Cationic Pd(II)/bipyridine-catalyzed conjugate addition of arylboronic acids to β,β-disubstituted enones: Construction of quaternary carbon centers

Article abstract of DOI:10.1021/ol100767u

Cationic Pd(II)-catalyzed addition of arylboronic acids to β,β-disubstituted enones in high yields was developed. This method provided an efficient method for the construction of quaternary carbon centers, and only 0.5 mol % of Pd(II) catalyst was needed.

Full text of DOI:10.1021/ol100767u

ORGANIC
LETTERS
2010
Vol. 12, No. 11
2536-2539
Cationic Pd(II)/Bipyridine-Catalyzed
Conjugate Addition of Arylboronic Acids
to ꢀ,ꢀ-Disubstituted Enones:
Construction of Quaternary Carbon
Centers
Shaohui Lin and Xiyan Lu*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
xylu@mail.sioc.ac.cn
Received April 1, 2010
ABSTRACT
Cationic Pd(II)-catalyzed addition of arylboronic acids to ꢀ,ꢀ-disubstituted enones in high yields was developed. This method provided an
efficient method for the construction of quaternary carbon centers, and only 0.5 mol % of Pd(II) catalyst was needed.
Transition metal catalysis provides mild and efficient meth-
ods for C-C bond formation,1 but it is still not easy for
quaternary carbon construction.2 Copper-catalyzed conjugate
addition of Grignard reagents to trisubstituted R,ꢀ-unsaturated
carbonyl compounds is well-known,3,4 but the reactions
involve air and moisture sensitive organometallic reagents
and some functional groups cannot be tolerated. In the past
decade, organoboron reagents attracted many organic chem-
ists’ interest for their tolerance of a broad range of functional
groups, low toxicity, and stability to water and air.5 In the
well-documented Rh(I)-catalyzed conjugate addition reaction
of boronic acids,6 Hayashi reported the use of sodium
tetraarylborates as effective nucleophiles in rhodium/diene-
catalyzed 1,4-addition to ꢀ,ꢀ-disubstituted R,ꢀ-unsaturated
(4) (a) d’Augustin, M.; Palais, L.; Alexakis, A. Angew. Chem., Int. Ed.
2005, 44, 1376. (b) Martin, D.; Kehrli, S.; d’Augustin, M.; Clavier, H.;
Mauduit, M.; Alexakis, A. J. Am. Chem. Soc. 2006, 128, 8416. (c) Wu, J.;
Mampreian, D. M.; Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127, 4584.
(d) He’non, H.; Mauduit, M.; Alexakis, A. Angew. Chem., Int. Ed. 2008,
47, 9122. (e) Vuagnoux d’Augustin, M.; Alexakis, A. Chem.sEur. J. 2007,
13, 9647. (f) May, T. L.; Brown, M. K.; Hoveyda, A. H. Angew. Chem.,
Int. Ed. 2008, 47, 7358. (g) Hawner, C.; Li, K.; Cirriez, V.; Alexakis, A.
Angew. Chem., Int. Ed. 2008, 47, 8211.
(1) (a) de Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling
Reactions, 2nd ed.; Wiley-VCH: Weinheim, Germany, 2004. (b) Beller,
M.; Bolm, C. Transition Metals for Organic Synthesis: Building Blocks
and Fine Chemicals; Wiley-VCH: New York, 1998.
(5) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457. (b) Suzuki,
A. J. Organomet. Chem. 1999, 576, 147. (c) Suzuki, A. J. Organomet. Chem.
2002, 653, 83.
(2) Trost, B. M.; Jiang, C. Synthesis 2006, 369.
(3) For reviews on conjugate additions, see: (a) Krause, N.; Hoffmann-
Roder, A. Synlett 2001, 171. (b) Alexakis, A.; Benhaim, C. Eur. J. Org.
Chem. 2002, 3221.
(6) (a) Fagnou, K.; Lautens, M. Chem. ReV. 2003, 103, 169. (b) Hayashi,
T. Acc. Chem. Res. 2000, 33, 354. (c) Hayashi, T.; Yamasaki, K. Chem.
ReV. 2003, 103, 2829.
10.1021/ol100767u  2010 American Chemical Society
Published on Web 05/07/2010

