Oxidative palladium(II) catalysis: A highly efficient and chemoselective cross-coupling method for carbon-carbon bond formation under base-free and nitrogenous-ligand conditions

Article abstract of DOI:10.1021/ja063710z

We report herein the development of a general and mild protocol of oxygen-promoted Pd(II) catalysis resulting in the selective cross-couplings of alkenyl- and arylboron compounds with various olefins. Unlike most cross-coupling reactions, this new methodology works well even in the absence of bases, consequently averting undesired homo-couplings. Nitrogen-based ligands including dimethyl-phenanathroline enhance reactivities and offer a highly efficient and stereoselective methodology to overcome challenging substrate limitations. For instance, oxidative palladium(II) catalysis is effective with highly substituted alkenes and cyclic alkenes, which are known to be incompatible with other known catalytic conditions. Most examined reactions progressed smoothly to completion at low temperatures and in short times. These interesting results provide mechanistic insights and utilities for a new paradigm of palladium catalytic cycles without bases.

Full text of DOI:10.1021/ja063710z

Published on Web 11/30/2006
Oxidative Palladium(II) Catalysis: A Highly Efficient and
Chemoselective Cross-Coupling Method for Carbon-Carbon
Bond Formation under Base-Free and Nitrogenous-Ligand
Conditions
Kyung Soo Yoo, Cheol Hwan Yoon, and Kyung Woon Jung*
Contribution from the Loker Hydrocarbon Research Institute and Department of Chemistry,
UniVersity of Southern California, Los Angeles, California 90089-1661
Received May 26, 2006; E-mail: kwjung@usc.edu
Abstract: We report herein the development of a general and mild protocol of oxygen-promoted Pd(II)
catalysis resulting in the selective cross-couplings of alkenyl- and arylboron compounds with various olefins.
Unlike most cross-coupling reactions, this new methodology works well even in the absence of bases,
consequently averting undesired homo-couplings. Nitrogen-based ligands including dimethyl-phenanathroline
enhance reactivities and offer a highly efficient and stereoselective methodology to overcome challenging
substrate limitations. For instance, oxidative palladium(II) catalysis is effective with highly substituted alkenes
and cyclic alkenes, which are known to be incompatible with other known catalytic conditions. Most examined
reactions progressed smoothly to completion at low temperatures and in short times. These interesting
results provide mechanistic insights and utilities for a new paradigm of palladium catalytic cycles without
bases.
Scheme 1
Introduction
Transition metal-catalyzed coupling reactions are extremely
powerful tools for carbon-carbon bond formation and have been
widely utilized in a great number of syntheses. In particular,
palladium-catalyzed arylation and vinylation of alkenes known
as Mizoroki-Heck (Y ) H),1 Suzuki-Miyaura (Y ) B(OR′)2),2
and Stille (Y ) SnR′′3)3 reactions have become classical vehicles
to various carbon-carbon bonds (Scheme 1). Among these
methods, the Heck reaction has been considered the best choice
presumably because Suzuki-Miyaura and Stille couplings often
require stereoselective syntheses of both substrates prior to
couplings. However, this methodology has been limited prima-
rily to monosubstituted olefins due to inefficiency, low selectiv-
ity, and harsh reaction conditions when used for di- and
trisubstituted olefins.
such as diazonium halide salt,5 triflate,6 acid chloride,7 tellu-
ronium salt,8 etc. These efforts to find new conditions have
provided high efficiency under mild conditions; yet these
methods are not widely used. Our group has pursued a combined
strategy of aforementioned approaches by changing halides to
boronic acids9 and modifying the reaction parameters such as
atmosphere.10 This approach presents a novel paradigm for these
types of coupling, which stems from a change in reaction
mechanism, Pd(0) to Pd(II) catalysis under an oxygen atmo-
sphere.
Recently, we reported early developments of an oxygen-
promoted palladium(II) catalysis for the cross-coupling of
To overcome these limitations, two distinct approaches have
been pursued by a number of research groups. In one approach,
mild conditions have been sought by changing reaction param-
eters as seen in recent reports by Fu4a and Hartwig.4b On the
contrary, other groups investigated alternative halide surrogates
(5) (a) Akiyama, F.; Miyazaki, H.; Kaneda, K.; Teranishi, S.; Fujiwara, Y. J.
Org. Chem. 1980, 45, 2359. (b) Kikukara, K.; Nagira, K.; Wada, F.;
Matsuda, T. Tetrahedron 1981, 37, 31. (c) Sengupta, S.; Bhattacharyya, S.
J. Chem. Soc., Perkin Trans. 1 1993, 1943.
(6) (a) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120, 7369. (b)
Fu, X.; Thiruvengadam, T. K.; Zhang, F. Tetrahedron Lett. 2002, 43, 573.
(c) Fu, X.; Zhang, S.; Yin, J.; Schumacher, D. P. Tetrahedron Lett. 2002,
43, 6673. (d) Roy, A. H.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125,
8704. (e) Roy, A. H.; Hartwig, J. F. Organometallics 2004, 23, 194. (f)
Klapars, A.; Campos, K. R.; Chen, C.-Y.; Volante, R. P. Org. Lett. 2005,
7, 1185. (g) Hanse, A. L.; Skrydstrup, T. Org. Lett. 2005, 7, 5585.
(7) (a) Blaser, H.-U.; Spencer, A. J. Organomet. Chem. 1982, 233, 267. (b)
Spencer, A. J. Organomet. Chem. 1983, 247, 117. (c) Spencer, A. J.
Organomet. Chem. 1984, 270, 115.
(1) For reviews of the Heck reaction, see: (a) Heck, R. F. Org. React. 1982,
27, 345. (b) Gu¨rtler, C.; Buchwald, S. L. Chem.-Eur. J. 1999, 5, 3107. (c)
Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100, 3009. (d)
Whitcombe, N. J.; Hii, K. K.; Gibson, S. E. Tetrahedron 2001, 57, 7449.
(e) Kondolff, I.; Doucet, H.; Santelli, M. Tetrahedron Lett. 2003, 44, 8487.
(2) For reviews of the Suzuki-Miyaura reaction, see: (a) Miyaura, N. J.
Organomet. Chem. 2002, 653, 54. (b) Miyaura, N. Top. Curr. Chem. 2002,
219, 11. (c) Suzuki, A. J. Organomet. Chem. 1999, 576, 147. (d) Miyaura,
N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(3) For a review of the Stille reaction, see: Farina, V.; Krishnamurthy, V.;
Scott, W. J. Org. React. 1997, 50, 1-652.
