Asymmetric intermodular heck-type reaction of acyclic alkenes via oxidative palladium(II) catalysis

Article abstract of DOI:10.1021/ol701584f

Herein, we report an asymmetric intermolecular Heck-type reaction of acyclic alkenes by using a palladium-pyridinyl oxazoline diacetate complex under oxidative palladium(II) catalysis conditions. A premade palladium-ligand complex afforded higher enantioselectivities than a corresponding premixed palladium-ligand system, while offering enhanced asymmetric induction when compared to known intermolecular Heck-type protocols.

Full text of DOI:10.1021/ol701584f

ORGANIC
LETTERS
2007
Vol. 9, No. 20
3933-3935
Asymmetric Intermolecular Heck-Type
Reaction of Acyclic Alkenes via
Oxidative Palladium(II) Catalysis
Kyung Soo Yoo, Chan Pil Park, Cheol Hwan Yoon, Satoshi Sakaguchi,
Justin O’Neill, and Kyung Woon Jung*
Loker Hydrocarbon Research Institute and Department of Chemistry,
UniVersity of Southern California, Los Angeles, California 90089-1661, and
Department of Chemistry, UniVersity of South Florida, Tampa, Florida 33620
kwjung@usc.edu
Received July 5, 2007
ABSTRACT
Herein, we report an asymmetric intermolecular Heck-type reaction of acyclic alkenes by using a palladium−pyridinyl oxazoline diacetate
complex under oxidative palladium(II) catalysis conditions. A premade palladium
−ligand complex afforded higher enantioselectivities than a
corresponding premixed palladium
Heck-type protocols.
−ligand system, while offering enhanced asymmetric induction when compared to known intermolecular
In recent years, one of the major objectives in synthetic
organic chemistry has been asymmetric catalyses for C-C
bond formations including asymmetric Heck-type reactions,1
which have rarely been used in practice due to their
limitations and harsh conditions. Although high enantiose-
lectivities were observed in a number of intramolecular Heck-
type cyclizations, intermolecular reactions have given poor
enantioselectivities, except with cyclic olefins such as
dihydrofuran and dihydropyrrole.2-4 For instance, Uemura
and co-workers reported the first example of an enantiose-
lective intermolecular arylation of prochiral acyclic alkenes;
however, the observed enantioselectivity was only 17% ee.5
In an effort to mitigate these shortcomings, we applied our
oxidative Pd(II) method to an intermolecular coupling of
acyclic alkenes, presumably the most challenging substrates
for this type of asymmetric conversion.
(1) For recent reviews of the asymmetric Heck reaction, see: (a)
Shibasaki, M.; Boden, C. D. J.; Kojima, A. Tetrahedron 1997, 53, 7371.
(b) Shibasaki, M.; Erasmus, M. V.; Ohshima, T. Heck Reaction. In
ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yama-
moto, H., Eds.; Springer-Verlag: Berlin, 1999; Chapter 14. (c) Donde, Y.;
Overman, L. E. Catalytic Asymmetric Synthesis of All Carbon Quarternary
Stereocenters. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; Wiley-
VCH: New York, 2000; Chapter 8G. (d) Tietze, L. T.; Ila, H.; Bell, H. P.
Chem. ReV. 2004, 104, 3453. (e) Dai, L. X.; Tu, T.; You, S. L.; Deng, W.
P.; Hou, X. L. Acc. Chem. Res. 2003, 36, 659. (f) Shibasaki, M.; Vogl, E.
M.; Ohshima, T. AdV. Synth. Catal. 2004, 346, 1533.
While extensively researching C-C bond formation using
oxidative Pd(II) catalysis, we found that the coupling of
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© 2007 American Chemical Society
Published on Web 08/31/2007

