Catalytic asymmetric synthesis of substituted 3-hydroxy-2oxindoles

Article abstract of DOI:10.1002/anie.200904393

Chemical equation presented Chemical equation presented No more double trouble: The competing double-addition pathway was suppressed when chiral scandium(III) and indium (III) complexes were used to catalyze the addition of indoles and other π nucleophile

Full text of DOI:10.1002/anie.200904393

Communications
DOI: 10.1002/anie.200904393
Synthetic Methods
Catalytic Asymmetric Synthesis of Substituted 3-Hydroxy-2-
Oxindoles**
Nadine V. Hanhan, Aziza H. Sahin, Toby W. Chang, James C. Fettinger, and Annaliese K. Franz*
Substituted 3-hydroxy-2-oxindoles are important core struc-
tures found in many natural products[1] and pharmaceutical
lead compounds.[2] Despite the prevalence of bioactive
oxindole structures, there is not currently a general asym-
metric method for the addition of a broad range of
unactivated electron-rich p nucleophiles to isatins (indole-
2,3-diones).[3,4] Although the development of an asymmetric
reaction is the primary challenge, the addition of electron-rich
arenes is further complicated by the competing formation of
achiral 3,3-diaryl oxindole products (such as B, Scheme 1).[5,6]
three criteria: reactivity, selectivity for the monoaddition
product 3, and enantioselectivity (Table 1). Metal complexes
with slower reaction rates were observed to be active for the
addition reaction with limited (or no) formation of the 3,3’-
bisindolyl product 4; however, both the use of a low temper-
ature and the presence of a chiral ligand also promoted the
Table 1: Metal and ligand effects for the addition of N-methylindole.[a]
Scheme 1. Competing formation of monoaddition (A) and double-
addition (B) oxindole products in the Lewis acid catalyzed addition of
nucleophiles to isatin. TMS=trimethylsilyl.
M(OTf)n
Ligand
T [8C] t [h]
Yield [%][b] ee [%][c]
3a
4
Herein, we compare the activity and selectivity of diverse
Lewis acid catalysts and show that chiral scandium(III) and
indium(III) complexes offer a general method to control both
the reactivity of the direct monoaddition of indole and arene
nucleophiles to isatins and the absolute configuration of the
product. Reactions involving catalytic asymmetric addition to
isatins have been reported previously; however, this direct
method is the first catalytic asymmetric addition of indole
nucleophiles to an isatin.
Sc(OTf)3
Sc(OTf)3
ScCl3
Y(OTf)3
Y(OTf)3
In(OTf)3
Cu(OTf)2
Zn(OTf)2
none
none
none
none
none
none
none
none
À20
23
23
0.25 40
0.08 45
58
51
0
25
0
50
83
0
0
0
0
0
4
0
14
0
0
0
0
0
0
0
0
0
0
0
0
0
0
18
4
96
0.5
3
72
24
1
1
1
99
67
99
47
15
95
62
98
95
98
96
99
84
94
23
17
17
10
58
41
23
À20
À20
À20
23
À20
À20
À20
À20
23
[Pd(MeCN)4](BF4)2 none
0
We examined a series of Lewis acid catalysts (PdII, CuII,
InIII, ScIII, LaIII, and YIII complexes) capable of activating 1,2-
dicarbonyl electrophiles to classify the effects of the metal,
ligand, and temperature for addition reactions of nucleophiles
to isatins. We used the addition of N-methylindole (2) to 5-
bromo-N-methylisatin (1a) as a model reaction and evaluated
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
ScCl3
5a
5b
5c
5c
5c
5c
5c
5c
73 (R)
73 (S)
99 (R)
93 (R)
78 (R)
52 (R)
99 (R)
0
1 (R)
5 (R)
2 (R)
1 (R)
7 (R)
1
23
23
43
50
1
72
76
73
94
76
94
Y(OTf)3
In(OTf)3
Zn(OTf)2
Cu(OTf)2
Cu(OTf)2
PdCl2
À20
À20
(S)-iPr-box À20
[*] N. V. Hanhan, A. H. Sahin, T. W. Chang, Dr. J. C. Fettinger,
Prof. A. K. Franz
5c
À20
À20
À20
À20
(R)-binap
(R)-binap
Department of Chemistry, University of California
One Shields Ave, Davis, CA 95616 (USA)
E-mail: franz@chem.ucdavis.edu
PdCl2/AgSbF6
[Pd(MeCN)4](BF4)2 (R)-binap
0
Homepage: http://chemgroups.ucdavis.edu/~franz/
[a] All reactions were performed in CH2Cl2 (0.2m) under argon with
3 equivalents of the indole 2 in the presence of 4 ꢀ molecular sieves.
[b] Yield of the isolated product. [c] The ee value was determined by
HPLC analysis on a chiral phase with an AD-H column. binap=2,2’-
bis(diphenylphosphanyl)-1,1’-binaphthyl, Tf=trifluoromethanesulfonyl,
[**] This research was supported by start-up funds from the University
of California, Davis and a grant from the ACS-PRF (49I8I-DNI1).
N.V.H. is a recipient of the Eugene Cota-Robles Graduate Fellow-
ship.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200904393.
iPr-box=2,2-bis((4S)-(—)-4-isopropyloxazoline)propane,
bis(oxazolinyl)pyridine.
pybox=
744
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Angew. Chem. Int. Ed. 2010, 49, 744 –747

