Catalytic oxidations of alcohols to carbonyl compounds by oxygen under solvent-free and transition-metal-free conditions

Article abstract of DOI:10.1016/j.tetlet.2005.10.123

A green catalytic oxidation of alcohols to carbonyl compounds by oxygen was developed by using catalytic amounts of [bis(acetoxy)iodo]benzene/TEMPO/ KNO₂. In addition, the use of a catalytic amount of poly[4-(bis(acetoxy)iodo)]styrene led to yields (up to 99%) comparable to the non-supported hypervalent iodine reagent, while offering the advantage of an efficient recovery and the subsequent recycling of the hypervalent iodine reagent.

Full text of DOI:10.1016/j.tetlet.2005.10.123

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 13–17
Catalytic oxidations of alcohols to carbonyl compounds by
oxygen under solvent-free and transition-metal-free conditions
a
b
a,
*
´
Clara I. Herrerıas, Tony Y. Zhang and Chao-Jun Li
aDepartment of Chemistry, McGill University, 801 Sherbrooke St. West, Montreal QC, Canada H3A 2K6
bChemical Product R&D, Eli Lilly and Company, Lilly Corporate Centre, IN 46285, USA
Received 6 October 2005; accepted 25 October 2005
Available online 11 November 2005
Abstract—A green catalytic oxidation of alcohols to carbonyl compounds by oxygen was developed by using catalytic amounts of
[bis(acetoxy)iodo]benzene/TEMPO/KNO2. In addition, the use of a catalytic amount of poly[4-(bis(acetoxy)iodo)]styrene led to
yields (up to 99%) comparable to the non-supported hypervalent iodine reagent, while offering the advantage of an efficient recovery
and the subsequent recycling of the hypervalent iodine reagent.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
metal. To meet such a challenge, we chose hypervalent
iodine reagents for the oxidation of alcohols.
Oxidations in general and oxidation of alcohols in
particular are key reactions in the synthesis of complex
organic molecules and fine chemicals.1 Most oxidation
reactions in organic chemistry are contradictory to the
principles of Green Chemistry and Sustainable Develop-
ments2 due to the lack of selectivity, the use of toxic
metal reagents or catalysts that are persistent pollutants,
or the use of halogenated solvents. Therefore, there is a
great interest in the development of green oxidations for
chemical manufacturing. In this regard, the use of
organocatalysts for oxidation of organic compounds,
avoiding transition-metals completely, appears very
Hypervalent iodine reagents are becoming increasingly
appreciated by organic chemists for their mild and
highly chemoselective oxidizing properties.4 For exam-
ple, the Dess–Martin periodinane (DMP), and to a
lesser extent, its precursor 2-iodoxybenzoic acid (IBX)
(both are iodine(V)-based reagents) have been widely
used as oxidants for the chemoselective transformation
of alcohols to their corresponding carbonyl com-
pounds.5 In spite of the extensive use of these com-
pounds in synthesis, their potentially explosive nature
constitutes a serious disadvantage. Thus, a facile and
efficient use of the readily available and relatively stable
iodine(III)-based reagents has been desired in place of
iodine(V)-based reagents. However, only a few examples
of effective oxidations of alcohols using iodine(III)-
based reagents have been described.6 One such example
is the highly selective and efficient oxidation of alcohols
to carbonyl compounds carried out by Piancatelli et al.,6a
without overoxidation to carboxylic compounds. They
used, as reagents, a combination of [bis(acetoxy)iodo]-
benzene (BAIB) in a stoichiometric amount together
2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO), a nitroxyl
radical and the species responsible for the selective oxi-
dation of alcohols,7,8 in a catalytic amount, leading to
a procedure highly selective for the oxidation of primary
alcohols to aldehydes and highly chemoselective in the
presence of secondary alcohols and other oxidizable
functional groups. This same reaction has been carried
appealing and constitutes
a significant challenge.
Recently, Hu et al. described an efficient aerobic
transition-metal-free catalytic oxidation of alcohols in
water.3 The oxidation was carried out under a high pres-
sured-air atmosphere and promoted by a mixture of
TEMPO/1,3-dibromo-5,5-dimethylhydantoin/NaNO2 in
catalytic amounts. The use of NO activates the mole-
cular oxygen, thus completing the catalytic oxidation
cycle. On the other hand, recently we have explored
the use of selective oxidation of alcohols by oxygen in
the presence of organocatalysts. To be successful, we
need a highly efficient organic oxidant that has proven
high oxidation efficiency and chemoselectivity and can
be regenerated in situ without using any transition
*
Corresponding author. Fax: +1 514 398 3797; e-mail: cj.li@mcgill.ca
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.123

