Asymmetric intermolecular boron heck-type reactions via oxidative palladium(II) catalysis with chiral tridentate NHC-amidate-alkoxide ligands

Article abstract of DOI:10.1021/jo901977n

(Chemical Equation Presented) Chiral dimeric tridentate NHC-amidate-alkoxide palladium(II) complexes, 3a and 3b, effected oxidative boron Heck-type reactions of aryl boronic acids with both acyclic and cyclic alkenes at room temperature to afford the corresponding coupling products with high enantioselectivities. The high degree of enantioselection, far superior to existing methods, stems from differences in the nonbonding interactions in the proposed transition states, due to the influence from bulky substituents of the alkene substrates and the "counter axial groups" of the palladium(II) catalysts. 2009 American Chemical Society.

Full text of DOI:10.1021/jo901977n

pubs.acs.org/joc
Asymmetric Intermolecular Boron Heck-Type Reactions via Oxidative
Palladium(II) Catalysis with Chiral Tridentate NHC-Amidate-Alkoxide
Ligands
Kyung Soo Yoo, Justin O’Neill, Satoshi Sakaguchi, Richard Giles, Joo Ho Lee, and
Kyung Woon Jung*
Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California,
Los Angeles, California 90089-1661
kwjung@usc.edu
Received September 15, 2009
Chiral dimeric tridentate NHC-amidate-alkoxide palladium(II) complexes, 3a and 3b, effected
oxidative boron Heck-type reactions of aryl boronic acids with both acyclic and cyclic alkenes at
room temperature to afford the corresponding coupling products with high enantioselectivities. The
high degree of enantioselection, far superior to existing methods, stems from differences in the
nonbonding interactions in the proposed transition states, due to the influence from bulky
substituents of the alkene substrates and the “counter axial groups” of the palladium(II) catalysts.
Introduction
Heck-type variants are important in providing an alternative
to the traditional asymmetric Mizoroki-Heck reaction,2 as
well as extending the synthetic scope of the asymmetric
Fujiwara-Moritani reaction,3 which is initiated through
C-H activation by chiral palladium(II) species. One of
the most attractive palladium(II)-catalyzed reactions is the
organoboron-mediated Heck-type reaction, which proceeds
through transmetalation of a palladium(II) species with an
organoboronic acid as the initial step, rather than oxidative
addition of an organohalide to a palladium(0) species.4 Due
to the commercial availability of organoboronic acids as
nucleophilic substrates and the ability to introduce boronic
acids and esters late in complex syntheses, Heck-type reac-
tions are very attractive in synthetic organic chemistry. In
addition, these boron Heck-type reactions which do not
often require high temperatures or the use of bases are made
Asymmetric palladium catalyzed carbon-carbon bond
formation is one of the most useful protocols in organic syn-
thesis and medicinal chemistry.1 In particular, asymmetric
(1) (a) Beccalli, E. M.; Broggini, G.; Martinelli, M.; Sottocornola, S.
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Chem. Commun. 2004, 1822. (f) Nishikata, T.; Yamamoto, Y.; Gridnev, I. D.;
Miyaura, N. Organometallics 2005, 24, 5025. (g) Delcamp, J. H.; Brucks,
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Ed. 2001, 40, 3284. (d) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem. Res.
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DOI: 10.1021/jo901977n
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Published on Web 12/02/2009
J. Org. Chem. 2010, 75, 95–101 95
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possible by avoiding the oxidative addition of organohalides
to palladium(0) species. Due to these advantages, the palla-
dium(II) catalyzed organoboron-mediated Heck-type reac-
tions with Cu(OAc)21a,5 and molecular oxygen6 as oxidants
have recently been reported. However, the challenges of the
asymmetric oxidative palladium catalyzed Heck-type reac-
tions of organoborons have not been well studied.7
metal-ligand complexes than common bidentate ligands.
