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C O M M U N I C A T I O N S
Table 2. Highly Selective Halogenation of Substituted
the presence of oxidative chloride sources, such as FeCl3 or CuCl2.
With LiCl as a chloride source, 2a was also observed from 4 with
much lower efficiency. However, combining PhI(OAc)2 with LiCl
increased the efficiency of this transformation, and 2a was obtained
from 4 in 40% isolated yield. Obviously, the use of a proper oxidant
is important for the efficient formation of C-X in this transforma-
tion. Thus, the catalytic pathway may go through a Pd(IV)
intermediate C-Pd-X that reductively eliminates to afford the final
product. It should be noted that a mechanism involving the common
Pd(0)-Pd(II) catalytic cycle could not be completely excluded, in
which copper salts may play a role in oxidizing Pd(0) species to
Pd(II) to complete the catalytic cycle.
Acetanilidesa
In summary, we have developed a highly regioselective halo-
genation of acetanilide via palladium-mediated C-H functional-
ization. Further investigations to understand this catalytic transforma-
tion and to evaluate the process with a broader scope of substrates
and to construct complex structures are in progress in our lab.
Acknowledgment. This research was supported by Peking
University and National Natural Science Foundation of China
(20542001, 20521202).
Supporting Information Available: Experimental details, X-ray
structures of 2a, 2m, and other spectral data for products 2. This material
a All the reactions were carried out in the presence of 0.5 mmol of 1,
0.05 mmol of Pd(OAc)2, 1.0 mmol of Cu(OAc)2, and 1.0 mmol of CuCl2
in 4 mL of DCE at 90 °C for 48 h. b Isolated yields. c GC yields with
n-decane as internal standard. d 5 mol % of Pd(OAc)2 was employed in
these reactions. e 5 mol % of Pd(OAc)2 or Pd(OTFA)2 was employed in
these reactions; however, the yields were not enhanced obviously.
References
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Scheme 1
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effects, and only the less hindered ortho-chlorinated acetanilides
were produced (entries 12, 15, and 17, Table 2). The exact structures
of products 2a and 2m were further determined by single-crystal
X-ray crystallography (S26, Supporting Information). When polysub-
stituted acetanilides were employed as substrates, the corresponding
chlorinated acetanilides were produced in poor to good yields
depending on substrates (entries 17, 19, and 21, Table 2). ortho-
Chlorination of 4-chloro-acetanilide was also tested, and the
corresponding product was obtained with the original C-Cl bond
untouched (entry 16, Table 2). The relatively low yield of this
reaction might be due to the weak electron-withdrawing effect of
the chloride substituent. In addition, we found that the method could
be applied to construct C-Br groups in relatively electron-rich
acetanilides (entries 13, 18, 20, and 22, Table 2). Fused rings, such
as 1r, also serve as good substrates (entry 23, Table 2).
We conducted further studies to probe the mechanism of this C-H
functionalization/halogenation reaction. It is well-known that cy-
clopalladation of acetanilide can be achieved under mild conditions
in the presence of Pd(OAc)2.12 Following the reported procedure,
palladacycles 3 and 4 were obtained in 78 and 70% isolated yields,
respectively. Complex 3 could catalyze the formation of 2m from
1m in 75% isolated yield in the presence of 2.0 equiv of Cu(OAc)2
and CuCl2 (Scheme 1). It indicated that palladacycle 3 could also
be an active species during this catalytic cycle. Furthermore, product
2a could be produced from palladacycles 3 and 4 in poor yields in
(10) Giri, R.; Chen, X.; Yu, J.-Q. Angew. Chem., Int. Ed. 2005, 44, 2112.
(11) Roy, A. H., Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 1232.
(12) Horino, H.; Inoue, N. J. Org. Chem. 1981, 46, 4416.
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