Safe and convenient nitroxyl radical and imide dual catalyzed NaOCl oxidation of alcohols to aldehydes/ketones

Article abstract of DOI:10.1016/j.tetlet.2015.04.115

A novel and practical oxidation of alcohols to carbonyl compounds using NaOCl in the presence of catalytic amounts of imide compound and nitroxyl radical has been developed. A wide variety of aliphatic, benzylic primary alcohols, and secondary alcohols were oxidized to afford the corresponding aldehydes and ketones in up to 98% yield without undesired halogenation on aromatic rings or double bonds. The oxidation safely proceeded not only in the presence of K₂CO₃ but also by a slow addition of NaOCl without tedious pH adjustment.

Full text of DOI:10.1016/j.tetlet.2015.04.115

Tetrahedron Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Safe and convenient nitroxyl radical and imide dual catalyzed NaOCl
oxidation of alcohols to aldehydes/ketones
a
b
a,
⇑
Naohiro Fukuda , Minoru Izumi , Tomomi Ikemoto
a
Chemical Development Laboratories, CMC Center, Takeda Pharmaceutical Company Limited, Yodogawa-ku, Osaka 532-8686, Japan
Graduate School of Environmental and Life Science, Okayama University, Kita-ku, Okayama 700-8530, Japan
b
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and practical oxidation of alcohols to carbonyl compounds using NaOCl in the presence of cat-
alytic amounts of imide compound and nitroxyl radical has been developed. A wide variety of aliphatic,
benzylic primary alcohols, and secondary alcohols were oxidized to afford the corresponding aldehydes
and ketones in up to 98% yield without undesired halogenation on aromatic rings or double bonds. The
Received 19 March 2015
Revised 22 April 2015
Accepted 28 April 2015
Available online xxxx
oxidation safely proceeded not only in the presence of K
tedious pH adjustment.
2
CO
3
but also by a slow addition of NaOCl without
Keywords:
Oxidation
Alcohol
Ó 2015 Elsevier Ltd. All rights reserved.
NaOCl
Nitroxyl radical
Imide
Since the selective oxidation of alcohols to the corresponding
carbonyl compounds is one of the most significant and widely used
transformations in synthetic organic chemistry, a number of useful
amounts of waste as byproduct, for instance, iodobenzene, m-
chlorobenzoic acid, and imides, which need to be removed by col-
Ò
umn chromatography. The combination of TEMPO and Oxone
1
methods have been developed. Among them, metal catalyzed sys-
easily oxidizes benzylic alcohols to the corresponding aldehydes,
however, the yields from non-activated alcohols, such as aliphatic
2
3
tems using co-oxidants such as oxygen, hydrogen peroxide, ace-
tone or sodium hypochlorite5 have recently attracted much
attention due to the growing environmental requirement.
However, trace metal contamination of products is especially a
concern for pharmaceutical manufacturing, even though the meth-
ods are useful in terms of producing less-metal containing waste.
Meanwhile, the oxidation of alcohols by oxoammonium salts has
4
9
alcohols, are moderate. The reaction with a halogen source some-
times proceeds to give halogenation along with the oxidation of
alcohols. The large scale synthesis using O
strict safety consideration due to the explosion risk associated with
the combination of O , organic solvents, and reagents.
