Use of acetate as a leaving group in palladium-catalyzed nucleophilic substitution of benzylic esters

Article abstract of DOI:10.1016/j.tetlet.2007.06.157

The palladium complex prepared in situ from [Pd(η³-C₃H₅)(cod)]BF₄ and bidentate phosphine DPPF was a good catalyst for the nucleophilic substitution of benzyl acetate. Significant acceleration of the palladium-catalyzed substitution was observed when an alcohol was employed as a reaction solvent. The palladium catalyst was effective for the benzylation of various stabilized carbanions, amines, and benzenesulfinate with benzylic acetates.

Full text of DOI:10.1016/j.tetlet.2007.06.157

Tetrahedron Letters 48 (2007) 6109–6112
Use of acetate as a leaving group in palladium-catalyzed
nucleophilic substitution of benzylic esters
Masashi Yokogi and Ryoichi Kuwano*
Department of Chemistry, Graduate School of Sciences, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812–8581, Japan
Received 9 June 2007; revised 26 June 2007; accepted 28 June 2007
Available online 4 July 2007
Abstract—The palladium complex prepared in situ from [Pd(g3-C3H5)(cod)]BF4 and bidentate phosphine DPPF was a good cata-
lyst for the nucleophilic substitution of benzyl acetate. Significant acceleration of the palladium-catalyzed substitution was observed
when an alcohol was employed as a reaction solvent. The palladium catalyst was effective for the benzylation of various stabilized
carbanions, amines, and benzenesulfinate with benzylic acetates.
Ó 2007 Elsevier Ltd. All rights reserved.
Palladium-catalyzed nucleophilic substitutions of allylic
carboxylates1 have often been used for removal of the
allyl protective groups2 as well as carbon–carbon and
carbon–heteroatom bond formation in organic synthe-
sis.3 In the catalytic allylic substitutions, acetate is com-
monly chosen as a leaving group because of its
accessibility as well as simplicity. Recently, we devel-
oped a palladium-catalyzed substitution of benzylic car-
bonates.4 As with the allylic substitution, the benzylic
carbon–oxygen bond of the benzylic carbonate is acti-
vated by palladium(0) to form (g3-benzyl)palladium
intermediate, which is readily attacked by various
nucleophiles.5 Fiaud and Legros reported the catalytic
benzylic substitution of (naphthyl)methyl acetates,6
while use of the acetate leaving group remains formida-
ble for the palladium-catalyzed reaction of simple benzyl
esters.7–9 Here, we report that the palladium-catalyzed
nucleophilic substitution of benzylic acetates proceeded
efficiently in an alcoholic solvent. The palladium cataly-
sis employed in alcohol was effective in a broad range of
substrate combinations of benzylic acetates and
nucleophiles.
silyl)acetamide (BSA)–KOAc base, affording benzylated
malonates 3a and 4 in the highest yield (Scheme 1).4a
However, the use of benzyl acetate (1a) in place of 1a0
under the identical reaction conditions resulted in little
production of 3a. Meanwhile, we found previously that
the Suzuki-Miyaura cross-coupling of benzylic acetates
is significantly accelerated by use of tert-amyl alcohol
as a reaction solvent.11 Thus, we attempted the catalytic
benzylic substitution of 1a in the tertiary alcohol and
were pleased to obtain the desired benzylated products
3a and 4 in 59% and 13% yields, respectively (Table 1,
entry 1).12 The choice of solvent and base was crucial
for the palladium catalysis. Product 3a was scarcely de-
tected in the reaction conducted in non-polar solvents
In our recent report, the nucleophilic substitution of
benzyl methyl carbonate (1a0) with dimethyl malonate
(2a) was carried out in THF at 80 °C with [Pd(g3-C3H5)-
(cod)]BF4–DPPF10 catalyst and N,O-bis(trimethyl-
Keywords: Palladium; Homogeneous catalysis; Nucleophilic substitu-
tion; Benzyl acetate.
*
Scheme 1. Nucleophilic substitution of benzyl esters with dimethyl
malonate:benzyl carbonate (1a0) versus acetate (1a).
Corresponding author. Tel.: +81 92 642 2572; fax: +81 92 642
2607; e-mail: rkuwascc@mbox.nc.kyushu-u.ac.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.06.157

