Pd(II)-bipyridine catalyzed conjugate addition of arylboronic acid to α,β-unsaturated carbonyl compounds

Article abstract of DOI:10.1021/jo051561h

A Pd(II)-catalyzed conjugate addition of arylboronic acid to α,β-unsaturated ketones, aldehydes, esters, etc. in the presence of 2,2′-bipyridine was developed. A mechanism involving transmetalation, insertion of the carbon-carbon double bond into the C-Pd bond, and protonolysis of the resulting C-Pd bond is proposed. The reaction conditions are mild and the yield is high. The presence of 2,2′-bipyridine is crucial for the reaction to inhibit β-hydride elimination.

Full text of DOI:10.1021/jo051561h

SCHEME 1
Pd(II)-Bipyridine Catalyzed Conjugate
Addition of Arylboronic Acid to
r,â-Unsaturated Carbonyl Compounds
Xiyan Lu* and Shaohui Lin
into a C-Rh bond.2h,3,4 â-Hydride elimination will easily
occur in the former case, resulting in the formation of
the Heck-type coupling products. Recently, Miyaura
reported that the cationic Pd(II) complexes can catalyze
the conjugate addition of arylboronic acids with enones,
affording the addition products in excellent yields,2h,i and
the detailed mechanism was also reported.5
State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences, 354 Fenglin Lu, Shanghai 200032, China
xylu@mail.sioc.ac.cn
Received July 26, 2005
From the reported Pd(II)-catalyzed conjugate addition
of arylboronic acid to enones, it was known that the easily
occurring â-hydride elimination represents the main
drawback of the reaction.2g,5 Thus, a method of suppress-
ing â-hydride elimination is important in developing
Pd(II)-catalyzed conjugate additions. In our ongoing
studies in the Pd(II)-catalyzed nucleophile-alkene-R,â-
unsaturated carbonyl coupling through nucleopalladation
and conjugate addition, we found that the presence of
halide ions (Cl-, Br-, and I-)6 and bidentate nitrogen
ligands (e.g., 2,2′-bipyridine and phenanthroline)7 are
crucial for inhibiting the â-hydride elimination. In all of
these reactions, the carbon-palladium bonds are formed
from the nucleopalladation (nucleophiles ) halides,
nitrogen, and oxygen) of the alkenes or alkynes, and it
occurred to us whether the conjugate addition reaction
could take place with the carbon-palladium bond formed
from the transmetalation of arylboronic acid and Pd(II)
species. Herein, we wish to report the Pd(II)-catalyzed
conjugate addition of arylboronic acid to R,â-unsaturated
ketones, aldehydes, esters, etc. in the presence of 2,2′-
bipyridine.
First, we examined the reaction of phenylboronic acid
1 (1.0 mmol) and methylvinyl ketone 2 (2.0 mmol) in the
presence of Pd(OAc)2 (5 mol %) and 2,2′-bipyridine (bpy,
10 mol %) in acetic acid (1 mL) at 20 °C (Scheme 1). The
reaction proceeded smoothly, yielding conjugate addition
product 3 in 47% yield (based on PhB(OH)2), together
with a trace amount of Heck-type coupling product,
4-phenylbut-3-en-2-one (4). In the absence of bpy, 5%
yield of 4 was isolated. When the reaction was performed
in the absence of Pd(OAc)2, no reaction occurred. The
introduction of LiBr blocked the reaction.
A Pd(II)-catalyzed conjugate addition of arylboronic acid to
R,â-unsaturated ketones, aldehydes, esters, etc. in the
presence of 2,2′-bipyridine was developed. A mechanism
involving transmetalation, insertion of the carbon-carbon
double bond into the C-Pd bond, and protonolysis of the
resulting C-Pd bond is proposed. The reaction conditions
are mild and the yield is high. The presence of 2,2′-bipyridine
is crucial for the reaction to inhibit â-hydride elimination.
The conjugate addition of organometallic reagents to
R,â-unsaturated carbonyl compounds is a powerful tool
for the construction of C-C bonds.1 While the Rh(I)-
catalyzed conjugate addition of organo-boron, silicon, and
tin reagents to R,â-unsaturated carbonyl compounds has
been well developed,1d the reports on Pd-catalyzed con-
jugate addition are rare. Different kinds of oganometallic
reagents2 have been surveyed in Pd-catalyzed conjugate
addition. Most of them were troubled by the formation
of the Heck-type coupling products. The reason might be
that a palladium catalyst yields C-bound enolates in the
insertion of enones into a C-Pd bond in contrast to the
formation of O-bound enolates in the insertion of enones
(1) (a) Rossiter, B. E.; Swingle, N. Chem. Rev. 1992, 92, 771. (b)
Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033. (c) Krause, N.;
Hoffmann-Ro¨der, A. Synthesis 2001, 171. (d) Hayashi, T.; Yamasaki,
K. Chem. Rev. 2003, 103, 2829.
(2) For conjugate additions using Hg reagents, see: (a) Cacchi, S.;
La Tore, F.; Misiti, D. Tetrahedron Lett. 1979, 20, 4591. (b) Cacchi, S.;
Misiti, D. Tetrahedron 1981, 37, 2941. (c) Cacchi, S.; Misiti, D. J. Org.