phenylboronic acid and trans-2-methyl-2-butenal produced
exclusively the rearrangement compound 1, generating a new
stereogenic center (eq 1-a). In addition, with a bidentate
amine ligand, such as 2,9-dimethylphenanthroline (eq 1-b),
the coupling reaction provided the desired product in a high
yield even at room temperature without a base.6,7 Notably,
the corresponding Heck reaction proceeded poorly (5%) even
at high temperatures (eq 2). These results prompted us to
investigate asymmetric Heck-type reaction by employing
various chiral ligands.
reaction mixture was then stirred for 16 h under a molecular
oxygen atmosphere.
Utilizing ligands 2 and 3, phenylboronic acid underwent
the rearranged arylation of trans-2-methyl-2-butenal to afford
1 in 71 and 66% yields, respectively, with low enantiose-
lectivities (9-16% ee; entries 1 and 2). Unsymmetrical
oxazoline ligands 4 and 5 induced higher enantioselectivities
than symmetrical ones 2 and 3 (entries 3 and 4). However,
chiral induction was still disappointing (21-25% ee). By
increasing the size of the oxazoline substituent, enantiose-
lectivity was improved to 42% ee (entry 5). Although these
were significant improvements over other asymmetric Heck
reactions, our results did not meet our expectations.
We suspected that moderate enantioselectivities were due
to incomplete formation of palladium-ligand complexes and/
or relatively easy disassociation of palladium and ligands.
For instance, the coupling reaction gave lower enantiose-
lectivity (31% ee) when all the reagents were added at once
without premixing Pd(OAc)2 and the ligand 6. Lower asym-
metric induction was presumably ascribed to the background
reaction with a free palladium catalyst, which would be more
efficient than the ligand-chelated catalyst. Hence, we sought
to employ a pure palladium-ligand catalyst such as 8 derived
from oxazoline ligand 6 (Scheme 1). When pyridinyl-
As summarized in Table 1, we screened well-known
bidentate N,N-ligands for possible asymmetric Heck-type
Table 1. Effect of Various Ligands Premixed with Pd(OAc)2
a The reaction was carried out premixing 5 mol % of Pd(OAc)2 and 5.5
mol % of ligand before the addition of coupling substrates. b Isolated yield.
c Determined by chiral HPLC analysis (Daicel Chiracel OD) (Mobile phase:
iPrOH/hexanes ) 5:95 v/v %, rate )1 mL/min).
Scheme 1
reactions, while phosphine-based ligands turned out to be
inefficient due to side reactions, including homocoupling and
phenol formation.8 During the course of our study, Mikami
et al. reported their results,3 conforming to our data. To avoid
redundancy, we are not reporting these results, which are
slightly better perhaps due to better handling of oxidative
Pd(II) catalysis we have developed. Included in this study
were bisoxazoline ligands (29c and 39a) and pyridinyl oxa-
zoline ligands (4,9a 5,9b and 69b). Prior to the addition of the
boron compound and alkene, Pd(OAc)2 and a ligand were
premixed in DMF at room temperature for 20 min, and the
oxazoline ligand 6 was treated with Pd(CH3CN)2Cl2 in
dichloromethane at room temperature, a palladium-ligand
dichloride complex 7 was produced cleanly in a high yield,
and its structure was unambiguously confirmed by 1H NMR
and X-ray crystallography analysis.10 Subsequently, construc-
tion of the Pd-pyridinyl-oxazoline acetate complex 8 was
accomplished by treating the dichloride adduct 7 with 2 equiv
of silver acetate in dichloromethane. Although the diacetate
complex 8 was relatively stable, it started decomposing in a
few days. Therefore, we usually used freshly prepared
catalytic complex for the couplings.
As shown in Table 2, our hypothesis was validated by
using the complex 8. For example, the asymmetric reaction
with phenylboronic acid and trans-2-methyl-2-butenal af-
forded 1 (Ar ) Ph) in a dramatically improved enantiose-
lectivity compared to the premixed conditions (entry 1). In
addition, the reaction of p-methoxyphenylboronic acid and
p-N,N-dimethylaminophenyl boronic acid possessing electron-
donating groups took place smoothly to provide the desired
(2) (a) Diederich, F.; Stang, P. J. In Metal-Metal Cross-Coupling
Reaction; Wiley-VCH: New York, 1999. (b) Trost, B. M.; Jiang, C. H.
Synthesis 2006, 369. (c) Guiry, P. J.; Kiely, D. Curr. Org. Chem. 2004, 8,
781. (d) Dounay, A. B.; Overman, L. E. Chem. ReV. 2003, 103, 2945. (e)
Penn, L.; Shpruhman, A.; Gelman, D. J. Org. Chem. 2007, 72, 3875.
(3) Alkiyama, K.; Wakabayashi, K.; Mikami, K. AdV. Synth. Catal. 2005,
347, 1569.
(4) Dodd, D. W.; Toews, H. E.; Carneiro, F.; Jennings, M. C.; Jones, N.
D. Inorg. Chim. Acta 2006, 359, 2850.
(5) Yonehara, K.; Mori, K.; Hashizume, T.; Chung, K.-G.; Ohe, K.;
Uemura, S. J. Organomet. Chem. 2000, 603, 40.
(6) (a) Yoon, C. H.; Yoo, K. S.; Yi, S. W.; Mishra, R. K.; Jung, K. W.
Org. Lett. 2004, 6, 4037. (b) Jung, Y. C.; Mishra, R. K.; Yoon, C. H.;
Jung, K. W. Org. Lett. 2003, 5, 2231. (c) Parrish, J. P.; Jung, Y. C.; Shin,
S. I.; Jung, K. W. J. Org. Chem. 2002, 67, 7127.
(7) (a) Yoo, K. S.; Yoon, C. H.; Mishra, R. K.; Jung, Y. C.; Yi, S. W.;
Jung, K. W. J. Am. Chem. Soc. 2006, 128, 16384. (b) Enquist, P.-A.; Lindh,
J.; Nilsson, P.; Larhed, M. Green Chem. 2006, 8, 338. (c) Andappan, M.
M. S.; Nilsson, P.; Larhed, M. Chem. Commun. 2004, 218. (d) von Schenck,
H.; Akermark, B.; Svensson, M. J. Am. Chem. Soc. 2003, 125, 3503.
(8) Moreno-Manas, M.; Perez, M.; Pleixats, R. J. Org. Chem. 1996, 61,
2346.
(9) (a) Bolm, C.; Weickhardt, K.; Zehnder, M.; Ranff, T. Chem. Ber.
1991, 124, 1173. (b) Brunner, H.; Obermann, U. Chem. Ber. 1989, 122,
499. (c) Sakakura, A.; Kondo, R.; Ishihara, K. Org. Lett. 2005, 7, 1971.
(10) For X-ray crystallography analysis data, see the Supporting Informa-
tion.
3934
Org. Lett., Vol. 9, No. 20, 2007