(8) Zeni, G.; Lu, D. S.; Panatieri, R. B.; Braga, A. L. Chem. ReV. 2006, 106,
1032.
(4) (a) Littke, A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989. (b) Stambuli,
J. P.; Stauffer, S. R.; Shaughnessy, K. H.; Hartwig, J. F. J. Am. Chem.
Soc. 2001, 123, 2677.
(9) As compared to the time when Heck discovered the original conditions,
there are currently an astronomical number of commercially available
boronic acids and esters.
9
16384
J. AM. CHEM. SOC. 2006, 128, 16384-16393
10.1021/ja063710z CCC: $33.50 © 2006 American Chemical Society

Oxidative Palladium(II) Catalysis
A R T I C L E S
Scheme 2
Scheme 3
Table 1. Coupling of 1-Hexenyl Boronic Ester 1 with tert-Butyl
Acrylate under Various Conditions
First, we considered the value of using bases. Reactions run
in the absence of base consequently yielded cross-coupled
compound 2 without any concomitant formation of 3 (entry 2).
Despite the success, the base-free conditions needed a longer
reaction time. Meanwhile, the palladium catalyst started to
precipitate out. Therefore, we next pursued stabilizing the
palladium catalysts and maximizing their catalytic efficiency.
This goal was successfully achieved by adopting amine ligands
such as 1,10-phenanthroline resulting in the exclusive formation
of the desired cross-coupling product in just 2 h (entry 3).15
We believe that these newly developed methods can serve
as the optimal conditions for these types of cross-coupling
reactions. The current account addresses these control elements,
the scope of each methodology, and mechanistic insights. On
the basis of the observed results, a new mechanism is proposed
herein to account for the desired catalytic cycle, avoidance of
byproducts, base-free and ligand-present conditions, and most
importantly the mildness and efficiency relative to known
methodologies.
yield (%)
entry
base
ligand
temp (
°C)
time (h)
2
3
1
2
3
Na2CO3
23
50
50
3
6
2
85
95
98
10
-
phena
a phen ) 1,10-phenanthroline.
organoboron compounds and alkenes to afford aryl-alkene and
alkene-alkene compounds (Scheme 2).11 In this carbon-carbon
bond formation protocol, the most characteristic feature is
utilization of molecular oxygen as a reoxidant of palladium(0)
species.13 Coupling reactions proceed smoothly with various
substrates, and the reactions are highly efficient and stereose-
lective presumably due to mildness of the reaction conditions
employed. In this definitive report, we offer general conditions
for wide applications.
As representatively shown in Table 1, we have discovered
benign conditions to enhance the desired cross-coupling process.
Our early studies on oxidative Pd(II) catalysis exhibited superior
activities and selectivities; however, these conditions ac-
companied homo-couplings to a small extent (entry 1).14
Although these undesired homo-coupled products can be easily
separated out by column chromatography, it would be ideal to
avoid them for wide application, especially in library generation.
In this context, we embarked on efforts to eliminate homo-
coupling products by scrutinizing possible mechanisms and
control elements.
Results and Discussion
1. Cross-Coupling Reaction of Alkenylboron Compounds
and Olefins. 1.1. Base Effect on the Cross-Coupling Reaction.
Generally, bases are well known to be a pivotal component in
palladium-catalyzed coupling reactions such as the Miyaura-
Suzuki reaction.2 The role of the bases in these reactions is to
facilitate transmetallation of organoboron compounds via forma-
tion of organoborate salts resulting in the enhancement of
coupling reactions. Likewise, in our protocol, the reactive borate
salts 5 should accelerate the coupling processes as shown in
Scheme 3. However, homo-coupled compounds 8 were con-
comitantly formed albeit in low yields due to the reactive borate
salts 5. Therefore, we anticipated exclusive cross-coupling by
avoiding generation of reactive borate salts. On the basis of
this assumption, we conducted oxidative Pd(II) cross-coupling
reaction in the absence of bases, and the results are summarized
in Table 2.
We examined the base effect on the cross-coupling of trans-
1-hexenyl pinacolboron ester (1) and tert-butyl acrylate. The
cross-coupling reaction in the presence of Na2CO3 as a base at
room temperature provided 85% yield of conjugated diene
compound 2 and 10% of homo-coupled compound 3 (entry 1).
At a higher temperature, 50 °C, although reaction rate was
accelerated, the yield of homo-coupled compound was also
increased to 23% (entry 2). In the absence of a base, the
reactivity was attenuated significantly to effect low conversion;
however, the desired cross-coupling was observed exclusively
(entry 3). Hence, an elevated temperature was required to
(10) For oxygen-promoted Pd-catalyzed cross-coupling reactions, see: (a)
Andappan, M. M. S.; Nilsson, P.; Larhed, M. Chem. Commun. 2004, 218.
(b) Zou, G.; Zhu, J.; Tang, J. Tetrahedron Lett. 2003, 44, 8709. (c) Dams,
M.; De Vos, D. E.; Celen, S.; Jacobs, P. A. Angew. Chem., Int. Ed. 2003,
42, 3512. (d) Matoba, K.; Motofusa, S.-I.; Cho, C. S.; Ohe, K.; Uemura,
S. J. Organomet. Chem. 1999, 574, 3. (e) For Pd-catalyzed cross-coupling
reactions with Cu(II) as an oxidant: Du, X.; Suguro, M.; Hirabayashi, K.;
Mori, A. Org. Lett. 2001, 3, 3313.
(11) (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.
(12) (a) Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43, 3400. (b) Steinhoff, B.
A.; Fix, S. R.; Stahl, S. S. J. Am. Chem. Soc. 2002, 124, 766. (c) Stahl, S.
S.; Thorman, J. L.; Nelson, R. C.; Kozee, M. A. J. Am. Chem. Soc. 2001,
123, 7188. (d) Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2001, 123,
7725. (e) Jensen, D. R.; Pugsley, J. S.; Sigman, M. S. J. Am. Chem. Soc.
2001, 123, 7475. (f) Brink, G. T.; Arends, I. W. C. E.; Sheldon, R. A.
Science 2000, 287, 1636. (g) Peterson, K. P.; Larock, R. C. J. Org. Chem.
1998, 63, 3185.
