Palladium-catalyzed benzylation of active methine compounds without additional base: Remarkable effect of 1,5-cyclooctadiene

Article abstract of DOI:10.1021/ol048540e

(Chemical Equation Presented) The palladium complex prepared from DPPF and Cp(η³-C₃H₅)Pd is an effective catalyst for the alkylation of active methine compounds with benzylic carbonates under neutral conditions. The additi

Full text of DOI:10.1021/ol048540e

ORGANIC
LETTERS
2004
Vol. 6, No. 20
3545-3547
Palladium-Catalyzed Benzylation of
Active Methine Compounds without
Additional Base: Remarkable Effect of
1,5-Cyclooctadiene
Ryoichi Kuwano* and Yutaka Kondo
Department of Chemistry, Graduate School of Sciences, Kyushu UniVersity,
6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan
rkuwascc@mbox.nc.kyushu-u.ac.jp
Received July 26, 2004
ABSTRACT
The palladium complex prepared from DPPF and Cp(η
3-C3H5)Pd is an effective catalyst for the alkylation of active methine compounds with
benzylic carbonates under neutral conditions. The addition of 1,5-cyclooctadiene brought about remarkable improvement in the lifetime of the
palladium catalyst, which led to high yields of the desired benzylation products.
The alkylation of active methylene and methine compounds
is a fundamental reaction in organic synthesis, and has
usually been carried out under basic conditions.1 Recently,
we disclosed a palladium-catalyzed benzylation of malonates
using various benzylic carbonates.2,3 A palladium complex
generated from DPPF and [Pd(η3-C3H5)(cod)]BF4 was the
best catalyst for the benzylation, which required a stoichio-
metric amount of base, N,O-bis(trimethylsilyl)acetamide
(BSA). A plausible mechanism for catalytic benzylation is
shown in Figure 1. DPPF-ligated (η3-allyl)palladium(II) A
is reduced to the palladium(0) species B via nucleophilic
attack of malonate carbanion. Benzyl methyl carbonate (C)
is activated by palladium(0) B4 and forms a (η3-benzyl)-
palladium species which can react with soft nucleophiles.5
It is noteworthy that methoxide is liberated through the
oxidative addition of C followed by decarboxylation. The
methoxide was expected to function as a base for the
deprotonation of the malonate. This mechanistic consider-
ation prompted us to develop a new catalytic benzylation of
active methine compounds without an additional base. Tsuji
et al. had developed palladium-catalyzed allylation under
(1) Smith, M. B.; March, J. AdVanced Organic Chemistry: Reactions,
Mechanisms, and Structure, 5th ed.; John Wiley & Sons: New York, 2001;
Chapter 10-104, pp 548-551.
(2) Kuwano, R.; Kondo, Y.; Matsuyama, Y. J. Am. Chem. Soc. 2003,
125, 12104-12105.
(3) (a) Legros, J.-Y.; Fiaud, J.-C. Tetrahedron Lett. 1992, 33, 2509-
2510. (b) Legros, J.-Y.; Toffano, M.; Fiaud, J.-C. Tetrahedron 1995, 51,
3235-3246. (c) Legros, J.-Y.; Primault, G. l.; Toffano, M.; Rivie`re, M.-
A.; Fiaud, J.-C. Org. Lett. 2000, 2, 433-436.
Figure 1. Plausible reaction mechanism of catalytic benzylation.
10.1021/ol048540e CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/10/2004