Chem. 1982, 47, 2995. For conjugate additions using Sb reagents, see:
(d) Cho, C. S.; Tanabe, K.; Uemura, S. Tetrahedron Lett. 1994, 35, 1275.
(e) Matoba, K.; Motofusa, S.; Cho, C. S.; Uemura, S. J. Orgnomet.
Chem. 1999, 574, 3. (f) Cho, C. S.; Motofusa, S.; Ohe, K.; Uemura, S.
Bull. Chem. Soc. Jpn. 1996, 69, 2341. For conjugate additions using B
reagent, see: (g) Cho, C. S.; Motofusa, S.; Ohe, K.; Uemura, S. J. Org.
Chem. 1995, 60, 883. (h) Nishikata, T.; Yamamoto, Y.; Miyaura, N.
Angew. Chem., Int. Ed. 2003, 42, 2768. (i) Nishikata, T.; Yamamoto,
Y.; Miyaura, N. Chem. Lett. 2005, 34, 720. For conjugate additions
using Sn reagents, see: (j) Ohe, T.; Wakita, T.; Motofusa, S.; Uemura,
S. Bull. Chem. Soc. Jpn. 2000, 73, 2149. For conjugate additions using
Bi reagents, see: (k) Cho, C. S.; Yoshimori, Y.; Uemura, S. Bull. Chem.
Soc. Jpn. 1995, 68, 950. (l) Nishikata, T.; Yamamoto, Y.; Miyaura, N.
Chem. Commun. 2004, 1822. For conjugate additions using Si reagents,
see: (m) Nishikata, T.; Yamamoto, Y.; Miyaura, N. Chem. Lett. 2003,
32, 752. (n) Denmark, S. E.; Amishiro, N. J. Org. Chem. 2003, 68, 6997.
(3) Sough, G. A.; Bergmann, R. G.; Heathcock, C. H. J. Am. Chem.
Soc. 1989, 111, 938.
(4) Jeffery, T. In Advances in Metal-Organic Chemistry; Liebeskind,
L. S., Ed.; JAI: Greenwich, 1996; Vol. 5, p 153.
(5) Nishikata, T.; Yamamoto, Y.; Miyaura, N. Organometallics 2004,
23, 4317.
(6) For the reactions of inhibiting â-hydride elimination in the
presence of excess halide ions, see: (a) Wang, Z.; Lu, X. Chem.
Commun. 1996, 535. (b) Wang, Z.; Lu, X.; J. Org. Chem. 1996, 61,
2254; Wang, Z.; Lu, X. Tetrahedron Lett. 1997, 38, 5213. (d) Wang, Z.;
Lu, X.; Lei, A.; Zhang, Z. J. Org. Chem. 1998, 63, 3806. (e) Wang, Z.;
Zhang, Z.; Lu, X. Organometallics 2000, 19, 775. (f) Xie, X.; Lu, X.
Synlett 2000, 707. (g) Lei, A.; Lu, X. Org. Lett. 2000, 2, 2699. (h) Liu,
G.; Lu, X. Org. Lett. 2001, 3, 3879. (i) Liu, G.; Lu, X. Tetrahedron Lett.
2003, 44, 127.
(7) For the reactions of inhibiting â-hydride elimination in the
presence of bidentate nitrogen ligands, see: (a) Zhao, L.; Lu, X. Org.
Lett. 2002, 4, 3903. (b) Zhao, L.; Lu, X. Angew. Chem., Int. Ed. 2002,
41, 4343. (c) Zhao, L.; Lu, X.; Xu, W. J. Org. Chem. 2005, 70, 4059.