(13) Adamo, C.; Amatore, C.; Ciofini, L.; Jutand, A.; Lakmini, H. J. Am. Chem.
Soc. 2006, 128, 6829.
(14) For oxygen-promoted Pd-catalyzed homocoupling reactions, see: (a)
Yoshida, H.; Yamaryo, Y.; Ohshita, J.; Kunai, A. Tetrahedron Lett. 2003,
44, 1541. (b) Mukhopadhyay, S.; Rothenberg, G.; Lando, G.; Agbaria, K.;
Kazanci, M.; Sasson, Y. AdV. Synth. Catal. 2001, 343, 455. (c) Hossain,
K. M.; Kameyama, T.; Shibata, T.; Tagaki, K. Bull. Chem. Soc. Jpn. 2001,
74, 2415. (d) Wong, M. S.; Zhang, X. L. Tetrahedron Lett. 2001, 42, 4087.
(e) Ohe, T.; Tanaka, T.; Kuroda, M.; Cho, C. S.; Uemura, S. Bull. Chem.
Soc. Jpn. 1999, 72, 1851. (f) Smith, K. A.; Campi, E. M.; Jackson, W. R.;
Marcuccio, S.; Maeslund, C. G. M.; Deacon, G. B. Synlett 1997, 131.
(15) Without amine ligands, the reaction mixture turned black, while the solution
stayed clear in the presence of amine ligands.
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A R T I C L E S
Yoo et al.
Table 4. Effect of Palladium Catalysts on the Cross-Coupling
Reactions of Alkenyl Boronic Ester with Alkene under Base-Free
Conditions
Table 2. Effect of Bases and Temperature on the Cross-Coupling
Reactions of Alkenyl Boronic Ester with Alkenea
yield (%)
yield (%)
entry
base
temp (
°
C)
time (h)
2
3
entry
catalyst
2
3
1b
2b
3
Na2CO3
Na2CO3
23
50
23
50
3
1
6
6
85
75
17
95
10
23
1
2
3
4
Pd(OAc)2
PdCl2
Pd2(dba)3
Pd(PPh3)4
95
21
no reaction
46
4
51
a All reactions were carried out with 1 (0.5 mmol), tert-butyl acrylate
(1.5 mmol), and Pd(OAc)2 (5 mol %) in DMA (dimethylacetamide, 2.5
mL). b Na2CO3 (1.0 mmol).
Table 5. Cross-Coupling Reactions of Hexenyl Boronic Ester with
Various Alkenes under Base-Free Conditions
Table 3. Effect of Solvents on the Cross-Coupling Reactions of
Alkenyl Boronic Ester with Alkene under Base-Free Conditions
entry
solvent
yield (%)
1
2
3
4
5
DMA
CH3CN
DMF
THF
toluene
95
89
92
12
17
facilitate the catalysis. At 50 °C, the cross-coupling reaction
proceeded smoothly to give 95% yield of the desired diene
compound 2, and no homo-coupled compound 3 was detected
(entry 4). These results implied that the homo-coupled reaction
should be prohibited under the base-free conditions due to the
avoidance of the reactive borate salts as we hypothesized.
On the basis of these results, we screened the reaction
conditions by varying solvents and palladium catalysts to
determine optimal base-free conditions (Table 3). In the cases
of THF and toluene, the reactions were incomplete even after
36 h, and the yields were very low (entries 4, 5). However, in
polar solvents such as DMA, acetonitrile, and DMF, the desired
(E,E)-conjugated diene 2 was obtained in excellent yields
(entries 1-3). The homo-coupled product was not detected at
all in any of those cases.
The effect of the palladium catalyst was investigated as
demonstrated in Table 4. In the case of PdCl2, the conversions
were unsatisfactorily low (entry 2). With Pd2(dba)3, the reaction
did not proceed at all. These results were contrary to our
expectation because the cross-coupling reaction took place well
in the presence of bases independent of palladium species
described in our previous communications.
a Isolated yields. b E:Z ) 3:2. c 1,4-Diene and 1,3-diene ratio is 2.8 to
1. d EE and EZ ratio is 6 to 1.
the cases of PdCl2 and Pd2dba3, which may explain the low
yield and no reaction. Interestingly, coupling reaction with Pd-
(PPh3)4 afforded homo-coupled compound 3 as the major
product along with 46% of the desired compound 2.16 These
results indicate that palladium ligands can play a key role in
the coupling reactions under base-free conditions, which
prompted us to investigate studies on the use of various ligands
(vide infra).
Having established optimized conditions, various alkenes
were examined for the feasibility of the methodology as shown
in Table 5. Styrene reacted with hexenyl boronic ester efficiently
to generate diene compound 9 in a high yield (entry 2).
Furthermore, the unreactive allyl ether was subjected to coupling
reaction to deliver product 10 in a good yield of 87% (entry 3).
These couplings were highly stereoselective to furnish E,E-
These phenomena can be rationalized by considering the
reactivity of the oxo-palladium complex in-situ generated by
reaction of PdL2 (L ) Cl, dba) with bases (OH-, R′O-, and
RCO2-).2a The ligand (RO) on the oxo-palladium complex will
coordinate to the boron atom, which can facilitate the transfer
of the organic group on the boron atom to the palladium atom
resulting in the enhancement of transmetallation. In the absence
of bases, there would be no such oxo-palladium complex in
(16) For an example of homocoupling with Pd(OAc)2 in the presence of
phosphine ligands, see: Yoshida, H.; Yamaryo, Y.; Ohshita, J.; Kunai, A.
Tetrahedron Lett. 2003, 44, 1541.
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Oxidative Palladium(II) Catalysis
A R T I C L E S
Table 6. Cross-Coupling Reactions of tert-Butyl Acrylate with
Various Alkenyl Boron Compounds under Base-Free Conditions
than that for the corresponding acids due to the repulsion
between the alkenylpalladium complex and the sterically
hindered ketal group of alkenylboronic esters, averting the
unwanted homo-couplings. For example, the cross-coupling
reaction with hexenyl boronic acid (16) and tert-butyl acrylate
afforded 64% of diene compound 2 along with 35% of homo-
coupled product 3 even under base-free conditions (entry 1).
For these reasons, we conducted the coupling reactions with
boron ester compounds, which were easily prepared from the
corresponding boronic acids in nearly quantitative yields.
