Highly efficient aerobic oxidation of alcohols by using less-hindered nitroxyl-radical/copper catalysis: Optimum catalyst combinations and their substrate scope

Article abstract of DOI:10.1002/asia.201403245

The oxidation of alcohols into their corresponding carbonyl compounds is one of the most fundamental transformations in organic chemistry. In our recent report, 2-azaadamantane N-oxyl (AZADO)/copper catalysis promoted the highly chemoselective aerobic oxidation of unprotected amino alcohols into amino carbonyl compounds. Herein, we investigated the extension of the promising AZADO/copper-catalyzed aerobic oxidation of alcohols to other types of alcohol. During close optimization of the reaction conditions by using various alcohols, we found that the optimum combination of nitroxyl radical, copper salt, and solution concentration was dependent on the type of substrate. Various alcohols, including highly hindered and heteroatom-rich ones, were efficiently oxidized into their corresponding carbonyl compounds under mild conditions with lower amounts of the catalysts.

Full text of DOI:10.1002/asia.201403245

DOI: 10.1002/asia.201403245
Full Paper
Oxidation
Highly Efficient Aerobic Oxidation of Alcohols by Using Less-
Hindered Nitroxyl-Radical/Copper Catalysis: Optimum Catalyst
Combinations and Their Substrate Scope
Yusuke Sasano, Naoki Kogure, Tomohiro Nishiyama, Shota Nagasawa, and
[a]
Yoshiharu Iwabuchi*
Abstract: The oxidation of alcohols into their corresponding
carbonyl compounds is one of the most fundamental trans-
formations in organic chemistry. In our recent report, 2-azaa-
damantane N-oxyl (AZADO)/copper catalysis promoted the
highly chemoselective aerobic oxidation of unprotected
amino alcohols into amino carbonyl compounds. Herein, we
investigated the extension of the promising AZADO/copper-
catalyzed aerobic oxidation of alcohols to other types of al-
cohol. During close optimization of the reaction conditions
by using various alcohols, we found that the optimum com-
bination of nitroxyl radical, copper salt, and solution concen-
tration was dependent on the type of substrate. Various al-
cohols, including highly hindered and heteroatom-rich ones,
were efficiently oxidized into their corresponding carbonyl
compounds under mild conditions with lower amounts of
the catalysts.
Introduction
structure, were capable of the highly efficient oxidation of al-
cohols into carbonyl compounds (in particular, the oxidation of
highly sterically hindered alcohols), the one-pot oxidation of al-
The oxidation of alcohols into their corresponding carbonyl
compounds is a ubiquitous but important transformation in or-
ganic chemistry; thus, numerous reagents for and methods of
conducting this transformation in an efficient manner have
[8]
cohols into carboxylic acids, the one-pot oxidative cleavage
[9]
of vicinal diols into (di)carboxylic acids, and the oxidation of
[10]
silyl enol ethers into diketones. Notably, we have developed
highly efficient and mild methods for the oxidation of alcohols
[
1]
been developed. However, various aspects such as increased
molecular size and complexity of the alcohol substrates, and
sustainability demand more affordable and suitable methods
into carbonyl compounds, namely, NO -mediated aerobic alco-
x
[6]
hol oxidation and alcohol oxidation by using diisopropyl azo-
[
2]
[11]
for the alcohol-oxidation reactions.
dicarboxylate (DIAD) as a terminal oxidant. These alcohol-ox-
We have developed a series of highly active, nitroxyl-radical-
type catalysts for oxidation reactions, namely, 2-azaadaman-
idation methods had broad substrate scope and excellent
functional-group tolerance. However, to our dissatisfaction, we
encountered an issue: Most of these aforementioned methods
failed to oxidize unprotected amino alcohols in an efficient
manner. The selective oxidation of unprotected amino alcohols
[
3]
tane N-oxyl (AZADO),
9-azabicyclo[3.3.1]nonane N-oxyl
[
4]
[5]
(ABNO),
9-azanoradamantane N-oxyl (Nor-AZADO),
and
[
6]
their derivatives (Scheme 1), and demonstrated their synthet-
[
7]
[12]
ic use. These nitroxyl radicals, which featured a less-hindered
is recognized as an inherently highly challenging reaction.
