Pd-catalyzed allylic substitution using nucleophilic N-heterocyclic carbene as a ligand

Article abstract of DOI:10.1021/ol026961v

(Matrix presented) A nucleophilic N-heterocyclic carbene has been successfully used in a Pd(0)-catalyzed allylic substitution for the first time. It was found that allylic substitution with a soft nucleophile using a Pd-carbene catalyst proceeds via retention of configuration, the stereochemical reaction pathway being the same as that of the reaction using a Pd-phosphine complex.

Full text of DOI:10.1021/ol026961v

ORGANIC
LETTERS
2003
Vol. 5, No. 1
31-33
Pd-Catalyzed Allylic Substitution Using
Nucleophilic N-Heterocyclic Carbene as
a Ligand
Yoshihiro Sato, Taro Yoshino, and Miwako Mori*
Graduate School of Pharmaceutical Sciences, Hokkaido UniVersity,
Sapporo 060-0812, Japan
mori@pharm.hokudai.ac.jp
Received September 25, 2002
ABSTRACT
A nucleophilic N-heterocyclic carbene has been successfully used in a Pd(0)-catalyzed allylic substitution for the first time. It was found that
allylic substitution with a soft nucleophile using a Pd−carbene catalyst proceeds via retention of configuration, the stereochemical reaction
pathway being the same as that of the reaction using a Pd−phosphine complex.
Since the first isolation and X-ray crystallographical char-
acterization of nucleophilic N-heterocyclic carbenes,1 these
compounds have attracted considerable attention not only
as a stable isolable carbene species but also as molecules
for coordination to various transition metals.2 Nucleophilic
carbenes are regarded as strong σ-donor ligands and have
reactivities similar to tertiary phosphines. In recent palladium
chemistry, high catalytic efficiency has been found in a
variety of reactions, including Suzuki-Miyaura coupling,3
Kumada-Tamao-Corriu-type coupling,4 Mizoroki-Heck
reaction,5 amination of aryl halide,6 and Sonogashira cou-
pling,7 using nucleophilic carbenes as ligands. A palladium-
mediated allylic substitution was reported for the first time
as a stoichiometric reaction by Tsuji in 1965.8 Later, this
reaction was expanded to a catalytic reaction by Hata and
Atkins in 1970,9 independently. At present, this reaction has
been recognized as one of the most synthetically useful C-C
bond-forming reactions.10 However, there have been no
reports on Pd(0)-catalyzed allylic substitution using a nu-
(4) (a) Huang, J.; Nolan, S. P. J. Am. Chem. Soc. 1999, 121, 9889. For
Ni-catalyzed Kumada-Tamao cross-coupling reactions using nucleophilic
N-heterocyclic carbenes, see: (b) Bo¨hm, V. P. W.; Weskamp, T.; Gsto¨tt-
mayr, C. W. K.; Herrmann, W. A. Angew. Chem., Int. Ed. 2000, 39, 1602.
(5) (a) Herrmann, W. A.; Elison, M.; Fischer, J.; Ko¨cher, C.; Artus, G.
R. J. Angew. Chem., Int. Ed. Engl. 1995, 34, 2371. (b) Herrmann, W. A.;
Fischer, J.; Elison, M.; Ko¨cher, C.; Artus, G. R. J. Chem. Eur. J. 1996, 2,
772. (c) Enders, D.; Gielen, H.; Raabe, G.; Runsink, J.; Teles, H. Chem.
Ber. 1996, 129, 1483. (d) McGuinness, D. S.; Green, M. J.; Cavell, K. J.;
Skelton, B. W.; White, A. H. J. Organomet. Chem. 1998, 565, 165. (e)
McGuinness, D. S.; Cavell, K. J. Organometallics 1999, 18, 1596. (f) Clyne,
D. S.; Jin, J.; Genest, E.; Gallucci, J. C.; RajanBabu, T. V. Org. Lett. 2000,
2, 1125. (g) Yang, C.; Lee, H. M.; Nolan, S. P. Org. Lett. 2001, 3, 1511.
(6) (a) Huang, J.; Grasa, G.; Nolan, S. P. Org. Lett. 1999, 1, 1307. (b)
Stauffer, S. R.; Lee, S.; Stambuli, J. P.; Hauck, S. I.; Hartwig, J. F. Org.
Lett. 2000, 2, 1423.
(7) (a) Herrmann, W. A.; Bo¨hm, V. P. W.; Gsto¨ttmayr, C. W. K.;
Grosche, M.; Reisinger, C.-P.; Weskamp, T. J. Organomet. Chem. 2001,
616, 617. (b) Yang, C.; Nolan, S. P. Organometallics 2002, 21, 1020.
(8) (a) Tsuji, J.; Takahashi, H.; Morikawa, M. Tetrahedron Lett. 1965,
4387. (b) Tsuji, J. Acc. Chem. Res. 1969, 2, 144.
(9) (a) Hata, G.; Takahashi, K.; Miyake, A. Chem. Commun. 1970, 1392.
(b) Atkins, K. E.; Walker, W. E.; Manyik, R. M. Tetrahedron Lett. 1970,
3821.
(1) Arduengo, A. J., III; Harlow, R. L.; Kline, M. J. Am. Chem. Soc.
1991, 113, 361.
(2) For reviews, see: (a) Herrmann, W. A. Angew. Chem., Int. Ed. 2002,
41, 1290. (b) Herrmann, W. A.; Weskamp, T.; Bo¨hm, V. P. W. AdV.
Organomet. Chem. 2002, 48, 1. (c) Jafarpour, L.; Nolan, S. P. AdV.
Organomet. Chem. 2001, 46, 181. (d) Bourissou, D.; Guerret, O.; Gabba¨ı,
F. P.; Bertrand, G. Chem. ReV. 2000, 100, 39. (e) Herrmann, W. A.; Ko¨cher,
C. Angew. Chem., Int. Ed. Engl. 1997, 36, 2162.
(3) (a) Herrmann, W. A.; Reisinger, C. P.; Spiegler, M. J. Organomet.
Chem. 1998, 557, 93. (b) Bo¨hm, V. P. W.; Gsto¨ttmayr, C. W. K.; Weskamp,
T.; Herrmann, W. A. J. Organomet. Chem. 2000, 595, 186. (c) Zhang, C.;
Huang, J.; Trudell, M. L.; Nolan, S. P. J. Org. Chem. 1999, 64, 3804. (d)
Lee, H. M.; Nolan, S. P. Org. Lett. 2000, 2, 2053. (e) Zhang, C.; Trudell,
M. L. Tetrahedron Lett. 2000, 41, 595. (f) Fu¨rstner, A.; Leitner, A. Synlett,
2001, 290.
10.1021/ol026961v CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/11/2002