neutral conditions on the basis of the working hypothesis
mentioned above.6 Herein we report a new palladium catalyst
system for conducting the benzylation independent of the
additional base.
Table 1. Alkylations of Active Methine Compounds (2) with
(Naphthyl)methyl Carbonates (1)a
Our initial work focused on the alkylation of diethyl
phenylmalonate (2a) with (1-naphthyl)methyl methyl carbon-
ate (1a) (Scheme 1). In the presence of BSA base, the
Scheme 1. Evaluation of Palladium Catalyst Precursors
reaction of 1a was complete within 1 h at a catalyst loading
of 1 mol % DPPF-[Pd(η3-C3H5)(cod)]BF4, yielding the
desired product 3a quantitatively. However, the palladium-
(II) complex scarcely exhibited catalytic activity for alkyla-
tion without an additional base, even if the reaction was
conducted in the presence of the 5 mol % palladium. This
observation indicates that the DPPF-[Pd(η3-C3H5)(cod)]BF4
complex is not appropriately reduced to the active palladium-
(0) catalyst without the malonate carbanion or base. The use
of other palladium(II) compounds, Pd(OAc)2 and PdCl2(cod),
resulted in no reaction. Pd(dba)2 (dba ) dibenzylidene-
acetone), which is commonly used as a palladium(0) catalyst
precursor, exhibited an insufficient reaction rate. The DBA
ligand might inhibit oxidative addition of 1a to DPPF-
palladium(0) because the coordination of the dba ligand is
not weak enough to be displaced by 1a.7 The in-situ-
generated palladium catalyst from DPPF and (η3-allyl)-
(cyclopentadienyl)palladium(II) [Cp(η3-C3H5)Pd], which is
known to readily provide palladium(0) species via reductive
elimination in the presence of tertiary phosphine,8 gave the
alkylation product 3a in the highest yield (88%). The catalyst
loading was successfully reduced to 1 mol % palladium at a
high concentration of the substrates (1.0 M), and the desired
product 3a was obtained in 99% isolated yield.
a Reactions were conducted on a 1 mmol scale in THF (1.0 mL) at 80
°C for 1 h unless otherwise noted. Isolated yields are given. Np ) naphthyl.
b The reaction was conducted for 24 h. c The reaction was conducted for
3 h.
(2c) and methoxymalonate (2d) were converted completely
into 3d and 3e within 1 h the same as the phenylmalonate.
These heterosubstituents attached to the reaction site of
malonates did not cause deactivation of the palladium catalyst
and formation of undesirable side products. Compounds
3f-h were obtained in high yields through the alkylation of
the corresponding â-ketoester and 1,3-diketone using the
DPPF-Cp(η3-C3H5)Pd catalyst. Azlactones derived from
phenylglycine and valine afforded 4,4-dialkylated azlactones
3i and 3j, which will be readily converted into R-alkylated
R-amino acids.9 In most cases, the desired alkylation products
were obtained in quantitative yields.
We attempted to apply the DPPF-Cp(η3-C3H5)Pd catalyst
to the alkylation of 2a with benzyl methyl carbonate (4a).
However, no benzylation occurred, and the reaction mixture
turned into a dark brown solution immediately after heating
at 80 °C. This observation suggested that the DPPF-
A wide range of active methine compounds 2 underwent
the palladium-catalyzed alkylation with (naphthyl)methyl
carbonates 1a and 1b as shown in Table 1. The production
of 3c was slower than that of 3a and 3b, while acetamido-
(4) (a) Nagayama, K.; Shimizu, I.; Yamamoto, A. Bull. Chem. Soc. Jpn.
1999, 72, 799-803. (b) Narahashi, H.; Yamamoto, A.; Shimizu, I. Chem.
Lett. 2004, 33, 348-349.
(5) (a) Nettekoven, U.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124,
1166-1167. (b) Utsunomiya, M.; Hartwig, J. F. J. Am. Chem. Soc. 2003,
125, 14286-14287.
(6) (a) Tsuji, J.; Shimizu, I.; Minami, I.; Ohashi, Y. Tetrahedron Lett.
1982, 23, 4809-4812. (b) Tsuji, J.; Shimizu, I.; Minami, I.; Ohashi, Y.;
Sugiura, T.; Takahashi, K. J. Org. Chem. 1985, 50, 1523-1529.
(7) Amatore, C.; Jutand, A.; Khalil, F.; M’Barki, M. A.; Mottier, L.
Organometallics 1993, 12, 3168-3178.
(8) Matsumoto, M.; Yoshioka, H.; Nakatsu, K.; Yoshida, T.; Otsuka, S.
J. Am. Chem. Soc. 1974, 96, 3322-3324.
(9) Trost, B. M.; Ariza, X. J. Am. Chem. Soc. 1999, 121, 10727-10737.
Org. Lett., Vol. 6, No. 20, 2004
3546