The alcohol groups of amino alcohols are typically oxidized
after the protection of amino groups as amides or carbamates.
To overcome this challenge of the chemoselective oxidation
of alcohols in the presence of unprotected amino groups, we
were interested in adapting another nitroxyl-radical-mediated
method, namely, a combined catalytic system of a nitroxyl radi-
[13]
cal and copper.
Since the seminal work of Semmelhack
Scheme 1. Structures of selected nitroxyl radicals.
et al., who used TEMPO/copper catalysis in the aerobic oxida-
[14]
tion of benzylic and allylic alcohols in 1984, this combination
catalysis has been extensively investigated as a promising
method for the oxidation of alcohols by using an ideal oxidant,
that is, molecular oxygen. In 2011, Hoover and Stahl reported
a highly practical aerobic oxidation reaction of alcohols by
using TEMPO/copper catalysis, which efficiently oxidized unac-
tivated aliphatic primary alcohols that contained various func-
[
a] Dr. Y. Sasano, N. Kogure, T. Nishiyama, S. Nagasawa, Prof. Dr. Y. Iwabuchi
Department of Organic Chemistry
Graduate School of Pharmaceutical Sciences
Tohoku University
6
-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578 (Japan)
E-mail: y-iwabuchi@m.tohoku.ac.jp
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/asia.201403245.
[15]
tional groups at room temperature in air. Nitroxyl-radical/
Chem. Asian J. 2015, 00, 0 – 0
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copper catalysis generate a copper-complex-type active spe-
cies, thereby distinguishing itself from other nitroxyl-radical-
mediated catalyses, which generate an oxoammonium-ion-
Results and Discussion
We began by optimizing the reaction conditions for the oxida-
[
16]
type active species (Scheme 2). We expected that a nitroxyl-
radical/copper catalytic system that contained an active spe-
cies other than an oxoammonium ion could achieve the che-
moselective oxidation of unprotected amino alcohols. Gratify-
ingly, we found that AZADO/copper catalysis successfully oxi-
dized alcohols with unprotected tertiary, secondary, and even
primary amines into their corresponding amino carbonyl com-
tion of menthol (1a), a highly sterically hindered secondary al-
cohol, which required elevated temperatures and an O atmos-
2
[18]
phere under ABNO/copper catalysis (Table 1). The catalytic
activities of various nitroxyl radicals were compared under the
Table 1. Optimization of the reaction conditions.
[
17]
pounds at room temperature in open air.
Entry Nitroxyl radical
mol%]
x/y Additive MeCN
[m]
t
Conversion
[
a]
[
[h] [%]
1
2
3
4
5
6
7
8
9
1
AZADO (3)
Nor-AZADO (3)
ABNO (3)
1-Me-AZADO (3)
TEMPO (3)
5-F-AZADO (3)
ketoABNO (3)
Nor-AZADO (1)
Nor-AZADO (1)
Nor-AZADO (1)
AZADO (1)
ABNO (1)
Nor-AZADO (0.1)
Nor-AZADO (1)
6:3 NMI 0.2
6:3 NMI 0.2
6:3 NMI 0.2
6:3 NMI 0.2
6:3 NMI 0.2
6:3 NMI 0.2
6:3 NMI 0.2
6:3 NMI 0.2
4
3
5
12
12
5
100
100
100
96
0
100
100
100
7
4
1:1
NMI
1
1
1
1
1
1
10 100
100
24 100
48 98
48 100
64
0
1:1 DMAP
1:1 DMAP
1:1 DMAP
1:1 DMAP
1:1 DMAP
6
1
1
1
1
1
2
3
4
Scheme 2. Simplified mechanism of the alcohol-oxidation reaction by using
nitroxyl-radical/copper catalysis compared with that using oxoammonium-
based catalysis.
[
b]
6
[
a] Determined by gas chromatography. [b] CuCl was used instead of
CuOTf. Tf=trifluoromethanesulfonyl, TEMPO=2,2,6,6-tetramethylpiperi-
dine-1-oxy radical.
