Palladium-catalyzed nucleophilic benzylic substitutions of benzylic esters

Article abstract of DOI:10.1021/ja037735z

A palladium complex generated in situ from [Pd(η³-C₃H₅)(cod)]BF₄ and DPPF is a good catalyst for benzylic alkylation of benzyl methyl carbonate with the carbanion of dimethyl malonates. The catalytic reaction is applicable to a wide range of the benzylations of benzylic esters with malonates. The catalytic activity was heavily affected by the bite angle of the bidentate phosphine ligand on palladium. DPEphos ligand is superior to DPPF in the case of palladium-catalyzed benzylic amination of benzylic esters. Copyright

Full text of DOI:10.1021/ja037735z

Published on Web 09/12/2003
Palladium-Catalyzed Nucleophilic Benzylic Substitutions of Benzylic Esters
Ryoichi Kuwano,* Yutaka Kondo, and Yosuke Matsuyama
Department of Chemistry, Graduate School of Sciences, Kyushu UniVersity, 6-10-1 Hakozaki, Higashi-ku,
Fukuoka 812-8581, Japan
Received August 4, 2003; E-mail: rkuwascc@mbox.nc.kyushu-u.ac.jp
Table 1. Benzylic Alkylation of 3a with Dimethyl Malonatea
η3-Allyl-metal complex 1 is a key intermediate of many organic
reactions employing transition metal complexes. Palladium-
catalyzed allylic substitution of allylic esters is representative of
the reactions mediated by 1.1 The analogous η3-benzyl-metal
complex intermediate 22 has often been cited in rationalization of
regioselectivities in catalytic additions to vinylarenes using a
transition metal complex.3 However, palladium-catalyzed nucleo-
philic benzylic substitution of benzylic esters has not been well-
established despite its potential usefulness. Fiaud and Legros had
reported that a DPPE-palladium complex displayed catalytic activity
for benzylic substitutions of naphthylmethyl and quinolylmethyl
esters.4 The palladium catalyst, however, failed to promote reaction
of benzyl acetate.4a This paper discloses that a palladium complex
is a good catalyst for benzylic substitutions of benzyl esters with
malonates and amines. The palladium catalyst is applicable to
reaction with a wide range of benzylic esters.
convn
(3a), %
yield
(4a), %
c
d
d
entry
[Pd]b
ligand
DPPF
DPPF
DPPF
DPPF
DPPF
DPPF
2 PPh3
DPPE
base
4a:5ae
1
2
3
4
5
6
7
8
9
A
B
C
C
C
C
C
C
C
C
C
C
BSA
20
34
99
23
49
29
0
16
27
74
13
23
19
0
BSA
BSA
DBU
71:29
77:23
KO(t-Bu)
Cs2CO3
BSA
69:31
BSA
BSA
BSA
BSA
3
2
DPPP
16
39
74
71
10
41
62
62
10
11
12
DPPB
DPEphos
Xantphos
88:12
83:17
86:14
BSA
Various palladium catalyst precursors, ligands, bases, and
solvents were evaluated for the reaction of benzyl methyl carbonate
(3a) and dimethyl malonate. Selected results are shown in Table
1. The combination of [Pd(η3-C3H5)(cod)]BF4, DPPF, and BSA
provided the desired product 4a in the highest yield.5 The rate of
the reaction was heavily affected by the base and precursor of
palladium catalyst. The appropriate choice of the ligand on
palladium is also important for catalysis. Palladium complex
containing monodentate phosphine promoted no benzylic alkylation.
DPPE, which had been used for benzylic substitution of naph-
thylmethyl esters,4 was ineffective in the catalytic benzylic alky-
lation of 3a. Increasing the ligand bite angle enhanced the reaction
rate.6 The highest conversion of 3a and yield of 4a was observed
in a reaction using DPPF ligand. However, DPEphos and Xantphos,
providing a larger P-Pd-P angle, were less effective than DPPF.7
The amount of the palladium catalyst was reduced to 1 mol %
without a significant loss of yield of 4a (Scheme 1). Although
considerable formation of 5a was observed in the reaction of 3a,
the ortho-substituent of the benzylic ester suppressed the formation
of a dibenzylated product. The benzylic alkylation of 3b produced
the monoalkylated malonate 4b in 82% isolated yield with a small
amount of 5b.
a Reactions were conducted in THF (1.0 mL) at 80 °C for 3 h. The ratio
of 3a (0.2 mmol):dimethyl malonate:base:Pd:ligand ) 20:30:30:1:1.1. b A,
Pd(dba)2; B, [Pd(η3-C3H5)Cl]2; C, [Pd(η3-C3H5)(cod)]BF4. c KOAc (15
µmol) was added to the reaction mixture when BSA was used as a base.
d Determined by GC. e The ratios were calculated from the GC areas.
Scheme 1
reaction possesses high functional group compatibility. The ben-
zylations of acetamido- (6c) and methoxymalonate (6d) proceeded
with no deactivation of the palladium catalyst to produce R-het-
erosubstituted benzylmalonates in high yields. The former reactions
may provide a good synthetic approach to functionalized phenyl-
alanine derivatives.8 Reactions of naphthylmethyl esters were
completed within 1 h to give the coupling products 7p and 7q in
high yields.
To clarify the substituent effect of 3 on the reaction rate, reactions
