Aerobic oxidation of secondary alcohols in water with ABNO/tert-butyl nitrite/KPF6catalytic system

Article abstract of DOI:10.1016/j.tetlet.2017.01.012

A green and efficient transition-metal free ABNO/tert-butyl nitrite/KPF₆-catalyzed aerobic oxidation of secondary alcohols in water has been achieved. Under the optimal reaction conditions, a number of secondary aliphatic alcohols and secondary benzylic alcohols can be converted to their corresponding ketones in excellent yields (up to 99%).

Full text of DOI:10.1016/j.tetlet.2017.01.012

Accepted Manuscript
Aerobic oxidation of secondary alcohols in water with ABNO/tert-butyl nitrite/
KPF6 catalytic system
Jiaqi Ma, Chao Hong, Yan Wan, Meichao Li, Xinquan Hu, Weimin Mo,
Baoxiang Hu, Nan Sun, Liqun Jin, Zhenlu Shen
PII:
S0040-4039(17)30012-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.01.012
TETL 48515
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
10 December 2016
2 January 2017
3 January 2017
Please cite this article as: Ma, J., Hong, C., Wan, Y., Li, M., Hu, X., Mo, W., Hu, B., Sun, N., Jin, L., Shen, Z.,
Aerobic oxidation of secondary alcohols in water with ABNO/tert-butyl nitrite/KPF6 catalytic system, Tetrahedron
Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.01.012
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Aerobic oxidation of secondary alcohols in water with ABNO/tert-butyl
nitrite/KPF6 catalytic system
Jiaqi Ma, Chao Hong, Yan Wan, Meichao Li, Xinquan Hu, Weimin Mo, Baoxiang Hu, Nan Sun,
Liqun Jin, Zhenlu Shen*
College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, China
E-mail address: zhenlushen@zjut.edu.cn
Tel.: +86-571-88320416, fax: +86-571-88320103
ABSTRACT:
A green and efficient transition-metal free ABNO/tert-butyl nitrite/KPF6-catalyzed aerobic oxidation
of secondary alcohols in water has been achieved. Under the optimal reaction conditions, a number of
secondary aliphatic alcohols and secondary benzylic alcohols can be converted to their corresponding
ketones in excellent yields (up to 99%).
Keywords: Oxidation; ABNO; Secondary alcohols; Oxygen; Water

The oxidation of primary and secondary alcohols to their corresponding carbonyl compounds is one of
the most fundamental reactions in organic synthesis.1 Traditionally, various kinds of classical oxidation
methods with stoichiometric oxidants were adopted, including Corey Oxidation with pyridinium
chlorochromate(PCC),2 Dess-Martin Oxidation with periodinane(DMP),3 Ley’s Oxidation,4 Swern
Oxidation5 and so on. However, these reactions generate or use toxic reagents which would cause
serious environmental problems. Molecular oxygen has attracted great attention due to its remarkable
advantages, such as abundant, inexpensive and clean. There is no doubt that molecular oxygen as
oxidant for alcohol oxidation was the best alternative from both economical and environmental
considerations.6 Stable nitroxyl radicals 2,2,6,6-tetramethylpiperidine-1-oxyl(TEMPO) and its
derivatives have been widely used to catalyze the oxidation of alcohols. Many of the highly efficient
TEMPO/transition-metal catalytic systems have been developed for aerobic alcohol oxidation.7
However, toxic or expensive metal catalysts are still involved in these systems. Previously, we have
reported several transition-metal free aerobic alcohol oxidation systems, such as
TEMPO/Br2/NaNO2/O2,8
TEMPO/1,3-dibromo-5,5-dimethylhydantoin/NaNO2/O2,9
TEMPO/HBr/tert-butyl nitrite (TBN) /O2,10 TEMPO/TBN/O211 and TEMPO/DDQ/TBN/O2.12 Recent
years, several types of less structurally hindered bicyclic nitroxyls such as 2-azaadamantan-N-oxyl
(AZADO), 1-Me-AZADO, 1,3-dimethyl-AZADO, 5-F-AZADO, and Nor-AZADO were reported by
Iwabuchi and co-workers.13 AZADO and its derivatives are more active alternatives to TEMPO for the
efficient catalytic oxidation of various alcohols, especially structurally hindered secondary alcohols.
However, these AZADO types of bicyclic nitroxyls are difficult to be synthesized. Compared with

AZADOs, 9-azabicyclo[3.3.1]nonagn-N-oxyl (ABNO) was reported to have the similar activity
(Scheme 1).Moreover, the synthetic route of ABNO is much shorter and simpler than that of AZADOs.
ABNO exhibits highly catalytic activity in the aerobic oxidation of alcohols combined with NOx, Cu or
Fe.14
Scheme 1. Structures of different types of nitroxyl radicals
Water has been identified as a “green” and desirable solvent because it is benign to the
environment.15 The choice of water as a reaction medium is a charming research orientation. As a
replacement for conventional organic solvents in chemical reactions, water is abundantly available,
cheap, odorless, non-toxic and non-flammable. In addition to these advantages, ease of product
isolation through simple phase separation, decantation or extraction is possible because most organic
compounds are lipophilic. Catalytic oxidations of alcohols with nitroxyl radical/transition-metal in
aqueous reaction media also have been studied.16 Because of the limited solubility of reagents and the