ketones.7 In the palladium-catalyzed conjugate addition of
organometallic reagents to R,ꢀ-unsaturated carbonyl com-
pounds, to the best of our knowledge, only a few examples
were reported.8 Recently, Miyaura reported the addition of
arylboronic acids to enones catalyzed by cationic palla-
dium(II)/phosphine complexes with successful results.9
We developed the Pd(OAc)2/bipyridine-catalyzed con-
jugate addition of arylboronic acids to R,ꢀ-unsaturated
carbonyl compounds10a with high yields and its application
in aqueous media.10b Also it was found that cationic Pd(II)
complexes with bipyridine (bpy) as ligands catalyzed
the addition of arylboronic acids to nitriles10c,d and
aldehydes10e efficiently. This may be due to the high Lewis
acidity and the vacant coordination site, making the cationic
Pd(II) catalysts more active than neutral Pd(II) species in
transmetalation, coordination with carbon-carbon multiple
bonds or carbon-heteroatom multiple bonds, and the inser-
tion steps.9b Herein, we report the cationic Pd(II)/bipyridine-
catalyzed highly efficient conjugate addition of arylboronic
acids to ꢀ,ꢀ-disubstituted enones for the construction of
quarternary carbon centers.
solvents demonstrated an important effect in this reaction
and a 94% yield of the product was isolated in MeOH at 80
°C in a sealed tube (Table 1, entry 3). But in EtOH, the
yield dropped sharply (Table 1, entry 4), and the reactions
also gave poor yields in n-PrOH or n-BuOH (Table 1, entries
5 and 6). At the same time, palladium black was observed
in these three solvents. However, t-BuOH showed similar
result as MeOH (Table 1, entry 7).
Different catalysts showed different activities. When
cationic palladium [Pd(dppe)(CH3CN)2]2+·2BF4- was used,
no reaction occurred (Table 1, entry 8). But when the catalyst
was changed to the cationic Pd(II) with bpy as the ligand
(C1), the reaction proceeded smoothly at room temperature
with excellent yield (Table 1, entry 9). The high yield was
maintained even when the catalyst loading was decreased
to 0.5 mol % (Table 1, entry 10).
With these results in hand, we began to survey the scope
of the reaction with different ꢀ,ꢀ-disubstituted R,ꢀ-unsatur-
ated carbonyl compounds. The results of the conjugate
addition are summarized in Table 2.
Cationic Pd(II) catalyst C1 showed high activity for the
addition reaction of arylboronic acids to cyclic ꢀ,ꢀ-
disubstituted enones. For 3-methylcyclopent-2-enone (3)
and 3-butylcyclohex-2-enone (5), excellent yields of
conjugate addition were obtained (Table 2, entries 2 and
3). For the substrates with bulky substituents (Table 2,
entries 4 and 5), the reactions gave lower conversion with
0.5 mol % of cationic palladium catalyst. Increasing the
catalyst loading to 2.5 mol % made higher yields, but
higher temperature did not help further conversion. It is
worth noting that ꢀ-phenyl-substituted enones (3-phenyl-
cyclohex-2-enone (11)) showed no reactivity with either
cationic or neutral palladium catalysts (Table 2, entry 6),
which might be due to the steric hindrance or the
conjugation with enones of the phenyl group. Interestingly,
when cyclohex-1,3-dione (12) and 3-ethoxycyclohex-2-
enone (13) were used as the substrates to react with
phenylboronic acid, the reaction did not afford the normal
conjugate addition products but gave 3-phenylcyclohex-
2-enone (11) in moderate yields (Table 2, entries 7 and
8). When mesityl oxide (14) was performed in the
optimized cationic palladium conditions, a trace of the
product was detected, but 70% yield was afforded in
neutral palladium conditions (Table 2, entry 9).
In our initial study, we tried the addition of phenylboronic
acid to 3-methylcyclohex-2-enone under neutral Pd(OAc)2/
bpy catalyst conditions. The reaction can hardly proceed in
acetic acid at 50 °C, and only a trace of the desired product
was detected (Table 1, entry 1). Then it was found that in
dioxane/H2O the reaction afforded a moderate yield of
conjugate addition product (Table 1, entry 2). Alcoholic
Table 1. Pd(II)/bpy-Catalyzed Conjugate Addition of
Phenylboronic Acid to 3-Methylcyclohex-2-enonea
temp time yield
entry
catalyst
solvent
HOAc
dioxane/
H2O
(°C)
(h)
(%)b
1
2
Pd(OAc)2/bpy
Pd(OAc)2/bpy
50
80
12
12
trace
70
The influence of different arylboronic acids in this reaction
was evaluated, and moderate to excellent yields were
obtained (Table 2, entries 11-14). Even the bulky 2-naph-
3
4
5
6
7
8
Pd(OAc)2/bpy
Pd(OAc)2/bpy
Pd(OAc)2/bpy
Pd(OAc)2/bpy
MeOH
EtOH
n-PrOH
n-BuOH
t-BuOH
MeOH
80
80
80
80
80
80
12
12
12
12
12
12
94
20
21
17
91
0c
(7) Shintani, R.; Tsutsumi, Y.; Nagaosa, M.; Nishimura, T.; Hayashi,
T. J. Am. Chem. Soc. 2009, 131, 13588.
Pd(OAc)2/bpy
[Pd(dppe)(CH3CN)2]2+
(8) (a) Cho, C. S.; Tanabe, K.; Uemura, S. Tetrahedron Lett. 1994, 35,
1275. (b) Cho, C. S.; Motofusa, S.; Ohe, K.; Uemura, S. J. Org. Chem.
1995, 60, 883. (c) Cho, C. S.; Motofusa, S.; Ohe, K.; Uemura, S. Bull.
Chem. Soc. Jpn. 1996, 69, 2341. (d) Denmark, S. E.; Amishiro, N. J. Org.
Chem. 2003, 68, 6997. (e) Gini, F.; Hessen, B.; Minnaard, A. J. Org. Lett.
2005, 7, 5309. (f) He, P.; Lu, Y.; Dong, C.-G.; Hu, Q.-S. Org. Lett. 2007,
9, 343.
-
2BF4
9
10
C1
C1
MeOH
MeOH
25
25
4
12
96d
96e
a Reaction conditions: PhB(OH)2 (0.50 mmol), 3-methylcyclohex-2-
enone (0.25 mmol), Pd(OAc)2 (0.0125 mmol, 5 mol %), and bpy (0.015
mmol, 6 mol %) in a sealed tube at 80 °C. b Isolated yield. c [Pd(dppe)-
(CH3CN)2]2+·2BF4- (0.0125 mmol, 5 mol %). d Catalyst C1 (0.0062 mmol,
2.5 mol %). e PhB(OH)2 (0.75 mmol), 3-methylcyclohex-2-enone (0.50
mmol), and catalyst C1 (0.0025 mmol, 0.5 mol %).
(9) (a) Nishikata, T.; Yamamoto, Y.; Miyaura, N. Angew. Chem., Int.
Ed. 2003, 42, 2768. (b) Nishikata, T.; Yamamoto, Y.; Miyaura, N.
Organometallics 2004, 23, 4317. (c) Yamamoto, Y.; Nishikata, T.; Miyaura,
N. J. Synth. Org. Chem., Jpn. 2006, 64, 1112.
Org. Lett., Vol. 12, No. 11, 2010
2537