During our aforementioned studies, we expected that
AZADO/copper catalysis would efficiently oxidize not only un-
protected amino alcohols but also other various secondary al-
cohols. In fact, Steves and Stahl recently reported that ABNO/
modified reaction conditions reported by Hoover and Stahl,
who employed TEMPO, CuOTf, 2,2’-bipyridyl (bpy), and N-
methylimidazole (NMI) as catalysts in MeCN at ambient tem-
[
18]
copper catalysis oxidized several secondary alcohols. Howev-
er, the ABNO/copper system required a rather high catalyst
loading compared to our AZADO/copper system and heating
to oxidize sterically demanding substrates. We envisaged that
the judicious combination of an AZADO-type nitroxyl radical,
a copper salt, and an additive(s) would realize a highly efficient
aerobic alcohol oxidation with broad substrate applicability on
the basis of the following key observations: 1) slight differen-
ces in the steric and electronic properties of AZADO-type ni-
troxyl radicals often exert marked effects on their catalytic ac-
[
15]
perature in air (Table 1, entries 1–7).
Catalytic activity was
higher when a less sterically hindered nitroxyl radical was
used. Thus, Nor-AZADO-oxidized-menthol (1a) afforded quanti-
tative conversion within only 3 h (Table 1, entries 1–5). Notably,
sterically hindered nitroxyl radical TEMPO did not oxidize men-
thol (1a), and the electron-deficient nitroxyl radicals 5-F-
[6]
[20]
AZADO and ketoABNO
showed lower activities than
AZADO and ABNO, respectively (Table 1, entries 5–7). Decreas-
ing the amount of the catalysts was examined by using Nor-
AZADO as the nitroxyl radical (Table 1, entries 8–11). Lowering
the amount of Nor-AZADO to 1 mol% had a negligible effect
on the reaction efficiency (Table 1, entry 8). Although lowering
the amounts of CuOTf (1 mol%), bpy (1 mol%), and NMI
(2 mol%) significantly slowed the reaction rate, a concentrated
(1m) solution minimized the deceleration to oxidize the alco-
hol in quantitative yield within 10 h (Table 1, entry 9). After sev-
eral alternative additives to NMI were examined, 4-dimethyla-
minopyridine (DMAP) was found to catalyze the reaction more
[
4–6,17,19]
tivities
and 2) the AZADO/copper system has a different
optimum combination of a copper salt and an amine additive
[
17]
to the TEMPO/copper and ABNO/copper systems.
Herein, we report a highly efficient aerobic alcohol-oxidation
reaction with broad substrate scope by using AZADO/copper
catalysis. Optimization of the reaction conditions by using vari-
ous alcohols led us to determine several optimal combinations
of a nitroxyl radical and a copper salt, depending on the struc-
ture and characteristics of the alcohol substrate. The optimum
catalyst combinations efficiently oxidized various alcohols, in-
cluding highly hindered and heteroatom-rich substrates, in air
at or below room temperature.
[
21]
efficiently (Table 1, entry 10). Re-comparison of the catalytic
efficiencies of Nor-AZADO, AZADO, and ABNO revealed that
slight steric differences between these nitroxyl radicals led to
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considerable differences between their reaction efficiencies
Table 1, entries 10–12). Notably, even 0.1 mol% Nor-AZADO
Table 3. Optimization of the reaction conditions.
(
was sufficient to oxidize menthol (1a) in quantitative yield, al-
though the reaction time was prolonged to 48 h (Table 1,
entry 13). CuCl, which has shown good activity for oxidizing
[
17]
amino alcohols, was not suitable for the oxidation of men-
Entry Nitroxyl radi- Cu catalyst
MeCN
[m]
t
Conversion
thol (1a; Table 1, entry 14). Although several ligands, including
[
a]
cal
[mol%]
[h] [%]
[
18,21b,22]
4
,4’-dimethoxy-2,2’-bipyridyl,
and solvents were also ex-
[
[
b]
b]
[
23]
1
2
3
4
5
6
7
8
9
Nor-AZADO
AZADO
ABNO
1-Me-AZADO CuOTf (1)
TEMPO
1-Me-AZADO
1-Me-AZADO
1-Me-AZADO
1-Me-AZADO
CuOTf (1)
CuOTf (1)
CuOTf (1)
1
1
1
1
1
1
0.2
0.2
0.2
6
6
6
65
67
69
78
11
79
93
97
>99
amined, bpy and MeCN gave the best results.
