coe, D. M.; Pratt,
N. E.; Griedel, B. D. J. Org. Chem. 1994, 59, 6161–6163.
(21) A control experiment demonstrated that the allylation of isatin
with allyltrichlorosilane and DMF proceeded without the Sc(III)-pybox
catalyst, affording the product with a comparable (71%) yield.
(22) Narayanan, B. A.; Bunnelle, W. H. Tetrahedron Lett. 1987, 28,
6261–6264.
(14) (a) Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J.
Am. Chem. Soc. 2002, 124, 392–393. (b) Lee, P. H.; Seomoon, D.; Kim,
S.; Nagaiah, K.; Damle, S. V.; Lee, K. Synthesis 2003, 2189–2193. (c)
Miranda, P. O.; Carballo, R. M.; Martin, V. S.; Padron, J. I. Org. Lett.
2009, 11, 357–360.
(15) Catalytic activity was not observed with either NaSbF6 or
AgOTf when evaluated in the presence of the chiral pybox ligand and
TMSCl promoter.
(16) (a) Onishi, Y.; Ito, T.; Yasuda, M.; Baba, A. Eur. J. Org. Chem.
2002, 1578–1581. (b) Saito, T.; Nishimoto, Y.; Yasuda, M.; Baba, A. J.
Org. Chem. 2006, 71, 8516–8522.
Org. Lett., Vol. 14, No. 9, 2012
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generally afforded similar yields and enantioselectivities
comparedto NaSbF6 (entries 7ꢀ9). Inplaceof TMSCl, the
use of another silyl chloride, such as PhMe2SiCl, was also
effective in promotingthe reaction(entry 10). The selection
of solvent has an important effect on enantioselectivity,
and performing the reaction in CH2Cl2 afforded 2a with
only 78% ee (entry 11). Under these conditions, we also
observed formation of the spirofused tetrahydrofuran
product, which was isolated in 14% yield (see Supporting
Information).11 The ScCl3-indapybox catalyst proceeded
with lower enantioselectivity compared to the triflate var-
iant, and the cationic ScCl2(SbF6) complex was essential for
efficient activity (entries 12, 13).11 When other pybox
ligands (e.g., isopropyl, phenyl) were investigated, these
reactions proceeded with slower rates and lower enantios-
electivity (e.g., 28ꢀ61% ee, not shown).
We proceeded to investigate the scope of isatins in
the allylation reaction, utilizing 30 mol % of NaSbF6 as
an optimal condition to ensure reproducible yields with a
wide scope of isatins (Table 2). Although the substituents on
isatins can affect the reaction rate, the yield and
enantioselectivity are maintained within 72ꢀ99% yield
and 80ꢀ91% ee across all isatins tested. The scandium
catalyst complex is equally efficient for N-substituted and
unsubstituted NH isatins, affording high yields and enan-
tioselectivity for both. In many cases, using NaSbF6 was
preferred, because it is less hygroscopic and easier to handle.
Various allylsilanes were investigated to identify the
ability of the scandium catalyst to control the product
ratio (allylation vs annulation) and enantioselectivity for
varying steric and electronic effects (Table 3). While bulky
allylsilanes are known to promote a [3 þ 2] annulation
pathway,18 here allylation is maintained as the major
product using the Sc(OTf)3-pybox catalyst. Using an
aryldimethylsilyl group afforded the allylation product
with overall identical performance to the trimethylsilyl
group (entry 1). Although the increased steric bulk of the
triisopropylallylsilane did not affect the rate of the reac-
tion, the yield of the reaction was reduced to 66% (entry 2)
due to formation of the annulation product.19
Investigating several electron-deficient allylsilanes de-
monstrated the limitations of the Sc(OTf)3-pybox catalyst;
poor or no reactivity was observed with chloro- and meth-
oxy-substituted allylsilanes (entries 3ꢀ5). We proceeded to
investigate if the Sc(OTf)3-pybox catalyst would be compa-
tible with a Lewis base additive, such as DMF, which can be
used to activate the nucleophilicity of the allyl group by
formation of the pentacoordinate siliconate.20 While the
allyltrichlorosilane afforded no product, adding 4 equiv of
DMF to the reaction promoted allylation in 74% yield, albeit
with no enantioselectivity (compare entry 4 to 6). The
formation of the racemic product is attributed to the
These optimization studies demonstrated that a silyl
chloride activator, such as TMSCl, is essential for effi-
cient catalytic activity while the counterion additive
had less effect on the rate or the enantioselectivity. Our
1
previous studies using H NMR spectroscopy11 suggest
that interactions of TMSCl with the metalꢀligand complex
may enhance the Lewis acidity of the catalyst.16 TMSCl may
also serve as a cooperative Lewis acid to preactivate the
electrophile, or a transmetalation between TMSCl and the
chiral scandium complex is possible.17
Table 2. Scope of Isatins with Allyltrimethylsilanea
Table 3. Reactivity of Silyl Groups for Scandium-Catalyzed
Allylationa
a All reactions performed under argon using 3 equiv of allylsilane.
b Isolated yield. c Determined by HPLC analysis on chiral stationary phase.
d Performing the reaction at 6 °C for 24 h afforded 95% yield and 92% ee.
a All reactions performed under argon using 3 equiv of allylsilane.
