Oxidation of alcohols with nitroxyl radical under polymer-supported two-phase conditions

Article abstract of DOI:10.1039/b307190c

The oxidation of alcohols to carbonyl compounds was studied using potassium hexacyanoferrate(III) mediated by nitroxyl radical as the catalyst under polymer-supported organic-aqueous two-phase conditions. Primary alcohols are readily oxidized to the corresponding aldehydes in excellent yield with no over-oxidation to carboxylic acids. Secondary alcohols are converted to the corresponding ketones with a much lower efficiency. The oxidation reactions of primary alcohols in the presence of secondary alcohols is strongly favored. Primary-secondary diols are selectively transformed into hydroxy aldehydes with small amounts of ketoaldehydes, the amount of isomeric keto alcohols remaining is less than 1%.

Full text of DOI:10.1039/b307190c

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Oxidation of alcohols with nitroxyl radical under polymer-supported
two-phase conditions
Yoshitomo Kashiwagi,* Shinya Chiba and Jun-ichi Anzai
Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki, Aoba-ku, Sendai
980-8578, Japan. E-mail: kashi@mail.pharm.tohoku.ac.jp; Fax: +81-22-217-6840;
Tel: +81-22-217-6842
L e t t e r
Received (in Montpellier, France) 24th June 2003, Accepted 12th August 2003
First published as an Advance Article on the web 19th September 2003
The oxidation of alcohols to carbonyl compounds was studied
using potassium hexacyanoferrate(III) mediated by nitroxyl radi-
cal as the catalyst under polymer-supported organic–aqueous
two-phase conditions. Primary alcohols are readily oxidized to
the corresponding aldehydes in excellent yield with no over-
oxidation to carboxylic acids. Secondary alcohols are converted
to the corresponding ketones with a much lower efficiency. The
oxidation reactions of primary alcohols in the presence of sec-
ondary alcohols is strongly favored. Primary-secondary diols
are selectively transformed into hydroxy aldehydes with small
amounts of ketoaldehydes, the amount of isomeric keto alcohols
remaining is less than 1%.
Oxoammonium ions1 are known as nonmetallic oxidizing
reagents of alcohols to the corresponding carbonyl compounds
under mild reaction conditions2 and are easily available from
the corresponding nitroxyl radicals by one-electron oxidation.
Several oxidation reactions of alcohols in organic–aqueous
two-phase solutions have been reported using regenerating
oxidants such as positive halogen sources3–6 and high valency
metal salts,7,8 which were mediated by the oxidation of
nitroxyl radical to oxoammonium ion. However, almost all
of the reactions require the same amount of organic solvent
as water. The use of water instead of organic solvents is
strongly desired from the viewpoint of environmental safety
and economical cost. For this reason, we tried to use a small
amount of swelled organic solvent, which may be kept in a
polystyrene (PS) resin by hydrophobic interactions, as the
organic layer of a two-phase reaction system. Herein we report
on the first efficient oxidation of alcohols to carbonyl com-
pounds using potassium hexacyanoferrate(III) [K3Fe(CN)6]
mediated by nitroxyl radical as the catalyst under polymer-
supported organic–aqueous two-phase conditions (Fig. 1).
We first tried the oxidation of benzyl alcohol using
K3Fe(CN)6 mediated by 4-benzoyloxy-2,2,6,6-tetramethyl-
pipridin-1-yloxyl (4-benzoyloxy-TEMPO) as the nitroxyl radical
catalyst in a two-phase system of toluene and 1 M aqueous
KOH (1:1) at room temperature; the corresponding benzalde-
hyde was obtained quantitatively in 3 h.
