Palladium-bipyridine catalyzed conjugate addition of arylboronic acids to α,β-unsaturated carbonyl compounds in aqueous media

Article abstract of DOI:10.1016/j.tetlet.2006.07.154

Palladium/bipyridine catalyzed conjugate addition of arylboronic acids to α,β-unsaturated carbonyl compounds in aqueous media was developed with high yields.

Full text of DOI:10.1016/j.tetlet.2006.07.154

Tetrahedron Letters 47 (2006) 7167–7170
Palladium–bipyridine catalyzed conjugate addition
of arylboronic acids to a,b-unsaturated
carbonyl compounds in aqueous media
Shaohui Lin and Xiyan Lu*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
Received 2 July 2006; revised 28 July 2006; accepted 31 July 2006
Available online 17 August 2006
Abstract—Palladium/bipyridine catalyzed conjugate addition of arylboronic acids to a,b-unsaturated carbonyl compounds in aque-
ous media was developed with high yields.
Ó 2006 Elsevier Ltd. All rights reserved.
A significant amount of research has been devoted re-
cently in the pursuit of alternative solvents that are more
environmentally benign. The use of aqueous systems for
carrying out traditional organic transformations was the
first choice because of its cost, safety and environmental
concerns.1 In general, due to the low water solubility of
most organic compounds and the water-sensitivity of
some reagents especially for organometallic reagents,
organic reactions can not proceed in aqueous media eas-
ily.2 Recently, with the development of environmentally
benign reactions, there has been increasing interests for
chemists to perform the reactions in aqueous media.2c
The use of water as solvent for organic reactions is
advantageous in many respects which may include the
cost, safety, synthetic efficiency, simple operation and
environmental concerns.2b Thus, basic research on aque-
ous organic reactions could provide the foundation for
the development of environmentally friendly synthetic
processes.
catalyzed conjugate addition are rare because the later
were troubled by the formation of Heck type coupling
products by b-hydride elimination. Recently, Miyaura
reported the use of cationic Pd(II) complexes to catalyze
the conjugate addition of arylboronic acids to enones
with excellent yields4 and our group also developed
the use of Pd(OAc)2/2,20-bipyridine(bpy) catalyst system
for the conjugate addition of arylboronic acids to a,b-
unsaturated carbonyl compounds with high yields
(Scheme 1).5 The key point may be that the presence
of bpy can inhibit the b-hydride elimination and pro-
mote the protonolysis of the carbon–palladium bond.6
In the Pd(OAc)2/bpy catalyzed conjugate addition of
arylboronic acids to a,b-unsaturated carbonyl com-
pounds developed by our group,5 water is necessary
for high yields. It occurred to us that whether water
could be used as the solvent in this reaction. The air
and moisture stability of divalent palladium catalyst,
arylboronic acids, and a,b-unsaturated carbonyl com-
pounds makes this reaction in aqueous media possible.
The conjugate addition of organometallic reagents to
a,b-unsaturated carbonyl compounds is a powerful tool
for the construction of C–C bonds.3 While the Rh(I)-
catalyzed conjugate addition of organo-boron, silicon,
and tin reagents to a,b-unsaturated carbonyl com-
pounds has been well developed,3d the reports on Pd-
O
Ar
O
Cat. Pd(OAc)2 /bpy
ArB(OH)2
+
R1
R2
R1
R2
Solvent, 40 o
C
R1 = H, alkyl, aryl.
R2 = H, alkyl, OEt, etc.
Keywords: Palladium; Arylboronic acids; a,b-Unsaturated carbonyl
compounds; Aqueous media; Conjugate addition.
*
Scheme 1. Conjugate addition of arylboronic acids to a,b-unsaturated
Corresponding author. Tel.: +86 21 54925158; fax: +86 21
carbonyl compounds.
64166128; e-mail: xylu@mail.sioc.ac.cn
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.154

