Palladium-catalyzed asymmetric benzylation of 3-aryl oxindoles

Article abstract of DOI:10.1021/ja1079755

Herein we report palladium-catalyzed asymmetric benzylic alkylation with 3-aryl oxindoles as prochiral nucleophiles. Proceeding analogously to asymmetric allylic alkylation, asymmetric benzylation occurs in high yield and enantioselectivity for a variety

Full text of DOI:10.1021/ja1079755

Published on Web 10/20/2010
Palladium-Catalyzed Asymmetric Benzylation of 3-Aryl Oxindoles
Barry M. Trost* and Lara C. Czabaniuk
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received September 3, 2010; E-mail: bmtrost@stanford.edu
3-phenyl oxindoles using 5 mol % (η3-C3H5)PdCp and 7.5 mol %
Abstract: Herein we report palladium-catalyzed asymmetric ben-
zylic alkylation with 3-aryl oxindoles as prochiral nucleophiles.
Proceeding analogously to asymmetric allylic alkylation, asym-
metric benzylation occurs in high yield and enantioselectivity for
a variety of unprotected 3-aryl oxindoles and benzylic methyl
carbonates using chiral bisphosphine ligands. This methodology
represents a novel asymmetric carbon-carbon bond formation
between a benzyl group and a prochiral nucleophile to generate
a quaternary center.
L1 in DME. Unprotected oxindole 2a exhibited the highest
enantioselectivity and complete chemoselectivity for 3-benzylation
(Table 1, entry 1). Coordinating solvents induced the highest
enantioselectivity, with dioxane providing 3a in 70% ee (Table 1,
entries 1-4). Decreasing the reaction temperature was detrimental
to reactivity and mildly beneficial to enantioselectivity (Table 1,
entry 5). Other chiral bisphosphine ligands utilized (Figure 1)
exhibited similar reactivity but lower enantioselectivity (Table 1,
entries 6-8). As in previous studies on oxindole allylation,9a
addition of 5 equiv of tert-butanol to the reaction mixture increased
the yield and ee of 3a (Table 1, entry 9). Increasing the reaction
concentration furnished 3a in 93% isolated yield and 86% ee (Table
1, entry 10). The isolated yield and enantioselectivity were
unchanged at 6 mol % ligand loading and the 10 h reaction time
(Table 1, entry 11).
Asymmetric allylic alkylation (AAA) is a powerful method for
catalytic construction of stereocenters.1 Proceeding through an η3-
allyl-metal complex, these reactions allow for allylic substitution
with carbon, nitrogen, oxygen, and sulfur nucleophiles (eq 1).
Several methods for asymmetric induction exist, and the synthetic
utility of AAA has been demonstrated in multiple natural product
syntheses.1b
Table 1. Selected Optimization Experiments
The analogous η3-benzyl-metal species is less common since
aromaticity is disrupted. However, the η3-benzyl-palladium species
has been utilized as an intermediate in catalytic benzylation2 of
carbon and heteroatom nucleophiles (eq 2).3 Catalytic asymmetric
benzylation, wherein asymmetry is introduced at the electrophile,
provides high enantioselectivity only when yields are very low with
90% ee but only 11% yield as the best case.4 Interpreting these
results in part as a kinetic resolution due to the absence of a facile
racemization mechanism, we began studies on asymmetric benzyl-
ation of prochiral nucleophiles to obviate such an issue.5
entry
L*
solvent
temp (°C)
% yieldb
% eec
1
2
3
4
5
6
7
8
L1
L1
L1
L1
L1
L2
L3
L4
L1
L1
LI
DME
80
80
35
80
25
25
25
25
25
25
25
92
41
86
93
11
17
6
66
63
45
70
77
43
38
12
86
86
86
toluene
CH2Cl2
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
9
9
10
11
24d
93d e
,
93d e f
,
,
We selected oxindoles as nucleophiles for asymmetric benzyl-
ation due the prevalence of 3-tetrasubstituted oxindoles in biologi-
cally active molecules.6 This moiety has been synthesized in a
number of ways, many of which utilize the nucleophilicity of the
oxindole 3-position. Asymmetric alkylation of oxindoles has been
achieved via auxiliary-containing electrophiles and phase transfer
catalysis; however, no catalytic asymmetric benzylations have been
reported to date.7,8 Our group has reported asymmetric allylation
of oxindoles employing palladium and molybdenum catalysts.9
Herein we report a method for palladium-catalyzed asymmetric
benzylation of 3-aryl oxindoles. To the best of our knowledge, this
represents the first report of asymmetric benzylation of prochiral
nucleophiles. Moreover, benzylation is most efficient on unprotected
oxindoles, in contrast to most methods for oxindole alkylation
requiring nitrogen protection.
a Reactions performed on 0.2 mmol scale at 0.2 M using 1 equiv of
1, 1 equiv of 2a, 5 mol % (η3-C3H5)PdCp, and 7.5 mol % ligand for
20 h. b Isolated yield. c Determined by chiral HPLC. d Reaction run with
5 equiv of tert-butanol. e Reaction performed at 0.4 M. f Reaction
performed using 6 mol % ligand for 10 h.
Our initial studies investigated the catalytic reaction between
(naphthyl)methyl methyl carbonate 1 and differentially protected
Figure 1. Chiral ligands utilized for asymmetric benzylation.
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10.1021/ja1079755  2010 American Chemical Society