Fig. 1 Oxidation of alcohols with K3Fe(CN)6 mediated by the
nitroxyl radical catalyst in a resin-supported organic–aqueous two-
phase solution system.
performed based on these experimental conditions. About 2
ml of a toluene solution containing alcohol and 4-benzyloxy-
TEMPO was completely absorbed by 300 mg of PS resin, by
mixing the two. Then, the swelled resin was added to 10 ml
of a 1 M aqueous KOH solution containing 2.45 g (7.5 mmol)
of K3Fe(CN)6 . The leakage of toluene from the polymer under
the reaction conditions was ca. 1.5%. The reaction mixture was
stirred at room temperature. During the oxidation reaction,
aliquots of the reaction mixture were occasionally analyzed
by GC and HLPC. The results from the oxidation reactions
of benzyl alcohol are shown in Fig. 2 and Table 1. If only
small amounts of the catalyst were employed, the yield of
benzaldehyde was low although the turnover number (given
Fig. 2 PS resin-supported two-phase oxidation of benzyl alcohol to
benzaldehyde with K3Fe(CN)6 mediated by 4-benzoyloxy-TEMPO.
The reaction was performed under the same conditions as those given
in the Experimental. Amount of 4-benzoyloxy-TEMPO: (X) 0.05, (S)
0.02, (`) 0.01, (G) 0.005, (K) 0.001 and (L) 0 equiv.
Therefore, the oxidation reactions of alcohols under polymer-
supported organic–aqueous two-phase conditions were
DOI: 10.1039/b307190c
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The results of the oxidation of a variety of primary and sec-
Table 1 PS resin-supported two-phase oxidation of benzyl alcohol
with K3Fe(CN)6 mediated by 4-benzoyloxy-TEMPO
ondary alcohols are given in Table 2. The primary alcohols
(entries 1–7) such as 1-hexanol, 7-octen-1-ol, nerol, benzyl
alcohol, 4-methoxybenzyl alcohol, 4-nitrobenzyl alcohol and
cinnamyl alcohol were oxidized to the corresponding alde-
hydes. Under standard reaction conditions aliphatic and
benzylic primary alcohols are oxidized within 0–8 h. The turn-
over number based on the amount of 4-benzoyloxy-TEMPO
was calculated to be > 97. In the case of benzylic alcohols,
electron-donating groups slow down the reaction (entry 5)
whereas electron-withdrawing groups accelerate it (entry 6).
Allyl alcohols (entries 3 and 7) are also oxidized to the corres-
ponding aldehydes in adequate yields.
On the other hand, the secondary alcohols (entries 8–12)
such as 2-hexanol, cyclohexanol, 1-phenylethanol, 4-phenyl-
3-buten-2-ol and 1-hydroxyindan are converted to the corres-
ponding ketones with a much lower efficiency under the same
conditions. This observation suggests the possible chemoselec-
tive oxidation of primary alcohols in the presence of secondary
alcohols. The results from the oxidation of a 1:1 mixture of
1-hexanol and 2-hexanol are shown in Fig. 3 and Table 3
(entry 1). Indeed, the present oxidation system proved to be
4-benzoyloxy-
TEMPOa /
TON of
% Benzaldehyde 4-benzoyloxy-
Run equiv.
Time/h yieldb
TEMPOc
1
2
3
4
5
6
0.05
0.02
0.01
0.005
0.001
0
2
4
98
98
75
62
40
0
39
98
20
20
20
20
150
248
800
–
a
b
Based on benzyl alcohol. Yield was determined by calibrated
c
quantitative HLPC analysis using an internal standerd. Turnover
number given by the ratio of mol of products  2 per mol of 4-benzoyl-
oxy-TEMPO.
by the ratio of mol of products  2 per mol of nitroxyl radical
catalyst) was high, as shown in Table 1. The results depicted in
Fig. 2 indicate that more than 2 mol % nitroxyl radical based
on benzyl alcohol is needed to obtain quantitative oxidation.
Table 2 PS resin-supported two-phase oxidation of primary and secondary alcohols to the corresponding aldehydes and ketones with K3Fe(CN)6
mediated by 4-benzoyloxy-TEMPO
Entry
Substrate
Time/h
Product
% Yielda
TON of 4-benzoyloxy-TEMPOb
1
2
4
97
92
97
92
24
3
3
98
98
4
5
2
8
98
96
98
96
6
0.5
98
98
7
8
3
6
85
28
85
28
9
6
4
30
72
30
72
10
11
24
3
58
58
12
64
64
a
Yields were determined by calibrated quantitative GC and HPLC analysis using an internal standard. b Turnover number given by the ratio of
mol of products  2 per mol 4-benzoyloxy-TEMPO.
