Palladium-catalyzed asymmetric allylation of prochiral nucleophiles: Synthesis of 3-allyl-3-aryl oxindoles

Article abstract of DOI:10.1002/anie.200460335

Excellent yields and enantioselectivies are attained in the synthesis of 3-alkyl-3-aryl oxindoles based on the Pd-catalyzed asymmetric allylic alkylation (AAA) reaction. This approach utilizes a nonbasic hydroxylic additive in the transformation of 3-aryl

Full text of DOI:10.1002/anie.200460335

Communications
Allylations
bases showed better compatibility with this reaction (Table 1,
entries 4 and 5). Interestingly, 10 mol% KF gave essentially
identical results to the stoichiometric reaction (Table 1,
Palladium-Catalyzed Asymmetric Allylation of
Prochiral Nucleophiles: Synthesis of 3-Allyl-
3-Aryl Oxindoles**
Barry M. Trost* and Mathias U. Frederiksen
The generation of quaternary centers with control of
absolute stereochemistry represents a fundamental
challenge in synthetic organic chemistry.[1] In this area,
we have examined the ability of asymmetric allylic
alkylation (AAA) to control stereochemistry at prochi-
ral nucleophiles, a particularly daunting challenge given
its direct attack at the face of the allyl fragment opposite
to that bound to the metal. Our success with a few classes of
nucleophiles exemplified by b-ketoesters,[2] ketones,[3] among
others,[4–6] encouraged us to examine new classes of nucleo-
philes of particular significance such as lactam enolates.
The 3-alkyl-3-aryl oxindole structural motif is a prominent
feature in a number of biologically active natural products, for
example, diazonamide A[7] and leptosin D,[8] as well as several
pharmaceutically active compounds.[9] In spite of the impor-
tance of this structural motif, few general methods exist for its
construction. Aside from the elegant asymmetric intramolec-
ular Heck reaction developed by Overman and co-workers,[10]
only scattered examples based on Pd-catalyzed a arylation[11]
and asymmetric acyl transfer have been reported.[12] Pd-
catalyzed AAA represents a conceptually novel and flexible
approach to this important structural class, especially when
combined with the powerful Pd-catalyzed a-arylation proto-
cols for the synthesis of 3-aryl oxindoles developed by
Hartwig and co-workers.[11,13] When used in concert, these
processes would readily give access to structurally complex
oxindoles endowed with a quaternary stereocenter from
simple and readily available starting materials [Eq (1)].
Herein we report the successful development of this strategy.
Our studies commenced with a comprehensive matrix
screen of bases in the presence of our standard set of ligands
5–7 in the Pd-catalyzed AAA reaction of oxindole 8 to form 9
(Table 1).[14] These experiments revealed large variations in
yield and enantioselectivity, for example, the use of potassium
carbonate in conjunction with ligands 5–7 showed a dramatic
increase in both yield and ee values (Table 1, entries 1–3)
relative to other counterions (results not shown). Weaker
Table 1: Selected optimization studies in the AAA of oxindole 8.
Entry
Ligand
Base (equiv)
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
9
5
6
7
7
7
7
7
7
7
7
K2CO3 (1.1)
K2CO3 (1.1)
K2CO3 (1.1)
AcOK (1.1)
KF (1.1)
68
81
83
92
86
84
66
66
91
59
19
28
56
47
64
65
73
78
40
76
KF (0.1)
Et3N (1.1)
Et3N (0.1)
BSA[c] (1.1)
BSA[c] (0.1)
10
[a] Yield of isolated product after chromatography. In all cases, the yields
based on recovered starting material are nearly quantitative (>98%).
[b] Determined by chiral HPLC. [c] BSA=N,O-bis(trimethylsilyl)aceta-
mide.
entries 5 and 6). This trend was also observed when nonmetal
bases such as Et3N (Table 1, entries 7 and 8) were used. When
BSA was utilized, a spectacular increase in the ee value by
36% (from 40 to 76% ee) was observed when the base
loading was lowered from 1 to 0.1 equivalent (Table 1,
entries 9 and 10).
These observations combined with the proficiency of
AcOK in this reaction suggested that the addition of only a
catalytic amount of base was necessary to initiate the
enolization, as ionization of allyl acetate maintained the
catalytic concentration of base. However, either the enolate
or enol may function as the nucleophile. As oxindoles
tautomerize to hydroxyindoles, it seemed reasonable to
probe whether it was in fact the latter that acted as the
[*] Prof. B. M. Trost, Dr. M. U. Frederiksen
Department of Chemistry
Stanford University
Stanford, CA 94305-5080 (USA)
Fax: (+1)650-725-0002
E-mail: bmtrost@stanford.edu
[**] We thank the National Science Foundation and the Institute of
General Medical Sciences of the NIH (GM 13598) for their
generous support of our programs and GlaxoSmithKline Research
and Development (M.U.F.) for partial postdoctoral fellowship
support.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
308
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DOI: 10.1002/anie.200460335
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Angewandte
Chemie
Table 3: Scope of Pd-catalyzed AAA of 3-aryl oxindoles.
nucleophile. In this case, the reaction should proceed without
any external base. It was expected that the rate of tautome-
rization, and thus the rate of reaction, would be influenced by
the polarity of the solvent (Table 2).
Entry Substrate
Product
R
Yield ee
[%][a] [%][b]
Table 2: Selected additive effects in the AAA of oxindole 8.
1
72
68
97
79
Entry
Solvent
t
Yield
[%][a]
ee
2
[h]
[%][b]
1
2
3
DME
THF
CH2Cl2
PhMe
PhMe
2
2
12
12
12
95
75
31
72
93
61
72
61
78
81
3
4
5
p-Me
m-Me
o-Me
75
96
75
80
77
70
4
5[c]