cleophilic carbene as a ligand. Herein we report the first
application of a nucleophilic carbene as a ligand to this
reaction.
Initially, reactions of acetate 1 with sodio dimethyl
malonate (4) were investigated using various Pd-carbene
catalysts (3a-d) formed by treatment of PdCl2 with BuLi
in the presence of imidazolium salts (2a-d)11 (Table 1). To
It has recently been reported that Pd-carbene species can
be formed in situ from a palladium complex and imidazolium
salts in the presence of Cs2CO3 as a base, and this
Pd-carbene catalyst has been used in various C-C coupling
reactions.3c Thus, reactions of 1 with dimethyl malonate were
again investigated using a Pd-carbene catalyst formed from
Pd2dba3‚CHCl3 and imidazolium salt 2d in the presence of
Cs2CO3 (Table 2).
Table 1. Allylic Substitution of 1 with 4 Using a Pd-Carbene
Complex
Table 2. Reaction of 1 with Dimethyl Malonate Using Pd2dba3
and Imidazolium Salt 2d
run
base
NaH
Cs2CO3
time (h)
yield (%)
1
2
2
10
98
100
Surprisingly, when a THF solution of acetate 1 and sodio
dimethyl malonate (4) was treated with a Pd-carbene
catalyst formed from Pd2dba3‚CHCl3 (2.5 mol %), imidazo-
lium salt 2d (5.0 mol %), and Cs2CO3 (10 mol %), the
reaction was completed in 2 h to give the desired product 5
in excellent yield (98%) (Table 2, run 1). In addition, the
reaction of 1 and dimethyl malonate using Pd2dba3‚CHCl3
and imidazolium salt 2d in the presence of an excess amount
of Cs2CO3 at 50 °C gave the desired product 5 in quantitative
yield, although the reaction time was slightly prolonged (run
2). These results indicate that the Pd-carbene species
generated from Pd2dba3‚CHCl3, 2d, and Cs2CO3 is more
reactive than the above-mentioned Pd-carbene catalyst
prepared from PdCl2, 2d, and BuLi and that prior preparation
of sodio dimethyl malonate (4) from dimethyl malonate and
NaH is unnecessary in this catalyst system. Next, a control
experiment without imidazolium salt 2d was carried out in
order to confirm whether a nucleophilic carbene, generated
from imidazolium salt 2d and Cs2CO3, operates as a ligand
in this reaction. The reaction of 1 and sodio dimethyl
malonate (4) with Pd2dba3‚CHCl3 (2.5 mol %) in the absence
of imidazolium salt 2d in THF at 50 °C produced a trace
amount of desired product 5 in 3% yield, and the starting
material 1 was recovered in 97% yield. This result indicates
that the addition of imidazolium salt 2d is necessary in this
reaction and that a nucleophilic carbene formed from 2d
plays an important role as a ligand to afford the product 5
in good yield.
a THF suspension of PdCl2 (5 mol %) and imidazolium salt
2a (5 mol %) was added a solution of BuLi-hexane (15
mol %) at 0 °C, and the mixture was stirred for about 1 h at
the same temperature. To the mixture of Pd-carbene catalyst
(3a) was added a THF solution of 1 followed by addition of
a solution of 4 at 0 °C, and the mixture was heated at 50 °C
for 24 h. As a result, the desired substitution product 5 was
afforded in only 6% yield, and starting material 1 was
recovered in 76% yield along with alcohol 6, which would
be derived from 1, in 13% yield (Table 1, run 1). It was
found that the reaction of 1 and 4 with Pd-carbene catalyst
3c or 3d, having aromatic rings on nitrogens in the imidazol-
2-ylidene skeleton, improved the yield of desired product.
The use of 3d, having a sterically bulky substituent on the
aromatic ring, showed the best reactivity in this reaction,
giving 5 in 77% yield (run 4).
To evaluate the scope of this reaction, allylic substitution
of various substrates using a Pd2dba3-imidazolium salt 2d-
Cs2CO3 system was investigated. The reaction of 7 and
dimethyl malonate required heating to reflux, and allylation
products were produced in a total yield of 89% (R-adduct
8a, 55%; γ-adduct 8b, 18%; double allylation product 8c,
16%) (Scheme 1). In the case of cyclic lactone 9, the reaction
(10) For reviews, see: (a) Trost, B. M. Acc. Chem. Res. 1980, 13, 385.
(b) Harrington, P. M. In ComprehensiVe Organometallic Chemistry II; Abel,
E. W., Stone, F. G. A., Wilkinson, G., Eds.; Elsevier Science, Ltd.: Oxford,
UK, 1995; Vol. 12, p 797. (c) Tsuji, J. Palladium Reagents and Catalysts:
InnoVations in Organic Synthesis; Wiley & Sons, Ltd.: Chichester, UK,
1995.
(11) Recently, we have reported a preparation of Ni-carbene complexes
from NiCl2 and imidazolium salts by treatment with BuLi; see: Sato, Y.;
Sawaki, R.; Mori, M. Organometallics 2001, 20, 5510.
32
Org. Lett., Vol. 5, No. 1, 2003