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oxidation of an end 1,2-diol produced an intermolecular
hemiacetal (entry 10). The oxidation of 6,7-dodecanediol as a
secondary-secondary diol produced the corresponding dike-
tone in 60% yield without any cleavage of the carbon-carbon
bonds (entry 11).
A possible reaction mechanism is shown in Fig. 4. The
nitroxyl radical catalyst is first oxidized by Fe(III) to give
oxoammonium ion at the organic–aqueous interface. Subse-
quently, the alcohol is oxidized by the oxoammonium ion in
the organic phase of the PS resin to give an adduct made up
of the alcohol and the oxoammonium ion, which is attacked
by a Lewis base to form the second intermediate. This leads
to the carbonyl compounÀd,9 hydroxylamine and a protic acid
Fig. 3 PS resin-supported two-phase oxidation of a 1:1 mixture of
1-hexanol and 2-hexanol with K3Fe(CN)6 mediated by 4-benzoyloxy-
TEMPO. The reaction was performed under the same conditions as
those shown in Table 3. (X) 1-hexanol, (S) 2-hexanol.
+
II
such as H K3[Fe (CN)6] , which is neutralized by KOH to
give potassium ferrocyanide. Either the hydroxylamine is oxi-
dized to the nitroxyl radical by Fe(III) or the reaction of
the hydroxylamine and the oxoammonium ion produces the
nitroxyl radical. In either case, the nitroxyl radical is re-
oxidized chemically by Fe(III) to complete a catalytic cycle.
In conclusion, we have demonstrated the first efficient oxida-
tion of alcohols using K3Fe(CN)6 mediated by 4-benzoyloxy-
TEMPO in a polymer-supported organic–aqueous two-phase
solution system. Primary alcohols are readily oxidized with
no over-oxidation to carboxylic acids. Furthermore, this pro-
cess exhibits chemoselectivity for the oxidation of primary
hydroxy groups in the presence of secondary hydroxy groups.
exceptionally chemoselective: under standard reaction condi-
tions the primary alcohol was converted quantitatively into
aldehyde after 3 h whereas virtually no ketone ( < 0.1%) could
be detected by GC. The competitive oxidation of benzyl alco-
hol and 1-phenylethanol exhibits a similar degree of selectivity.
An even more difficult problem of selectivity is that of cinna-
myl alcohol versus 4-phenyl-3-buten-2-ol as allyl alcohols. A
88:5 ratio of aldehyde to ketone was obtained after 4 h.
The results of the oxidation of various diols are shown in
Table 4. Oxidative cyclization of 1,4- and 1,5-diols to g- and
d-lactones, respectively, proceeded nicely (entries 1, 2, 6 and
7). cis-Cyclohexane-1,2-dimethanol is also converted into a
cyclization product (entry 5). However, 1,n-diols (n > 5) gave
predominately non-cyclization products such as 1,n-dialde-
hyde or n-hydroxyalkanal (entries 3 and 8). 1,4-Benezene-
dimethanol, a benzylic primary-primary diol, is oxidized to the
corresponding dialdehyde with excellent yield (entry 4). As
an example of interamolecular competition between primary
and secondary alcohols, oxidation of 1,10-undecanediol gave
an 82% isolated yield of 10-hydorxyundecanal with 5% ketoal-
dehyde, the amount of isomeric keto alcohol remaining being
less than 0.1% (entry 8). Even in the case of doubly activated
secondary alcohols the method ensures oxidation of the
primary alcohols with a high chemoselectivity (entry 9). The
Experimental
Materials
PS resin (1% cross-linked, 75–150 mesh) was purchased from
Agronaut Technologies Inc. 4-Benzoyloxy-TEMPO was pur-
chased from Tokyo Chemical Industry. Potasium hydroxide
and K3Fe(CN)6 were purchased from Nakari Tesque. All alco-
hols and symmetrical diols used for the oxidations were of
commercially available reagent grade except trans-4-phenyl-
3-buten-2-ol obtained in 70% yield by reduction of 4-phenyl-
3-buten-2-one as the commercial ketone by NaBH4/CeCl3 .10
Primary-secondary diols, already known, were prepared
Table 3 PS resin-supported two-phase oxidation of primary alcohols in the presence of secondary alcohols with K3Fe(CN)6 mediated by
4-benzoyloxy-TEMPOa
Entry
1
Substrate
Time/h
3
Product
% Yieldb
98
TON of 4-benzoyloxy-TEMPOc
49
< 0.1
98
2
3
49
< 0.1
88
3
4
47
5
a
The reactions were carried out, on a 1:1 mixture of primary and secondary alcohols. b Yields were determined by calibrated quantitative GC and
c
HPLC analysis using an internal standard. Turnover number given by the ratio of mol of products  2 per mol 4-benzoyloxy-TEMPO.