Pinacol boron esters 17 and 19 containing the alcohol
functional moieties were subjected to base-free oxidative Pd-
(II) catalysis, giving rise to the exclusive formation of (E,E)-
dienes 18 and 20 in high yields, respectively. Highly substituted
alkenylboron ester compounds were also compatible with this
protocol. Isopropenyl pinacol boron ester (21) prepared from
the corresponding bromide via Grignard reaction with the alkyl
borate18,25 reacted smoothly to offer diene compound 22 in 86%
yield and with high selectivity. Aryl-substituted boronic ester
23 gave the corresponding (E,E)-dienoate 24 efficiently. Fur-
thermore, palladium-catalyzed cross-coupling with cis-hexenyl
pinacolboronic ester 2519 yielded (E,Z)-diene 26 with full
retention of the olefin stereochemistry. Advantageously, highly
functionalized structural groups can be incorporated for further
manipulation utilizing this protocol.
a Isolated yields. b TMS group was deprotected during column chroma-
tography. c The reaction time is 8 h.
On the basis of these results, we would like to suggest a
plausible catalytic mechanism for base-free oxygen-promoted
Pd(II) catalysis as follows (Figure 1): initial transmetallation
should be feasible with an alkene boron compound even without
activating it to an “ate” complex, giving the palladium(II)
intermediate I; the second incorporation of an alkenyl group
can be carried out by migratory insertion, which would be
followed by â-hydride elimination to produce cross-coupling
product III and Pd(0) species without the aid of bases; molecular
oxygen would then oxidize the resulting Pd(0) to a peroxopal-
ladium complex V,12 which can react with another alkenylboron
compound to regenerate alkene-Pd(II)-L complex I.13 As we
confirmed in previous work,11 oxygen is crucial for the catalytic
cycle, acting as an efficient Pd(0) reoxidant. The most notable
feature of the proposed mechanism is that transmetallation takes
place in the first alkenylation process, facilitating the whole
catalysis under mild conditions. We believe that this transmet-
allation operation is facile due to lack of steric repulsion, which
isomers only. However, acrylonitrile furnished a mixture of E-
and Z-isomers as expected, mainly due to the lack of steric
presence (entry 4).17 We examined a number of cases in addition
to the reported ones here and came to a conclusion that the
E-selectivity was prominent.
The reaction with disubstituted alkenes such as tert-butyl
methacrylate and ethyl crotonate afforded the corresponding
methyl-substituted diene products 12 and 13 in 90% and 89%
yields, respectively, while exhibiting excellent E-selectivities
(entries 5 and 6). Interestingly, in the case of R-methyl styrene,
the coupling reactions provided the isomeric mixtures of diene
compounds 14 due to the different pathways of â-hydride
elimination during the reaction cycle (entry 7). The reaction
with cis-â-methyl styrene also provided an isomeric mixture
of coupling compound 15 in moderate yield (entry 8).
Regardless of the steric and electronic nature of the alkenes,
the reaction under the base-free conditions delivered the
corresponding cross-coupled products exclusively without homo-
coupled products. To our delight, yields were generally desirably
high due to excellent chemoselectivities, and stereoselective
outcomes were outstandingly in favor of the E-isomer. In
particular, E-selective preparation of trisubstituted alkenes
should be of great value because of known difficulty in their
stereoselective synthesis.
(18) (a) Molander, G. A.; Ribagorda, M. J. Am. Chem. Soc. 2003, 125, 11148.
(b) Ueda, M.; Saitoh, A.; Miyaura, N. J. Organomet. Chem. 2002, 642,
145.
(19) (a) Costa, A.; Najera, C.; Sansano, J. M. J. Org. Chem. 2002, 67, 5216.
(b) Gelpke, A. E. S.; Veerman, J. J. N.; Goedheijt, M. S.; Kamer, P. C. J.;
van Leeuwen, P. W. M. N.; Hiemstra, H. Tetrahedron 1999, 55, 6657. (c)
Genet, J. P.; Blart, E.; Savignac, M. Synlett 1992, 715.
(20) (a) Enquist, P.-A.; Lindh, J.; Nilsson, P.; Larhed, M. Green Chem. 2006,
8, 338. (b) Andappan, M. M. S.; Nilsson, P; Larhed, M. Chem. Commun.
2004, 218. (c) von Schenck, H.; Akermark, B.; Svensson, M. J. Am. Chem.
Soc. 2003, 125, 3503. (d) von Schenck, H.; Akermark, B.; Svensson, M.
Organometallics 2002, 21, 2248. (e) Olofsson, K.; Larhed, M.; Hallberg,
A. J. Org. Chem. 2000, 65, 7235. (f) Cabri, W.; Candiani, I.; Bedeschi, A.
J. Org. Chem. 1993, 58, 7421.
(21) Portnoy, M.; Ben-David, Y.; Roussa, I.; Milstein, D. Organometallics 1994,
13, 3465.
(22) Moreno-Manas, M.; Perez, M.; Pleixats, R. J. Org. Chem. 1996, 61, 2346.
(23) (a) Roques, B. P.; Florentin, D.; Callanquin, M. J. Heterocycl. Chem. 1975,
12, 195. (b) Florentin, D.; Fournie-Zaluski, M. C.; Callanquin, M.; Roques,
B. P. J. Heterocycl. Chem. 1976, 13, 1265.
To further examine the method versatility, we carried out
cross-coupling reactions of various alkenylboronic esters with
tert-butyl acrylate (Table 6). The coupling reaction with boronic
acids furnished considerable amounts of homo-coupled products
because alkenylboronic acids are known to be more reactive
than the corresponding boronic esters. However, the second
transmetallation for the alkenylboronic esters may be slower
(24) For the Heck reaction with cyclohexenone, see: (a) Krishna, T. R.;
Jayaraman, N. Tetraheron Lett. 2004, 60, 10325. (b) Gupta, A. K.; Song,
C. H.; Oh, C. H. Tetrahedron Lett. 2004, 45, 4113. (c) Gelpke, A. E. S.;
Veerman, J. J. N.; Goedheijt, M. S.; Kamer, P. C. J.; van Leeuwen, P. W.
N. M.; Hiemstra, H. Tetrahedron 1999, 55, 6657.
(17) (a) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2002, 100, 3009. (b)
Crisp, G. T.; Glink, P. T. Tetrahedron 1994, 50, 2623. (c) Kim, J.-I.; Patel,
B. A.; Heck, R. F. J. Org. Chem. 1981, 46, 1067.
(25) Laurent, D.; Morris, S. J. Org. Chem. 1994, 59, 6871.