palladium(0) complex aggregated to form a palladium cluster
because of both its coordinative unsaturation and the low
reactivity of benzyl methyl carbonate.10 Thus, we presumed
that the undesirable aggregation could be suppressed by an
additional labile ligand such as olefin. Various weak ligands
were evaluated for the reaction of p-methoxybenzyl methyl
carbonate (4b) with 2 (Table 2). Both DBA and tri-
Table 3. Benzylations of Active Methine Compounds (2)a
Table 2. Effects of Additional Labile Ligands on the Reaction
of 4b with 2aa
entry
additiveb
yield,c %
1
2
3
4
5
6
7
none
11
2
2
20
15
69
dibenzylideneacetone (DBA) (2)
Ph3PdO (2)
1-octene (10)
2,5-norbornadiene (NBD) (2)
1,5-cyclooctadiene (COD) (2)
1,5-cyclooctadiene (COD) (10)
>99 (98)d
a Reactions were conducted on a 1 mmol scale in THF (1.0 mL) at 80
°C for 3 h. b Molar equivalents of additive to Pd are shown in parentheses.
c GC yields at 3 h. d Isolated yield of 5a is shown in parentheses.
phenylphosphine oxide caused inhibition of the catalytic
benzylation. Small change was observed when the benzy-
lation was conducted in the presence of 1-octene or 2,5-
norbornadiene. Surprisingly, a catalytic amount of 1,5-
cyclooctadiene(COD)broughtaboutaconsiderableimprovement
in the lifetime of the catalyst. The benzylation product 5a
was obtained in 98% isolated yield when the catalytic
reaction was conducted for 3 h in the presence of 10 mol %
additional COD.
The addition of COD to DPPF-Cp(η3-C3H5)Pd catalyst
was effective for the reaction of diverse benzylic methyl
carbonates (Table 3). Benzyl methyl carbonate (4a) was less
reactive than the other benzylic carbonates. It was converted
into 5b in 84% yield for 24 h at a catalyst loading of 2 mol
% palladium. The reactions of electron-poor 4d and 4e
yielding 5d and 5e were as fast as that of electron-rich 4b.
However, an unidentified side product was observed in the
reaction of p-(trifluoromethyl)benzyl methyl carbonate and
seemed to cause a low yield of 5e (65% yield at a catalyst
loading of 1% palladium). The desired 5e was successfully
obtained in 90% isolated yield by use of 2 mol % catalyst.
Substituted malonates other than phenylmalonate 2a under-
went the palladium-catalyzed reaction under the present
reaction conditions. The palladium catalyst system DPPF-
Cp(η3-C3H5)Pd-COD was applicable to the benzylations of
a Reactions were conducted on a 1 mmol scale in THF (1.0 mL) at 80
°C. Isolated yields are given. b The reactions were conducted with 2 mol
% of DPPF-Pd catalyst.
â-ketoester 2e and 1,3-diketone 2f. However, azlactones
failed to react with 4b by means of the DPPF-palladium
catalyst.
In conclusion, the in-situ-generated palladium(0) complex
from DPPF and Cp(η3-C3H5)Pd is a useful catalyst for the
benzylation of active methine compounds in the absence of
an additional base. The addition of COD brought about a
remarkable improvement in the yields of the desired ben-
zylation products 5. The additional COD would prevent the
DPPF-palladium(0) from aggregating to form inactive
palladium species without loss of the catalytic activity and
could prolong the lifetime of the catalyst.
Acknowledgment. This work was supported by the
Sumitomo Foundation and a Grant-in-Aid for Young Sci-
entists (A) (no. 16685011) from the MEXT.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(10) Sisak, A.; Ungvy, F.; Kiss, G. J. Mol. Catal. 1983, 18, 223-235.
OL048540E
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3547