14
C. I. Herrerı´as et al. / Tetrahedron Letters 47 (2006) 13–17
out using poly[4-(bis(acetoxy)iodo)]styrene (PBAIS) in-
stead of BAIB.9 PBAIS has recently attracted much
attention because of its similar reactivity to BAIB but
with the additional advantages of simple workup proce-
dure and easy recovery and recycling.10 Building upon
these achievements, we have developed a green catalytic
oxidation of alcohols to carbonyl compounds under
oxygen atmosphere using catalytic amounts of a mixture
of BAIB or PBAIS/TEMPO/KNO2 (Eq. 1).
As a result, efficient agitation of the reaction mixture
is also critical to achieve the maximum yield.
With the optimized neat reaction conditions [BAIB:
TEMPO:KNO2 = 4:1:4 (mol %) and a temperature of
80 °C], we applied the procedure to a wide range of
alcohols in order to evaluate the versatility of this novel
catalytic system. The preparation of PBAIS allowed us
to compare the results of homogeneous and hetero-
geneous conditions. Table 2 shows the range of oxidized
alcohols under these conditions.
OH
CHO
PS
PhI(OAc)2
PhI(OAc)2 or
:
As it was shown, moderate to excellent yields were
obtained when benzylic alcohols were used, and the
overoxidized carboxylic acid was not observed in any
case. However, the yields were affected by the electronic
properties of the substituents and their position in the
aromatic ring: while an electron-donating group on the
aryl ring leads to satisfactory yields, an electron-with-
drawing group decreases the yields (Table 2, entries 2–
8). It has been reported that iodine(III) and TEMPO/
primary oxidant systems oxidize sulfur functional
groups.12 Surprisingly, the current catalytic system
exhibited high chemoselectivity toward the alcoholic
moiety even in the presence of a sulfur heteroatom
(Table 2, entry 8). An a-methyl benzyl alcohol can be
also be oxidized into acetophenone with a reason-
able yield (Table 2, entry 9). The use of PBAIS led to
similar results, albeit a longer reaction time was needed.
At the end of the reaction, the polymer species was
recovered by precipitation with diethyl ether, filtra-
tion from the reaction medium, and regeneration by
treatment with peracetic acid. The polymer was success-
fully recycled in three successive reactions (Table 2,
entry 1).
TEMPO : KNO2 = 4:1:4 (molar ratio)
O2, 80ºC
R
R
up to
yield
99%
ð1Þ
2. Results and discussion
The initial experiments were carried out using benzyl
alcohol as the model substrate utilizing 4 mol % of
BAIB, 1 mol % of TEMPO and 4 mol % of KNO2 as
catalysts in water and under an oxygen atmosphere
(Table 1).
Our first result (Table 1, entry 1), using 3 mL of water as
solvent, showed clearly the catalytic nature of this reac-
tion since the yield (26%) is higher than the percentage
of the catalyst used. The reduction of the amount of
water increased the yield of the product significantly
and the best results are obtained when no solvent was
used. A 96% yield of the oxidation product was achieved
when neat conditions were utilized in spite of the low
solubility of KNO2 in the alcohol. These results could
be explained by the known dehydrogenating properties
of BAIB due to the highly electrophilic character of
iodine(III), and the fact that the presence of water
hydrolyzes BAIB to give iodosylbenzene (PhI@O) or
other species11 deprived of catalytic properties. In addi-
tion, the use of less solvent or neat conditions allows a
better contact between the catalysts and the oxygen.
In spite of the good results with benzylic alcohols, the
yields obtained with aliphatic or allylic alcohols under
the same conditions are quite low. Hu et al. described10
that the use of a larger amount of catalyst in their sys-
tem improved the yield. Indeed using 10% of each cata-
lytic component (Table 2, entries 10–13), our catalytic
mixture afforded a 61% yield of the aldehyde for the
neopentyl alcohol.
These results suggested a potential chemoselectivity be-
tween primary and secondary alcohols and also between
primary benzylic and aliphatic alcohols. The competing
reaction of an equimolecular mixture of benzyl alcohol
and a-methyl benzyl alcohol resulted in 97% of yield
in the aldehyde whereas the yield of the ketone was very
low (Table 3, entry 1). The presence of benzylic and ali-
phatic alcohols in the same molecule led to the forma-
tion of the benzyl aldehyde derivative as the only
oxidation product (Table 3, entry 2).
Table 1. Oxidation of benzyl alcohol using water as solventa
OH
CHO
BAIB:TEMPO:KNO2=4:1:4 (molar ratio)
H2O, O2, 80oC
Entry
H2O (mL)
Time (h)
Yield (%)b
1
2
3
4
3
1
0.1
0
3
3
3
3
26
57
68
96
A tentative mechanism of this catalytic oxidation based
on previous studies8 is shown in Scheme 1. The oxoam-
monium cation, which is oxidized from TEMPO, would
be the active oxidant in this reaction. The role of BAIB
is to regenerate TEMPO, and subsequently, BAIB
would be also reoxidized to its initial state by KNO2.
The oxidation of NO into NO2 can be carried out easily
a Reactions were carried out using the following conditions: benzyl
alcohol (10 mmol), BAIB (0.4 mmol), TEMPO (0.1 mmol), KNO2
(0.4 mmol), O2 (balloon), 80 °C.
b Yield was determined by 1H NMR using mesytilene as internal
standard.