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M. Yokogi, R. Kuwano / Tetrahedron Letters 48 (2007) 6109–6112
Table 1. Effects of solvent and base on the palladium-catalyzed
nucleophilic substitution of 1a with 2aa
Table 2. Nucleophilic substitution of benzylic acetates with stabilized
carbanionsa
Entry
Solvent
Base
Yieldb (%)
3a
4a
1
2
3
4
5
6
7
8
9
t-AmOHc
Toluene
THF
MeCN
DMF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
Cs2CO3
Na2CO3
DBU
59
0
2
15
16
0
13
0
0
0
0
EtOH
0
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
32
43
14
9
11
17
0
0
28e
Entry 1
2
Product (3)
Yieldb
(%)
10
11d
K2CO3
59e
a Reactions were conducted on 0.2 mmol scale in a solvent (1.0 mL) at
80 °C for 3 h. The ratio of 1a:2a:base:[Pd(g3-C3H5)(cod)]BF4:DPPF
was 20:30:30:1.0:1.1.
1
1a 2b
1b 2b
1c 2b
1d 2b
1e 2b
1f 2b
3b: R = H
3c: R = p-MeO
3d: R = p-MeO2C 89
3e: R = p-CF3
3f: R = p-F
3g: R = o-Me
90
92
2c
3d
4
b GC yields (average of two runs) were given unless otherwise noted.
c tert-Amyl alcohol.
95
95
90
5
6
d The reaction was conducted on 1 mmol scale for 24 h with 1 mol %
palladium.
e Isolated yield.
7
1b 2c
3h
96
(entries 2 and 3). Polar aprotic solvents improved the
production of 3a to some degree (entries 4 and 5). Use
of primary alcohol brought about the solvolysis of 1a
in the presence of potassium carbonate (entry 6). In
tert-amyl alcohol, solvolysis was concurrent with the
substitution of 1a when potassium phosphate and ce-
sium carbonate were used (entries 7 and 8). The side
reaction was evaded with sodium carbonate or DBU,
while the yield of 3a was low (entries 9 and 10). The
amount of the DPPF–palladium catalyst was success-
fully reduced to 0.01 equiv of 1a, and the desired prod-
ucts 3a and 4 were obtained in high combined yield
(entry 11).13
8c
1b 2d
1d 2d
1e 2d
3i: R = p-MeO
3j: R = p-CF3
3k: R = p-F
88
86
90
9c
10d
11c
1b 2fe
3l
83
12
13
1b 2f
1b 2g
3m: R = EtO2C
3n: R = Ac
87
85
a Reactions were conducted on 1.0 mmol scale in tert-amylalcohol
(1.0 mL) at 80 °C for 48 h. The ratio of 1:2:K2CO3:[Pd(g3-
C3H5)(cod)]BF4:DPPF was 50:55:55:1.0:1.1.
b Isolated yield.
c The reactions were conducted with 1 mol % palladium.
d The reactions were conducted for 24 h.
The scope of the palladium-catalyzed substitution of
benzylic acetates with stabilized carbanions is summa-
rized in Table 2. As with 2a, 2-phenylmalonate 2b
underwent catalytic benzylation with acetate 1a, giving
product 3b in 90% yield with 2% catalyst loading (entry
1). The a-substituent of 2b hardly hindered the reaction
with 1a. Even heteroatom substituents binding to the
reaction site of 2d or 2e did not decrease the yield of 3
(entries 8–11). These malonate carbanions reacted with
a broad range of benzylic acetates. The electron-donat-
ing group of 1b accelerated the catalytic nucleophilic
substitution with 2b, which produced 3c in 92% yield
with 1 mol % catalyst loading (entry 2). The reaction
of electron-poor substrates 1c–e required 2 mol % of
palladium catalyst for the efficient production of 3d–f
(entries 3–5).14 The ortho-methyl group of 1f did not
cause significant deterioration of the reaction rate (entry
6). The catalyst system was effective for the benzylation
of 1,3-diketone 2g as well as b-ketoester 2f (entries 12
and 13).
amount (entry 1). Using ethanol in place of tert-amyl
alcohol allowed the catalytic amination to proceed effi-
ciently in the presence of 5% DPPF–palladium (entry
2). The decomposition of 1a to benzyl alcohol was ob-
served when the catalyst loading decreased to 1%. The
competitive solvolysis was successfully suppressed by
the addition of triethylamine to the reaction mixture
(entry 3).15 Under the optimized conditions, a variety
of p- or o-substituted benzylic acetates reacted with 5a
in good yields (entries 4–7). Other secondary amines,
morpholine (5b) and N-methylaniline (5c), were con-
verted into tertiary amines 6f–h in good yields (entries
8–10). Primary amines were usable as nucleophiles for
catalytic substitution but gave the corresponding sec-
ondary benzylamines as a mixture with dibenzylamines.
The reaction of cyclohexylamine with 1a gave the mono-
and dibenzylated products in 22% and 34% isolated
yields, respectively.
Benzylic acetates underwent palladium-catalyzed substi-
tution with secondary amines (Table 3). Initially, the
benzylic amination of 1a with dibutylamine 5a was at-
tempted in tert-amyl alcohol, but yielded 6a in a trace
Palladium-catalyzed sulfonylation of 1a was accom-
plished using sodium benzenesulfinate (7) as a nucleo-