C O M M U N I C A T I O N S
Our subsequent efforts investigated the substrate scope. A variety
of unprotected 3-aryl oxindoles were reacted with 1. Introduction
of an electron-donating or electron-withdrawing group at the para-
position of the 3-phenyl group did not significantly affect the
yield or enantioselectivity (Table 2, entries 1-2). A meta-
substituted oxindole was highly reactive and provided 3d in 77%
ee. (Table 2, entry 3). Ortho-substitution was deleterious to
reactivity, and a higher reaction temperature was required (Table
2, entry 4). A heteroaromatic substituent at the oxindole
3-position was well-tolerated (Table 1, entry 5). Substitution at
the 5-position of the oxindole furnished 3g in 83% yield and
85% ee with sonication required for complete reaction of less-
soluble 2g (Table 1, entry 6).
carbon at the 3-position were highly reactive and enantioselective
with greater than 90% yield and ee obtained for 5b-c (Table 3,
entries 2-3). Furan electrophiles were competent monocyclic
substrates for asymmetric benzylation of 2a and were unaffected
by substitution at the 5-position (Table 3, entries 4-6).
Table 3. Asymmetric Benzylation Electrophile Scopea
Table 2. Asymmetric Benzylation Nucleophile Scopea
a Reactions performed on 0.2 mmol scale at 0.4 M in dioxane using 1
equiv of 4a-f, 1 equiv of 2a, 5 mol % (η3-C3H5)PdCp, 6 mol %
(R,R)-L1, and 5 equiv of tert-butanol for 10-14 h. b Isolated yield.
c Determined by chiral HPLC.
Acylation of benzylated prouduct 3g with 4-bromobenzoyl
chloride furnished 6 in 71% yield (Scheme 1). An X-ray crystal
structure of 6 allowed for determination of the absolute configu-
ration unambiguously.10 The stereochemistry for the other examples
has been assigned by analogy.
In conclusion, we have developed a method for catalytic
asymmetric benzylic alkylation to generate a quaternary center. This
method introduces a benzyl group at the 3-position of oxindoles in
high yield and enantiomeric excess. The absence of any observable
a Reactions performed on 0.2 mmol scale at 0.4 M in dioxane using 1
equiv of 1, 1 equiv of 2b-g, 5 mol % (η3-C3H5)PdCp, 6 mol %
(R,R)-L1, and 5 equiv of tert-butanol for 10-14 h. b Isolated yield.
c Determined by chiral HPLC. d Reaction performed at 50 °C. e Reaction
performed in sonicator.
Scheme 1. Acylation of 3g
We also investigated the reaction scope with respect to the
electrophile (Table 3). Oxindole 2a was reacted with a series of
benzylic methyl carbonates employing the previously optimized
reaction conditions. Electrophile 4a, substituted at the 4-position
of naphthalene, furnished 5a in 80% yield and 79% ee (Table 3,
entry 1). Indole and benzofuran electrophiles with the benzylic
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C O M M U N I C A T I O N S
2005, 16, 1183. (c) Assie, M.; Meddour, A.; Fiaud, J.-C.; Legros, J.-Y.
Tetrahedron: Asymmetry 2010, 21, 1701.
oxindole N-benzylation is also noteworthy. Further investigations
into the asymmetric benzylation scope are underway.
(5) (a) Trost, B. M.; Radinov, R.; Grenzer, E. M. J. Am. Chem. Soc. 1997,
119, 7879. (b) Trost, B. M.; Schroeder, G. M. J. Am. Chem. Soc. 1999,
121, 6759. (c) Trost, B. M.; Ariza, X. Angew. Chem., Int. Ed. 1997, 36,
2635. (d) Trost, B. M.; Ariza, X. J. Am. Chem. Soc. 1999, 121, 10727. (e)
Mohr, J. T.; Behenna, D. C.; Harned, A. M.; Stoltz, B. M. Angew. Chem.,
Int. Ed. 2005, 44, 6924. (f) Behenna, D. C.; Stoltz, B. M. J. Am. Chem.
Soc. 2004, 126, 15044. (g) Trost, B. M.; Xu, J.; Schmidt, T. J. Am.
Chem. Soc. 2009, 131, 6640. (h) Trost, B. M.; Xu, J.; Reichle, M. J. Am.
Chem. Soc. 2007, 129, 282. (i) Trost, B. M.; Xu, J.; Schmidt, T. J.
Am. Chem. Soc. 2009, 131, 18343.
Acknowledgment. We thank the National Science Foundation
(CHE 0846427) for their generous support of our programs. We
thank Dr. Allen Oliver from Notre Dame for X-ray crystal analysis
and Johnson-Matthey for their generous gift of palladium salts.
Supporting Information Available: Experimental details and
spectral data for all unknown compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(6) Zhou, F.; Liu, Y.-L.; Zhou, J. AdV. Synth. Catal. 2010, 352, 1381.
(7) (a) Pallavicini, M.; Valoti, E.; Villa, L.; Resta, I. Tetrahydron: Asymmetry
1994, 5, 363. (b) Emura, T.; Esaki, T.; Tachibana, K.; Shimizu, M. J. Org.
Chem. 2006, 71, 8559.
(8) Lee, T. B. K.; Wong, G. S. K. J. Org. Chem. 1991, 56, 872.
(9) (a) Trost, B. M.; Fredriksen, M. Angew. Chem., Int. Ed. 2005, 44, 308. (b)
Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2006, 128, 4590. (c) Trost,
B. M.; Zhang, Y. J. Am. Chem. Soc. 2007, 129, 14548.
(10) The obtained absolute stereochemistry is the opposite of that obtained in
the palladium-catalyzed allylation of oxindoles (ref 9a). We believe the
significantly different structure of the electrophile (benzyl vs allyl) is an
important source for the change in absolute stereochemistry. The difference
in the substituents on the oxindole nitrogen may also contribute since we
have noted that substitution does play a role in absolute stereochemistry.
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