C. I. Herrerı´as et al. / Tetrahedron Letters 47 (2006) 13–17
15
Table 2. Oxidation of alcoholsa
Entry
Substrate
Product
Yield (%)b
PhI(OAc)2
PS
PhI(OAc)2
CHO
OH
1
2
96 (3 h)
98 (15 h) (1st)
100 (15 h) (2nd)
98 (15 h) (3rd)
CHO
OH
OH
97 (15 h)
99 (24 h)
88 (24 h)
65 (24 h)
55 (24 h)
50 (24 h)
MeO
MeO
MeO
MeO
CHO
OMe
3
4
5
6
70 (15 h)
73 (15 h)
59c (15 h)
60 (15 h)
OMe
CHO
NO2
OH
NO2
CHO
OH
O2N
Cl
O2N
Cl
CHO
OH
NO2
NO2
CHO
OH
7
8
9
77c (15 h)
75 (15 h)
72 (24 h)
73 (24 h)
29 (24 h)
I
I
CHO
OH
MeS
MeS
51 (15 h)
75e (15 h)
OH
O
20e (15 h)
23e (15 h)
26d (15 h)
61e (15 h)
—
HO
CHO
10
11
12
13
OH
OHC
3
3
CHO
OH
—
(Z and E)
(Z and E)
CHO
OH
—
CHO
32e (24 h)
OH
a Neat reactions were carried out using the following conditions: (A) With BAIB:alcohol (10 mmol), BAIB (0.4 mmol), TEMPO (0.1 mmol), KNO2
(0.4 mmol), O2 (balloon), 80 °C; (B) With PBAIS:alcohol (5 mmol), BAIB (0.2 mmol), TEMPO (0.05 mmol), KNO2 (0.2 mmol), O2 (balloon),
80 °C.
b Yield was determined by 1H NMR using mesytilene as internal standard.
c Reaction carried out at 90 °C to allow the alcohol to reach liquid state.
d Alcohol:BAIB:TEMPO:KNO2 10:0.5:0.5:0.5 (mmol).
e Alcohol:BAIB/PBAIS:TEMPO:KNO2 10:1:1:1 (mmol).
with molecular oxygen and completed the catalytic
cycles in the absence of any transition metal. The iden-
tity of the reduced BAIB species has not been deter-
mined yet. Iodobenzene was detected at the end of
the reaction; however several reactions utilizing this
compound, either alone or with different amounts of
BAIB, failed to display any catalytic activities.
In conclusion, we have developed an effective catalytic
system for the oxidation of alcohols under an oxygen

16
C. I. Herrerı´as et al. / Tetrahedron Letters 47 (2006) 13–17
Table 3. Oxidation of primary benzylic alcohols in the presence of secondary or aliphatic alcohols
Entry
1b
Substrate
Product
CHO
Yield (%)a
97 (15 h)
OH
OH
15 (15 h)
O
CHO
OH
2c
21d (15 h)
HO
O
HO
O
3
3
a Yield was determined by 1H NMR using mesytilene as internal standard.
b Reaction was carried out using the following conditions: benzyl alcohol (10 mmol), methyl benzyl alcohol (10 mmol), BAIB (0.4 mmol), TEMPO
(0.1 mmol), KNO2 (0.4 mmol), O2 (balloon), 80 °C.
c Reaction was carried out using the following conditions: 3-(4-hydroxymethylphenoxy)propan-1-ol13 (2 mmol), BAIB (0.08 mmol), TEMPO
(0.02 mmol), KNO2 (0.08 mmol), O2 (balloon), 100 °C.
d Isolated yield.
OH
(0.4 mmol, 34 mg) were added in a 25 mL round-bottom
flask. The mixture was put into an oil bath pre-heated at
80 °C, kept under an oxygen atmosphere (with a bal-
loon) and stirred vigorously for the desired reaction
time. Then, the reaction mixture was cooled to room
temperature and mesytilene was added as an internal
standard for the determination of the results by 1H
NMR.
CHO
N
O
N
OH
Acknowledgements
I
I(OAc)2
2AcOH
+
We thank Eli Lilly and Company, NSERC and Canada
Research Chair (to C.J.L.) for support of this research.
C.I.H. thanks the Spanish Ministry of Education and
Science, for a postdoctoral scholarship.
NO2
NO + H2O
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