.
Angewandte
Communications
pounds, 4) the ester group itself can be further utilized in
decarboxylative coupling and decarboxylation reactions to
provide convenient access to various biaryl and aromatic
compounds (Scheme 1).
TfOH is most suitable for furnishing monochlorinated
products. In contrast, larger amount of TfOH
a
(> 3.0 equiv) and a co-oxidant (> 2.0 equiv) will lead to
significant formation of the dichlorinated benzoate as the
major product (entry 16). In general, 0.05 equivalents of
Pd(OAc)2[12] was enough to effectively promote the reaction.
Typically the reaction will proceed to completion within
6 hours at 60–908C. Delightfully, we found that the ortho-
bromination product of 1 can also be readily prepared with
NBS as the bromine source under the same reaction
conditions (entry 17).
Firstly, a model study with ethyl benzoate (1) was
conducted in the presence of Pd(OAc)2 in AcOH with
commercially available NCS as the chlorinating reagent and
[9]
Na2S2O8 as the co-oxidant (Table 1). However, no desired
Table 1: Optimization of the reaction conditions.[a]
With the optimal reaction conditions in hand, we explored
the scope for this new halogenation reaction. As displayed in
Table 2, a variety of benzoates were smoothly transformed
into the corresponding ortho-chlorinated and ortho-bromi-
nated products in moderate to excellent yields. The scope of
the substituents was found to be very broad. The ortho-, meta-
, and para-substituted aryl groups, as well as electron-with-
drawing and electron-donating groups were well tolerated.
When using Selectfluor as the oxidant, satisfactory yields
were observed with substrates containing strong electron-
withdrawing groups (5, 7, 8). All meta-substituted substrates
Entry Conditions
Yield [%][a]
1
1, Pd(OAc)2, Na2S2O8, NCS, HOAc
n.r.
21
26
2
1, Pd(OAc)2, Na2S2O8, NCS, TFA
3
4
5
6
1, Pd(OAc)2, Na2S2O8, NCS, TFA/TFAA (9:1)
1, Pd(OAc)2, Na2S2O8, NCS, TFA, DCE
1, Pd(OAc)2, Na2S2O8, NCS, TfOH, DCE
1, Na2S2O8, NCS, TfOH, DCE
n.r.
74(69)[b]
n.r.
n.r.
n.r.
n.r.
n.r.
38
7
8
9
1, Pd(OAc)2, NCS, TfOH/Tf2O (1:1), DCE
1, Pd(OAc)2, Na2S2O8, CuCl2, TfOH, DCE
1, Pd(OAc)2, K2S2O8, CuCl2, TfOH, DCE
1, PdCl2, Na2S2O8, NCS, TfOH, DCE
1, Pd(OAc)2, K2S2O8, NCS, TfOH, DCE
1, Pd(OAc)2, (NH4)2S2O8, NCS, TfOH, DCE
1, Pd(OAc)2, Selectfluor, NCS, TfOH, DCE
1, Pd(OAc)2, PhI(OAc)2, NCS, TfOH, DCE
1, Pd(OAc)2, NFPy·BF4, NCS, TfOH, DCE
1, Pd(OAc)2, Na2S2O8, NCS, TfOH (3 equiv), DCE
Pd(OAc)2, Na2S2O8, NBS, TfOH (3 equiv), DCE
10
11
12
13
14
15
16
17
Table 2: Mono- and dihalogenation of benzoates.[a]
44
60
10
59
45[c]
72
[a] Conversion ratio. [b] Yield of isolated product. [c] Yield for dihalo-
genated product. n.r. =no reaction. TFA=trifluoroacetic acid.
product was detected even when the reaction was run at high
temperature for a prolonged time. After screening many
additives, co-oxidants, solvents, and temperatures, we turned
our attention to TFA.[10] To our delight, the chlorinated
product 2 was observed in 21% yield after stirring for
10 hours at 908C with TFA as the solvent (entry 2). Further
investigation revealed that TFA is not a prerequisite for this
reaction and it can be replaced by DCE with a small amount
of TfOH (1.0 equiv). A control reaction showed that omission
of the palladium catalyst resulted in complete inactivity of this
catalytic system. Remarkably, in the absence of strong
oxidants, the regioselecitivity of the reaction was very poor
with the major product being that of an eletrophilic aromatic
substitution (meta-chlorination). Encouraged by the prelimi-
nary results, we optimized the reaction conditions. We found
that Na2S2O8 and Selectfluor were generally superior over
other co-oxidants with a remarkably high level of efficiency
(for details, see the Supporting Information). Using oxi-
dants[11] such as persulfate and F+ has been well developed by
Yu and co-workers as an efficient strategy to achieve selective
reductive elimination in PdII/PdIV catalysis. Our results
indicate that the use of proper oxidant is an essential factor
for the ortho selectivity of this reaction. Notably, it was found
the amount of TfOH significantly affects both the rate and
outcome of the reaction. For example, 1–2 equivalents of
[a] Yield is that of the isolated product. NBS=N-bromosuccinimide.
2
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
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