Therefore, newly designed tridentate ligands would afford
higher enantioselectivities by keeping stereocontrol elements
locked in place during the entire catalytic processes. On the
basis of these criteria, we designed and synthesized the NHC
ligand 1, which is composed of benzimidazole and a chiral
amino alcohol. We then produced their corresponding chiral
silver complexes, which underwent transpalladation to give
monomeric NHC-Pd complexes 2 and dimeric catalysts 3.9
Surprisingly, we found that the cross-coupling reaction of
4-methoxy phenylboronic acid and methyl tiglate by triden-
tate Pd complex 2 and 3 gave drastically different enantio-
selectivities as depicted in eq 2.9 While the dimeric chiral
NHC-Pd complex 3 gave excellent enantioselective rearran-
gement product, the monomeric NHC-Pd complex 2 gave
poor selectivity. Herein, we wish to discuss our rationale and
transition states to account for the observed high enantio-
selection using dimeric tridentate chiral NHC-Pd complexes.
In addition, we would like to disclose various cases of
asymmetric oxidative Heck-type reactions, as our previous
publication focused mainly on these catalysts and reported
only a few examples of successful coupling reactions. In
particular, arylboronic acids coupled easily with both acyclic
and cyclic alkenes.
Several approaches to asymmetric oxidative Heck reac-
tions that are initiated by transmetalation of organoborons
have been reported in the past several years. Mikami et al.
have employed a palladium(II)-chiraphos ligand system that
is catalytically active in inter- and intramolecular oxidative
boron Heck-type coupling reactions,7a,d and Gelman et al.
demonstrated a protocol for the enantioselective palladium-
(II)-catalyzed Heck-type reaction between arylboronic acids
and 2,3-dihydrofuran in the presence of an (R)-BINAP
ligand.7b In addition, we have succeeded in developing
intermolecular asymmetric oxidative boron Heck-type reac-
tions between arylboronic acids and acyclic trisubstituted
alkenes assisted by a chiral PyOX ligand-palladium(II)
complex under an oxygen atmosphere.7c In this study, we
observed that nonchelated free palladium catalysts played
a critical role in racemic couplings that resulted in low
enantioselectivities under commonly used premixed condi-
tions, demonstrating the significance of utilizing a preformed
tight well-bound palladium(II)-ligand complex.
To develop a tighter chiral palladium(II)-ligand complex,
we considered the use of an N-heterocyclic carbene (NHC) as
a ligand due to its ability to strongly coordinate to transition
metals.8 We also envisioned that tridentate ligands including
an NHC, amidate, and alkoxide would constitute stronger
Results and Discussion
According to recent reports, highly enantioselective asym-
metric Heck reactions have been observed in a number of
intramolecular Heck-type cyclizations; however, intermole-
cular reactions have thus far given poor enantioselectivities
except when using cyclic olefins such as dihydrofuran and
dihydropyrrole.10 While extensively investigating carbon-
carbon bond formation with oxidative Pd(II) catalysis of
organoborons, we found that the cross-coupling reaction of
4-methoxyphenyl boronic acid (4) and methyl tiglate (5) in
the presence of the novel chiral NHC-Pd(II) complex 3a
produced the rearrangement compound 6 exclusively, gen-
erating a new stereogenic center. Under an O2 atmosphere
(1 atm), this reaction gave methyl 2-methylene-3-(4-meth-
oxyphenyl)butanoate (6) in 52% yield (cross-coupling compound)
with 4-methoxyphenol (43%, deboronylation) and a small
amount of the corresponding biaryl compound (2%, homo-
coupled compound) (Table 1, entry 1). More importantly, it was
(5) (a) Du, X.; Suguro, M.; Hirabayashi, K.; Mori, A.; Nishikata, T.;
Hagiwara, N.; Kawata, K.; Okeda, T.; Wang, H. F.; Fugami, K.; Kosugi, M.