10.1021/jo051561h CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/12/2005
J. Org. Chem. 2005, 70, 9651-9653
9651

TABLE 1. Pd(II)-Bipyridine Catalyzed Conjugate
Addition of Phenylboronic Acid to 2-Cyclohexenonea
TABLE 2. Pd(II)-Bipyridine Catalyzed Conjugate
Addition of Arylboronic Acid to r,â-Unsaturated
Carbonyl Compoundsa
entry 1/5 molar ratio bpy (mol %)
additive
6 yield (%)b
entry
Ar
alkene
product yieldb (%)
1c
2
3
4
5
6
7
1.5
1.5
3.0
3.0
3.0
3.0
3.0
10
10
10
20
20
20
0
none
0
58
73
78
96
94
6f
none
1
2
3
4
5
6
7
8
9
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
CH2dCHCOCH3
3
6
75
94
90
93
84
96
64
42
53c
11
21
99
99
81
94
90
94
89
98
95
92
none
2-cyclohexenone
none
2-cyclopentenone
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
KF‚2H2Od
H2Oe
(E)-PhCHdCHCHO
(E)-CH3CHdCHCHO
(E)-PhCHdCHCO2Et
(E)-CH3CHdCHCO2Et
CH2dCHCONH2
H2Oe
a Reaction conditions: 2-cyclohexenone (1.0 mmol), Pd(OAc)2
(0.05 mmol) and bpy (0.20 mmol) in solvent (HOAc/THF ) 1.0 mL/
0.5 mL) at 40 °C. b Isolated yield. c Reaction temperature was 20
°C. d 3.0 mmol of KF‚2H2O. e 17.0 mmol of H2O. f 10 mol % of
Pd(OAc)2 was loaded; 12% of biphenyl and 5% of 7 were formed
with the precipitation of Pd black.
(E)-PhCHdCHNO2
10 p-MeOC6H4 2-cyclohexenone
11 p-MeOC6H4 (E)-PhCHdCHCO2Et
12 m-MeOC6H4 2-cyclohexenone
13 m-MeOC6H4 (E)-PhCHdCHCO2Et
14 p-MeC6H4
15 p-MeC6H4
16 p-ClC6H4
17 p-ClC6H4
18 p-FC6H4
19 p-FC6H4
2-cyclohexenone
(E)-PhCHdCHCO2Et
2-cyclohexenone
(E)-PhCHdCHCO2Et
2-cyclohexenone
(E)-PhCHdCHCO2Et
SCHEME 2
20 2-naphthyl 2-cyclohexenone
21 2-naphthyl (E)-PhCHdCHCO2Et
a Reaction conditions: arylboronic acid (3.0 mmol), alkene (1.0
mmol), Pd(OAc)2 (0.05 mmol), and bpy (0.20 mmol) in solvent
(HOAc/THF/H2O ) 1.0 mL/0.5 mL/0.3 mL) at 40 °C. b Isolated
yield. c Solvent is THF/H2O ) 1.0 mL/0.3 mL.
Then, 2-cyclohexenone (5) was used as the substrate
to optimize the reaction conditions. The reaction can
proceed at 40 °C, but no reaction occurred at 20 °C (Table
1, entries 1 and 2). Higher temperature led to the fast
protonolysis of PhB(OH)2. Through the survey of PhB-
(OH)2/enone/Pd(OAc)2/bpy ratio and additives, we found
that using 3 equiv of PhB(OH)2 is the key for the com-
plete conversion of the enone (Table 1, entry 3). In the
absence of bpy, the addition product 6 (6%), together
with biphenyl (12%) and 5% of the â-hydride elimina-
tion product, 3-phenylcyclohex-2-enone (7), was formed
(Table 1, entry 7). The addition of 20 mol % of bpy can
prevent the formation of biphenyl, the Heck-type coupling
product, and the precipitation of palladium black. Con-
jugate addition product 6 was obtained without the
detection of the â-hydride elimination product 7. The
addition of 3 equiv of KF‚2H2O improved the yield to
96% (Table 1, entry 5), and the parallel experiments
showed that the addition of 17 equiv of water did the
same job (Table 1, entry 6). To simplify the condition,
PhB(OH)2 (3 mmol), enone (1 mmol), Pd(OAc)2 (5 mol %),
and bpy (20 mol %) in HOAc (1 mL), THF (0.5 mL), and
H2O (0.3 mL) at 40 °C were chosen as the optimized
conditions.
Other ligands such as pyridine, 1,10-phenanthroline,
(R)-pymox-Ph (8), phenyl-substituted bisoxazoline (2,2′-
isopropylidene-bis(4R)-phenyl-2-oxazolilne, 9), and N-
salicylideneaniline (10) (Scheme 2) were tried, but all
afforded the product in poor yields.
Using the optimized conditions, results of the conjugate
addition of phenylboronic acid to different R,â-unsatur-
ated carbonyl compounds are summarized in Table 2.
