Anionic four-electron donor-based palladacycles as catalysts for addition reactions of arylboronic acids with α,β-unsaturated ketones, aldehydes, and α-ketoesters

Article abstract of DOI:10.1021/ol062814b

(Chemical Equation Presented) Anionic four-electron donor-based palladacycle-catalyzed 1,4-additions of arylboronic acids with α,β-unsaturated ketones and 1,2-additions of arylboronic acids with aldehydes and α-ketoesters are described. Our study demonstrated that palladacycles were highly efficient, practical catalysts for these addition reactions. The work described here not only opened a new paradigm for the application of palladacycles, but may also pave the road for other metalacycles as practically useful catalysts for such addition reactions including asymmetric ones.

Full text of DOI:10.1021/ol062814b

ORGANIC
LETTERS
2007
Vol. 9, No. 2
343-346
Anionic Four-Electron Donor-Based
Palladacycles as Catalysts for Addition
Reactions of Arylboronic Acids with
r
,
â
-Unsaturated Ketones, Aldehydes,
r
and -Ketoesters
Ping He, Yong Lu, Cheng-Guo Dong, and Qiao-Sheng Hu*
Department of Chemistry, College of Staten Island and the Graduate Center of the
City UniVersity of New York, Staten Island, New York 10314
qiaohu@mail.csi.cuny.edu
Received November 19, 2006
ABSTRACT
Anionic four-electron donor-based palladacycle-catalyzed 1,4-additions of arylboronic acids with
r
,
â
-unsaturated ketones and 1,2-additions of
arylboronic acids with aldehydes and
r-ketoesters are described. Our study demonstrated that palladacycles were highly efficient, practical
catalysts for these addition reactions. The work described here not only opened a new paradigm for the application of palladacycles, but may
also pave the road for other metalacycles as practically useful catalysts for such addition reactions including asymmetric ones.
Anionic four-electron donor-based palladacycles, one of the
two general types of palladacycles (Figure 1), are readily
forming reactions including cross-coupling reactions.1,3 Mecha-
nistic studies suggested that in cross-coupling reactions such
as the Suzuki couplings, palladacycles served as the sources
of catalytically active species by undergoing transmetalation
with organometallic reagents to form transmetalated inter-
mediates such as A followed by reductive elimination
(Scheme 1). As it has been established that the Pd(II) center
in palladacycles could act as a Lewis acid,1 we reasoned that
when carbonyl moieties were present in the reaction system,
in addition to undergoing reductive elimination to form Pd-
Figure 1. General types of palladacycles.
(3) For recent examples: (a) Strieter, E. R.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2006, 45, 925-928. (b) Moncada, A. I.; Manne, S.; Tanski,
J. M.; Slaughter, L. M. Organometallics 2006, 25, 491-505. (c) Navarro,
O.; Marion, N.; Oonishi, Y.; Kelly, R. A., III; Nolan, S. P. J. Org. Chem.
2006, 71, 685-692. (d) Consorti, C. S.; Flores, F. R.; Rominger, F.; Dupont,
J. AdV. Synth. Catal. 2006, 348, 133-141. (e) Mino, T.; Shirae, Y.;
Sakamoto, M.; Fujita, T. J. Org. Chem. 2005, 70, 2191-2194. (f) Barder,
T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc.
2005, 127, 4685-4696. (g) Rosa, G. R.; Rosa, C. H.; Rominger, F.; Dupont,
J.; Monteiro, A. L. Inorg. Chim. Acta 2006, 359, 1947-1954. (h) Chen,
C.-L.; Liu, Y.-H.; Peng, S.-M.; Liu, S.-T. Organometallics 2005, 24, 1075-
1081.
accessible and air/moisture stable.1,2 They have been dem-
onstrated as efficient catalyst systems for a number of bond
(1) For recent reviews: (a) Dupont, J.; Consorti, C. S.; Spencer, J. Chem.
ReV. 2005, 105, 2527-2572. (b) Beletskaya, I. P.; Cheprakov, A. V. J.
Organomet. Chem. 2004, 689, 4055-4082. (c) Bedford, R. B. Chem.
Commun. 2003, 1787-1796.
(2) Most Type I palladacycles are known to exist as bridged dimers and
to dissociate into monomeric forms during reactions. All Type I pallada-
cycles in this paper were drawn in monomeric forms.
10.1021/ol062814b CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/16/2006