Org. Lett. 2001, 3, 3313. (b) Xiong, D.-C.; Zhang, L.-H.; Ye, X.-S. Org. Lett.
2009, 11, 1709. (c) Hirabayashi, K.; Ando, J.-i.; Kawashima, J.; Nishihara,
Y.; Mori, A.; Hiyama, T. Bull. Chem. Soc. Jpn. 2000, 73, 1409.
(6) (a) Jung, Y. C.; Mishra, R. K.; Yoon, C. H.; Jung, K. W. Org. Lett.
2003, 5, 2231. (b) Andappan, M. M. S.; Nilsson, P.; Von Schenck, H.;
Larhed, M. J. Org. Chem. 2004, 69, 5212. (c) Andappan, M. M. S.; Nilsson,
P.; Larhed, M. Chem. Commun. 2004, 218. (d) Yoon, C. H.; Yoo, K. S.; Yi,
S. W.; Mishra, R. K.; Jung, K. W. Org. Lett. 2004, 6, 4037. (e) Yoo, K. S.;
Yoon, C. H.; Jung, K. W. J. Am. Chem. Soc. 2006, 128, 16384. (f) Lindh, J.;
Enquist, P. A.; Pilotti, A.; Nilsson, P.; Larhed, M. J. Org. Chem. 2007, 72,
7957.
(7) (a) Akiyama, K.; Wakabayashi, K.; Mikami, K. Adv. Synth. Catal.
2005, 347, 1569. (b) Penn, L.; Shpruhman, A.; Gelman, D. J. Org. Chem.
2007, 72, 3875. (c) Yoo, K. S.; Park, C. P.; Yoon, C. H.; Sakaguchi, S.;
O’Neill, J.; Jung, K. W. Org. Lett. 2007, 9, 3933. (d) Akiyama, K.; Mikami,
K. Heterocycles 2007, 74, 827.
(8) (a) Bourissou, D.; Guerret, O.; Gabbaı, F. P.; Bertrand, G. Chem. Rev.
2000, 100, 39. (b) Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1291.
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K. W. Angew. Chem., Int. Ed. 2008, 47, 9326.
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(c) Cesar, V.; Bellemin-Laponnaz, S.; Gade, L. H. Chem. Soc. Rev. 2004, 619.
(d) Sigman, M. S.; Jensen, A. D. Acc. Chem. Res. 2006, 39, 221. (e) Douthwaite,
R. E. Coord.Chem. Rev.2007, 251, 702. (f) Gade, L. H.; Bellemin-Laponnaz, S. In
Topics in Organometallic Chemistry; Glorius, F., Ed.; Spronger-Verlag: Berlin,
Germany, 2007; Vol. 21, pp 117-157. (g) Kantchev, E. A. B.; O'Brien, C. J.;
Organ, M. G. Angew. Chem., Int. Ed. 2007, 46, 2768.
(10) Diederich, F.; Stang, P. J. In Metal-Metal Cross-Coupling Reaction;
Wiley-VCH: New York, 1999. (b) Trost, B. M.; Jiang, C. Synthesis 2006, 369.
(c) Guiry, P. J.; Kiely, D. Curr. Org. Chem. 2004, 8, 781. (d) Dodd, D. W.;
Toews, H. E.; Carneiro, F. d. S.; Jennings, M. C.; Jones, N. D. Inorg. Chem.
Acta 2006, 359, 2850.
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TABLE 1. Effect of Oxidants on Asymmetric Oxidative Coupling
Reactions of 4-Methoxyphenylboronic Acid (4) with Methyl Tiglate (5)
entrya
catalyst
oxidant
O2
Air
CuCl2
Cu(OAc)2
BQ
yield (%)b
ee (%)c
91
1
2
3a
3a
3a
3a
3a
3a
2a
52
11
>1
>1
0
3d
4d
5d
6
FIGURE 1. Possible transition state for orientation of olefin to the
Pd complex 7.