Scheme 1
Scheme 3
with dimethyl malonate proceeded at 50 °C to give the
product 10 in 63% yield as a single diastereomer (Scheme
2).
tion for the first time. It has been proven that an imidazolium
salt 2d having the bulky aromatic rings attached to the
nitrogens in its imidazol-2-ylidene skeleton is suitable as a
ligand and that a Pd2dba3-imidazolium salt 2d-Cs2CO3 system
is highly efficient for producing Pd-carbene catalyst in this
reaction. It has also been found that allylic substitution with
a soft nucleophile such as dimethyl malonate using a Pd-
carbene catalyst proceeds via overall retention to give the
product in a stereospecific manner, the stereochemical
reaction course obviously being the same as that of the
reaction using a Pd-phosphine complex. Further studies to
expand the scope of this reaction and to apply this method
to asymmetric synthesis are ongoing.
Scheme 2
To examine the stereochemical reaction course in the
allylic substitution using a Pd-carbene catalyst, reactions
of 11-R and 11-â were investigated (Scheme 3). In the
reactions of 11-R and 11-â under similar conditions, 12-R
and 12-â were stereospecifically produced in 83 and 94%
yields, respectively. These results indicate that allylic
substitution using a Pd-carbene catalyst proceeds via an
overall retention mode in a manner similar to that using a
Pd-phosphine complex.
Acknowledgment. This work was financially supported
by a Grand-in-Aid for Scientific Research from the Japan
Society of the Promotion of Science (No. 14703031).
Supporting Information Available: Typical experimen-
tal procedures for allylic substitution of 1 with 4 and spectral
data for 12-R. This material is available free of charge via
the Internet at http://pubs.acs.org.
In summary, a nucleophilic N-heterocyclic carbene has
been successfully applied to Pd(0)-catalyzed allylic substitu-
OL026961V
Org. Lett., Vol. 5, No. 1, 2003
33