paradigm for palladacycle catalysis chemistry and may
provide powerful catalyst systems for organic synthesis. In
this letter, we established that Type I palladacycles could
indeed act as efficient catalysts for such addition reactions,
specifically, the 1,4-addition of arylboronic acids with R,â-
unsaturated ketones and the 1,2-additions of arylboronic acids
with aldehydes and R-ketoesters.
Scheme 1. Cross-Couplings vs Hypothetic Addition Reactions
for Type I Palladacycles
We began our study by testing reported palladacycles 1-3
for the room temperature 1,4-addition of phenylboronic acid
with chalcone, and our results are listed in Table 1. We found
(0) species (Path A), A might coordinate with a carbonyl
moiety to form complexes B (Path B) (Scheme 1). On the
basis that elevated temperature, typically higher than 100
°C, was required for palladacycles to generate catalytically
active species for cross-coupling reactions,1 we surmised that
the reductive elimination of A should be slow, especially at
lower temperature. We further envisioned that at lower
reaction temperature, such as room temperature, B might
undergo aryl transfer to form addition products much faster
than reductive elimination to form cross-coupling products
(Scheme 1), and Type I palladacycles could thus catalyze
addition reactions of arylboronic acids to carbonyl group-
containing compounds,4-6 a field that is currently dominated
by Rh(I) catalysis chemistry.7-12 The exploration of such
palladacycle-catalyzed addition reactions would create a new
Figure 2. Tested palladacycles.
although palladacycle 113 showed no catalytic activity (Table
1, entry 1), palladacycles 214 and 315 gave encouraging
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unsaturated compoundssfor Pd(0)/SbCl3 catalyst:Pd(0)/SbCl3 catalyst: (a)
Cho, C. S.; Motofusa, S.; Ohe, K.; Uemura, S. J. Org. Chem. 1995, 60,
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Gridnev, I. D.; Miyaura, N. Organometallics 2005, 24, 5025-5032. (c)
Nishikata, T.; Yamamoto, Y.; Miyaura, N. Organometallics 2004, 23, 4317-
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720-721. (d) Nishikata, T.; Yamamoto, Y.; Miyaura, N. Angew. Chem.,
Int. Ed. 2003, 42, 2768-2770. For Pd(OAc)2/pyridine catalyst: (e) Lu, X.;
Lin, S. J. Org. Chem. 2005, 70, 9651-9653. For Pd(OCOCF3)2/(R,R)-Me-
Duphos catalyst: (f) Gini, F.; Hessen, B.; Minnaard, A. J. Org. Lett. 2005,
7, 5309-5312. For Pd(0)/PPh3/CHCl3 catalyst: (g) Yamamoto, T.; Iizuka,
M.; Ohta, T.; Ito, Y. Chem. Lett. 2006, 35, 198-199.
(5) (a) For Pd(0)/PPh3/CHCl3-catalyzed 1,2-addition of arylboronic acids
with aldehydes at elevated temperature: Yamamoto, T.; Ohto, T.; Ito, Y.
Org. Lett. 2005, 7, 4153-4155. (b) A 3% yield of 1,2-addition product
was observed during the cross-coupling of phenylboronic acid with
3-methoxy-4-tosyloxybenzaldehyde catalyzed by Pd(OAc)2/Buchwald’s,
biarylphosphine: Nguyen, H. N.; Huang, X.; Buchwald, S. L. J. Am. Chem.
Soc. 2003, 125, 11818-1819.
(6) One example of 1,2-addition products of phenylboronic acid with
p-chlorobenzaldehyde, formed as byproducts during the cross-coupling
reaction catalyzed by a palladacycle at 130 °C, was previously reported:
Gibson, S.; Foster, D. F.; Eastham, G. R.; Tooze, R. P.; Cole-Hamilton, D.
J. Chem. Commun. 2001, 779-780.
(7) For recent reviews on Rh(I)-catalyzed addition reactions of aryl-
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Chem., Int. Ed. 2004, 43, 3364-3366. (b) Hayashi, T.; Yamasaki, K. Chem.
ReV. 2003, 103, 2829-2844. (c) Fagnou, K.; Lautens, M. Chem. ReV. 2003,
103, 169-196 and references cited therein.
(8) Selected recent examples of Rh(I)-catalyzed 1,4-additions of aryl-
boronic acids with R,â-unsaturated compoundsswith chiral dienes as
ligands: (a) Trenkle, W. C.; Barkin, J. L.; Son, S. U.; Sweigart, D. A.
Organometallics 2006, 25, 3548-3551. (b) Chen, F.-X.; Kina, A.; Hayashi,
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J. Am. Chem. Soc. 2006, 128, 5628-5629. (d) Hayashi, T.; Tokunaga, N.;
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J.-F.; Stephenson, C. R. J.; Defieber, C.; Carreira, E. M. Org. Lett. 2005,
7, 3821-3824. (f) Shintani R.; Kimura T.; Hayashi T. Chem. Commun.
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Y.; Kina, A.; Shintani, R.; Hayashi, T. Tetrahedron: Asymmetry 2005, 16,
(9) For room temperature Rh(I)-catalyzed 1,2-addition of arylboronic
acids with aldehydes: (a) Duan, H.-F.; Xie, J.-H.; Shi, W.-J.; Zhang, Q.;
Zhou, Q.-L. Org. Lett. 2006, 8, 1479-1481. (b) Ueda, M.; Miyaura, N. J.
Org. Chem. 2000, 65, 4450-4452. For Rh(I)-catalyzed addition of
arylboronic acids with aldehydes at elevated temperature: (c) Jagt, R. B.
C.; Toullec, P. Y; de Vries, J. G.; Feringa, B. L; Minnaard, A. J. Org.
Biomol. Chem. 2006, 4, 773-775. (d) Chen, J.; Zhang, X.; Feng, Q.; Luo,
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L.-C.; Krische, M. J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5421-5424.
(b) Cauble, D. F.; Gipson, J. D.; Krische, M. J. J. Am. Chem. Soc. 2003,
125, 1110-1111.
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344
Org. Lett., Vol. 9, No. 2, 2007

