for the preparation of benzyl ester,9 the most common way
to introduce a benzyl group to a carboxyl group is the
nucleophilic displacement of a carboxylate on benzyl
bromide.10 This reaction requires the use of toxic benzyl
bromide and produces a stoicheometric amount of bro-
mides as chemical waste. As such, it is attractive to develop
more efficient and atom-economic benzylation methods.
With the great advantages of CÀH activation taken into
consideration, direct CÀH acyloxylation should be an
intriguing solution to remedy the drawbacks of the tradi-
tional benzylation method. As early as the 1960s, Pd(OAc)2-
mediated benzylic acetoxylation of toluene in acetic acid was
reported,11 and the catalytic reaction was achieved in 1968.12
Recently, the Jiang group described R-CÀH acetoxylation
of 2-alkylpyridines and 2-alkylpyrazines.13 These reactions
required the use of an excessive amount of acetic acid
(normally as a solvent), which hampered the development
of acyloxylation with nonvolatile carboxylic aicds. Intrigu-
ingly, the Khan group reported NaBrO3/NaHSO3-enabled
benzylation of aromatic carboxylic acids with toluene.14
Subsequently, the Yu group disclosed an efficient oxidative
esterification of benzylic CÀH bonds using tetrabutylam-
monium iodide as the catalyst and tert-butyl hydroperoxide
as the co-oxidant.15 For both of these two methods, the use
of a stoichiometric amount of inorganic reagents is required.
Herein, we describe a facile Pd(II)-catalyzed benzylation
of carboxylic acids with toluene under 1 atm of oxygen
(Figure 1).
Figure 1. A new strategy for the benzylation of carboxylic acids.
Table 1. Survey of Reaction Conditions
toluene
(mL)
acid
additive
yield
(%)a
The research was initiated by investigating the benzyla-
tion of p-toluic acid. As shown in Table 1, when 0.5 mmol
of p-toluic acid was stirred with 10 mol % Pd(OAc)2 in
1.5 mL of toluene under 1 atm of O2 at 115 °C for 24 h,
benzyl 4-methylbenzoate was observed, albeit in a low
entry
(0.1 equiv)
(1.0 equiv)
1
2
3
4
5
6
7
8
9
1.5
1.5
1.5
1.5
1.5
0.5
0.5
0.5
0.5
none
none
25
none
DMF
DMSO
None
DMF
DMF
DMA
DMA
DMA
24
none
0
CF3SO3H
CF3SO3H
CF3SO3H
CF3SO3H
CF3SO3H
CF3SO3H
0
50
(7) For intermolecular acyloxylation of CÀH bonds, see: (a) Ye, Z.;
Wang, W.; Luo, F.; Zhang, S.; Cheng, J. Org. Lett. 2009, 11, 3974. (b)
Hua, C.-J.; Zhang, X.-H.; Ding, Q.-P.; Lv, T.; Ge, S.-P.; Zhong, P.
Tetrahedron Lett. 2012, 53, 2465. (c) Zhang, S.; Luo, F.; Wang, W.; Hu,
M.; Jia, X.; Cheng, J. Tetrahedron Lett. 2010, 51, 3317. (d) Dick, A. R.;
Kampf, J. W.; Sanford, M. S. J. Am. Chem. Soc. 2005, 127, 12790. (e)
Racowski, J. M.; Dick, A. R.; Sanford, M. S. J. Am. Chem. Soc. 2009,
131, 10974. For intramolecular acyloxylation of CÀH bonds, see: (a)
Cheng, X.-F.; Li, Y.; Su, Y.-M.; Yin, F.; Wang, J.-Y.; Sheng, J.; Vora,
H. U.; Wang, X.-S.; Yu, J.-Q. J. Am. Chem. Soc. 2013, 135, 1236. (b)
Yang, M.; Jiang, X.; Shi, W.-J.; Zhu, Q.-L.; Shi, Z.-J. Org. Lett. 2013, 15,
690. (c) Sun, C.-L.; Liu, J.; Wang, Y.; Zhou, X.; Li, B.-J.; Shi, Z.-J.
Synlett 2011, 883. (d) Li, Y.; Ding, Y.-J.; Wang, J.-Y.; Su, Y.-M.; Wang,
X.-S. Org. Lett. 2013, 15, 2574.
78
88 (82b)
0c
0d
a The yields were determined by 1H NMR analysis of crude products
using CHCl2CHCl2 as the internal standard. b Isolated yield. c No
Pd(OAc)2. d PdCl2 was used. DMF: N,N-dimethylformamide. DMA:
N, N-dimethylacetamide.
yield (25%). The addition of DMF failed to improve the
yield, and the use of DMSO or trifluoromethanesulfonic
acid suppressed the formation of the benzylation product.
Gratefully, when a combination of DMF (1.0 equiv) and
trifluoromethanesulfonic acid (10 mol %) was used, the
yield increased to 50%. The yield was further improved to
78% when the amount of toluene was reduced to 0.5 mL.
Finally, a good yield was obtained when DMA was used
in place of DMF. In the absence of Pd(OAc)2 or in the
presence of PdCl2 instead of Pd(OAc)2, no benzylation
products were observed.
The optimal conditions(0.5 mmol ofcarboxylicacidand
10 mol % Pd(OAc)2 in the presence of 1.0 equiv of DMA
and 10 mol % trifluoromethanesulfonic acid under 1 atm
of O2 in 0.5 mL of toluene at 115 °C for 24 h) proved to
be compatible with a wide array of benzoic acids. While
(8) (a) Vindigni, V.; Cortivo, R.; Iacobellis, L.; Abatangelo, G.;
Zavan, B. Int. J. Mol. Sci. 2009, 10, 2972. (b) Aliboni, A.; D’Andrea,
A.; Massanisso, P. J. Agric. Food Chem. 2011, 59, 282. (c) Pappas, C. S.;
Malovikova, A.; Hromadkova, Z.; Tarantilis, P. A.; Ebringerova, A.;
Polissiou, M. G. Carbohydr. Polym. 2004, 56, 465.
(9) Greene, T. W.; Wuts, P. G. M. Protection for the Carboxyl Group
Ester. In Protective Groups in Organic Synthesis, 3rd Ed.; John Wiley &
Sons, Inc.: 1999; Chapter 5, pp 369À453.
(10) Lee, J. C.Y.; Oh, S.; Cho, S. H.; Lee, J. I. Org. Prep. Proced. Int.
1996, 28, 480.
(11) (a) Davidson, J. M.; Triggs, C. Chem. Ind. 1966, 457. (b) Bryant,
D. R.; XcKeon, J. E.; Ream, B. C. Tetrahedron Lett. 1968, 30, 3371.
(12) Bryant, D. R.; XcKeon, J. E.; Ream, B. C. J. Org. Chem. 1968,
33, 4123.
(13) Jiang, H.; Chen, H.; Wang, A.; Liu, X. Chem. Commun. 2010, 46,
7259.
(14) Khan, K. M.; Maharvi, G. M.; Hayat, S.; Zia-Ullah; Choudhary,
M. I.; Atta-ur-Rahman Tetrahedron 2003, 59, 5549.
(15) Feng, J.; Liang, S.; Chen, S.-Y.; Zhang, J.; Fu, S.-S.; Yu, X.-Q.
Adv. Synth. Catal. 2012, 354, 1287.
B
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