9
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A R T I C L E S
Yoo et al.
Table 7. Effect of Ligands on the Cross-Coupling Reactions under
Base-Free Conditions
Figure 1. Proposed mechanism for the cross-coupling reactions under base-
free conditions.
is prevalent in a number of organometallic reactions. Other
known cross-coupling methods require transmetallation in the
second alkenylation step after already adsorbing the first alkenyl
group through Pd(0)-catalyzed oxidative addition. This is not
the case with our newly developed methodology.
a All reactions were carried out with 1 (0.5 mmol), tert-butyl acrylate (1
mmol), and Pd(OAc)2 (5 mol %) in DMA (dimethylacetamide, 2.5 mL).
b Isolated yields.
Table 8. Effect of Pd(II) Catalyst Amount Employed on the
Cross-Coupling Reactions in the Presence of Amine Ligands
1.2. Ligand Effect on Cross-Coupling Reaction of Alk-
enylboron Compounds and Olefins. The Heck-type reaction
is usually carried out in the presence of phosphine ligands, which
stabilize the active Pd(0) species and accelerate the reaction
rate.1c,d In our base-free reaction protocol, we found that
palladium catalyst was quite easily precipitated and the coupling
reaction was retarded. To stabilize and minimize the precipita-
tion of palladium catalysts, we decided to employ organic
ligands in our base-free conditions. The most suitable ligands
for cross-couplings we found during this study were bidentated
nitrogen ligands,20 which have been known to facilitate the
efficient redoxidation of Pd(0) by molecular oxygen and remain
stable upon exposure to air and moisture unlike their phosphine
counterparts. Many phosphine ligands are sensitive to air and
moisture, and subsequently convert to phosphine oxide species
upon exposure.
First, we examined the cross-coupling reaction of trans-1-
hexenyl pinacolboron ester (1) and tert-butyl acrylate by
screening with various bidentated aliphatic and aryl amines,
pyridine, and phosphine ligands as shown in Table 7. The
reactions with alkyl amines provided the cross-coupled com-
pound 2 in low yields (entries 1-3), whereas tetra-N-methyl-
propyldiamine resulted in an excellent yield (entry 4). However,
in the case of the phosphine analogue of tetra-N-methyl-
propyldiamine, the yield was dramatically reduced (entry 5).
In general, phosphine ligands were observed to be incompatible
with our coupling system. Aniline derivatives were similarly
inefficient for the coupling reaction (entries 6, 7). However,
reactions with 2,2′-bipyridine and 1,10-phenanthroline afforded
the desired compound in excellent yields (entries 8, 9).
In none of these cases was the precipitation of palladium
catalysts detected, which indicated stabilization of the Pd species
by the bidentate ligands. However, all ligands did not enhance
the coupling reaction. We envisioned the bidentate amine ligands
should be located at two adjacent sites among the square
chelating sites of palladium catalysts, leaving the other two sites
open for the coupling reaction. Notably, cis-configuration of
entry
Pd/ligand
T (
°
C)
t (h)
yield (%)a
1
2
3
4
5
5 mol %
2 mol %
2 mol %
1 mol %
0.5 mol %
23
23
50
50
50
12
12
2
2
2
95
32
98
81
54
a Isolated yields.
two ligand groups in the square-planar structure would be more
favorable for the migratory insertion steps during the catalytic
cycle, resulting in the enhancement of the coupling reaction.21
This idea was supported by the reaction with 4,4′-bipyridine as
a ligand (entry 10). Coupling reaction with 4,4′-bipyridine did
not proceed, and the palladium catalyst precipitated early in the
reaction presumably because 4,4′-bipyridine did not effectively
form a Pd-nitrogen complex due to its linear structure.
These results indicate the coupling reactions are sensitive to
the structure of the Pd-ligand complex: Pd-nitrogen chelating
length, coordination angle, and steric environment. On the basis
of these factors, phenanthroline was selected as the best choice
for the coupling reaction.
Subsequently, we sought optimal conditions by screening
various temperatures and Pd/ligand amounts. The results are
summarized in Table 8. At room temperature, reduction of
catalyst loading provided diminished yields (entry 2). However,
at a higher temperature, the reaction proceeded well in shorter
reaction time to afford the coupling compound in an excellent
yield. Further reduction of catalyst loading at 50 °C provided
slightly diminished yields. In conclusion, phenanthroline is the
ligand of choice under the optimal coupling reaction conditions.
These conditions are general and efficient to afford (E,E)-diene
as the exclusive product in high yields, when the undesirable
homo-coupled product is not observed. In particular, there is
9
16388 J. AM. CHEM. SOC. VOL. 128, NO. 50, 2006

Oxidative Palladium(II) Catalysis
A R T I C L E S
Table 9. Cross-Coupling Reactions of Hexenyl Boronic Ester with
Various Alkenes in the Presence of Ligand
Table 10. Effect of Bases and Temperature on the
Cross-Coupling Reactions of Aryl Boronic Acid with Alkene under
Base-Free Conditionsa
yield (%)b
entry
base
temp (
°
C)
t (h)
28
29
30
1c
2c
3c
4
Na2CO3
Na2CO3
23
50
23
50
8
1
78
81
28
35
2
7
15
5
10
11
>24d
>24d
a All reactions were carried out with phenylboronic acid (1 mmol), tert-
butyl acrylate (1.5 mmol), and Pd(OAc)2 (5 mol %) in DMF (2.5 mL).
b Isolated yield. c Na2CO3 (2 mmol). d The reaction was incomplete after
24 h.
Table 11. Effect of Substituent on the Arylboron Compounds on
the Cross-Coupling Reactions under Base-Free Conditions
1
a Isolated yields. b The ratio of 1,4- and 1,3-diene was 6:1 by H NMR
1
analysis. c The ratio of E to Z isomer was 9:1 by H NMR analysis.
no need for base, and a minimal loading of catalyst is sufficient
for high turnover up to 108.
By utilizing the optimized reaction conditions, we examined
the cross-coupling reaction of alkenylboronic ester 1 with
various olefins as shown in Table 9. All of the examined
monosubstituted alkenes reacted smoothly, furnishing exclu-
sively the corresponding conjugated dienes in excellent yields
(entries 1-3). Regardless of substituents, cross-couplings were
successful, and this protocol was generally applicable to a
number of alkene systems.
