Angewandte
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an “acceptorless” homogeneous ruthenium-catalyzed
To verify whether the observed catalysis for the present
oxygenation of secondary amines into amides.[15] However,
in this case the substrate scope was limited to cyclic secondary
amines. To the best of our knowledge, there is no precedent
for the a-oxygenation of aliphatic linear secondary and
tertiary amines using O2 as the terminal oxidant. Therefore,
the development of novel catalysts for amine a-oxygenation
with wide substrate scope; especially for the selective
a-oxygenation of unsymmetrical secondary and tertiary
amines; is highly desirable.
reaction was truly heterogeneous, Au/Al2O3 was removed by
hot filtration when the yield of 2a reached approximately
60%, and the reaction then carried out with the filtrate under
the same reaction conditions. As shown in Figure S2
(Supporting Information), the reaction completely stopped
upon removal of Au/Al2O3. Furthermore, analysis of the
filtrate by inductively coupled plasma atomic emission
spectroscopy (ICP-AES) revealed that gold species were
hardly present in the filtrate (that is, gold was not present in
quantities above the instrumental detection limit:
Au < 0.008%). These experimental results indicate that
catalysis did not originate from gold species leached from
the catalyst, and thus, the described catalyst is deemed
intrinsically heterogeneous.[16] After the reaction, Au/Al2O3
could be easily retrieved by simple filtration, achieving
> 95% recovery. The retrieved catalyst could be reused
several times, though the yields of the desired product
gradually decreased after repeated reuse experiments
(Supporting Information, Figure S3). This is likely because
of the aggregation of gold nanoparticles; the average particle
size of gold increased from 4.9 nm (fresh catalyst) to 9.9 nm
after the third recycling experiment (Supporting Information,
Figure S1).
With the optimized reaction conditions in hand, we
subsequently examined the substrate scope for a-oxygen-
ation. As shown in Table 1, various secondary cyclic and
linear amines could be oxygenated to produce the
corresponding amides in moderate to high yields. The
a-oxygenation of five-, six-, and seven-membered cyclic
amines efficiently proceeded to give the corresponding
lactams (Table 1, entries 1–8). When morpholine (1e) was
used as a substrate, it was exclusively oxygenated in the
3-position to give the corresponding amide, and oxygenation
did not occur at the 2-position (Table 1, entry 5). Further-
more, the a-oxygenation of tetrahydroisoquinoline deriva-
tives (1 f and 1g) effectively proceeded at the benzylic
positions (Table 1, entries 6 and 7). Although tetrahydro-
quinoline (1h) was oxygenated to afford the corresponding
amide (34%), quinoline (51%) was a major product in this
case (Table 1, entry 8). Various linear amines were oxy-
genated to give the corresponding amides in moderate yields
(Table 1, entries 9–12).[17]
Herein, we disclose for the first time a highly selective and
widely applicable route for heterogeneous a-oxygenation of
secondary and tertiary amines. The method uses O2 as the
oxidant and is catalyzed by gold nanoparticles supported on
alumina (Au/Al2O3, with an average particle size of
Au = 4.9 nm; see the Supporting Information, Figure S1;
Scheme 1b). The present reaction proceeds through the
following oxidation/hydration/oxidation sequence; 1) oxida-
tion of secondary/tertiary amines into imine/iminium inter-
mediates (Scheme 1b, step 1), 2) hydration of the imine/
iminium intermediates to form hemiaminals (Scheme 1b, step
2), and 3) oxidation of the hemiaminals into the desired amide
products (Scheme 1b, step 3). In the presence of Au/Al2O3,
a wide range of cyclic and linear secondary and tertiary
amines could be converted into the corresponding amides in
moderate to high yields. The catalysis in the present reaction
was truly heterogeneous, and the Au/Al2O3 catalyst could be
reused several times. This reaction is an efficient green
method for the a-oxygenation of secondary and tertiary
amines when it is considered that 1) water is used as the
oxygen atom source in the amide group, 2) O2 is employed as
the terminal oxidant, and 3) water is the only theoretical by-
product. Additionally, 18O-labeled amides were readily syn-
thesized using H218O as the oxygen source.
Initially, various supported metal catalysts (designated as
metal/support) were prepared (Supporting Information,
Table S1) and applied to the a-oxygenation of piperidine
(1a) into 2-piperidone (2a) (Supporting Information,
Table S2). The reaction was carried out in water at 1008C in
O2 (1 atm). Under these conditions, we confirmed that 2a was
not obtained in the presence of pure Al2O3 or in the absence
of catalysts (Supporting Information, Table S2, entries 14 and
15). In the presence of Pd/Al2O3, only a trace amount of 2a
was obtained (Supporting Information, Table S2, entry 1).
Other supported metal catalysts, such as Ru/Al2O3, Rh/Al2O3,
and Cu/Al2O3 did not show any catalytic activity for the
present transformation (Supporting Information, Table S2,
entries 2–4). Notably, Au/Al2O3 promoted the reaction sig-
nificantly (Supporting Information, Table S2, entry 5), and
a quantitative yield of 2a was obtained after 24 h (Supporting
Information, Table S2, entry 6). Among the various supports
examined, Al2O3 was the best (Table S2, entries 5–10). The
reaction using Au/Al2O3 in air (1 atm) only gave a trace
amount of 2a (Supporting Information, Table S2, entry 11),
while a 57% yield of 2a was obtained in pressurized air
(5 atm; Supporting Information, Table S2, entry 12). The
reaction did not proceed at all under Ar atmosphere
(Supporting Information, Table S2, entry 13), which indicates
that O2 is the terminal oxidant in the oxygenation reaction.
The present catalytic system was also applicable to the
a-oxygenation of tertiary amines. As shown in Table 2,
various kinds of cyclic and linear tertiary amines were
efficiently oxygenated to give the corresponding amides.
The present a-oxygenation method was especially powerful
for the selective synthesis of lactams from cyclic tertiary
amines. The five- and six-membered tertiary cyclic amines
were all exclusively oxygenated at ring positions to give the
corresponding lactams in high yields (Table 2, entries 1–8). A
cyclic tertiary amine with an alcohol group reacted well, and
the hydroxy group in 2p remained intact (Table 2, entry 4).
Tolperisone, a well-known muscle relaxant,[18] was also
a suitable substrate, and selectively oxygenated at the ring
position (Table 2, entry 5). Cloperastine,
a
cough
suppressant,[19] was also selectively oxygenated to give the
corresponding amide, leaving chloride and ether functional
Angew. Chem. Int. Ed. 2016, 55, 7212 –7217
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