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S. Lin, X. Lu / Tetrahedron Letters 47 (2006) 7167–7170
Table 1. Pd(II)-Bipyridine catalyzed conjugate addition of phenyl-
In our initial study, we used our previously developed
optimal conditions to try this reaction. The only differ-
ence is the use of water as the only solvent. Thus, when
PhB(OH)2 (1.5 mmol), 2-cyclohexen-1-one (0.5 mmol),
Pd(OAc)2 (0.025 mmol), bpy (0.1 mmol) in water
(1 mL) were reacted at 60 °C for 48 h, the reaction affor-
ded 85% yield of conjugate addition product 1 (Table 1,
entry 1).
boronic acid to 2-cyclohexen-1-one in watera
O
O
Cat. Pd(OAc)2/bpy
PhB(OH)2
+
H2O, Additive
60 oC
Ph
1
Entry PhB(OH)2/ Additive
enone
1 Yield
(%)b
Although phenylboronic acid is soluble in hot water, the
palladium/bipyridine catalyst and 2-cyclohexen-1-one
are only slightly soluble. With the suggestion that the
addition of surface active agents may ameliorate the
reaction, some sodium laurylsulfonate was added. To
our delight, the reaction system was more homogeneous
and the yield was improved to 92% (Table 1, entry 2).
Sodium dodecyl benzene sulfonate worked as well as so-
dium laurylsulfonate (Table 1, entry 3). The yield
dropped to 86% when PhB(OH)2 was decreased (Table
1, entries 4 and 5). Finally, 2.5 equiv of PhB(OH)2 main-
1
2
3
4
5
6
3.0
3.0
3.0
2.0
2.0
2.5
None
85
92
Sodium laurylsulfonatec
Sodium dodecyl benzene sulfonatec 93
Sodium laurylsulfonatec
Sodium dodecyl benzene sulfonatec 85
Sodium laurylsulfonatec
92
86
a Reaction conditions: 2-cyclohexen-1-one (0.5 mmol), Pd(OAc)2
(0.025 mmol) and bpy (0.10 mmol) in water (1.0 mL) at 60 °C for
48 h.
b Isolated yield.
c Additive: 20 mg.
Table 2. Pd(II)-Bipyridine catalyzed conjugate addition of aryl boronic acids to a,b-unsaturated carbonyl compoundsa
O
Ar
O
Pd(OAc)2/bpy
+
ArB(OH)2
R
Y
H2O, additive
60 oC
R
Y
Y = H, R', OR'
Entry
1
ArB(OH)2
a,b-Unsaturated carbonyls
Product
Yield (%)b
92
O
B(OH)2
1
B(OH)2
B(OH)2
B(OH)2
B(OH)2
B(OH)2
B(OH)2
B(OH)2
O
2
3
4
5
6
7
8
2
3
4
5
6
7
8
65
73
99
66
41
63
50
O
Ph
O
O
O
H
O
Ph
H
O
OEt

S. Lin, X. Lu / Tetrahedron Letters 47 (2006) 7167–7170
7169
Table 2 (continued)
Entry
ArB(OH)2
a,b-Unsaturated carbonyls
Product
Yield (%)b
B(OH)2
O
9
9
82
87
55
Ph
OEt
B(OH)2
B(OH)2
B(OH)2
O
10
11
10
11
Ph
Ph
OPh
NO2
O
12
13
14
12
13
14
63
96
95
OMe
B(OH)2
O
O
Me
B(OH)2
Cl
B(OH)2
O
O
15
16
15
16
78
85
F
B(OH)
a Reaction conditions: arylboronic acid (1.25 mmol), olefin (0.5 mmol), Pd(OAc)2 (0.025 mmol), sodium laurylsulfonate (20 mg) and bpy (0.10 mmol)
in water (1.0 mL) at 60 °C for 48 h.
b Isolated yield.
tained the yield at 92%, and this was chosen as the opti-
mized conditions (Table 1, entry 6).7
Next, the influence of different arylboronic acids was
evaluated. Interestingly, p-methoxyphenylboronic acid
afforded 63% yield of conjugate addition product (Table
2, entry 12) which only gave very low yield in our previ-
ously reported reactions in HOAc media.5 Maybe, it is
the weaker acidity of water that decreased the protonol-
ysis of p-methoxyphenylboronic acid and made the yield
of conjugate addition better. Among the arylboronic
acids tested, p-methylphenyl boronic (Table 2, entry
13) acid and p-chlorophenyl boronic acid (Table 2, entry
14) provided high yields of conjugate addition products
without the detection of b-H elimination products.
The scope of the reaction with different a,b-unsaturated
carbonyl compounds is outlined in Table 2. For acyclic
and cyclic enones (Table 2, entries 1–5), moderate to
excellent yields were obtained, among which 2-cyclopen-
ten-1-one gave the highest yield (Table 2, entry 3). From
these results, it seems that enones with bulky groups
(4,4-dimethyl cyclohex-2-en-1-one, Table 2, entry 5)
showed lower reactivity. Enals provided moderate yields
in water (Table 2, entries 6 and 7). It was worth noting
that a,b-unsaturated esters also afforded good yields of
conjugate addition products (Table 2, entries 8–10).
When 2-nitrostyrene was performed under the opti-
mized conditions, 55% yield of addition product was iso-
lated (Table 2, entry 11).
A plausible mechanism for the divalent palladium cata-
lyzed conjugate addition is shown in Scheme 2. First,
transmetallation between arylboronic acid and palla-
dium catalyst yields the aryl palladium species A

