Palladium(II)-catalyzed enantioselective aerobic dialkoxylation of 2-propenyl phenols: A pronounced effect of copper additives on enantioselectivity

Article abstract of DOI:10.1021/ja070263u

A direct O₂-coupled Pd(II)-catalyzed enantioselective dialkoxylation of 2-propenylphenols has been developed by utilizing chiral quinoline oxazoline ligands. A detrimental effect of added copper salts on enantioselectivity was observed which is attributed to the displacement of the chiral ligand off of Pd(II). Copyright

Full text of DOI:10.1021/ja070263u

Published on Web 02/14/2007
Palladium(II)-Catalyzed Enantioselective Aerobic Dialkoxylation of 2-Propenyl
Phenols: A Pronounced Effect of Copper Additives on Enantioselectivity
Yang Zhang and Matthew S. Sigman*
Department of Chemistry, UniVersity of Utah, 315 South 1400 East, Salt Lake City, Utah 84112-8500
Received January 12, 2007; E-mail: sigman@chem.utah.edu
Table 1. Evaluation of Chiral Ligands
Despite the potential synthetic utility, very few enantioselective
intermolecular olefin functionalization reactions have been reported
using Pd(II)-catalyzed oxidation reactions, especially those which
involve nucleopalladation.1,2 To achieve enantioselective nucleopal-
ladation, not only must a suitable ligand be identified in order to
differentiate the enantiotopic faces of the coordinated olefin, but
also reversible â-hydride elimination must be inhibited to avoid
erosion of the initial asymmetric induction. Recently, as part of
our program aimed at the development of Pd(II)-catalyzed olefin
functionalization reactions, we discovered a dialkoxylation reaction
of styrenes containing an o-phenol (eq 1).3 A key finding based on
isotopic labeling experiments was that â-hydride elimination is
avoided in the dialkoxylation process, making the development of
an enantioselective variant possible. Additionally, an enantioselec-
tive dialkoxylation reaction would allow rapid generation of a
common structural motif found in a number of biologically active
compounds.4 Herein, we present the discovery of an enantioselective
dialkoxylation reaction where removal of copper from the reaction,
a standard additive in Pd(II)-catalyzed oxidation reactions, proved
essential for effective asymmetric catalysis.
entry
ligand
CuCl2 (mol %)
yield (%)a
ee (%)b
1
2
3
4
5
6
7
8
9
(-)-sparteine
(-)-sparteine
iPr-biox
20
0
0
0
0
0
0
0
0
0
70
24
11
3
0
17
5
boxox
Ph-box
0
NR
10
14
10
85
67
NR
60
37
83
84
82
iPr-pyrox
Ph-quinox
tBu-quinox
Bn-quinox
iPr-quinox
10
Previous mechanistic studies suggested that the dialkoxylation
reaction proceeded through a regioselective nucleopalladation of
A via methanol addition to the â-carbon of the styrene B, followed
by formation of a quinone methide intermediate C with concomitant
reduction of Pd(II) (Scheme 1).3 Dialkoxylation is achieved by the
addition of a second equivalent of methanol to C where modest
diastereoselection is observed and attributed to the influence of the
chiral center of C. We therefore proposed that the initial alcohol
addition to the coordinated olefin would set the absolute stereo-
chemistry with identification of a suitable chiral ligand. To test
this hypothesis, Pd[(-)-sparteine]Cl2 was used in the dialkoxylation
reaction of 2-propenylphenol in MeOH using the previously
optimized conditions (Table 1, entry 1). To our surprise, a racemic
dialkoxylation product was observed. It was difficult to envision
why no enantioselective catalysis is observed using (-)-sparteine
even if it is not the optimal ligand. A plausible explanation for the
absence of asymmetric induction is that copper could displace the
chiral ligand from Pd, leading to the formation of a copper-ligand
complex. To test this possibility, copper was removed from the
reaction and, indeed, a modest enantiomeric excess of 17% was
observed albeit with a reduction in yield (entry 2, Table 1).5 It
should be noted that in the initial optimization phase of this reaction,
copper was found to be crucial for catalyst turnover.
With CuCl2
11
12
13
14
iPr-quinox
iPr-quinox
iPr-quinox
iPr-quinox
2.5
5
10
20
80
78
81
88
72
59
26
10
a GC yields using 5-nonanone as the internal standard; NR ) no reaction.
b Determined by GC equipped with a chiral stationary phase.
Scheme 1. Proposed Mechanism
ligands were evaluated (entries 3-10, Table 1). C2-symmetric
oxazolines were found to be poor ligands in this reaction; however,
in the absence of copper, excellent asymmetric catalysis is observed
using quinoline derived oxazolines (entries 7-10).6 These quinoline
oxazoline derivatives are readily synthesized in two steps from the
corresponding carboxylic acid and enantiopure â-amino alcohol
making this ligand class highly modular.7 Use of the (R)-benzyl
derivative leads to an 85% ee and an 84% GC yield of 2-(1S,2S)-
On the basis of the low enantiomeric excess found using (-)-
sparteine and that this ligand is very difficult to systematically
modify, oxidatively stable C2- and C1-symmetric oxazoline based
9
3076
J. AM. CHEM. SOC. 2007, 129, 3076-3077
10.1021/ja070263u CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Evidence for â-Nucleopalladation
Table 2. Scope of Pd(II)-Catalyzed Enantioselective
Dialkoxylation
the experiment, the product 11a was found to be racemic supporting