Table 2. Asymmetric Oxidative Heck Reaction Using Premade
Pd-Ligand Complex 8
Figure 1. ORTEP representation (include H) of the molecular
structure of 7 and proposed transition structures for the oxidative
Heck reaction using Pd-ligand complex 8.
migratory insertion into the Pd-Ph bond. Therefore, the
olefin can be envisioned to coordinate the catalyst in two
different conformations, A or B, which differ in the extent
of steric repulsion between the olefin substituents and the
tert-butyl group on the oxazoline ring. Consequently, the
reaction would proceed through the coordination model A,
which would lead to the observed enantioselectivity.
In conclusion, our asymmetric Heck-type catalysis repre-
sents a novel proof-of-concept, and we address three
important features in this paper: (a) Compared to conven-
tional Heck-type conditions, our oxidative Pd(II) catalysis
exhibited higher efficiency under milder conditions in cross-
coupling of highly substituted olefins. As a consequence,
this oxidative Heck facilitated the preparation of scalemic
coupling products. (b) We observed that the nonchelated free
palladium catalysis played an important role in couplings,
yielding low enantioselectivities under premixed conditions
which one would normally use. (c) Oxidative boron Heck
demonstrated significant improvements over existing meth-
ods in asymmetric catalysis (i.e., 17-75% ee). Keeping those
conditions in mind, we embarked on further studies in more
effective chiral Pd(II) complexes and coupling conditions,
which will be reported in due course.
a The reaction was carried out using 1.1 equiv of arylboronic acids with
5 mol % of 8. b Isolated yield. c Determined by chiral HPLC analysis (Daicel
Chiracel OD) (Mobile phase: iPrOH/hexanes ) 5:95 v/v % rate ) 1 mL/
min). d Absolute configuration. e Enantioselectivity was determined by NMR
analysis with a chiral Eu reagent.
products, and enantioselectivities were comparable (entries
2 and 3). In the case of 2-naphthalenylboronic acid and
6-methoxy-2-naphthalenylboronic acid, the desired rear-
rangement product was obtained with 72 and 68% ee (entries
4 and 5), respectively. The ester analogue reacted smoothly
to furnish similar enantioselectivities (62-75% ee; entries
6-8). The absolute configurations of 1, 9, 12, 13, 14, and
15 were determined as R-enriched by transforming11 the
products to the corresponding phenyl propionic esters12a and
comparing them with authentic samples.12b-e
On the basis of these results, we suggest a plausible olefin-
coordinated structure in the migratory insertion step to
determine enantioselectivity (Figure 1). Based on the X-ray
crystallographic data for the structure of Pd-pyridinyl-
oxazoline complex 7, the pyridine ring and the oxazoline
ring are placed in the same plane. After the transmetalation
step of arylboronic acid, trans-2-methyl-2-butenal would be
coordinated at right angles to the planar pyridinyl-oxazoline
ring.4 The carbonyl group and the R-methyl moiety then
would be located near the oxazoline ring to establish
Acknowledgment. We acknowledge generous financial
support from the National Institute of General Medical
Sciences of the National Institutes of Health (RO1 GM
71495).
(11) (a) Shi, M.; Chen, L.-H.; Li, C.-Q. J. Am. Chem. Soc. 2005, 127,
3790. (b) Kawahara, S.; Nakano, A.; Esumi, T.; Iwabuchi, Y.; Hatakeyama,
S. Org. Lett. 2003, 5, 3103.
(12) (a) For the reaction, see the Supporting Information. (b) Nishimura,
K.; Ono, M.; Nagaoka, Y.; Tomioka, K. Angew. Chem., Int. Ed. 2001, 40,
440. (c) Miyamoto, K.; Ohta, H. J. Am. Chem. Soc. 1990, 112, 4077. (d)
Miyamoto, K.; Tsuchiya, S.; Ohta, H. J. Fluorine Chem. 1992, 59, 225. (e)
Honda, Y.; Ori, A.; Tsuchihashi, G. Bull. Chem. Soc. Jpn. 1987, 60, 1027.
Supporting Information Available: Representative ex-
perimental procedures with spectral data and X-ray crystal-
lography data for compound 7. This material is available
free of charge via the Internet at http://pubs.acs.org.
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