2
Journal of Chemical Research 00(0)
entries 9 and 10). Having gained some crucial insight into
the effect of various additives, further studies were per-
formed to explore the effect of the oxidant. Interestingly,
TBHP proved to be the best oxidant, and the desired
product 3a was obtained in moderate yield, whereas other
oxidants such as DDQ and K2S2O8 disfavored the reac-
tion to varying degrees (Table 1, entries 11–13). The
effect of solvents was then tested. With the results indi-
cating that toluene was the most effective in comparison
with DMSO, dioxane, dimethyl formamide (DMF), and
dimethyl acetamide (DMA) (Table 1, entries 14–17).
Based on the optimized reaction conditions, the substrate
scope of the oxidative coupling reaction for the synthesis of
α-ketoamides was then studied. The results are described in
Table 2. The oxidative coupling reaction of 1a with various
methyl ketones was initially examined. The reactions were
smooth under the optimized conditions in most cases and
gave the α-ketoamides in moderate yields. Meanwhile, prod-
ucts 4a–i were also formed in poor yields. A variety of sub-
stituents, such as 4-Et, 3-Me, 2-Me, 4-nBu, 3,4-dimethoxy,
3,4-dimethyl, and 4-F, on the benzene ring of the methyl
ketones were well-tolerated for the synthesis of the 3 com-
pounds under the optimized conditions. However, the byprod-
uct 4e was formed in 43% yield, while only a trace of 3e was
detected. Subsequently, substituted pyridin-2-amines were
tested. The product 3j–n were afforded in 53%–73% yields.
Figure 1. Important amides.
Previous work:
O
O
O
I2, DMSO
TPHP, I2
Ph
Ph
+
+
a)
b)
N
N
Ph
Ph
N
H
O
O
O
O
N
H
O
CuCl2, O2
catalyst
+
c)
Ph
N
N
N
Ph
Ph
H
N
NH2
This work:
O
O
Mechanism
+
Ph
d)
N
N
H
NH2
O
To gain insight into the mechanism of the Cu-catalyzed trans-
formation, control experiments were performed. To prove
that an organic radical species was involved in the reaction,
we carried out the radical trapping reactions by adding a rad-
ical-trapping reagent (TEMPO) (Scheme 2(a)). The result
indicated that the reaction had been inhibited and that a radi-
cal process was involved in this Cu-catalyzed strategy. In
addition, the reaction of 1a with 2-oxo-2-phenylacetaldehyde
was also carried out and the products were detected by gas
chromatography–mass spectrometry (GC-MS) analysis. It
was found that 2-oxo-2-phenylacetaldehyde may form as an
intermediate in the reaction (Scheme 2(b)). Product 3a’ with
an 18O in the carbonyl group was not observed in the presence
of H218O (Scheme 2(c)). This result indicated that the oxygen
source (CON) of the product was O2 rather than H2O.
On the basis of the above experiment results, a plausible
mechanism is described in Scheme 3. Initially, radical
intermediate A is generated from 2a via a single electron
transfer (SET) oxidation in the presence of the Cu(II) spe-
cies and TBHP, which was further oxidized to intermediate
B. Next, intermediate C is formed by protonation of inter-
mediate B; subsequent nucleophilic attack of 1a gave the
intermediate D. Finally, intermediate D underwent dehy-
drogenation oxidation to give the product 3a.39,40
Scheme 1. Methods for the synthesis of amides.
N-(2-pyridyl)-α-ketoamides from methyl ketones and pyri-
din-2-amines (Scheme 1(d)).
Results and discussion
In our initial study, pyridin-2-amine (1a) and acetophe-
none (2a) were chosen as model substrates to optimize
the reaction conditions. The results are summarized in
Table 1. In a typical procedure, 1a (0.5 mmol), 2a (0.6
mmol), Cu(OAc)2 (5 mol%), and AcOH (5 mol%) were
stirred in DMSO using O2 as the oxidant at 120°C for 8 h.
Interestingly, the products 3a and 4a were formed in 18%
and 32% yields, respectively (Table 1, entry 1). We next
attempted to improve the yield of 3a by using different
catalysts. Thus, as catalysts CuCl2, Cu(OTf)2, CuI, and
CuBr were employed (Table 1, entries 2–5). Among
them, Cu(OAc)2 was the most efficient catalyst.
Subsequently, our investigation focused on the synthesis
of 3a by testing various additives. The product 3a was
formed in 14% and 11% yields by using trifluoroacetate
(TFA) or tosylic acid (TsOH) (Table 1, entries 6 and 7).
To our delight, an improved yield was obtained by the
addition of KI and acetic acid (AcOH) to the reaction
(Table 1, entry 8). When n-Bu4NI, or n-Bu4NBr with
AcOH were employed as co-additives, product 3a was
obtained in 34% and 26% yields, respectively (Table 1,
Conclusions
In conclusion, we have developed a novel and straightfor-
ward Cu-catalyzed reaction to prepare amides via oxida-
tive coupling of methyl ketones and pyridin-2-amines.
This strategy represents a simple process for the formation