126
W. Wang et al. / Tetrahedron Letters 55 (2014) 124–127
O
hindered secondary amine that are sluggish to perform the amida-
0.77 mol% Au/HAP, O2 balloon
NaOH, H2O, 40 oC, 24 h
Ph
tion (Table 2, entries 29–32), good to excellent yields of the corre-
sponding amides were still obtained. Ammonia could also be a
good substrate (Table 2, entries 33 and 34) though moderate yields
of benzamides 3ag–3ah were achieved. Gram scaled experiment
was performed with ethanol and aniline. And acetanilide, an
important intermediate in pharmaceutical industry, was achieved
with 97% yield (Scheme 1). This indicates that Au/HAP can be used
effectively as a catalyst for the large scale production of amides.
+
2 H2O
+
Ph NH2
OH
1a: 9.2 g
N
H
3a
: 1.31 g
2a: 0.93 g
Scheme 1. Au-catalyzed synthesis of acetanilide 3a on gram-scale.
Mechanistic studies for the reaction
To clarify the essential role of Au/HAP for the title reaction, we
further conducted several control experiments. The Au/HAP cata-
lyst was filtered off from the reaction mixture after 75% conversion
of aniline 2a. Continued stirring of the filtrate under identical reac-
tion conditions did not promote the reaction to proceed any more.
ICP-AES analysis of the filtrate showed only negligible amount of
Au (0.28 ppm corresponding to 1.7 wt % of initial charge) was lea-
ched into the solution. This confirmed that the oxidative coupling
reaction was indeed catalyzed by the heterogeneous catalyst. How-
ever, the average size of the gold particles obviously increased after
the catalytic reaction (up to 8.0 nm, Fig. 3). Furthermore, the color
of Au/HAP changed from red to purple. Actually, the recycled cat-
alysts showed very low activity and afforded 2a in only 7% yield
under the optimal reaction conditions. The change of the catalyst
state involved the gold nanoparticle size might account for the
decrease in the catalytic performance. The size-specific catalytic
activity of Au/HAP is somewhat explained in terms of the efficient
activation of O2 by small-sized gold nanoparticles to generate
Figure 3. HAADF-STEM image of Au/HAP after reuse experiment and histogram of
the Au particle size distribution.
in place of Au/HAP did not promote the amidation at all (Table 1,
entries 10 and 11). These results suggested that the high catalytic
activity of the Au/HAP is ascribed to the intrinsic activity of the
gold nanoparticles. It is evident from Table 1 (entries 12 and 13)
that both the oxidant (O2) and base (NaOH) are also crucial for
the oxidative amidation process.8
Extension of the methodology
superoxo-like species, which in turn facilitated the
a-C–H bond
To demonstrate the general applicability of our Au/HAP catalyst
for direct amide synthesis and the scope of the process, various
alcohols and amines were investigated, and the results are col-
lected in Table 2.9 First, a series of long-chain aliphatic alcohols,
which are always difficult to oxidize, could be smoothly converted
into the corresponding amides in high to excellent yields (Table 2,
entries 1–8). We also explored the reactions of ethanol with substi-
tuted aromatic amines and benzylamine under similar reaction
conditions, the catalyst still exhibited good activity in comparison
with aniline (Table 2, entries 9–13). As shown in Table 2, benzyl
alcohols with electron-donating groups (Me, i-Pr, MeO) reacted
smoothly (Table 2, entries 14–21), however, steric hindrance had
a negative influence on this reaction and 1.54 mol % Au was em-
ployed for 2-tolylmethanol (Table 2, entry 17). In addition, substi-
tution with electron-withdrawing groups (F, Cl) on the benzene
ring slightly decreased the reactivity (Table 2, entries 22 and 23).
It is worth noting that heterocycles such as pyridin-2-ylmethanol
and furan-2-methanol could also be used in this aerobic oxidative
amidation and gave the corresponding products in moderate to
good yields (Table 2, entries 24 and 25). Furthermore, besides alco-
hols, a series of amines 2 were also investigated (Table 2, entries
26–34) and the reaction proceeded smoothly. For sterically
breaking through a H2O2 pathway.10
The amidation followed the mechanism in Scheme 2 and did
not proceed through an intermediate ester.11 The latter was con-
firmed by treating ethyl acetate with aniline 2a under the standard
reaction conditions, which afforded none of the amide 3a. The
reaction between acetaldehyde and aniline 2a under the same con-
ditions led to the formation of the corresponding imine and amide
3a was not observed. This result indicated that the reaction would
proceed through an aldehyde route, but that the aldehyde kept
adsorbed on Au nanoparticles. Subsequent attack of the intermedi-
ate by the amine afforded the hemiaminal which also kept
adsorbed to Au nanoparticles. The amide was then formed after
b-hydride elimination. The reaction intermediate could not be a
free aldehyde or hemiaminal released from the catalyst since this
would lead to the formation of an unreactive imine.
Conclusion
In summary, we have successfully developed a hydroxyapatite-
supported gold catalyst for aerobic oxidative coupling of alcohols
and amines. The reaction can be performed smoothly under mild
R2 = H
- H2O
R1
N
R3
OH
O
O
H
N
Au/HAP, OH-, O2
R3
R2
R3
R2
R1
N
R1
H2O
N
R2
ad
R3
Au/HAP
OH-, O2
R1
R1 OH
Oad
H
N
O
H2O
ad: adsorbed
R2
R1 OH
R2
R3
R1
N
R3
R1
O
R1
Au/HAP, OH-, O2
Scheme 2. Probable reaction pathway for the conversion of alcohols and amines to amides over Au/HAP.