Enals are also good Michael acceptors. For cinnamalde-
hyde, 93% yield of the conjugate addition product was
isolated as the only product (Table 2, entry 4). To our
delight, 96% yield of 3,3-diphenylpropanoate (14) was
isolated as the only product under optimized conditions
from ethyl cinnamate (Table 2, entry 6). In the previous
reports on Pd-catalyzed conjugate addition reactions,
Heck-type reactions occurred almost exclusively for R,â-
unsaturated esters,2d,5 but in our optimized reaction
conditions, high-yielding conjugate addition occurred
without the formation of Heck-type products. In the
absence of Pd(OAc)2 or bpy, no conjugate addition product
was detected for R,â-unsaturated esters. Acrylamide also
reacted with PhB(OH)2 but with lower yield (Table 2,
entry 8). When 2-nitrostyrene was performed under the
optimized conditions, a little addition product was ob-
served after a week, but under neutral condition, 53%
yield of addition product was isolated (Table 2, entry 9).
The influence on the reaction of the substituents on
arylboronic acids was also studied. For p-tolyl-, p-chlo-
rophenyl-, p-fluorophenyl-, and 2-naphthylboronic acids,
excellent yields were observed with no influence of the
electronic properties of the substituent group (Table 2,
entries14-21). When 4-methoxyphenylboronic acid was
used, the yield decreased sharply (Table 2, entries 10 and
11). Gas chromatography studies revealed that most of
the 4-methoxyphenylborbonic acid was hydrolyzed to
anisole under the standard reaction condition. As a
comparison, 3-methoxyphenylboronic acid worked quite
well, affording the normal product in nearly quantitative
yield (Table 2, entries 12 and 13). This result implies that
strong electron-donating substituents in the para-position
diminish the efficiency of aryl transfer. The transmeta-
lation of p-methoxyphenylboronic acid occurred in de-
creased yield, whereas m-methoxyphenylboronic acid still
reacted in high yield.
9652 J. Org. Chem., Vol. 70, No. 23, 2005

SCHEME 3
formation of â-hydride elimination products. The use of
2,2′-bipyridine as the ligand here is crucial for the high
selectivity of the reaction. The development of asym-
metric version of the reaction is on the way in our
laboratory.
Experimental Section
Typical Procedure for Conjugate Addition of Phenyl-
boronic Acid to 2-Cyclohexenone. To a Schlenk tube were
added phenylboronic acid (366 mg, 3.0 mmol), 2-cyclohexenone
(96 mg, 1.0 mmol), Pd(OAc)2 (11.2 mg, 0.050 mmol), bpy (31.2
mg, 0.20 mmol), HOAc (1 mL), THF (0.5 mL), and H2O (0.3 mL)
under argon. The mixture was stirred and heated at 40 °C for 3
days until the substrate disappeared as monitored by TLC. The
reaction mixture was neutralized with saturated NaHCO3 and
then extracted with Et2O. The combined ether solution was
washed with saturated NaCl, dried (MgSO4), and concentrated.
The residue was purified by flash chromatography (EtOAc/
petroleum ether 1:20) to give the product 6 with 94% yield as a
colorless oil.2m 1H NMR (300 MHz, CDCl3): δ 7.39-7.19 (m, 5H),
3.07-2.94 (m, 1H), 2.30-2.64 (m, 4H), 2.02-2.22 (m, 2H), 1.93-
The possible mechanism for this divalent palladium-
catalyzed reaction was proposed as shown in Scheme 3.
First, transmetalation generates the arylpalladium spe-
cies A from arylboronic acid and palladium acetate, which
was followed by insertion of the alkene into the carbon-
palladium bond to give palladium enolate B or C. The
presence of bpy inhibits the â-hydride elimination of the
C-Pd bond in B. Protonolysis of B or C gives the
corresponding conjugate addition products D in a protonic
medium with the regeneration of the divalent palladium
species. The protonic medium will also lead to the
protonolysis of arylpalladium species A, which may be
stabilized by the coordination of bpy.7
1.71 (m, 2H). IR (KBr): ν 2939, 1710, 1452, 1224, 756, 700 cm-1
.
MS (70 eV, EI) m/z (%): 175 (M+ + 1), 174 (M+), 131, 117 (100),
104, 91, 42.
Acknowledgment. The Major State Basic Research
Program (Grant G2000077502-A). We thank the Na-
tional Natural Sciences Foundation of China and Chi-
nese Academy of Sciences for the financial support.
Supporting Information Available: Typical experimen-
tal procedure, characterization data of all products, and copies
1
of the H NMR spectra for compounds 3, 4, 6, 7, and 11-29.
In conclusion, we developed a Pd(II)-bipyridine cata-
lyzed conjugate addition of arylboronic acids to R,â-
unsaturated ketones, aldehydes, and esters to yield the
addition products with excellent yields without the
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO051561H
J. Org. Chem, Vol. 70, No. 23, 2005 9653