Because of difficulty and low stereoselectivity, highly
substituted olefins are poor substrates for Heck reaction as
pointed out earlier. Therefore, a coupling reaction compatible
with di- and trisubstituted olefins can be highly valuable,
prompting us to probe the feasibility of Pd-nitrogen ligand
catalysis. The reaction with R-methyl styrene (entry 4) furnished
an inseparable mixture of 1,4- and 1,3-diene compound 14 in
87% yield via two possible â-elimination pathways during the
reaction cycle. With cis-â-methyl styrene (entry 5), the 9:1
mixture of (E,E)- and (E,Z)-dienes was obtained in 91% overall
yield. As compared to the previous results in the base-free and
ligandless conditions (Table 5), the yields were dramatically
increased and the reactions went to completion faster. We
believe these reactivities and selectivities illustrate the efficiency
and feasibility of our carbon-carbon bond forming protocol
with palladium(II)-nitrogenous ligand complexes under oxida-
tive and base-free conditions.
2. Cross-Coupling Reaction of Aryl Compounds and
Olefins. 2.1. Base Effect on the Cross-Coupling Reaction of
Aryl Compounds and Olefins. The base-free oxidative ca-
talysis was next examined for the cross-coupling of arylboron
compounds and alkenes. In our previous communication, we
reported the development of an oxygen-promoted Pd(II)-
catalyzed coupling of arylboronic acids and alkenes in the
presence of bases. As with the alkenylboron compounds, the
homo-coupled side product was also generated under the
reaction conditions. In addition, phenol was unfortunately
formed by oxidation of the corresponding arylboron compounds
a Isolated yield.
by boron peroxide, which was generated during the catalytic
cycle.22 To prevent homo-couplings, we attempted the coupling
reaction of phenylboronic acid and tert-butyl acrylate in the
absence of bases, adopting the same methodology.
In the presence of Na2CO3 as a base, the reactions proceeded
smoothly to afford the coupling product 28 in good yields along
with homo-coupled compound 29 and phenol 30 at room
temperature (entry 1, Table 10). At an elevated temperature,
the reaction furnished the same products in similar yields, albeit
in shorter reaction time (entry 2). Under base-free conditions,
however, the coupling reaction did not proceed well despite
longer reaction time and higher temperature. Interestingly, the
homo-coupled products were not detected (entries 3 and 4).
We also examined coupling reactions with p-methoxy and
m-acetyl phenyl boronic acids. The yields for these coupling
reactions were 37% and 41%, respectively, indicating the
electronic variation in arylboron compounds does not affect the
coupling reaction under the base-free conditions (Table 11).
Based on these results, the bases seem to be a critical element
in the coupling reaction between arylboronic compounds and
alkenes contrary to the case of alkenylboron compounds. In
consideration of reaction time and temperature under the same
conditions, the rate of transmetallation for the aryl boron
compounds was slower than that for alkenyl boron compounds.
These results imply that transmetallation for aryl boron com-
9
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A R T I C L E S
Yoo et al.
Table 12. Effect of Ligands on the Cross-Coupling Reactions of
Table 13. Effect of Solvents on the Cross-Coupling Reactions of
Aryl Boronic Acid with Alkene under Base-Free Conditionsa
Aryl Boronic Acid with Alkene in the Presence of Liganda
yield (%)b
entry
solvent
28
29
30
1
2
3
4
5
DMF
DMA
NMP
MeCN
THF
84
77
77
63
35
13
22
23
37
42
23
a All reactions were carried out with phenylboronic acid (1 mmol), tert-
butyl acrylate (1.5 mmol), 1,10-dimethylphenanthroline (5 mol%), and
Pd(OAc)2 (5 mol %) in solvent (2.5 mL). b Isolated yield.
Table 14. Cross-Coupling Reactions of Phenyl Boronic Acid with
Various Alkenes in the Presence of Ligand
a All reactions were carried out with phenylboronic acid (1 mmol), tert-
butyl acrylate (1.5 mmol), and Pd(OAc)2 (5 mol %) in DMF (2.5 mL).
b Isolated yield.
pounds does not occur effectively and requires other elements
under base-free condtions.
2.2. Ligand Effect on Cross-Coupling Reaction of Aryl-
boron Compounds and Olefins. Shifting our attention to ligand
effect on the cross-coupling reaction of arylboron compounds
and olefins, we conducted the coupling reaction with phenyl
boronic acid and tert-butyl acrylate using various ligands in the
absence of bases at room temperature (Table 12).
Reaction with N,N,N′,N′-tetramethylpropylamine afforded
only 13% of the desired product, 17% of phenol, and 44% of
homo-coupled compound as the major product, which was
contrary to the previous results for the coupling with alkenyl-
boron compounds (entry 1). Using diphenylphosphonopropane
as a ligand, homo-coupling was also predominant (entry 2). With
1,10-phenanthroline, the coupling reaction proceeded smoothly
to give 28 in a good yield without homo-coupled compound
29, resembling the case of alkylboron compounds (entry 3).
Base-free conditions with 2,9-dimethyl-1,10-phenanthroline
afforded better yields than 1,10-phenanthroline as representa-
tively illustrated in entry 4, thus offering a general method of
aryl-alkenyl couplings devoid of homo-coupling side pathways.
In practice, phenolic side products are easily removed by
washing away during the aqueous workup.
a Isolated yields. b The yield was calculated on the basis of phenylboronic
acid. c The yield was calculated on the basis of olefin. d The ratio of Heck
and migrated products was 1:1.4 by H NMR analysis.
1
Using 2,9-dimethyl-1,10-phenanthroline as a palladium ligand,
we screened various solvents in the absence of bases. Reactions
performed in DMF, DMA, and NMP gave similarly satisfactory
results (Table 13). However, the reaction in CH3CN and THF
afforded the desired coupling compound in low yields. There-
fore, using 2,9-dimethyl-1,10-phenanthroline as a ligand and
DMF as a solvent proved to be the best choice for the coupling
reaction with arylboronic compounds.
propenamide 34 in 71% and 64% yields, respectively (entries
2, 3). Furthermore, styrene and acrylonitrile reacted with
phenylboronic acid to give 85% and 84% yields of (E)-stilbene
35 and (E)-3-phenyl-2-propenenitrile 36, respectively (entries
4, 5). The coupling with unreactive allyl benzyl ether proceeded
successfully, affording benzyl (E)-cinnamyl ether 37 in 78%
yield (entry 6).