Next, we optimized the reaction conditions for the oxidation
of benzylcarbamate-containing piperidinol 1b, which might
coordinate copper catalysts to attenuate the catalytic activity,
was examined (Table 2). The optimal reaction conditions for
menthol (1a) promoted the oxidation of piperidinol 1b in only
[b]
[
[
b]
b]
6
CuOTf (1)
CuCl (1)
CuCl (1)
CuCl (2)
CuCl (3)
12
6
9
9
6
45% conversion (Table 2, entry 1). Interestingly, inexpensive
[
a] Determined by gas chromatography. The conversion only increased
slightly after an extended reaction time. [b] CuOTf·0.5benzene was used
as the CuOTf source.
Table 2. Optimization of the reaction conditions.
1) The optimum combination of copper salt and solution
Entry Nitroxyl radi- Cu catalyst
MeCN
[m]
t
Conversion
concentration depends on the presence or absence of coordi-
nating groups in the substrate. CuOTf in a concentrated solu-
tion should be used for alcohols without coordinating groups
[
a]
cal
[mol%]
[h] [%]
[
b]
1
2
3
4
5
6
7
Nor-AZADO
Nor-AZADO
Nor-AZADO
Nor-AZADO
AZADO
CuOTf (1)
CuCl (1)
CuCl (1)
CuCl (2)
CuCl (2)
CuCl (2)
CuCl (2)
1
1
6
6
9
4
4
4
4
45
70
79
100
100
100
100
(
Table 4, Method A), whereas CuCl in a dilute solution should
0.2
0.2
0.2
0.2
0.2
be used for alcohols that contain coordinating groups (Table 4,
Method B).
ABNO
1-Me-AZADO
[a] Determined by gas chromatography. The conversion did not increase
after an extended reaction time. [b] CuOTf·0.5benzene was used as the
CuOTf source. Cbz=benzyloxycarbonyl.
Table 4. Substrate scope.
CuCl showed a higher activity than CuOTf, and dilute (0.2m)
conditions suppressed the deactivation of copper catalysis to
improve the conversion to 79% (Table 2, entries 2 and 3).
Quantitative oxidation of piperidinol 1b was achieved by in-
creasing the amount of CuCl to 2 mol% (Table 2, entry 4).
AZADO, ABNO, and 1-Me-AZADO showed almost the same cat-
alytic activity as Nor-AZADO, owing to the small steric hin-
drance of compound 1b (Table 2, entries 5–7).
We also optimized the reaction conditions for the oxidation
of sterically hindered primary alcohol 1c, which contained
a para-ethoxyphenyl group (Table 3). The optimal reaction con-
ditions for menthol (1a) oxidized compound 1c in 65% con-
version (Table 3, entry 1). Comparison of the catalytic activities
of nitroxyl radicals identified 1-Me-AZADO as a suitable catalyst
[
a]
Entry
1
Substrate
Method
t [h]
Yield [%]
96
[
b]
A
A
13
2
3
9
7
87
85
A
4
5
A
A
6
98
85
(
Table 3, entries 2–5). After optimization of the copper salt and
the solution concentration, we found that 3 mol% CuCl in
.2m MeCN solution gave almost-quantitative conversion of
22
0
the substrate (Table 3, entries 6–9).
6
A
A
12
98
Based on our optimization of the reaction conditions for the
oxidation of these three alcohols, we concluded that the opti-
mal reaction conditions were determined by the type of sub-
strate, as shown below:
[
c]
7
8
6
8
(73 )
97
B (x=1)
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alcohol 1m, which contained an unprotected secondary
amine, as well as heteroatom-rich alcohols 1n and 1o, al-
though higher amounts of the catalysts were needed (Table 4,
entries 14–16). This catalysis tolerated trisubstituted olefins,
which were sensitive to oxidative conditions (Table 4, entry 17).