O2 (6 atm)
O2
50
65
7
7
a4 (0.5 mmol) was reacted with 5 (1.5 mmol) in the presence of a
catalyst (0.02 mmol) in DMF (1.25 mL) at room temperature in the
presence of an oxidant for 16 h. bYields based on boronic acid (4) used.
cFor the determination of enantiomeric excess, see the Supporting
Information. d1 mmol of CuCl2, Cu(OAc)2, and BQ (benzoquinone)
added to entries 3, 4, and 5.
found that 6 was formed in 91% enantiomeric excess. As shown
in Table 1, we screened representative oxidants for the asym-
metric Heck-type reactions in the presence of 3a. However, under
an air atmosphere the reaction resulted in a low yield of 6 (11%)
(entry 2), and almost no reaction occurred by employing CuCl2,
Cu(OAc)2, or benzoquinone as oxidants (entries 3-5).1a,11 For-
mation of the cross-coupled product was not improved under
high pressure of O2 (entry 6). We also examined the coupling
reaction with the monomeric complex 2a (entry 7). Although the
reaction conversion was enhanced, enantioselectivity was much
lower (7% ee) than that observed in the reaction with dimeric
complex 3a.
FIGURE 2. Plausible catalytic mechanism.
boron-Heck-type reactions via oxidative palladium(II) cata-
lysis.
From these results, we suspected that higher enantioselec-
tivities via dimer catalyst 3a as compared to the monomeric
catalyst 2a were due to the steric effect of the borate group
transferred to the alkoxide of the catalyst 3a, which was not
the case with 2a. To account for this difference, we studied
the transmetalation step by identifying potential borate
intermediates such as 7 by the coupling of 3a and phenyl-
boronic acid (eq 3). The intended transmetalation of phe-
nylboronic acid was very slow in a DMF solution without
generating isolable products. However, phenyl-palladium
complex 7 comprising the borate moiety was detected
1
by H NMR spectra analysis.12 In particular, the chemical
shifts of the methylene protons (CH2O) in 7 were further
downfield than the corresponding ones in 2a and 3a, imply-
ing the formation of a boric ester. On the other hand,
transmetalation of monomeric catalyst 2a and phenylboro-
nic acid did not follow suit, presumably furnishing the
simple transmetalated intermediate 8 (eq 4). Consequently,
these observed intermediate structures could provide a rea-
sonable mechanistic rationale in asymmetric intermolecular
On the basis of the X-ray crystallographic data for struc-
ture 3a, we have suggested the proper spatial positions of the
NHC, isopropyl, phenyl, and borate groups in complex 7. As
shown in Figure 1, the phenyl group would be coordinated at
the open site to form the palladium(II) complex, and the
borate group would occupy the position remote to the axially
positioned isopropyl group based upon the calculated steric
energy value. It was also noted that the transmetalated
complex 7 would possess a concave shape, formed by the
benzimidazole and lactam rings. After the transmetalation
process, the olefin is envisioned to coordinate by either
pathway A (upward) or B (downward) to subsequently
undergo migratory insertion into the Pd-Ph bond, where
€
(11) (a) Backvall, J.-E.; Gogoll, A. J. Chem. Soc., Chem. Commun. 1987,
1237. (b) Sigman, M. S.; Schultz, M. J. Org. Biomol. Chem. 2004, 2, 2551.
(c) Eastgate, M. D.; Buono, F. G. Angew. Chem., Int. Ed. 2009, 48, 5958.
(d) Chen, X.; Li, J.-J.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem.
Soc. 2006, 128, 78. (e) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2009,
131, 9651.
(12) The details are described in the Supporting Information.
