also proceeds at lower loadings of the Pd/Cu cocatalyst or
the ligand, but with a substantial decrease in the reaction
yields (Table 1, entries 14–16).
To gain a better understanding of the reaction mechanism,
we carried out a series of reactions under the same reaction
conditions, but under different atmospheres. Interestingly,
the reaction resulted in a much lower yield of product 3a
under a nitrogen atmosphere than under aerobic conditions
(Table 2, entries 1 and 2). However, the reaction performed
mediate (D).[13,8h] Subsequently, heteroaryl copper interme-
diate D reacts with palladium species B to form the corre-
sponding diaryl palladium intermediate (C).[13] Upon
reductive elimination, the desired cross-coupling product 3a
is formed. Trace molecular oxygen, in the presence of CuII,
oxidizes the resulting Pd0 to peroxopalladium complex A,[14]
which reacts with aryl boronic acid to regenerate palladium
species B. At high oxygen concentrations, the oxidative hy-
droxylation of aryl boronic acid competes with the transme-
talation between species B and D, resulting in an increase in
byproduct formation.
Table 2. The influence of the atmosphere on the yield of 3a.[a]
Further experimentation has shown that various substitut-
ed aryl boronic acids allow the direct arylation of benzothia-
zole 1a under the optimum reaction conditions (Table 3).
Both electron-rich and electron-poor aryl boronic acids
were successfully converted to the corresponding cross-cou-
pling products in moderate to good yields. The treatment of
a heteroaryl boronic acid with 1a also gave the correspond-
ing product in moderate yield (Table 3, entry 10). Remarka-
bly, chloro-substituted aryl boronic acid readily underwent
direct arylation with 1a to generate the desired chloro-sub-
stituted benzothiazole (3i) in 62% yield (Table 3, entry 8).
This functional-group tolerance should allow further deriva-
tization of compound 3i through cross-coupling reactions
such as the Suzuki–Miyaura and Heck reactions.
Entry
Atmosphere
Yield [%][b]
3a
4a
5a
1
2
3
nitrogen
air
oxygen
24
89
17
12
8
16
2
3
48
[a] Reaction conditions: 1a (0.5 mmol), 2a (1 mmol), Pd
(5.0 mol%), Cu(OAc)2 (10 mol%), 1,10-phenanthroline (30 mol%),
K3PO4 (1.5 mmol), DMSO (3 mL), 1008C, 24 h. [b] GC yield.
ACHTUNGERTN(NUNG OAc)2
ACHTUNGTRENNUNG
under a pure oxygen atmosphere only afforded 3a in 17%
yield (Table 2, entry 3). Under these conditions, the predom-
inant byproducts are biphenyl (16%) and phenol (48%), as
determined by gas chromatography (see Supporting Infor-
mation, Figure S2). These results indicate that oxygen accel-
erates the cross-coupling reactions; however, with high con-
centrations of oxygen, the oxidative hydroxylation of phe-
nylboronic acid dominates the reaction.[12]
On the basis of these experimental data, a plausible cata-
lytic mechanism was proposed (see Scheme 1) for the
oxygen-promoted direct arylation of benzothiazole. The re-
action first proceeds by deprotonation of benzothiazole, fol-
lowed by transmetalation with organometallic copper com-
plex E to give the corresponding heteroaryl copper inter-
In another set of experiments, we carried out the direct
arylation of benzoxazole (1b) with various substituted aryl
boronic acids (Table 4). Similar to the arylation of 1a, vari-
ous substituted aryl boronic acids successfully reacted with
1b to afford the corresponding aryl-substituted benzoxa-
zoles under the optimum reaction conditions.
Although the groups of Daugulis and Miura have report-
ed the direct arylation of benzothiazoles with aryl halides,[15]
our method, reported herein, eliminates the use of aryl
halide precursors and proceeds under milder conditions.
More recently, Itamiꢁs group[16] has also reported an interest-
ing nickel-catalyzed direct arylation of azole compounds
with aryl halides and triflates, but the reactions with benzox-
azole resulted in a substantial reduction in yield. In our re-
actions, benzoxazole can be ef-
ficiently and selectively arylated
at the 2-position by electroni-
cally and structurally diverse
boronic acids.
To evaluate the suitability of
the reaction for further scaleup,
we prepared phenylbenzothia-
zole in DMSO (15 mL) by
treating
benzothiazole
1a
(5.0 mmol) with phenylboronic
acid 2a (10.0 mmol) in the pres-
ence of the Pd/Cu cocatalyst
(0.25:0.5 mmol), 1,10-phenan-
throline (1.5 mmol) and a large
excess of K3PO4 (15.0 equiv)
for 32 h at 1008C under aerobic
conditions (Scheme 2). The re-
À
Scheme 1. The proposed mechanism for the arylation of benzothiazole through C H activation.
1106
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Chem. Eur. J. 2011, 17, 1105 – 1108