With the optimized conditions in hand, we carried out the
coupling reaction of various alkenes with phenylboronic acid.
As shown in Table 14, tert-butyl acrylate was converted
efficiently to (E)-tert-butyl cinnamate 28 in 87% yield (entry
1). The reaction with methyl vinyl ketone and acryl amine
afforded (E)-4-phenyl-3-butene-2-one 33 and (E)-3-phenyl-2-
In the case of highly substituted alkenes, coupling reaction
of tert-butyl methyl methacrylate with phenylbronic acid
afforded a mixture of migrated product 38 along with R-methyl
cinnamte. Ethyl crotonate delivered ethyl â-methyl cinnamate
39 with exclusive (E)-configuration in 82% yield. Because
phenol was not factored in, the conversion yields based on
9
16390 J. AM. CHEM. SOC. VOL. 128, NO. 50, 2006

Oxidative Palladium(II) Catalysis
A R T I C L E S
Table 15. Cross-Coupling Reactions of tert-Butyl Acrylate with
Various Aryl Boron Compounds in the Presence of Ligand
Table 16. Effect of Bases and Ligands on the Cross-Coupling
Reaction of Cyclohexenone with Vinyl Boronic Compounds
entry
base
ligand
temp (
°
C)
time (h)
yield (%)
1
Na2CO3
23
50
50
6
6
2
76
37
82
2
3a
phenb
a Isolated yields. b TMS group was deprotected during column chroma-
tography. c The reaction time is 8 h.
Scheme 4
coupling compound 45 in 63% yield (entry 8). Reactions with
1-(phenylsulfonyl)-indol-2-boronic acid gave the cross-coupling
compound 46 in only moderate yields due to protodeboronation
(entry 9). It is well known that heteroarylboronic acids bearing
the boron atom ortho to the heteroatom are prone to protode-
boronation.23 Nontheless, this synthetic method appears to be
applicable to the synthesis of heterocyclic templates used in
medicinal chemistry. Overall, this oxidative palladium(II)
catalysis offers an efficient method for aryl-alkenyl C-C bond
formation under mild conditions.
3. Oxidative Pd(II) Catalysis for Unusual Cycloalkenyl
Substrates. During the catalytic cycle, â-elimination has been
known to occur through concerted syn-elimination of Pd-H
without aid of bases, which explained the high E-stereoselec-
tivity of the Heck-type reaction. Nonetheless, the Pd-H was
scavenged quickly by bases after the syn-elimination step, and
bases seem to play a key role in the â-elimination step. Contrary
to acyclic substrates, the base is found to be an important factor
for the coupling reaction with cyclic substrates in our protocol
as described below.
Although cyclohexenone has been known to be a difficult
substrate for direct Heck-type conversion, we obtained the
desired cross-coupling product 47 in a high yield along with
the homo-coupled product in the presence of bases (Table 16,
entry 1).24 However, the same base-free reaction conditions for
acyclic alkenes yielded diene compound 47 in a poor yield,
implying that â-elimination was inefficient in the absence of a
base (entry 2). However, when 1,10-phenanthroline was used
as a palladium ligand, the catalysis was rapid, and the yield
was increased to 82% without the homo-coupled product.
Likewise, the cross-coupling reaction of cyclohexeneone with
phenylboronic acid afforded the desired product 48 in a good
yield (Scheme 4).
a Isolated yields.
alkenes were generally higher up to 96% (yield B) than those
based on arylboron compounds (yield A), exhibiting excellent
efficiency and selectivity.
To further investigate the scope and limitation of this
methodology, we carried out cross-couplings of various aryl-
boronic acids and tert-butyl acrylate as summarized in Table
15. Reactions of 4-methoxy phenyl boronic acid and N,N-
dimethyl phenyl boronic acid, substituted with electron-donating
groups, took place smoothly to provide the desired compounds,
tert-butyl-(E)-4-methoxycinnamate 31 and tert-butyl-(E)-3-(4-
dimethylamino) phenyl) acrylate 40 and in 61% and 94% yields,
respectively (entries 1, 2). Also, the reactions with meta- and
para-acetyl phenyl boronic acids, substituted with an electron-
withdrawing group, afforded 32 and 41 in 72% and 71% yields,
respectively (entries 3, 4). 4-Nitro phenyl boronic acid and
4-cyano phenyl boronic acid possessing highly electron-
withdrawing groups reacted with tert-butyl acrylate to give
arylated products 42 and 43 in 57% and 69% yields, respectively
(entries 5, 6). The coupled reaction of sterically hindered
2-methyl phenyl boronic acid with tert-butyl acrylate afforded
84% yield of the desired product 44 (entry 7).
As shown in Scheme 5, we assumed two pathways for the
coupling reaction with cyclohexenone: (i) base-catalyzed
â-elimination via an E2-like mechanism (pathway A); and (ii)
palladotropic shift followed by normal syn-elimination (pathway
B).1c We thought that â-elimination in the presence of bases
would take place in an anti-fashion from VIII in pathway A,
because the syn-elimination in pathway B would not be affected
to a great extent by the presence of bases. In addition, Michael
addition product 49 was not observed at all, suggesting that
In addition, we examined the reaction of heterocyclic boronic
acids. The coupling reaction involving 1-(phenylsulfonyl)-indol-
3-boronic acid proceeded to afford the corresponding cross-
9
J. AM. CHEM. SOC. VOL. 128, NO. 50, 2006 16391

A R T I C L E S
Scheme 5
Yoo et al.
Scheme 6
Table 17. Bases and Temperature Effect on the Suzuki-Miyaura
Reaction in the Presence of Ligand
pathway B can be ruled out. Therefore, in the absence of bases,
pathway A was very slow, resulting in low yields of the coupled
product. These findings suggested a base-assisted â-elimination
process should be considered in the mechanism for the Heck-
type reaction with cyclic systems. Based on this assumption,
phenanthroline would work as not only a palladium ligand but
also a base participating in the â-elimination step.
4. Competition Experiments. To understand kinetic and
mechanistic differences, we studied intermolecular competition
reaction using p-methoxyiodobenzene, N,N-dimethylaminophe-
nyl boronic acid, and tert-butyl acrylate. As shown in Scheme
6, coupling reaction with an equimolar amount of each
compound under the oxidative conditions afforded only boron
Heck-type compound 40 without any other coupling compounds
such as Heck and Suzuki coupling products.
entry
base
temp
yield
1
2
3
room temp
room temp
50 °C
no reaction
<10%
95%
Na2CO3
Na2CO3
Scheme 7
This result implied that Heck reaction was suppressed under
these coupling conditions due to lack of bases, relatively low
temperature, or oxygen atmosphere. To confirm these assump-
tions, we conducted Heck coupling reaction of p-methoxyiodo-
benzene with tert-butyl acrylate under the same conditions
except nitrogen atomosphere (Table 17).