M. Yokogi, R. Kuwano / Tetrahedron Letters 48 (2007) 6109–6112
Table 3. Nucleophilic substitution of benzylic acetates with secondary aminesa
6111
Entry
1
5
Time (h)
Product (6)
Yieldb (%)
1c,d
2c
1a
1a
1a
5a
5a
5a
3
3
48
1e
49e (96)f
85
6a
3
4
5
6
7
1b
1c
1d
1f
5a
5a
5a
5a
48
72
72
72
6b: R = p-MeO
6c: R = p-MeO2C
6d: R = p-CF3
6e: R = o-Me
79
73
81
80
8
9
1a
1e
5b
5b
48
72
6f: R = H
6g: R = F
88
73
10
1a
5c
72
6h
82
a Reactions were conducted on 1.0 mmol scale in ethanol (1.0 mL) at 80 °C. The ratio of 1:2:Et3N:[Pd(g3-C3H5)(cod)]BF4:DPPF was
110:100:110:1.0:1.1.
b Isolated yields were given unless otherwise noted.
c The reactions were conducted on 0.2 mmol scale in the absence of Et3N with 5 mol % palladium.
d The reaction was conducted in tert-amyl alcohol.
e GC yield (average of two runs).
f GC yield after 24 h is given in the parentheses.
16685011) and Scientific Research on Priority Areas
(No. 19020051) from MEXT.
References and notes
Scheme 2. Nucleophilic substitution of 1a with 7.
1. (a) Hata, G.; Takahashi, K.; Miyake, A. J. Chem. Soc.,
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E.; Manyik, R. M. Tetrahedron Lett. 1970, 11, 3821; (c)
Tsuji, J. In Palladium Reagents and Catalysts; John Wiley
& Sons: West Sussex, 2004; pp 431–517.
phile (Scheme 2). The sulfonylation conducted in etha-
nol or tert-amyl alcohol was sluggish because of poor
solubility of 7 in these solvents. Addition of water to
the reaction mixture allowed the sulfinate salt to dissolve
in the reaction solvent, furnishing benzylsulfone 8 in
high yield.
´
2. Review: Guibe, F. Tetrahedron 1998, 54, 2967.
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128, 1828.
In conclusion, the nucleophilic substitution of benzyl
acetates proceeded in the presence of [Pd(g3-
C3H5)(cod)]BF4–DPPF catalyst. Use of alcoholic sol-
vent was critical for the palladium catalysis. A variety
of nucleophiles were utilized for the palladium-catalyzed
substitution. Generally, acetates were readily accessible
and treatable as compared to carbonates. The results de-
scribed here will make the palladium-catalyzed benzylic
substitution more useful in organic synthesis.
6. (a) Legros, J.-Y.; Fiaud, J.-C. Tetrahedron Lett. 1992, 33,
2509; (b) Legros, J.-Y.; Toffano, M.; Fiaud, J.-C. Tetra-
´
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J.-C. Tetrahedron: Asymmetry 2005, 16, 1183.
7. Chatani and Murai reported the cobalt-catalyzed homo-
logation of benzyl acetate involving the activation of the
benzylic carbon–oxygen bond: Chatani, N.; Sano, T.; Ohe,
K.; Kawasaki, Y.; Murai, S. J. Org. Chem. 1990, 55, 5923.
8. Jutand reported that the oxidative addition of the carbon–
oxygen bond in benzylic acetate was observed in the
reaction of [2-(acetoxymethyl)phenyl]diphenylphosphine
Acknowledgments
This work was supported by Tokuyama Science Foun-
dation, Iketani Science and Technology Foundation,
and Grant-in-Aids for Young Scientists (A) (No.