Notably, a lower temperature (08C) was effective for oxidizing
alcohols 1o and 1p, possibly owing to the suppressed deacti-
Table 4. (Continued)
[
a]
Entry
9
Substrate
Method
t [h]
Yield [%]
[
d]
A
12
4
(13
97
)
10
B (x=2)
11
B (x=1)
4
98
[23]
vation of the copper catalysis. Sterically hindered primary al-
1
1
2
3
B (x=2)
B (x=2)
5
3
99
95
cohols 1c and 1q were also oxidized in good-to-high yields
(
Table 4, entries 18 and 19). Disappointingly, AZADO/copper
catalysis did not efficiently oxidize 3-phenylpropanol (1r),
[
e]
14
B’
1
90
which was readily oxidized by TEMPO/copper catalysis (Table 4,
[15]
entries 20 and 21).
To explain why AZADO/copper catalysis did not efficiently
oxidize simple primary alcohol 1r, we compared the reactivi-
ties of AZADO and TEMPO. Equimolar mixtures of TEMPO/
AZADO and aldehyde 2r were subjected to copper-catalyzed
aerobic oxidation (Scheme 3). When TEMPO was used, almost
1
5
B’
2
99
[
f]
1
6
7
B’
4
3
98
93
[
[
f,g,h]
1
B (x=1)
B (x=3)
g]
1
1
8
9
7
2
95
79
[
g,i]
B’
[
g]
[j]
[j]
2
2
0
1
A
3
2.5
20
60
[
g]
B (x=2)
[a] Yield of isolated product. [b] MeCN (0.5m) was used. [c] Conversion
determined by gas chromatography. [d] Conversion determined by
1
H NMR spectroscopy. [e] The product was isolated after in situ Boc pro-
tection of the amino group; see Ref. [17]. [f] The reaction was performed
at 08C. [g] 1-Me-AZADO was used instead of Nor-AZADO. [h] MeCN (1m)
1
was used. [i] MeCN (0.1m) was used. [j] Yield determined by H NMR spec-
troscopy; 1,3,5-trimethoxybenzene was used as the internal standard.
Bz=benzoyl, Boc=tert-butoxycarbonyl.
Scheme 3. Reactivities of the nitroxyl radicals with aldehyde 2r.
2) The optimum nitroxyl radical depends on whether the
substrate is a primary or secondary alcohol. Nor-AZADO should
be used for secondary alcohols, especially sterically hindered
substrates, whereas 1-Me-AZADO should be used for primary
alcohols.
no reaction was observed, with recovery of compound 2r and
TEMPO in high yields. On the other hand, AZADO and com-
pound 2r reacted rapidly to afford ester 3 as the major prod-
uct, along with several other unidentified minor products.
Ester 3 was most likely generated by oxidation of hemiacetal
4, which in turn was formed by the addition of the corre-
sponding hydroxylamine of AZADO (AZADOL) to aldehyde 2r.
Based on these results, it was clear that less-sterically hindered
nitroxyl radicals were deactivated by simple aldehydes to form
esters, although highly hindered TEMPO survived.
With sets of optimum conditions (i.e., Methods A and B and
their 1-Me-AZADO variants) in hand, we applied them to exam-
ine the substrate scope (Table 4). Secondary alcohols 1a and
1
d–1h, which didn’t contain coordinating groups, were oxi-
dized by using Method A in high yield, including the highly
sterically hindered trans-2-(a-cumyl)cyclohexanol (1h; Table 4,
entries 1–6). Cyclohexanols 1i and 1j, which contained coordi-
native phenyl and benzoyloxy groups at the b positions, were
efficiently oxidized by using Method B, but not by Method A
Conclusion
(
Table 4, entries 7–10). Secondary alcohols 1k, 1b, and 1l,
Encouraged by the exceptional chemoselectivity of AZADO/
copper catalysis in the oxidation of amino alcohols, we exam-
ined the applicability of AZADO/copper catalysis to the oxida-
tion of other alcohols. During detailed optimization of the re-
which contained benzyl carbamate and benzyl amine substitu-
ents, were also oxidized in high yields (Table 4, entries 11–13).