Table 1. Reaction Optimizationa
Table 2. Palladacycle 4-Catalyzed Michael Addition of
Arylboronic Acids with R,â-Unsaturated Ketonesa
entry palladacycle
solvent
toluene
toluene
toluene
toluene
ClCH2CH2Cl K3PO4
CH2Cl2
THF
dioxane
toluene
toluene
toluene
toluene
toluene
base
conversion (%)b
1
2
1
2
3
4
4
4
4
4
4
4
4
4
4
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
0c
35c
55c
95c
57
63
54
72
99
79
99
68
36
3
4
5
6
K3PO4
K3PO4
K3PO4
K3PO4
Cs2CO3
KF
7
8
9
10
11
12
13
K2CO3
Ag2CO3
a Reaction conditions: chalcone (1.0 equiv), phenylboronic acid (1.5
1
equiv), solvent (2 mL), base (1 equiv), room temperature. b Based on H
NMR. c Reaction time: 1 h.
a Reaction conditions (not optimized): ketone (1.0 equiv), arylboronic
acid (1.2-2.0 equiv), 4 (5%), K3PO4 (1 equiv), toluene (2 mL), room
temperature. b Isolated yields (average of two runs). c Reaction time: 40
h.
results: 35% conversion was observed for 2 and 55%
conversion for 3 (Table 1, entries 2 and 3). It has been
established that ArPd(II)R(Ln) complexes with more electron-
rich organic groups and/or with less sterically hindered
ligands were more reluctant to undergo reductive elimina-
tion.16,17 We reasoned that increasing the electron-richness
of the Pd-bonded aromatic part of palladacycles and reducing
the size of their ligand part could minimize the reductive
elimination and thus might provide more efficient catalysts.
We thus prepared ferrocenyl-containing palladacycle 4.18 We
were pleased to find that 4 was indeed an excellent catalyst
for the addition reaction (Table 1, entry 4). We have further
employed 4 for the optimization of the reaction condition
and our results are also listed in Table 1. We found toluene
was the best solvent among the solvents we screened, and
K3PO4 and KF were the best bases.
1
systems,4 were not detected in H NMR suggested that the
reductive elimination process of the Pd(II)-enolate intermedi-
ates occurred much slower than that of their protonation
process.19
We have also employed 4 as the catalyst for the addition
reaction of arylboronic acids with aldehydes.5,6,7,9,12 We were
pleased to find that 4 efficiently catalyzed such addition
reactions at room temperature (Table 3). Complete conver-
sions and high yields were obtained not only for aromatic
aldehydes (Table 3, entries 1-12), but more impressively
also for aliphatic aldehydes (Table 3, entries 13 and 14).
Since only low yields (e35%) were observed for room
temperature Rh(I)-catalyzed additions of aliphatic aldehydes,9b
our results suggested that 4 might possess higher catalytic
efficiency than reported Rh(I) catalysts.
We have also employed 4 as the catalyst for the addition
reaction of arylboronic acids with R-ketoesters, a reaction
that could yield useful R-hydroxy esters with an R-quaternary
carbon center.20 Gratifyingly, we found that 4 also efficiently
catalyzed such addition reactions at room temperature (Table
4). To our knowledge, these are the first examples of the
addition reaction of arylboronic acids with R-ketoesters.21
In summary, we have demonstrated that anionic four-
electron donor-based, air/moisture stable palladacycle 4 was
a highly efficient, robust catalyst for the addition reactions
of arylboronic acids with R,â-unsaturated ketones, aldehydes,
With palladacycle 4 as the catalyst, toluene as the solvent,
and K3PO4 as the base, a number of arylboronic acids and
R,â-unsaturated ketones were examined, and our results are
listed in Table 2. We found 4 was a robust, general catalyst
for the room temperature 1,4-addition of arylboronic acids
with R,â-unsaturated ketones including cyclic and acyclic
ones (Table 2). The reaction, like other Pd(II)-catalyzed 1,4-
addition of arylboronic acids with R,â-unsaturated ketones,
most likely involved Pd(II)-enolates as the intermediates,
which could undergo reductive elimination to form Heck-
type cross-coupling products or protonation to generate the
1,4-addition products.4 The fact that the Heck coupling
products, which are sometimes seen in other Pd(II) catalyst
(16) Culkin, D. A.; Hartwig, J. F. Organometallics 2004, 23, 3398-
3416.
(19) For examples of protonation of palladium(II) enolates see refs 4b
and 16. Also see: (a) Hamashima, Y.; Hotta, D.; Sodeoka, M. J. Am. Chem.
Soc. 2002, 124, 11240-11241. (b) Fujii, A.; Hagiwara, E.; Sodeoka, M. J.
Am. Chem. Soc. 1999, 121, 5450-5458. (c) Lei, A.; Srivastava, M.; Zhang,
X. J. Org. Chem. 2002, 67, 1969-1971.
(17) For examples: (a) Grasa, G. A.; Viciu, M. S.; Huang, J.; Zhang,
C.; Trudell, M. L.; Nolan, S. P. Organometallics 2002, 21, 2866-2873.
(b) Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am. Chem.
Soc. 1999, 121, 9550-9561.
(18) 4 was prepared from ferrocenylmethylphosphine and Pd(OAc)2; for
its characterization, see the Supporting Information.
(20) Coppola, G. M.; Schuster, H. F. R-Hydroxy Acids in EnantioselectiVe
Synthesis; VCH: Weinhein, Germany, 1997.
Org. Lett., Vol. 9, No. 2, 2007
345