Angewandte
Chemie
selective formation of the monoaddition product 3a. The
choice of the chiral metal complex proved to be important for
yield and enantioselectivity, whereby the use of the inda-
pybox ligand led to high enantioselectivity with several metal
complexes.[7] In the presence of either the scandium(III)–
inda-pybox or the indium(III)–inda-pybox catalyst, the addi-
tion of N-methylindole proceeded efficiently to give the 3-
indolyl-3-hydroxyoxindole 3a with superb enantioselectivity
(99% ee) and complete suppression of the formation of the
3,3’-bisindolyl oxindole 4 at À208C.[8] These metal-catalyzed
reactions overcome the competing formation of the 3,3-diaryl
oxindole products and represent the first catalytic asymmetric
addition of an indole to an isatin. This direct addition method
complements the asymmetric addition of activated arenes and
alkenes reported previously,[4] as well as asymmetric hydrox-
ylation methods.[9]
We examined the scope of the reaction with respect to the
isatin electrophile with both commercially available NH isa-
tin reagents and isatins prepared in a single step by N-
alkylation (Table 2). Owing to their prevalence in oxindole
natural products and medicinal compounds, we focused
primarily on halogenated and oxygenated isatins substituted
in various positions. The scandium(III)-catalyzed reactions
proceeded with excellent yield and enantioselectivity (87–
99% ee) for the formation of 3-indolyl-3-hydroxy-2-oxindoles
3a–l, with a catalyst loading as low as 1 mol% for activated
isatins (Table 2, entries 1, 2, and 5). Initially, the reactions of
unprotected NH isatins 1 f–l proceeded with low yield and
enantioselectivity as a result of the limited solubility of the
reagent in CH2Cl2; however, high yields and enantioselectiv-
ities were observed when CH3CN was used as the solvent. The
indium(III)–pybox complex also showed excellent reactivity
and enantioselectivity with NH isatins (Table 2, entry 8).
Notably, substituents at the C4 position do not hinder this
reaction, and excellent enantioselectivity was observed even
at room temperature (Table 2, entry 13).[4d] Furthermore, the
scandium(III) and indium(III) complexes are among the very
few catalyst systems with which addition to unprotected NH
isatins is highly successful; thus, protecting-group manipula-
tions can be avoided.
We investigated the scope of this methodology further and
compared the effectiveness of scandium and indium catalysts
by examining reactivity and selectivity for the addition of a
series of electron-rich p nucleophiles (Table 3).[10] With both
scandium and indium complexes, unprotected indoles were
compatible with the reaction conditions, and the reaction
proceeded with high enantioselectivity (Table 3, entries 1–3).
Nucleophilic arenes, such as m-anisidine (8) and 2-methoxy-
furan (10), also reacted rapidly and with excellent enantio-
selectivity, at least in the presence of the scandium complex;
when the indium complex was used with 10, the product was
formed with 50% ee (Table 3, entries 4–7).[11] Under the same
conditions with the scandium(III)–pybox catalyst, allyla-
tion[12] and aldol reactions[13] also proceeded with high yield
and enantioselectivity (Table 3, entries 8–10). Although scan-
dium and indium complexes are known to have similar
reactivity profiles, herein we show that indium(III) complexes
are less effective for allylation and aldol reactions.[14] Thus, it
is particularly notable that a single scandium(III) catalyst
system is suitable for the addition of this wide range of
nucleophiles.
Table 2: Scope of the addition to isatins under the catalysis of Sc(OTf)3–
inda-pybox.[a]
The stereoinduction observed for this reaction can be
rationalized by an octahedral or pentagonal-bipyramidal
model (Figure 1). When the amide carbonyl group of the
Entry
1
R1
R2
Catalyst
t
Solvent Yield[b] ee[c]
loading [h]
[mol%]
[%]
[%]
1
2
3
1a 5-Br
1b 5-F
Me
Me
Ph
1.0
1.0
5.0
5.0
1.0
5.0
10.0
5.0
10.0
10.0
10.0
10.0
5.0
18 CH2Cl2 98
46 CH2Cl2 98
18 CH2Cl2 98
CH3CN 98
18 CH2Cl2 90
CH3CN 99
48 CH3CN 93
72 CH3CN 90
24 CH3CN 97
19 CH3CN 90
22 CH3CN 93
41 CH3CN 73[f]
17 CH3CN 97
99
99
95
96
99
90
94
99
95
88
91
87
94
1c
1d
H
H
4[d]
5
Me
1
1e 7-Br, 5-Me Me
6[d]
7
1 f
H
H
H
8
Figure 1. Stereochemical model for the addition reaction and X-ray
crystal structure of 3g.
1g 5-Br
1g
8[e]
9
1h 5-F
1i 7-F
1j 5-OCF3
1k 5-OCH3
1l 4-Cl
H
H
H
H
H
10
11
12[d]
13[d]
isatin is bound in the apical position, the nucleophile
approaches from the Si face,[7] consistent with the absolute
configuration of the observed products. To investigate the
isatin binding mode, we analyzed mixtures of the reaction
components by NMR spectroscopy.[15] When Sc(OTf)3 and
the pybox ligand were dissolved in either CD2Cl2 or CD3CN,
substantial changes in the resonance signals indicated the
formation of the scandium(III)–pybox complex; however, the
isatin peaks were not shifted when the substrate was mixed
with either Sc(OTf)3 or the scandium(III)–pybox complex.[16]
[a] All reactions were performed under argon (0.2m solution) with
3 equivalents of the indole 2 in the presence of 4 ꢀ molecular sieves.
[b] Yield of the isolated product. [c] The ee value was determined by
HPLC analysis on a chiral phase with an AD-H column. [d] The reaction
was performed at room temperature. [e] The reaction was performed
with In(OTf)3–inda-pybox. [f] The 3,3’-bisindolyl oxindole product was
also isolated in 15% yield.[6]
Angew. Chem. Int. Ed. 2010, 49, 744 –747
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745