[a] Yield of isolated product after chromatography. In all cases, the yields
based on recovered staring material are quantitative. [b] Determined by
chiral HPLC. [c] tBuOH (4 equiv) was used as an additive in this reaction.
6
7
8
F
Ph
Cl
73
90
81
75
73
70
In accord with our predictions, the reaction proceeded
when carried out in DME (1,2-dimethoxyethane) in the
absence of any additives. The reaction was completed in 2 h at
48C and afforded 9 in excellent yield with 61% ee (Table 2,
entry 1). The reactions in THF occurred with higher enantio-
selectivity than the reactions in DME (Table 2, entry 2).
Further optimization with respect to solvent showed that
toluene allowed the highest enantioselectivity, albeit in lower
yield (Table 2, entry 4). Reasoning that the oxindole–hydrox-
indole tautomerization would be significantly faster in
hydroxylic media, we next examined the effect of various
polar additives in their ability to promote the key tautome-
rization. After much experimentation, we found that the
addition of 4 equivalents of tBuOH was optimal and provided
the desired product 9 in 93% yield with 81% ee (Table 2,
entry 5).[15] Notably, the yields based on returned starting
material are always nearly quantitative, which serves as a
testament to the extraordinary selectivity of this reaction. In
summary, the use of tBuOH (4 equiv), [(h3-C3H5PdCl)2]
(2.5 mol%), and 7 (5 mol%) in toluene at 48C under neutral
conditions became our standard reaction conditions for the
synthesis of 3-aryl oxindoles.
With the optimized procedure established, we sought to
examine the scope of the reaction. Thus a number of different
aryl oxindoles were prepared and subjected to the standard
conditions (Table 3).[16] Significant structural variation in the
oxindole system can be accommodated in this reaction.[17] For
example, an ortho-methoxy group is tolerated (Table 3,
entry 1) and the sterically demanding product is obtained in
good yield (72%) with excellent enantioselectivity (97% ee).
Otherwise, the method is compatible with electron-rich
(Table 3, entries 2–5 and 7) and electron-poor (Table 3,
entry 6) aryl groups as well as aryl chloride substituents
(Table 3, entry 8). The oxindole core may also be modified.
Thus, both the benzo moiety (Table 3, entry 9) and the N-
protecting group may be changed as well (Table 3, entries 10–
14), for example, the trimethylsilylmethyl group (TMSM) can
9
83
93
74
10
11
12
13
14
Me
81
80
70
68
66
TMSM[c] 76
Bn
SEM
MOM
75
81
96
[a] Yield of isolated product after chromatography. [b] Determined by chiral
HPLC analysis, see Supporting Information for details. [c] TMSM=tri-
methylsilylmethyl.
be used (Table 3, entry 11). This group is interesting owing to
the known propensity of such substrates to undergo dipolar
cycloadditions,[18] and as such should give access to structur-
ally diverse scaffolds. Other protecting groups may be
incorporated, although at a slight detriment to the enantio-
selectivity. The lower ee values attained are intriguing: In the
case of aromatic protecting groups (Table 3, entry 12), the
lower enantioselectivity may be due to favorable interactions
with the phenylphosphino moiety of the ligands which alter
the approach of the nucleophile. MOM and SEM aminals
(Table 3, entries 13–14) are likely to form stable hydrogen-
bonded chelates that confer higher steric demands on the
hydroxyindole nucleophile. Simple substituents (e.g. TMSM)
may place their sterically demanding groups “outside” the
chiral pocket, thereby allowing an ideal approach of the
nucleophile to the Pd–allyl complex.
In summary, we have developed an enantioselective
palladium-catalyzed AAA reaction for the synthesis of 3-
alkyl-3-aryl oxindoles. The salient features of this approach
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Communications
tetrabutylammonium acetate (5 mol%) shows significant
exchange, whereas catalytic amounts of tetrabutylammonium
chloride does not. We attribute this to a general acid–general
base catalyzed enolization effected by tBuOH in combination
with the acetate anion generated in situ.
are: 1) extraordinarily mild reaction conditions, 2) good to
excellent enantioselectivity in the generation of sterically
congested quaternary stereocenters, 3) broad substrate scope,
and 4) enantioselective access to important structural motifs
from readily available and cheap starting material through
two Pd-catalyzed processes.
[16] 3-Aryl oxindoles were prepared by a arylation; see Supporting
Information for details.
[17] Despite the efficiency of this process, we have so far been unable
to expand the scope with respect to other electrophiles.
[18] L. M. Harwood, R. J. Vickers in Synthetic Applications of 1,3-
Dipolar Cycloaddition Chemistry Toward Heterocycles and
Natural Products (Eds.: A. Padwa, W. H. Pearson), Wiley, New
York, 2002.
Received: April 15, 2004
Revised: June 1, 2004
Keywords: allylation · asymmetric synthesis · heterocycles ·
.
homogenous catalysis · palladium
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[14] The depicted configuration is based on the absolute stereo-
chemistry of products derived from the Pd-catalyzed AAA of
the closely related 3-alkyl oxindoles, which were converted into
known compounds: B. M. Trost, M. U. Frederiksen, unpublished
results.
[15] The rate of tautomerization does not seem to be influenced by
1
the addition of tBuOH alone, as preliminary H NMR spectro-
scopic analyses of a solution of 8 in [D8]toluene in the presence
or absence of tBuOD do not differ appreciably. The addition of
310
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