Table 3. Palladacycle 4-Catalyzed Addition Reactions of
Arylboronic Acids with Aldehydesa
Table 4. Palladacycle 4-Catalyzed Addition Reactions of
Arylboronic Acids with R-Ketoestersa
a Reaction conditions (not optimized): R-ketoester (1.0 equiv), aryl-
boronic acid (1.5-2.0 equiv), K3PO4 (1 equiv), toluene (2 mL), room
temperature. b Isolated yields (average of two runs).
practical catalysts for addition reactions.22 Our future work
will be directed to determine the scope and limitation of
metalacycle-including palladacycle-catalyzed addition reac-
tions and to develop the asymmetric version of these
processes.
Acknowledgment. We gratefully thank the NIH
(GM69704) for funding. Partial support from the PSC-CUNY
Research Award Program is also gratefully acknowledged.
We also thank Prof. Shi Jin at CSI-CUNY for his help on
the solvent purification and Frontier Scientific, Inc. for its
generous gifts of arylboronic acids and Pd(OAc)2.
a Reaction conditions (not optimized): aldehyde (1.0 equiv), arylboronic
acid (1.2-2.0 equiv), K3PO4 (1 equiv), toluene (2 mL), room temperature.
b Isolated yields (average of two runs).
and R-ketoesters at room temperature. Our study suggested
that other readily available and air/moisture stable metala-
cycles including palladacycles might also be highly efficient,
Supporting Information Available: General procedures
and characterizations of palladacycle-catalyzed addition
reactions. This material is available free of charge via the
Internet at http://pubs.acs.org.
(21) (a) For Rh(I)-catalyzed addition of aryltin with R-ketoesters: Oi,
S.; Moro, M.; Fukuhara, H.; Kawanishi, T.; Inoue, Y. Tetrahedron 2003,
59, 4351-4361. For recent examples of dialkylzinc addition of R-keto-
esters: (b) Blay, G.; Fernandez, I.; Marco-Aleixandre, A.; Pedro, J. R. Org.
Lett. 2006, 8, 1287-1290. (c) Wieland, L. C.; Deng, H.; Snapper, M. L.;
Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127, 15453-15456. (d) Funabashi,
K.; Jachmann, M.; Kanai, M.; Shibasaki, M. Angew. Chem., Int. Ed. 2003,
42, 5489-5492. (e) DiMauro, E. F.; Kozlowski, M. C. J. Am. Chem. Soc.
2002, 124, 12668-12669. (f) DiMauro, E. F.; Kozlowski, M. C. Org. Lett.
2002, 4, 3781-3784.
OL062814B
(22) For anionic six-electron donor-based (Type II) palladacycle-catalyzed
allylic additions of aldehydes and imines: (a) Solin, N.; Wallner, O. A.;
Szabo, K. J. Org. Lett. 2005, 7, 689-691. (b) Solin, N.; Kjellgren, J.; Szabo,
K. J. J. Am. Chem. Soc. 2004; 126, 7026-7033.
346
Org. Lett., Vol. 9, No. 2, 2007