Communications
Table 3: Nucleophilic addition to isatin 1a and comparison of the Sc(OTf)3–inda-pybox and In(OTf)3–
inda-pybox catalysts.[a]
efficient scandium(III)–pybox com-
plex also promoted allylation and
aldol reactions. Because 1,2-dicar-
bonyl compounds are important
electrophiles, this comparison of
reactivity and selectivity with vari-
ous Lewis acid complexes will help
guide the selection of appropriate
Lewis acids in reactions of other
1,2-dicarbonyl compounds.
Entry
Metal
T
[8C]
t
[h]
NuH
Product
Yield[b]
[%]
ee[c]
[%]
1
2
3
Sc
Sc
In
À20
À40
À40
1
48
2
6a, X=H
6b, X=OMe
6b
7a, X=H
7b, X=OMe
7b
80
84
77
99
88
89
Received: August 6, 2009
Revised: November 10, 2009
Published online: December 22, 2009
4[d]
5[d]
Sc
In
À20
48
24
87
88
97
91
Keywords: asymmetric catalysis ·
heterocycles · indium ·
nucleophilic addition · scandium
23
.
6
7
Sc
In
À20
À40
0.08
0.17
82
82
94
50
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complexes
[Sc(OTf)2(inda-pybox)]+,
[Sc(OTf)2-
(CH3CN)(inda-pybox)+Na]+, and [Sc(OTf)(CH3CN)(inda-
pybox)(1a)ÀCH3+Na]+, respectively. Further structural and
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746
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Angewandte
Chemie
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