2
is also constrained by
2
Anelli and co-workers firstly reported the practical TEMPO cat-
alyzed oxidations with aqueous NaOCl as co-oxidant in 1987 and
6
also become a widely used non-metallic oxidation system. More
7
a
commonly, alcohol oxidations using TEMPO (2,2,6,6-tetram-
ethylpiperidine-1-oxyl) and its analogues are conducted in
catalytic systems that involve in situ generation of the oxoammo-
nium cation via one-electron oxidation with a stoichiometric
amount of co-oxidant, such as hypochlorite salt,7 mCPBA,
this is generally recognized as standard protocol. Since NaOCl is
generally inactive as an oxidant, it is necessary to adjust the pH
of the reaction condition to 7–9 with diluted aqueous NaHCO
3
and/or phosphate buffer, and to add KBr and phase transfer
catalyst as well as frequently used halogenated solvents in order
to complete the reaction. However, as a result of adding buffer
solution to increase the amount of HOCl (a more active oxidant
than NaOCl), the volume of the reaction mixture is increased,
resulting in reduced productivity. Also, this kind of oxidation
often suffers from halogenation of aromatic rings or double
bonds and over-oxidation to the carboxylic acids because of the
8
Ò 9
10
11
Oxone , [bis(acetoxy)iodo]benzene (BAIB),
2
I ,
N-chlorosuccin-
1
2
13
imide (NCS),
catalyst/O
1,3,5-trichloroisocyanuric acid (TCCA),
co-
1
4
15
2
,
and PyꢀHBr
3
.
Although these methods are useful
in terms of the mild reaction conditions, some drawbacks remain
from the viewpoints of safety, substrate versatility, and waste.
Oxidation with many co-oxidants generates equivalent molar
7
a,c
presence of HOCl.
In addition, there are safety concerns and
careful handling is required due to toxic chlorine gas generated
1
6
⇑
Corresponding authors. Tel.: +81 6 6300 6797; fax: +81 6 6300 6251.
E-mail address: tomomi.ikemoto@takeda.com (T. Ikemoto).
under acidic conditions. We herein describe the safe and conve-
nient oxidation of alcohols to the corresponding carbonyl
http://dx.doi.org/10.1016/j.tetlet.2015.04.115
040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
0
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2
N. Fukuda et al. / Tetrahedron Letters xxx (2015) xxx–xxx
compounds using aqueous NaOCl with a catalytic amount of the
imide compound and without pH adjustment.
The effect of additives (0.1 equiv) for TEMPO (0.03 equiv) cat-
alyzed aq NaOCl (1.2 equiv) oxidation at 0–10 °C for 2 h in ethyl
acetate was investigated using 1-octanol 1a as a representative
Table 2
Oxidation of various alcohols for nitroxyl radical/imide/NaOCl oxidation in the
presence of K CO
2 3
a
12% aq.NaOCl
TEMPO or AZADO
alcohol
aldehyde / ketone
substrate in the presence of K
be used safely in basic reaction conditions, and results are shown
in Table 1. The reaction without any additives or with n-Bu NCl
2 3
CO (2.0 equiv) because NaOCl can
1
cyanuric acid
K CO
2
2
3
4
proceeded only slightly toward oxidation of 1a (entries 1 and 2).
Addition of KBr improved the oxidation, however, the yield of 1-oc-
tanal 2a was still only 12% (entry 3). Interestingly, a combination of
Entry Substrate
Catalyst Time (h) Yield b (%)
OH
90c,d
1
TEMPO
8
4
n-Bu NCl and KBr decreased the yield (entry 4). However, to our
1
b
great delight, a catalytic amount of imide compound notably accel-
erated the oxidation, as well as the oxidation of sulfide reported
OH
2
3
TEMPO
TEMPO
4
6
90c
90
1
7
previously. The reaction with succinimide gave 2a in 86% yield,
albeit with also producing 1-octanoic acid 3a in 7% yield (entry
1c
OH
Ph
Ph
5). Also, 5,5-dimethylhydantoin afforded 2a in 74% yield (entry
6). Using cyanuric acid, the best result was afforded to give 2a in
91% yield (entry 7). When a sulfonamide was used for comparison
1d
4
OH
TEMPO
8
97
89
2
with the imide, TsNH was found to also slightly accelerate the
reaction (entry 8). The reaction rate was significantly decreased
in toluene or CPME (cyclopentyl methyl ether) as reaction solvent
1e
MeO
(
entries 9–11).