Ar = 4-methoxyphenyl. b Isolated yield. c Determined by HPLC analy-
sis on chiral stationary phase (Daicel CHIRALPAK AS-H column).
d The [3 þ 2]-annulation product was also isolated in 34% yield with
99% ee. See Supporting Information. e Reaction run with 4 equiv of
DMF. Without catalyst, this reaction yielded 71% in 48 h.
(23) We have also evaluated the reaction of propargylsilane under the
optimal reaction conditions, and the reaction affords the racemic allenyl
product.
(24) The absolute configuration of product 3a was assigned as the
(R)-enantiomer, based on X-ray diffraction analysis (CDCC 866520),
which matches the absolute configuration assigned for the addition of
allyltributyltin in ref 5a.
2220
Org. Lett., Vol. 14, No. 9, 2012

To test the scalability of the allylation reaction at a low
catalyst loading, a gram-scale reaction was performed
using a 0.1 mol % catalyst loading (Scheme 1). The addition
of methallylsilane to isatin 1o proceeds with 96% yield and
92% ee in 48 h at rt.
Table 4. Scope of Substituted Allylsilanes with Isatinsa
Scheme 1. Gram Scale Reaction with Methallyltrimethyl-
silane
a All reactions performed under argon; entries 1ꢀ5 performed with 3
equiv of allylsilane. b Isolated yield. c Determined by HPLC analysis on
chiral stationary phase. d Due to the small scale, reaction was run with 10
equiv of NaSbF6 with respect to Sc(OTf)3. e Reaction at 5 mol %
procceds with 93% yield and 91% ee in 3 h. f The reaction was run with
6 equiv of (E)-crotyltrimethylsilane to afford the product as a 5:1
mixture of diastereomers. g Reflects % ee of the major product, assigned
as the anti-product. The syn-product was obtained in 80% ee.
In conclusion, we have developed a catalytic asymmetric
allylation of isatins with allylsilanes that proceeds with
high yield and high enantioselectivity. The reaction utilizes
a chiral Sc(III)-pybox catalyst with a TMSCl activator and
additive such as NaSbF6. The reaction encompasses a wide
scope of isatins and various substituted allylic silanes at rt
with a catalyst loading as low as 0.05 mol %, which should
make this methodology useful for synthetic intermediates
and industrial applications.
enhanced Lewis acidity of the silicon and the six-membered
closed transition state that can be accessed by this reaction.21
The Sc(III)-catalyzed allylation with an allylchlorodimethyl-
silane reagent also afforded a racemic product (entry 3).
Next, a series of substituted allylic silanes were investi-
gated and shown to proceed with high efficiency and
selectivity using the Sc-catalyzed conditions. The 2-methyl-,
2-cyclohexyl-, and 2-phenyl-substituted allylsilanes22 proceed
with high yields (up to 98%) and enantioselectivities up to
99% ee (Table 4, entries 1ꢀ5).23 These reactions were
effective with as low as 0.05 mol % of the Sc(III) complex,
where a high yield and enantioselectivity were maintained
(entry3).24 The Sc-catalyzed methodology is also effective for
the crotylation of isatins using (E)-crotyltrimethylsilane.25
The crotylation affords anti-3d with 96% ee, isolated in 95%
yield as a 5:1 mixture of diastereomers (entry 6).26
Acknowledgment. We acknowledge the donors of the
American Chemical Society Petroleum Research Fund
and NIH/NIGMS (P41-GM0089153) for support of this
research. A.K.F. is a recipient of a 3M Nontenured faculty
grant. N.V.H. is a recipient of the Eugene Cota-Robles,
Bradford Borge, and Bryan Miller Graduate Fellowships.
N.T.T. is a recipient of the Bradford Borge Chemistry
Fellowship, the U.S. Department of Education GAANN
Fellowship, and Achievement Rewards for College Scien-
tists (ARCS).
Supporting Information Available. Experimental pro-
cedures, spectral data for all compounds, and X-ray data
for compound 3a. This material is available free of charge
via the Internet at http://pubs.acs.org.
(25) Tamao, K.; Sumitani, K.; Kiso, Y.; Zembayashi, M.; Fujioka,
A.; Kodama, S.; Nakajima, I.; Minato, A.; Kumada, M. Bull. Chem.
Soc. Jpn. 1976, 49, 1958–1969.
(26) The anti-product was assigned as the major diastereomer by
analogy with the isatin crotylation products reported in ref 4e.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 9, 2012
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