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TABLE 2. Asymmetric Oxidative Heck Reaction with Pd-Ligand Complexes 3a and 3b
aThe reaction was carried out with arylboronic acid (0.5 mmol) and alkene (1.5 mmol) in the presence of catalyst 3a (0.02 mmol). bYields based on
arylboronic acids. For determination of enantiomeric excess, see the Supporting Information. cAbsolute configuration. dEnantioselectivity was
determined by NMR analysis with a chiral Eu reagent.
pathway A would be disfavored by the steric hindrance due
to concave repulsion (coordination models C and D). There-
fore, pathway B would offer two possible transition states
(E and F) for the C-C bond formation, which would
determine enantioselection modes. In structural model E,
there would be significant steric repulsion between the
methyl substituent of the olefin and the borate group of the
ligand structure, whereas such an interaction would not
persist in the coordination model F. Consequently, the
reaction would be expected to proceed through the transition
state model F, which would lead to the observed excellent
enantioselectivity as well as the observed stereochemical (R)-
configuration. In summary, the concave conformation of
these catalysts would augment the steric effect of both the
upward axial isopropyl group and the downward axial
borate group. We would like to call this opposite alignment
of two groups including isopropyl and borate “counter axial
groups”, which could be a decisive factor in determining
enantioselectivity.13 In the transition states, the facial selec-
tivity of the incoming alkene substrates can be governed by
the axial borate group in 3a, which would not be present in
the monomer 2a. As a result, the “counter axial groups” and
the transition state models are an important feature of the
design for asymmetric catalysis.
On the basis of these results, we propose a plausible
catalytic mechanism as follows (Figure 2): (i) Initial transmeta-
lation between the palladium(II) complex and an arylboronic
(13) Bis-oxazoline type counter axial arrangement in metal catalyzed
reaction: (a) Cornejo, A.; Fraile, J. M.; Gracıa, J. I.; Gracıa-Verdugo, E.;
´ ´
Gil, M. J.; Legarreta, G.; Luis, S. V.; Martınez-Merino, V.; Mayoral, J. A.
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Org. Lett. 2002, 4, 3927. (b) Benaglia, M.; Benincori, T.; Mussini, P.; Pilati,
T.; Rizzo, S.; Sannicolo, F. J. Org. Chem. 2005, 70, 7488. (c) Zhang, W.; Xie,
F.; Matsuo, S.; Imahori, Y.; Kida, T.; Nakatsuji, Y.; Ikeda, I. Tetrahedron:
Asymmetry 2006, 17, 767. (d) Albano, V. G.; Bandini, M.; Monari, M.;
Marcucci, E.; Piccinelli, F.; Umani-Ronchi, A. J. Org. Chem. 2006, 71, 6451.
98 J. Org. Chem. Vol. 75, No. 1, 2010

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acid would form the intermediate I, which was detected
1
by H NMR when transmetalation was conducted in the
TABLE 3. Asymmetric Oxidative Heck Reaction of 1-Acetylcyclopetene
and Phenylboronic Acid
absence of alkenes. (ii) Incorporation of an alkene can be
carried out via migratory insertion to afford intermediate II,
which would be followed by β-hydride elimination to pro-
duce the migrated cross-coupling product. Simultaneously,
the amidate group is likely to be protonated to generate
palladium(0) species III. (iii) Molecular oxygen would then
oxidize the resulting palladium(0) to a peroxo-palladium
complex IV,14 which can react with another arylboronic acid
to regenerate complex I.15 As confirmed in our previous
work,16 oxygen was crucial for the catalytic cycle, acting as
an efficient palladium(0) reoxidant.
Having established optimized conditions, the representa-
tive asymmetric coupling reactions of arylboronic acids and
trisubstituted olefins were examined to evaluate the scope of
this methodology as shown in Table 2. The cross-coupling
reactions of phenylboronic acid and 2-naphthylboronic acid
with methyl tiglate took place smoothly to provide the
desired rearrangement products, 9 and 10 in 49% and
61% yields, respectively, with excellent enantioselectivities
(entries 1 and 2). Electron-donating groups on the arylboro-
nic acids offered comparable yields and enantioselectivities
entrya
solvent
DMF
DMF
DMF
acetonitrile
THF
methanol
toluene
DMA
temp (°C)
Pd (mol %)
yieldb (%)
1
2
3
4
5
6
7
8
rt
50
50
rt
rt
rt
rt
rt
5
5
10
5
5
5
70 (85% ee)
67
71
61
28
29
24
21
5
5
aThe reaction was carried out with olefin (1.5 mmol) and phenyl-
boronic acid (1.0 mmol) in DMF (1.5 mL) at room temperature for 16 h.