5
6
7
OH
TEMPO
TEMPO
TEMPO
3
3
5
Next, we examined the oxidation of a variety of primary and
1
f
secondary alcohols with 1.2 equiv of NaOCl in ethyl acetate and
the presence of 3 mol % of nitroxyl radical and 10 mol % of cyanuric
acid at 0–10 °C, as shown in Table 2. Aliphatic alcohols 1b–d were
oxidized to give the corresponding aldehydes 2b–d in high yield
and carboxylic acid derivatives were not observed. (entries 1–3).
Benzylic alcohols 1e–h were also readily oxidized to give the cor-
responding benzaldehydes 2e–h in high yield (entries 4–7). The
oxidation of 4-methoxybenzyl alcohol 1f interestingly proceeded
smoothly without undesired halogenation of the aromatic ring,
whereas the halogenated by-product was obtained using Anelli’s
MeO C
2
OH
86
1g
HO
98e
1h
CF3
OH
Ph
Ph
8
9
TEMPO
AZADO
7
2
88
90
1i
7
a
OH
conditions. Although the oxidation of cinnamyl alcohol 1i often
1i
7a
suffers from chlorination of its double bond, the cinnamyl
aldehyde 2i was obtained by oxidation for 7 h and the
halogenated product was not found (entry 8). When 2-
azaadamantane N-oxyl (AZADO), a less hindered class of stable
OH
10
Ph
F
TEMPO
TEMPO
6
6
95
93
1
j
OH
Table 1
a
11
12
2 3
Effect of additive for TEMPO/NaOCl oxidation in the presence of K CO
F
1k
1
2% aq.NaOCl
TEMPO
OH
CH (CH ) OH
CH
3
(CH
2
)
6
CHO CH
2a
3
(CH
2 6 2
) CO H
3
2 7
additive
K CO
2 3
1
a
3a
TEMPO
6
39
96
1
l
Entry
Solvent
Additive
Yieldb (%)
OH
1
a
2a
3a
1
1
3
4
AZADO
TEMPO
3
3
1
2
3
4
5
6
7
8
9
AcOEt
AcOEt
AcOEt
AcOEt
AcOEt
AcOEt
AcOEt
AcOEt
Toluene
Toluene
CPME
None
99
88
87
71
5
23
4
71
70
86
65
1
1
12
1
86
74
91
29
30
11
34
0
0
0
0
7
0
0
0
0
0
0
n-Bu
KBr
4
NCl
1l
n-Bu
4
NCl, KBr
OH
Succinimide
5,5-Dimethylhydantoin
Cyanuric acid
3d
c
1m
TsNH
2
OH
Succinimide
Cyanuric acid
Succinimide
99d
1
1
5
6
AZADO
TEMPO
3
6
1
1
0
1
1m
OH
a
Unless stated otherwise, the reaction was carried out with 1-octanol 1a
56
(
0.39 mmol), 12% aq NaOCl (0.47 mmol), nitroxyl radical (3 mol %),
K
2
CO
3
Ph
1n
(
0.78 mmol), additive (10 mol %) at 0-10 °C for 2 h.
b
The assay yields were calculated by GC using an internal reference standard.
c
The reaction time was prolonged to 3 h.
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N. Fukuda et al. / Tetrahedron Letters xxx (2015) xxx–xxx
3
Table 3
Table 2 (continued)
2 3
Oxidation of alcohols without K CO
by slow addition of NaOCla
Entry Substrate
Catalyst Time (h) Yield b (%)
1
2% aq.NaOCl
OH
TEMPO or AZADO
1
7
AZADO
3
96
alcohol
1
aldehyde / ketone
Ph
cyanuric acid
1
n
2
a
Unless stated otherwise, the reaction was carried out with 1 (0.39 mmol), 12%
aq NaOCl (0.47 mmol), nitroxyl radical (3 mol %), K CO (0.78 mmol), cyanuric acid
Yieldb (%)
Entry
Substrate
Catalyst
2
3
(
10 mol %) at 0–10 °C.
