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AZADO showed superior catalytic activity to TEMPO in the
oxidation of 1b to give the aldehyde 2b in 29% conversion
under the standard reaction conditions reported by Hoover
and Stahl (entries 1 and 2). The combination of CuCl and
DMAP gave better conversion than that of CuOTf and NMI
(entry 3). After screening nitroxyl radical catalysts, it was
found that the more bulky 1-Me-AZADO showed higher
activity than AZADO (entries 4–8). Previous structure–
activity relationship studies showed that less sterically hin-
dered nitroxyl radicals exhibited higher reactivity.[6c,d]
With the optimum reaction conditions in hand, we
compared the reactivity of AZADO/copper catalysis with
that of conventional selective alcohol oxidation methods,
namely, PCC oxidation,[18] Swern oxidation,[19] Dess–Martin
oxidation,[20] and TPAP oxidation,[21] by oxidizing secondary
alcohols with tertiary and secondary amines (Table 3). In the
control experiments, it was confirmed that all the methods
efficiently oxidized the N-Cbz-protected piperidinol 1c in
high yield. In contrast, the oxidation of the amino alcohols 1a,
1d, and 1e was ineffective in the cases of the conventional
methods, thereby giving the ketones in low or modest yield.
AZADO/copper catalysis exhibited excellent activities for all
the amino alcohols, including the highly functionalized amino
alcohol 1e, to give the amino ketones in high yields and it
worked well even on a 50 mmol scale. Notably, imino ketones
or imino alcohols were not obtained in the oxidation of the
benzylamino alcohol 1d or 1e even though nitroxyl radical/
copper catalysis can oxidize benzylic amines to imines.[12c,22]
Encouraged by the promising results, we applied the
optimum reaction conditions to examine the substrate scope
(Table 4 and Table 5). Note that the yields of amino carbonyl
products with aliphatic secondary and primary amines were
determined by isolating the Boc-protected products, because
of the difficulty in isolating the highly polar unprotected
products (Table 5). The benzylic alcohol 1 f and the allylic
alcohol 1g were efficiently oxidized with 1 mol% AZADO
(Table 4, entries 1 and 2). The examination of the functional-
group tolerance indicated that AZADO/copper catalysis
tolerated benzylic and allylic amines, an ester, and N-hetero-
cycles (entries 3–9). Furthermore, this catalysis selectively
oxidized not only the sterically bulky secondary alcohols 1o
and 1p but also the primary alcohol 1q in good yields
(entries 10–12). The oxidation of the chiral primary alcohols
1r and 1s proceeded with almost complete retention of their
stereochemistry (entries 13 and 14). Notably, 5-benzylamino-
1-pentanol (1t), which was converted into d-valerolactam by
ruthenium-catalyzed dehydrogenation,[23] was transformed
into the enamine dimer 4 in good yield (entry 15). Unfortu-
nately, the vicinal amino alcohol 1u was not oxidized
(entry 16). Secondary alcohols with aliphatic secondary and
primary amines were efficiently oxidized into the amino
ketones even in the case of the bulky alcohol 1w with a nitrile
group (Table 5, entries 1–4). The more challenging primary
alcohol 1z, having a secondary amine, was also selectively
oxidized to give the aldehyde in moderate yield (entry 5).
To demonstrate the utilization of the highly chemo-
selective alcohol oxidation, we applied AZADO/copper
oxidation to the synthesis of nitrogen-containing natural
products. The readily prepared pyridyl amino alcohol 1aa was
efficiently converted into myosmine (6) in 60% yield under
the standard reaction conditions, whereas the TPAP oxidation
of the alcohol 1aa afforded only a trace amount of myosmine
(6; Scheme 1a).[24] AZADO/copper catalysis also oxidized
mesembranol (1ab) to (À)-mesembrine (2ab) in high yield.
The reaction has recently been reported by Geoghegan and
Table 3: Comparison of known methods and AZADO/copper catalysis of
amino alcohol oxidation.[a]
Amino alcohol
PCC[b]
Swern[b] DMP[b]
TPAP[b] AZADO/Cu[c]
92%
/2 h
95%
/0.75 h /2 h
97%
90%
/0.75 h /1.5 h
97%
65%
/1 h
(10%) (17%)
20%
/3 h
32%
96%
/3 h
16%
/1.5 h
/3 h[d]
(29%)
26%
/1 h
(<5%)
0%
32%
68%
92%
/4 h
/2 h
/4 h
/1.2 h
(<29%) (13%)
97%
/2 h
14%
/2 h
(29%) (3%)
10%
Dec.
/2 h
/1 h
<1%
/12 h
(72%)
99%
/3.5 h[e]
[a] Reaction conditions: PCC: PCC (1.5 equiv), 4 ꢀ M.S. (500 mg/
1 mmol substrate), CH2Cl2 (0.2m), RT; Swern: (COCl)2 (2.0 equiv),
DMSO (4.0 equiv), Et3N (6.0 equiv), CH2Cl2 (0.17m), À788C to RT;
DMP: Dess–Martin periodinane (1.5 equiv), CH2Cl2 (0.2m),RT; TPAP:
TPAP (5 mol%), NMO (1.5 equiv), 4 ꢀ M.S. (500 mg/1 mmol substrate),
CH2Cl2 (0.1m), RT; AZADO/Cu: AZADO (3 mol%), CuCl (3 mol%), bpy
(3 mol%), DMAP (6 mol%), MeCN (0.2m), air (open), RT. Yields of
product/time (remaining substrate) are shown. [b] Yield determined by
1H NMR spectroscopy using 1,3,5-trimethoxybenzene as the internal
standard. [c] Yield of isolated product. [d] 1 mol% AZADO was used.
[e] 50 mmol scale. Cbz=benzyloxycarbonyl.
Scheme 1. Application to synthesis of natural alkaloids.
3238
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 3236 –3240