bYields based on phenylboronic acid.
similarly to acyclic cases with DMF at room temperature
(entry 1). In comparison, higher temperatures such as 50 °C
were not suitable because the desired cross-coupling dimini-
shed slightly due to the increase of homocoupling and
deboronylation (entries 2 and 3). Acetonitrile was compar-
able to DMF; however, other solvents including THF,
MeOH, toluene, and DMA provided only poor yields
(entries 4-8).
Interestingly, dimeric and monomeric catalysts exhibited
distinguished patterns similar to the those of acyclic system as
shown in the eq 5. The monomeric complex 2a afforded poor
enantioselectivity (21% ee); however, complex 3a induced an
asymmetric sense to a great extent (85% ee). The dimeric
complex also offered higher yield than the monomer. Once
again, the aforementioned transition state model accounts for
this difference and is thus general for these reactions.
(entries
3 and 4), whereas an electron-withdrawing
group gave a slightly lower yield with high enantioselectivity
(entry 5). As expected, a more sterically hindered o-tolyl-
boronic acid reacted sluggishly to give 29% yield of the
desired product 13 (entry 6). The absolute configurations of
6, 9, 11, and 12 were confirmed as (R)-enriched by transfor-
ming7c,9 the products to the corresponding phenyl propionic
esters and comparing them with authentic samples.17 This
observed stereochemistry matched the explanation using the
preferred transition state F (Figure 1).
With use of phenyl- and 2-naphthylboronic acids, we
varied alkene substrates including 2-methyl-2-pentenoic
methyl ester and trans-2-methyl-2-butenal, which exhibited
slightly lower yields and ee values (entries 7-9). The absolute
configuration of 15 was also determined as the (R)-enriched
form. Under similar conditions, NHC-Pd(II) complex 3b
provided the desired rearrangement products 9 and 6 in
moderate yields; however, this catalyst afforded higher en-
antioselectivities compared to 3a (entries 10 and 11). To our
knowledge, existing methods for the enantioselective inter-
molecular arylation of acyclic alkenes have provided only up
to 17% ee,18 whereas our chiral tridentate NHC-amidate-
Pd(II) complexes induced excellent enantioselectivities
(generally higher than 90% ee) despite moderate yields in
some cases due to the deboronylation side reaction.
Under optimized conditions, the substrate scope of the
reaction was examined as represented in Table 4. The use of
sterically hindered o-tolylphenylboronic acid resulted in a
lower yield than phenylboronic acid. However, unlike the
acyclic alkene (cf. Table 2, entry 6), the use of the cyclic
alkene 1-acetyl-1-cyclopentene furnished a moderate yield
and high enantioselectivity (entry 1). Electron donating and
withdrawing groups had little effect on the course of the
reaction, resulting in comparable yields and high enantio-
selectivities (entries 2-4). A slightly modified alkene, methyl
1-cyclopentene-1-carboxylate, was used for the same trans-
formation, which offered similar yields and enantioselecti-
vities (entries 5-7). In addition, we confirmed that the other
palladium(II) complex 3b generated similar results to 3a
(entry 8). Overall, this asymmetric oxidative palladium(II)
catalysis offered an efficient enantioselective protocol for
intermolecular cross-coupling reactions between arylboro-
nic acids and cyclic olefins under mild conditions.