6112
M. Yokogi, R. Kuwano / Tetrahedron Letters 48 (2007) 6109–6112
´
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stirred at room temperature for 5 min. Benzylic acetate 1
(1.0 mmol) and an active methylene compound
2
9. Shimizu and Yamamoto reported Heck reaction of benzyl
trifluoroacetate: Narahashi, H.; Yamamoto, A.; Shimizu,
I. Chem. Lett. 2004, 33, 348.
(1.1 mmol) were added into the reaction vessel by syringes.
The reaction mixture was stirred at 80 °C until 1 disap-
peared (monitored by GC). On cooling the vial, water was
added to the reaction mixture, and then it was extracted
several times with hexane or EtOAc. The combined
organic layer was washed with brine, dried with MgSO4,
and evaporated under reduced pressure. The residue was
purified with a flash column chromatography on silica gel
(EtOAc/hexane).
10. DPPF = 1,10-bis(diphenylphosphino)ferrocene: Bishop, J.
J.; Davison, A.; Katcher, M. L.; Lichtenberg, D. W.;
Merrill, R. E.; Smart, J. C. J. Organomet. Chem. 1971, 27,
241.
11. Kuwano, R.; Yokogi, M. Chem. Commun. 2005,
5899.
12. Although the effect of the alcoholic solvent is unclear, we
speculate that hydrogen bonding between alcoholic proton
and carbonyl oxygen of benzyl acetate may weaken the
benzylic carbon–oxygen bond.
13. General procedure for palladium-catalyzed nucleophilic
substitution of 1 with 2: In a nitrogen-filled drybox,
potassium carbonate (152 mg, 1.1 mmol), [Pd(g3-
C3H5)(cod)]BF4 (6.8 mg, 20 lmol), and DPPF (12.2 mg,
22 lmol) were put into a 5 mL screw capped vial equipped
with a stirring bar. After sealing with a screw cap
containing a PTFE/silicone septum, the vial was removed
from the drybox. Dry tert-amyl alcohol (1.0 mL) was
added by a syringe, and then the resulting suspension was
14. As with the reaction of benzylic carbonates (Ref. 4a), the
reactivity of benzyl acetate 1a was lower than those of
both electron-rich and -poor substrate. We speculated that
the electron-donating group of 1 weakened the benzylic
C–O bond. Meanwhile, the electron-withdrawing group
may favor the pre-coordination of the palladium(0) on the
aromatic ring of the benzylic ester.
15. Dibutylamine inherently possesses nucleophilicity enough
for attacking the g3-benzyl ligand on palladium. Trieth-
ylamine might be required for neutralizing the acetic acid
liberated from benzyl acetate. The reaction conditions
were insufficient for the reaction of 1a with malonates,
resulting in no formation of 3.