thylboronic acid gave 61% yield of conjugate addition
product (Table 2, entry 14).
A plausible mechanism for the cationic palladium-
catalyzed addition of arylboronic acids to ꢀ,ꢀ-disubstituted
enones is shown in Scheme 1.8a,9a It involves transmetalation
Table 2. Cationic Pd(II)/bpy-Catalyzed Conjugate Addition of
Arylboronic Acids to ꢀ,ꢀ-Disubstituted R,ꢀ-Unsaturated
Carbonyl Compoundsa
Scheme 1. Plausible Mechanism for the Cationic
Palladium-Catalyzed Addition of Arylboronic Acids to
ꢀ,ꢀ-Disubstituted Enones
between arylboronic acid and cationic palladium yielding the
arylpalladium species A. Then, the insertion of the double
bond of enones into the carbon-palladium bond gives
palladium enolate B or C with the construction of the
quaternary carbon center. Protonolysis of the palladium
enolate11 yields the corresponding conjugate addition product
D and regenerates the divalent palladium species to complete
the catalytic cycle. In the case of cyclohex-1,3-dione (12)
or 3-ethoxycyclohex-2-enone (13) (Table 2, entries 7 and
8), it might be possible to eliminate the potential leaving
Scheme 2
.
Possible Pathways for the Elimination of Hydroxy or
Methoxy Groups in C or B
a Reaction conditions: ArB(OH)2 (0.75 mmol), enone (0.50 mmol),
catalyst C1 (0.0025 mmol, 0.5 mol %), and MeOH (0.4 mL) at 25 °C.
b Isolated yield. c Catalyst C1 (2.5 mol %). d Pd(OAc)2 (0.025 mmol, 5
mol %) and bpy (0.030 mmol, 6 mol %) in a sealed tube at 80 °C.
2538
Org. Lett., Vol. 12, No. 11, 2010