Independently from acyclic alkenes, we also examined the
use of cyclic olefins for these asymmetric oxidative boron-
Heck reactions by screening various solvents, temperatures,
and catalyst loadings (Table 3). Optimal yields were obtained
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TABLE 4. Asymmetric Oxidative Heck Reaction with Pd-Ligand Complexes 3a and 3b
aThe reaction was carried out with arylboronic acid (0.5 mmol) and alkene (1.5 mmol) in the presence of catalyst 3 (0.02 mmol). bOn the basis of
arylboronic acids. For determination of enantiomeric excess, see the SupportingInformation. cEnantioselectivity was determined by NMR analysis with
a chiral Eu reagent.
Conclusion
DAD: 230.4-450.80 nm) and europium tris[3-(heptafluoropropyl-
hydroxylmethylene)-(þ)-camphorate] as a shift reagent, respec-
tively. Compounds 6, 9, 10, 15, and 16 were identified through
comparing their spectral data of the products with those of the
previously reported ones,7c and other acyclic coupling products
were described below. The data analysis on cross-coupling com-
pounds with cyclic olefins and arylboronic acids is included in the
Supporting Information.
In conclusion, chiral tridentate amidate/alkoxy/carbene
palladium(II) complexes 3a and 3b successfully catalyzed
oxidative Heck-type reactions of arylboronic acids with both
acyclic and cyclic alkenes to offer high enantioselectivities
unprecedented in intermolecular Heck-type couplings. The
high degree of asymmetric catalysis was presumably due to
the biased facial selection of the alkenes, which was caused
by counter axial groups (isopropyl and borate groups)
embedded in the possible transition states. These ligand
architectures can be readily altered by using different chiral
components for general use. Thus, we hope that these types
of catalysts and the transition state concepts will be utilized
for a wide array of asymmetric cross-coupling reactions.
Methyl 3-(4-(dimethylamino)phenyl)-2-methylenebutanoate
1
(11): H NMR (CDCl3) δ 7.08 (d, J = 8.8 Hz, 2H), 6.68 (d,
J = 8.8 Hz, 2H), 6.21 (s, 1H), 5.56 (s, 1H), 3.94 (q, J = 6.8 Hz,
1H), 3.67 (s, 3H), 2.01 (s, 6H), 1.38 (d, J = 6.8 Hz, 3H). 13C
NMR (CDCl3) δ 167.9, 158.8, 145.4, 132.3, 128.1, 123.2, 112.9,
51.8, 40.9, 39.5, 20.8. Anal. Calcd for C14H19NO2: C 72.07, H
8.21, N 6.00. Found: C 72.25, H 8.14, N 5.81. HRMS-ESI (m/z)
[M þ Hþ] calcd for C14H19NO2 234.1489, found 234.1493;
[R]20 -48.9 (c 1.01, CHCl3). HPLC (Daicel CHIRALCEL
D
OD-H; 99:1 hexanes/isopropanol, detection wavelength=254 nm,
flow rate=1.0 mL/min) tr = 6.8 (minor) and 7.5 min (major).
Methyl 3-(4-acetylphenyl)-2-methylenebutanoate (12): 1H
NMR (CDCl3) δ 7.88 (d, J = 8.8 Hz, 2H), 7.30 (d, J =8.8 Hz,
2H), 6.35 (s, 1H), 5.68 (s, 1H), 4.07 (q, J=6.8 Hz, 1H), 3.66 (s,
3H), 2.57 (s, 3H), 1.42 (d, J=6.8 Hz, 3H). 13C NMR (CDCl3) δ
197.9, 167.0, 150.1, 143.8, 135.4, 128.5, 127.5, 124.4, 51.8, 40.5,
26.4, 20.4. Anal. Calcd for C14H16O3: C 72.39, H 6.94. Found: C
72.07, H 7.03. HRMS-ESI (m/z) [M þ Hþ] calcd for C14H16O3
233.1172, found 233.1176. [R]20D -68.1 (c 0.10, CHCl3). HPLC
(Daicel CHIRALCEL OD-H; 99:1 hexanes/isopropanol, detec-
tion wavelength = 254 nm, flow rate = 1.0 mL/min) tr = 21.9
(minor) and 22.5 min (major).