7170
S. Lin, X. Lu / Tetrahedron Letters 47 (2006) 7167–7170
Supplementary data
N
N
ArB(OH)2
Pd(II)
O
Experimental procedure and characterization data for
compounds 1–16 are provided. Supplementary data
associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2006.07.154.
Ar
D
N
N
N
N
A
Pd(II)
References and notes
Pd(II)
Ar
H2O
O
O
C
1. Anastas, P. T.; Williamson, T. Green Chemistry-Frontiers in
Benign Chemical Syntheses and Processes; Oxford Univer-
sity Press: Oxford, 1998.
Ar
2. (a) Aqueous Phase Organometallic Catalysis—Concepts and
Applications; Cornils, B., Herrmann, W. A., Eds.; Wiley-
VCH: Weinheim, Germany, 1998; (b) Li, C.-J.; Chan, T.-H.
Organic Reactions in Aqueous Media; John Wiley & Sons:
New York, 1997; (c) Li, C.-J. Chem. Rev. 2005, 105, 3095;
(d) Li, C.-J.; Chen, L. Chem. Soc. Rev. 2006, 35, 68.
3. (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.
N
N
O
Pd(II)
B
Ar
Scheme 2. Mechanism of the Pd(II) catalyzed conjugate addition
reaction.
4. (a) Nishikata, T.; Yamamoto, Y.; Miyaura, N. Angew.
Chem., Int. Ed. 2003, 42, 2768; (b) Nishikata, T.; Yamam-
oto, Y.; Miyaura, N. Organometallics 2004, 23, 4317.
5. Lu, X.; Lin, S. J. Org. Chem. 2005, 70, 9651.
6. (a) Lu, X. Topics in Catalysis 2005, 35, 75; (b) Zhao, L.; Lu,
X.; Xu, W. J. Org. Chem. 2005, 70, 4059; (c) Zhao, L.; Lu,
X. Org. Lett. 2002, 4, 3903.
followed by insertion of the olefin into the carbon–palla-
dium bond giving palladium enolate B or C. b-H elimi-
nation of the C–Pd bond in B is suppressed in the
presence of bpy and protonolysis of B in water gives
the corresponding conjugate addition product
D
with the regeneration of divalent palladium species
making the catalytic cycle possible.
7. Typical procedure for the conjugate addition of phenylbo-
ronic acid to 2-cyclohexen-1-one: To a schlenk tube,
phenylboronic acid (153 mg, 1.25 mmol), 2-cyclohexen-1-
one (48 mg, 0.5 mmol), Pd(OAc)2 (5.6 mg, 0.025 mmol),
bpy (15.6 mg, 0.10 mmol), sodium laurylsulfonate (20 mg)
and distilled water (1.0 mL) were added. The mixture was
stirred and heated at 60 °C for two days until the substrate
disappeared as monitored by TLC. The reaction mixture
was extracted with Et2O. The combined ether solution was
washed with saturated NaCl, dried (MgSO4) and concen-
trated. The residue was purified by flash chromatography
(EtOAc: petroleum ether 1:20) to give the product 1 with
92% yield as a colorless oil. 1H NMR (300 MHz, CDCl3): d
7.40–7.17 (m, 5H), 3.09–2.94 (m, 1H), 2.30–2.66 (m, 4H),
2.22–2.01 (m, 2H), 1.94–1.68 (m, 2H); IR (KBr): m 2939,
2867, 1710, 1497, 1452, 1224, 756, 700 cmꢀ1; MS (70 eV,
EI) m/z (%): 175 (M++1), 174 (M+), 131, 117 (100), 104, 91,
78, 42.
In conclusion, we developed a palladium–bipyridine cat-
alyzed conjugate addition of arylboronic acids to a,b-
unsaturated carbonyl compounds in aqueous media.
The addition of surface active agent made the reaction
system more homogeneous and improved the yields.
Moderate to excellent yields of conjugate addition prod-
ucts were obtained even for the reactions of a,b-unsatu-
rated esters.
Acknowledgements
We thank the National Natural Sciences Foundation of
China (20472099) and Chinese Academy of Sciences for
financial Support.