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Table 4 PS resin-supported two-phase oxidation of various diols with K3Fe(CN)6 mediated by 4-benzoyloxy-TEMPO
Entry
1
Substrate
Time/h
4
Product
% Yielda
96
TON of TEMPOb
192
194
184
190
2
3
4
3
4
6
97
92
95
5
2
94
188
6
7
6
5
88
90
176
180
80c
5
8
2
90
76d
12
9
3
100
10
5
8
70
70
12
60
11
132
a
Yields based on weight of pure product after chromatography. b Turnover number given by the ratio of mol of products such as lactones, keto-
c
d
aldehydes, dialdehydes and diketones  4 per mol of 4-benzoyloxy-TEMPO. Ketoalcohol could not be detected. 0.5% ketoalcohol and 7%
starting diol were isolated.
by simplified procedures except for 1,4-pentanediol, 1,5-
hexanediol and 1,2-tetradecanediol as commercial diols;
1,10-undecenediol11 was prepared with a 78% yield by oxymer-
curation-demercuration of 10-undecene-1-ol and a-phenyl-1,4-
benzenedimethanol12 in 90% yield by borane/THF reduction
of 4-benzoylbenzoic acid.
KOH solution containing 2.45 g (7.5 mmol) of K3Fe(CN)6 .
The reaction mixture was stirred at room temperature and
the reaction monitored by HPLC and/or GC. The HPLC ana-
lysis was carried out using a Daisel CHIRALCEL1 OD col-
umn (46 mm f  250 mm). The column temperature kept
constant at 40 ꢀC. The analytes were eluted by PriOH–n-
hexane (2:33) at 0.7 ml minÀ1 flow rate and detected by UV
adsorption at 254 nm. The GC analysis was carried out using
CP-cyclodextrin-b-2,3,6-M-19 capillary column (0.25 mm
f  25 m). The column temperature was increased at 3 ꢀC
minÀ1 from 80 to 150 ꢀC. The injection and detector tempera-
tures were 200 ꢀC and 240 ꢀC, respectively. At the end of the
reaction, the swelled resin was separated, washed three times
with water, extracted three times with toluene and filtered
in vacuo. This extracted solution was dried with magnesium
General procedure for the oxidation of alcohols
PS resin (300 mg) was added to the toluene solution (4 ml) con-
taining alcohol (2 mmol), 4-bezoyloxy-TEMPO (0.04 mmol)
and tetralin (0.5 mmol; internal standard). This PS resin dis-
persed solution was stirred for 1 h at room temperature and
then was separated. The swelled resin was washed three times
with water and then was added to 10 ml of a 1 M aqueous
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Fig. 4 Schematic diagram of PS resin-supported two-phase oxidation
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Oxidation products
Simple aldehydes, ketones and lactones obtained by oxidation
were characterized by the usual spectral data (mass, IR, 1H
and 13C NMR) and compared with the literature values. The
oxidation products of primary-secondary diols were already
described: 10-hydroxyundecanal,4c 10-oxoundecan-1-ol,11 10-
oxoundecanal,3b 4-(a-phenylhydroxymethyl)benzaldehyde,13
4-(hydroxymethyl)benzophenone,12 4-benzoyl benzaldehyde.12
6
7
8
9
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This work was supported in part by a Grant-in-Aid for Scien-
tific Research on Encouragement Research (No. 13750792)
from the Ministry of Education, Culture, Sports, Science and
Technology of Japan.
New J. Chem., 2003, 27, 1545–1549
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