of 6b with equimolar mixtures of 3a and 3c, 3a and 3e, and 3c and
3e were conducted, and the results of these experiments are shown
in Scheme 2. Both p-methoxy and p-trifluoromethyl groups
accelerated the benzylic substitution. The findings indicate that the
inductive effect of the substituent on the aromatic ring may control
the reaction rate rather than the resonance effect.
Reactions of various combinations of benzylic carbonate 3 and
substituted malonates 6 were conducted in the presence of 1 mol
% of the [Pd(η3-C3H5)(cod)]BF4-DPPF catalyst, providing the
corresponding benzylated products 7 in high yields as shown in
Table 2. The ortho-substituent on an aromatic ring of 3 did not
hinder the alkylation of 6. Both electron-rich and electron-poor
benzylic esters, 3c and 3e, respectively, underwent benzylic
alkylation without deterioration in the reaction rate. The catalytic
A palladium complex generated from [Pd(η3-C3H5)(cod)]BF4 and
a bidentate phosphine ligand exhibited high catalytic activity for
9
12104
J. AM. CHEM. SOC. 2003, 125, 12104-12105
10.1021/ja037735z CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Catalytic Benzylic Amination of Benzylic Estersa
Table 2. Catalytic Benzylations of 2-Substituted Malonatesa
b
entry
3
8
time, h
product
yield, %
1
3a
3b
3c
3e
3g
3h
3h
3h
8a
8a
8a
8a
8a
8a
8b
8c
96
24
24
3
1
1
9a
9b
9c
9d
9e
9f
73
80
90
88
96
93
98
94
2c
3c
4
5c
6
7
1
24
9g
9h
b
entry
3
6
time, h
product
yield, %
8
1c
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
3a
3a
3a
3a
3b
3b
3c
3c
3c
3d
3d
3e
3e
3f
6a
6b
6c
6d
6c
6d
6b
6c
6d
6b
6c
6b
6d
6b
6b
6a
6a
48
24
48
48
48
24
4
24
24
24
48
48
48
48
24
1
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
61
95
89
88
84
92
94
>99
94
98
89
78
83
79
86
92
92
a Reactions were conducted in DME (1.0 mL) at 80 °C. The ratio of 3
(1.0 mmol):8:[Pd(η3-C3H5)(cod)]BF4:DPEphos was 100:110:1:1.1 unless
otherwise noted. b Isolated yield. c 2 mol % of catalyst was used.
philic benzylic substitution of benzylic esters with high generality.
This finding may prove the usefulness of (η3-benzyl)palladium as
an intermediate in catalytic processes such as that of the (η3-allyl)-
palladium complex.
Acknowledgment. This work was supported by the Kurata
Memorial Hitachi Science and Technology Foundation.
Supporting Information Available: Experimental procedures and
characterization data for all new compounds (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
3g
3h
3i
1
References
a Reactions were conducted in THF (1.0 mL) at 80 °C. The ratio of 3
(1.0 mmol):6:base:KOAc:[Pd(η3-C3H5)(cod)]BF4:DPPF was 100:110:110:
7.5:1:1.1 unless otherwise noted. b Isolated yield. c 1.5 mmol of 6a and BSA
was used.
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Scheme 2
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(5) The reaction of 3a employing Pd(dba)2 or [Pd(η3-C3H5)(cod)]BF4-DPPF
catalyst yielded neither 4a nor 5a in the absence of base.
(6) Bite angles of DPPE, DPPP, DPPB, and DPPF in the palladium dichloride
complexes are 86°, 91°, 95°, and 99°, respectively: (a) Steffen, W. L.;
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benzylic amination of benzylic esters as well as alkylation. DPEphos
ligand is superior to DPPF in the reaction of 3a with dibutylamine
(8a).9,10 The scope of the benzylic amination using the palladium-
DPEphos catalyst is shown in Table 3. A wide range of benzylic
amines can be prepared by the palladium-catalyzed reaction. Of
note is that the benzylations of amines proceeded with no base to
give the desired products in high yields, while common benzylations
of amines with benzylic halides have required a stoichiometric
amount of base for neutralization of hydrogen halide. The reaction
may be useful for benzyl protection of amino groups in base-
sensitive compounds.
(7) Calculated values for the natural bite angles of DPEphos and Xantphos
are 102° and 112°, respectively: Kranenburg, M.; van der Burgt, Y. E.
M.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Goubitz, K.; Fraanje, J.
Organometallics 1995, 14, 3081-3089.
(8) Snyder, H. R.; Shekleton, J. F.; Lewis, C. D. J. Am. Chem. Soc. 1945,
67, 310-312.
(9) We evaluated DPPF, DPEphos, and Xantphos for the reaction of 3a and
8a with 5 mol % of catalyst. GC yields (3 h) were 7%, 23%, and 8%,
respectively.
(10) No benzylic amine 9f was detected by GC analysis in the reaction of 3h
and 8a at 80 °C in DME without the palladium catalyst.
In conclusion, palladium complexes with a bisphosphine ligand
bearing an appropriate bite angle were found to catalyze nucleo-
JA037735Z
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J. AM. CHEM. SOC. VOL. 125, NO. 40, 2003 12105