AZADO/copper catalysis even efficiently oxidized highly polar
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action conditions for various alcohols, we found that tailor-
made combinations of the AZADO-type nitroxyl radical, copper
salt, and solution concentration afforded highly efficient aero-
bic oxidation of the alcohol substrates. The efficient oxidation
of highly sterically hindered secondary alcohols was achieved
by employing the least-hindered nitroxyl radical, Nor-AZADO.
Alcohols that contained coordinative groups, which may at-
tenuate the activity of the copper catalysis, were efficiently oxi-
dized by CuCl instead of CuOTf under dilute conditions. These
findings successfully expanded the substrate scope of the
aerobic oxidation reaction of alcohols by using AZADO/copper
catalysis: The optimized conditions efficiently oxidized various
alcohols, including highly hindered and heteroatom-rich sub-
strates, under mild conditions with smaller amounts of cata-
lysts. In addition, a deactivation pathway of AZADO was identi-
fied. Notably, all of the catalysts employed herein, even Nor-
AZADO and 1-Me-AZADO, are currently commercially available.
This study should make the aerobic oxidation of alcohols using
nitroxyl-radical/copper catalysis a practical “method of choice”.
We expect that this reaction will be employed as a powerful
tool for the synthesis of natural products and fine chemicals.
General Procedure for Aerobic Alcohol Oxidation by Using
AZADO/Copper Catalysis (Method B)
CuCl (10.0x mmol, x mol%) was added to a solution of the alcohol
(1.00 mmol), Nor-AZADO (1.38 mg, 10.0 mmol), bpy (1.56 mg,
1
0.0 mmol), and DMAP (2.44 mg, 20.0 mmol) in MeCN (5.0 mL) at RT.
The mixture was stirred in air at RT until the alcohol was no longer
detectable (TLC), and the reaction was quenched with a saturated
aqueous solution of NaHCO (3.0 mL) and extracted with CH Cl .
3
2
2
The organic layer was washed with brine, dried over MgSO , and
4
concentrated under reduced pressure. The crude product was puri-
fied by flash column chromatography (Et O/n-hexane) to afford the
2
corresponding carbonyl compound.
1
2
-(4-Ethoxyphenyl)-2-methylpropanal (2c): Colorless oil; H NMR
(
400 MHz, CDCl ): d=9.44 (s, 1H), 7.17 (dd, J=6.8, 2.4 Hz, 2H), 6.89
3
(
1
d, J=6.8, 2.4 Hz, 2H), 4.02 (q, J=7.2 Hz, 2H), 1.43 (s, 6H),
.40 ppm (t, J=7.2 Hz, 3H); C NMR (100 MHz, CDCl ): d=202.1,
3
13
158.0, 132.7, 127.7, 114.7, 63.3, 49.6, 22.4, 14.7 ppm; IR (neat): n˜ =
À1
+
1724 cm ; MS (EI): m/z 192 [M] , 163 (100%); HRMS (EI): m/z calcd
+
for C H O : 192.1150 [M] ; found: 192.1130.
12 16
2
Reaction of AZADO with Aldehyde 2r Under Copper-Catalyzed
Aerobic Oxidation Conditions
CuOTf·0.5benzene (8.00 mg, 31.8 mmol) was added to a solution of
aldehyde 2r (42.5 mg, 0.312 mmol), AZADO (47.7 mg, 0.313 mmol),
bpy (2.74 mg, 17.5 mmol), and NMI (2.69 mg, 32.8 mmol) in MeCN
(
1.5 mL) at RT. After stirring for 5 min in air, a saturated aqueous so-
Experimental Section
lution of NaHCO was added and the mixture was extracted with
3
CH Cl . The organic layer was washed with brine, dried over
2
2
General
MgSO , and concentrated under reduced pressure to give the
4
The reactions were monitored by thin-layer chromatography (TLC)
on Merck Silica Gel 60 F254 TLC plates (0.25 mm), or by gas chroma-
tography (GC) on an Agilent 7890A GC system with an Agilent
J&W HP-5 GC column (30 m, 0.32 mm, 0.25 mm). Column chroma-
tography was performed on Kanto Silica Gel 60 N (spherical, neu-
tral, particle size: 0.063–0.210 mm) or Kanto Silica Gel 60 N (spheri-
crude product. The yield of O-acylhydroxylamine 3 was determined
to be 45% by H NMR analysis of the crude product by using 1,3,5-
trimethoxybenzene as an internal standard. Compound 3 was par-
1
tially isolated by flash column chromatography on silica gel
1
(EtOAc/n-hexane, 1:8 v/v) as a yellow oil. H NMR (400 MHz, CDCl ):
3
d=7.30–7.19 (m, 5H), 3.37 (s, 2H), 2.99 (t, J=7.8 Hz, 2H), 2.65 (t,
J=7.8 Hz, 2H), 2.21–2.15 (m, 4H), 1.93–1.90 (m, 2H), 1.83–1.77 (m,
1
cal, neutral, particle size: 0.040–0.050 mm). H NMR spectra were
13
recorded on a JEOL JNM-AL400 (400 MHz) spectrometer. Chemical
shifts are reported relative to tetramethylsilane (d=0.00 ppm).