â-nucleopalladation as the enantio-determining step. Additionally,
the minor product diastereomer for all substrates in Table 2 has a
very similar enantiomeric excess as the major diastereomer which
is consistent with the absolute configuration set by initial nucleopal-
ladation.
In conclusion, we have successfully developed a direct O2-
coupled Pd(II)-catalyzed enantioselective dialkoxylation of 2-pro-
penylphenols by utilizing chiral quinoline oxazoline ligands. In this
process, evidence for enantioselective â-nucleopalladation has been
garnered. Of most significance, without removing the Cu salts, it
is unlikely that this enantioselective catalytic process would have
been discovered. Considering that copper is a standard cooxidant
in Pd(II) oxidation chemistry, this finding should provide the
foundation for the development of other Pd(II)-catalyzed asym-
metric oxidative transformations. Future efforts are directed toward
this goal.
Acknowledgment. This work was supported by the National
Institutes of Health (Grant NIGMS RO1 GM3540). M.S.S. thanks
the Dreyfus Foundation (Teacher-Scholar) and Pfizer for their
support. We are grateful to Johnson Matthey for the gift of various
Pd salts.
a Yield is reported as a mixture of a and b and is an average of two
experiments. b Determined by GC or HPLC equipped with chiral stationary
1
phase. c Determined by H NMR and GC. d The reaction was carried out
at 0 °C.
Supporting Information Available: Experimental procedures and
full spectroscopic data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
1,2-dimethoxypropyl)phenol (entry 9).8 Additionally, as the [copper]
is increased under these conditions, a significant reduction in the
ee is observed, consistent with a ligand exchange process (entries
10-14). This result may explain why there are very few examples
of enantioselective Pd(II)-catalyzed oxidation reactions in the
presence of copper salts.
References
(1) For reviews, see: (a) Tietze, L. F.; Ila, H.; Bell, H. P. Chem. ReV. 2004,
104, 3453-3516. (b) Palladium Reagents and Catalysis; Tsuji, J., Ed.;
Wiley: Chichester, U.K., 1995.
(2) For examples of intermolecular enantioselective nucleopalladation, see:
(a) El-Qisairi, A. K.; Qaseer, H. A.; Henry, P. M. J. Organomet. Chem.
2002, 656, 168-176. (b) Itami, K.; Palmgren, A.; Thorarensen, A.;
Ba¨ckvall, J.-E. J. Org. Chem. 1998, 63, 6466-6471. For recent intramo-
lecular examples, see: (c) Yip, K.-T.; Yang, M.; Law, K.-L.; Zhu, N.-Y.;
Yang, D. J. Am. Chem. Soc. 2006, 128, 3130-3131. (d) Trend, R. M.;
Ramtohul, Y. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 17778-
17788. (e) Uozumi, Y.; Kato, K.; Hayashi, T. J. Am. Chem. Soc. 1997,
119, 5063-5064.
With the optimized ligand and reaction conditions established,
the scope of the enantioselective dialkoxylation reaction was
examined for a number of 2-propenylphenols (Table 2). Modest to
good yields are observed for both electron rich and electron poor
substrates with enantiomeric excesses up to 92%. Of note, for
substrates with an additional substituent ortho to the phenol (entries
i
(3) (a) Schultz, M. J.; Sigman, M. S. J. Am. Chem. Soc. 2006, 128, 1460-
1461. For a related example, see: Chevrin, C.; Bras, J. L.; He´nin, F.;
Muzart, J. Synthesis 2005, 2615-2618.
5 & 6), the Pr-quinox ligand proves to be more effective for this
substrate class. Ethanol and ethylene glycol were also examined to
probe whether other alcohols could act as the nucleophile in this
reaction (entries 9 & 10). Both solvents led to successful dialkoxy-
lation with good enantiomeric excesses albeit in modest yields. An
exciting aspect of developing these direct-O2 coupled reactions is
that the scope of the process has been extended to substrates which
did not undergo the dialkoxylation reaction previously (entries 2
and 6-8).
Our next goal was to probe if the absolute configuration is set
by â-nucleopalladation. To explore this, trisubstituted olefin 11 was
subjected to the dialkoxylation reaction (Scheme 2). If the reaction
involves an R-nucleopalladation, an enantiomeric excess comparable
to other examples above in product 11a was predicted. In contrast,
if â-nucleopalladation occurs, a racemic product was expected. In
(4) (a) Bols, M.; Binderup, L.; Hansen, J.; Rasmussen, P. Carbohydr. Res.
1992, 235, 141-149. (b) Tanaka, Y.; Graefe, U.; Yazawa, K.; Mikami,
Y. J. Antibiot. 1998, 51, 589-591. (c) Takenaka, M.; Watanabe, T.;
Sugahara, K.; Harada, Y.; Yoshida, S.; Sugawara, F. Biosci., Biotechnol.,
Biochem. 1997, 61, 1440-1444. (d) Huang, L.; Kashiwada, Y.; Cosentino,
L. M.; Fan, S.; Chen, C.-H.; McPhail, A. T.; Fujioka, T.; Mihashi, K.;
Lee, K.-H. J. Med. Chem. 1994, 37, 3947-3955.
(5) Catalyst decomposition was observed.
(6) For recent enantioselective reactions utilizing chiral quinoline oxazolines,
see: (a) Abrunhosa, I.; Bioton, L.; Gaumount, A.; Gulea, M.; Masson, S.
Tetrahedron 2004, 60, 9263. (b) Chelucci, G.; Sanna, M.; Gladiali, S.
Tetrahedron 2000, 56, 2889.
(7) For a recent review of oxazoline synthetic methods, see: Desimoni, G.;
Faita, G.; Jorgensen, K. A. Chem. ReV. 2006, 106, 3561-3651.
(8) The absolute configuration of the product was determined by comparison
to an independently prepared authentic sample. See Supporting Information
for details.
JA070263U
9
J. AM. CHEM. SOC. VOL. 129, NO. 11, 2007 3077