Experimental Section
Typical Catalytic Asymmetric Boron-Heck Coupling Reac-
tion. To a solution of the Pd-ligand complex 3a or 3b (10 mg) in
DMF (2.5 mL) was added olefin (1.5 mmol) and arylboronic
acid (0.5 mmol). The reaction flask was fitted with an oxygen
balloon, and the reaction mixture was stirred at room tempera-
ture for 16 h, then diluted with EtOAc (10 mL), and washed with
water (2 ꢀ 10 mL). The separated organic layer was dried over
anhydrous Na2SO4 and filtered. The filtrate was concentrated in
vacuo, and the residue was chromatographed on silica gel
(hexanes/EtOAc = 40/1) to give a cross-coupled product. To
determine enantiomeric excess of the products, HPLC analysis
and 1H NMR analysis were performed with chiral Daicel (eluent:
n-hexane/isopropyl alcohol = 95/5 or 99/1; flow: 1.00 mL/min;
Methyl 2-methylene-3-o-tolylbutanoate (13): 1H NMR
(CDCl3) δ 7.07-7.15 (m, 4H), 6.27 (s, 1H), 5.52 (s, 1H), 4.22
100 J. Org. Chem. Vol. 75, No. 1, 2010

Yoo et al.
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(q, J=6.8 Hz, 1H), 3.68 (s, 3H), 2.36 (s, 3H), 1.36 (d, J=6.8 Hz,
3H). 13C NMR (CDCl3) δ 167.4, 144.8, 142.4, 138.6, 135.9,
130.4, 126.1, 125.9, 123.8, 51.8, 36.1, 19.9, 19.3. Anal. Calcd for
C13H16O2: C 76.44, H 7.90. Found: C 76.19, H 8.02. HRMS-ESI
(m/z) [M þ Hþ] calcd for C13H16O2 205.1223, found 205.1229.
ESI (m/z) [M þ Hþ] calcd for C17H19O2 255.1340, found
255.1342; [R]20D -71.8 (c 0.75, CHCl3). HPLC (Daicel CHIR-
ALCEL OD-H; 95:5 hexanes/isopropanol, detection wavelength=
270 nm, flow rate = 1.0 mL/min) tr = 4.5 (minor) and 5.4 min
(major).
[R]20 -56.7 (c 0.65, CHCl3). HPLC (Daicel CHIRALCEL
D
OD-H; 99:1 hexanes/isopropanol, detection wavelength=254 nm,
flow rate =1.0 mL/min) tr =21.3 (minor) and 22.2 min (major).
Methyl 2-methylene-3-(2-naphthalenyl)pentanoate (14): 1H
NMR (CDCl3) δ 7.81-7.74 (m, 3H), 7.65 (m, 1H), 7.46-7.33
(m, 3H), 6.34 (s, 1H), 5.72 (s, 1H), 3.91 (m, 1H), 3.65 (s, 3H), 1.94
(m, 2H), 0.89 (t, J = 7.5 Hz, 3H). 13C NMR (CDCl3) δ 167.5,
143.7, 140.1, 133.4, 132.3, 127.8, 127.7, 127.5, 126.9, 126.6,
125.8, 125.3 129.3, 51.8, 48.0, 27.4, 12.4. Anal. Calcd for
C17H18O2: C 80.28, H 7.13. Found: C 80.25, H 7.14. HRMS-
Acknowledgment. The authors acknowledge generous fina-
ncial support from the National Institute of General Medical
Sciences of the National Institutes of Health (RO1 GM 71495).
Supporting Information Available: 1H and 13C NMR spec-
tra for all compounds in addition to experimental data for
compounds 11-14 and 19-26. This material is available free
of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 1, 2010 101