CH (CH ) OH
3
2 7
b
1
2
TEMPO
TEMPO
90
93
Isolated yield.
1a
c
1
.05 equiv of NaOCl was used.
d
e
Ph
Ph
OH
Yield was determined by GC analysis by using an internal standard.
Yield was determined by HPLC analysis by using an authentic standard.
1d
3
4
OH
TEMPO
TEMPO
98
93
nitroxyl radical with a high catalytic activity, was used, the
1e
OH
reaction was accelerated and completed within 2 h to give 2i in
1
8
9
0% yield (entry 9). Regarding secondary alcohols, the oxidation
Ph
was found to be relatively slow for benzylic alcohols, however,
good to excellent yields were obtained by extending the reaction
time. The oxidation of 1-phenylethanol 1j and 4,4 -difluorobenzhy-
1j
OH
0
drol 1k gave the corresponding ketones in 95% and 93% yields,
respectively (entries 10 and 11). Although the oxidation of fluo-
ren-9-ol 1l, 4-methyl-2-pentanol 1m, and 4-phenyl-2-butanol 1n
with TEMPO did not obtain the corresponding ketones in sufficient
yield with alcohols recovered, the oxidations went to completion
within 3 h when using AZADO, to afford the corresponding ketones
in excellent yield (entries 12–17).
5
6
AZADO
AZADO
99
92
1
l
OH
Ph
1
n
a
The reaction was performed by a slow addition of 12% aq NaOCl (0.47 mmol)
A plausible catalytic dual redox cycle in the case of using
TEMPO is postulated as shown in Scheme 1. NaOCl first reacts with
the imide catalyst in the aqueous layer to produce N-chloroimide,
which transfers to the organic layer. Then, the reaction of TEMPO
with the resulting N-chloroimide affords the oxoammonium salt
A. This salt reacts with alcohol to give the corresponding aldehyde
or ketone and generates hydroxylamine B, which is oxidized by N-
chloroimide to regenerate the oxoammonium salt A.
into a mixture of 1 (0.39 mmol), nitroxyl radical (3 mol %), cyanuric acid (10 mol %)
in AcOEt at 0–10 °C, then the mixture was stirred for 1 h.
b
Isolated yield.
alcohols went to near completion, to give the corresponding car-
bonyl compounds in excellent yield after finishing NaOCl addition.
Since this reaction system does not accumulate NaOCl in the reac-
tion mixture, the side reactions such as chlorination and chlorine
gas emission could be avoided.
2 3
The reaction without K CO was completed by dropwise addi-
tion of NaOCl with the reaction mixture remaining at >pH 7, as
shown in Table 3. When a portion of NaOCl was added to a mixture
of alcohol, cyanuric acid, and nitroxyl radical in ethyl acetate, pH of
the reaction mixture was briefly raised. After that, it was gradually
neutralized as the reaction progressed. Although the addition of
NaOCl took more than 3 h, the oxidation of primary or secondary
In conclusion, we have developed a simple and efficient oxida-
tion of alcohols to the corresponding carbonyl compounds employ-
ing an imide compound-nitroxyl radical catalyst system without
pH adjustment. Various alcohols, including primary aliphatic, func-
tionalized benzylic, and secondary alcohols are converted into the
corresponding aldehydes and ketones in excellent yield.
A
O
O
N
H
O
NaOCl
N
O
Cl
N
O
N
O
A
OH
2
R : H or alkyl
R1
R2
O
N
O
H
NaOCl
O
R1
R2
O
N
O
N
Cl
OH
B
Scheme 1. Plausible catalytic dual redox cycle for TEMPO.
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4
N. Fukuda et al. / Tetrahedron Letters xxx (2015) xxx–xxx
noteworthy feature is that this oxidation can be carried out even
under basic conditions (>pH 12) in the presence of K CO and
imide catalyst. In addition, the slow addition of NaOCl without
CO also completed the oxidation of alcohols.
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