Multiplicities are described as follows: s singlet, d doublet, t triplet,
4H), 1.43–1.35 ppm (m, 2H); C NMR (100 MHz, CDCl ): d=171.3,
3
140.4, 128.5, 128.3, 126.3, 55.7, 36.6, 36.2, 35.0, 31.2, 30.3, 26.2,
À1
+
25.8 ppm; IR (neat): n˜ =1750 cm ; MS (EI): m/z 285 [M] , 153
13
+
q quartet, m multiplet, br broad. C NMR spectra were recorded
on a JEOL JNM-AL400 (100 MHz) spectrometer. Chemical shifts are
(100%); HRMS (EI): m/z calcd for C H NO : 285.1729 [M] ; found:
18
23
2
285.1736.
1
3
reported relative to CDCl (d=77.0 ppm). IR spectra were record-
3
ed on a JASCO FTIR-410 Fourier-transform infrared spectrophotom-
eter. Low-resolution mass spectra were recorded on a JEOL JMS- Acknowledgements
DX303 mass spectrometer. High-resolution mass spectra were re-
corded on a JEOL JMS-700 mass spectrometer.
This work was supported by a Grant-in-Aid for Scientific Re-
search on Innovative Areas “Advanced Molecular Transforma-
tions by Organocatalysts” from MEXT, Japan, by the JSPS Asian
Core Program on Cutting-Edge Organic Chemistry in Asia, by
a Grant-in-Aid for Scientific Research (B) (24390001), and by
a Grant-in-Aid for Young Scientists (B) (25860001).
General Procedure for Aerobic Alcohol Oxidation by Using
AZADO/Copper Catalysis (Method A)
CuOTf·0.5benzene (2.52 mg, 10.0 mmol) was added to a solution of
the alcohol (1.00 mmol), Nor-AZADO (1.38 mg, 10.0 mmol), bpy
Keywords: alcohols · copper
oxidation · radicals
· homogeneous catalysis ·
(
1.56 mg, 10.0 mmol), and DMAP (2.44 mg, 20.0 mmol) in MeCN
(
1.0 mL) at RT. The mixture was stirred in air at RT until the alcohol
was no longer detectable (TLC), and the reaction was quenched
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Published online on && &&, 0000
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ÝÝ These are not the final page numbers!

Full Paper
FULL PAPER
Oxidation
Yusuke Sasano, Naoki Kogure,
Tomohiro Nishiyama, Shota Nagasawa,
Yoshiharu Iwabuchi*
New radicals: A highly efficient aerobic
oxidation of alcohols by using AZADO-
type nitroxyl-radical/copper catalysis has
been developed. The optimum combi-
nation of the nitroxyl radical, copper
salt, and solution concentration was de-
pendent on the type of substrate. The
optimum conditions efficiently oxidized
various alcohols, including highly hin-
dered and heteroatom-rich alcohols,
under mild conditions.
&& – &&
Highly Efficient Aerobic Oxidation of
Alcohols by Using Less-Hindered
Nitroxyl-Radical/Copper Catalysis:
Optimum Catalyst Combinations and
Their Substrate Scope
Chem. Asian J. 2015, 00, 0 – 0
www.chemasianj.org
7
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