groups (OH in 12 and OEt in 13) simultaneously during the
protonolysis of the palladium enolate especially in the
presence of the boron compounds.12 Of course, another
pathway for the trans ꢀ-heteroatom elimination13 of B to
give 3-arylcyclohex-2-enone (E) as the product and divalent
palladium species for regeneration of the catalyst cannot be
excluded (Scheme 2).
It is worth noting that this reaction involved the proto-
nolysis of the palladium enolate in alcoholic solvents (see
Scheme 1), and an alkoxypalladium species was formed
during the reaction. For the alkoxypalladium species with a
ꢀ-hydrogen atom, ꢀ-hydride elimination will occur to gener-
ate Pd(0) species making the catalytic cycle impossible to
occur and leading to poor yields. That the reaction gave better
yields in MeOH may be due to the slower ꢀ-hydride
elimination of methoxypalladium species compared with
other alkoxypalladium species.14 For the solvent with no
ꢀ-hydrogen atom, like t-BuOH, the reaction preceeds with
high yield.
In conclusion, we found that cationic Pd(II)/bpy species
did catalyze the addition of arylboronic acids to ꢀ,ꢀ-
disubstituted enones in high yields with only 0.5 mol %
catalyst loading for the construction of a quaternary carbon
center.
Acknowledgment. We thank the Major State Basic
Research Program (2006CB806105), the National Natural
Sciences Foundation of China (20423001, 20732005), and
the Chinese Academy of Sciences for the financial support.
Supporting Information Available: Typical experimental
procedure and characterization data of all products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(10) (a) Lu, X.; Lin, S. J. Org. Chem. 2005, 70, 9651. (b) Lin, S.; Lu,
X. Tetrahedron Lett. 2006, 47, 7167. (c) Zhao, B.; Lu, X. Tetrahedron
Lett. 2006, 47, 6765. (d) Zhao, B.; Lu, X. Org. Lett. 2006, 8, 5987. (e) Lin,
S.; Lu, X. J. Org. Chem. 2007, 72, 9757.
(11) Wang, Z.; Zhang, Z.; Lu, X. Organometallics 2000, 19, 775.
(12) Both hydroxy and ether groups can be activated by boron
compounds to become easily leaving groups, see: (a) Lu, X.; Jiang, X.;
Tao, X. J. Organomet. Chem. 1988, 344, 109. (b) Lu, X.; Jiang, X. J.
Organomet. Chem. 1989, 359, 139.
OL100767U
(13) Zhu, G.; Lu, X. Organometallics 1995, 14, 4899.
(14) Lloyd, W. G. J. Org. Chem. 1967, 32, 2816.
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