Conclusion
We have demonstrated the first example of oxygen-promoted
palladium-catalyzed cross-coupling of alkenyl and aryl boron
compounds with various alkenes in the absence of bases, which
afford the corresponding conjugated diene compounds without
homo-coupled products. While Heck- and Suzuki-type reactions
require bases to facilitate coupling reactions, bases are not a
requisite element for the oxidative palladium(II) catalysis, but
useful in transmetallation and â-hydride elimination steps
resulting in the enhancement of reaction rates. Additionally,
base-free and bidentated nitrogen ligands stabilized palladium-
(II) species successfully catalyzed cross-coupling reactions to
prevent precipiation of Pd(0) species and enhanced reactivity
of palladium catalysts, resulting in the enhancement of yields
Independent of bases, Heck coupling reaction was not
efficient at room temperature (entries 1 and 2). Only at high
temperature, the coupling reaction proceeded well to afford the
coupling compound 31 with good yield in the presence of bases
(entry 3). These results showed that oxidative boron Heck was
more feasible than Heck reaction.
With these results, we undertook intramolecular competition
experiment with 4-iodophenylboronic acid and tert-butyl acrylate
(Scheme 7). As expected, boron Heck reaction product 51 was
exclusively produced, and no other coupling products were
obtained. This established high chemoselectivity would open
the door to wide application.
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Oxidative Palladium(II) Catalysis
A R T I C L E S
(2.5 mL) for 30 min were 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 temperature for 12 h, then
diluted with ethyl acetate (20 mL), and washed with saturated aqueous
NaHCO3, water, and brine (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 to give a cross-coupled product.
Procedures for the Coupling of Cyclohexenone. (1E)-3-Hex-1-
enyl-cyclohex-2-enone (47). Following the general procedure A, cross-
coupling reaction of boronic ester 1 with cyclohexenone afforded diene
47 (37%). Following the general procedure B, cross-coupling reaction
of boronic ester 1 with cyclohexenone afforded diene 47 for 2 h (82%).
1H NMR (250 MHz, CDCl3): δ ) 6.19 (m, 2H), 5.85 (s, 1H), 2.41
(m, 4H), 2.16 (m, 2H), 2.00 (m, 2H), 1.35 (m, 4H), 0.89 (t, J ) 7.0
Hz, 3H). 13C NMR (63 MHz, CDCl3): δ ) 200.5, 157.7, 139.2, 131.3,
126.4, 37.7, 32.9, 31.0, 25.0, 22.3, 22.2, 13.9. Anal. Calcd for
C12H18O: C, 80.85; H, 10.18. Found: C, 80.82; H, 10.19.
(1E)-3-Phenyl-cyclohex-2-enone (48). Following the general pro-
cedure C, cross-coupling reaction of phenylboronic acid with cyclo-
hexenone afforded 48 (81%). 1H NMR (300 MHz, CDCl3): δ ) 7.52
(m, 2H), 7.39 (m, 3H), 6.40 (s, 1H), 2.76 (t, J ) 5.6 Hz, 2H), 2.47 (t,
J ) 6.8 Hz, 2H), 2.14 (q, J ) 6.8 Hz, 2H). 13C NMR (75.5 MHz,
CDCl3): δ ) 199.9, 159.8, 138.6, 130.0, 128.7, 126.0, 125.3, 115.4,
37.1, 28.0, 22.7. Anal. Calcd for C12H12O: C, 83.69; H, 7.02. Found:
C, 83.69; H, 7.05.
under milder reaction conditions. Therefore, our new synthetic
protocol is advantageous over the conventional and modified
Heck conditions and allows a wide array of substrates otherwise
difficult or impossible to utilize. Because of its easy and
convenient nature, this methodology for carbon-carbon bond
formation is highly practical, holding great promise for wide
use in organic and medicinal chemistry fields. Studies on
asymmetric catalysis are currently in progress by using chiral
amine ligands, and their successful results will be reported in
due course.
Experimental Section
General Procedure A for the Coupling Reaction with Alkenyl
Pinacolboronic Ester and Olefin in the Absence of Base (Base-Free
Conditions). To a solution of olefin (1.5 mmol) in N,N-dimethylac-
etamide (2.5 mL, C ) 0.2 M) were added pinacolboronic ester (0.5
mmol) followed by a single addition of Pd(OAc)2 (0.025 mmol). The
reaction flask was fitted with an oxygen balloon. The resulting reaction
was stirred for 6 h at 50 °C, diluted with ethyl acetate (20 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 subjected to flash chromatography, affording a cross-coupling
compound.
General Procedure B for the Coupling Reaction with Alkenyl
Pinacolboronic Ester and Olefin in the Presence of 1,10-Phenan-
throline as a Ligand. To a premixed solution of palladium acetate
(0.025 mol) and 1,10-phenanthroline as a ligand (0.028 mmol) in DMF
(2.5 mL) for 30 min were added olefin (1.5 mmol) and pinacolboronic
ester (0.5 mmol). The reaction flask was fitted with an oxygen balloon,
and the reaction mixture was stirred at room temperature for 12 h, then
diluted with ethyl acetate (20 mL), and washed with water and brine
(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 to give a cross-coupled
product.
Acknowledgment. We acknowledge generous financial sup-
port from the National Institute of General Medical Sciences
of the National Institutes of Health (RO1 GM 71495). We thank
Professor Chulbom Lee for helpful discussions. This paper is
dedicated to Professor William Weber for his retirement from
37 years of service at USC.
Supporting Information Available: Full experimental pro-
cedures and spectral data (1H and 13C NMR) for all products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
General Procedure C for the Coupling Reaction with Arylbo-
ronic Acid and Olefin in the Presence of 2,9-Dimethyl-phenanthro-
line as a Ligand. To a premixed solution of palladium acetate (0.025
mol) and 2,9-dimethyl-phenanthroline as a ligand (0.028 mmol) in DMF
JA063710Z
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J. AM. CHEM. SOC. VOL. 128, NO. 50, 2006 16393