activity of the catalysts, transition-metal free aerobic oxidation of alcohols with stable nitroxyl radicals
in water is still uncommon. Previously, we reported
a
TEMPO/NaNO2/1,3-dibromo-5,5-dimethylhydantoin system,9 which was suitable for the oxidation of
benzylic alcohols in water, however, it was not efficient for aliphatic alcohols. Kakimoto et al
developed a 1-Me-AZADO/NaNO2/HNO3 system,17 it could be simply applied to various benzylic
alcohols under mild conditions, however, the obtain of 1-Me-AZADO needs a six-step synthesis from
commercially available 1,3-adamantanediol. Zhang et al described an example of Cu/DMAP catalyst
system,18 which was applied in the aerobic oxidation of a variety of primary and secondary alcohols in
water at room temperature, in the presence of TEMPO or ABNO. However, metal Cu was still
involved. Overall, to develop a transition-metal free aerobic oxidation of alcohols with ABNO in water
is still full of significance.
Herein, we report a new ABNO/TBN/KPF6/O2 system for the aerobic oxidation of secondary
alcohols in water (eq 1). Under the optimal reaction conditions, a variety of secondary aliphatic
alcohols and benzylic alcohols can be converted to their corresponding ketones in good to excellent
yields.
At the outset, cyclohexanol (1a) was selected as a model substrate to identify the optimal
reaction conditions (Table 1). The oxidation of 1a to cyclohexanone (1b) was carried out with 5
o
mol% ABNO, 5 mol% TBN in 10 mL water at 80 C under 0.5 MPa of oxygen, it was found

that the conversion of 1a was only 45% in 1.5 h (entry 1). When 5 mol% NaCl was added in the
reaction system, the conversion of 1a increased to 64%, this result showed that NaCl had
played an important role in this reaction (entry 2). Other salts, including NaBF4, KBr and KPF6
were also tested under the same reaction conditions (entries 3-5). We were delighted to find that
the conversion of 1a could be improved to 97% when KPF6 was employed (entry 5). The effects
of additives on the reaction might be relevant to the formal redox potential of oxoammonium
salt/nitroxyl radical in the presence of different anions.19 An investigation of the effect of
nitroxyl radicals (entries 5-8) revealed that use of ABNO greatly increased the conversion of
1a. The reactions with TEMPO, 4-acetamido-TEMPO and keto-ABNO did not proceed well,
the conversion of 1a was only 71%, 44% and 45%, respectively. Increasing the loading of
ABNO from 5 mol% to 6 mol%, 1a could be fully converted to 2a (entry 9, >99%).
Encouraged by these results, the oxygen pressure and the reaction temperature were also
tested. Entries 9-13 illustrate the impact of oxygen pressure and reaction temperature on the
efficiency of this reaction. Reducing the oxygen pressure from 0.5 MPa to 0.4 MPa led to a
o
lower conversion of 1a (entries 9 and 10). To our delight, the reaction temperature of 70 C and
o
60 C were also suitable for the ideal transformation of 1a (entries 11 and 12, >99%). Further
o
decreasing the reaction temperature to 50 C led to lower conversion of 1a (entries 13, 68%).
o
Thus 60 C was chosen as the optimal reaction temperature. When the loading of TBN was
reduced to 4 mol%, the conversion of 1a went down to 80% accordingly (entry 14). In addition,
reducing the loading of KPF6 to 4 mol% could also obtain an excellent conversion of 1a (entry

15, >99%). We wondered whether removing the water from reaction system, in other words,
solvent-free system, would have the same or similar results, but the conversion of 1a dropped
into 14%, this low conversion suggested that water was important in the reaction. After detailed
exploration of the reaction conditions with 1a as the substrate, we chose 6 mol% ABNO, 5
o
mol% TBN and 4 mol% KPF6 in 10 mL water at 60 C under 0.5 MPa of O2 as the optimal
reaction conditions, 2a could be obtained with 96% yield as determined by GC using an internal
standard method in 1.5 h (entry 15).
Table 1.
Optimization of the Reaction Conditions for Cyclohexanol Oxidation a
Entry nitroxyl
Cat.
TBN
P(O2)
Tb
X
Conv.c
(%)
45
Select.c
(%)
98
(mol%) (mol%) (MPa) (oC)
(mol%)
---
1
2
3
4
5
6
7
ABNO
5
5
5
5
5
5
5
5
5
5
5
5
5
5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
80
80
80
80
80
80
80
ABNO
NaCl(5)
64
99
ABNO
NaBF4(5) 74
98
ABNO
KBr(5)
69
97
71
44
99
ABNO
KPF6(5)
KPF6(5)
KPF6(5)
99
TEMPO
4-Acetamido-
TEMPO
Keto-ABNO
ABNO
98
93
8
5
6
6
5
5
5
0.5
0.5
0.4
80
80
80
KPF6(5)
KPF6(5)
KPF6(5)
45
96
99
99
9
>99
85
10
ABNO

11
12
13
14
15
16
17e
ABNO
ABNO
ABNO
ABNO
ABNO
ABNO
ABNO
6
6
6
6
6
6
6
5
5
5
4
5
5
5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
70
60
50
60
60
60
60
KPF6(5)
KPF6(5)
KPF6(5)
KPF6(5)
KPF6(4)
KPF6(3)
KPF6(4)
>99
>99
68
99
99
98
80.
>99
78
99
99(96)d
99
14
93
a Reaction conditions: 1a (30 mmol), H2O (10 mL).
b Oil bath temperature.
c Determined by GC with area normalization method.
d Value in parenthesis was yield of 2a determined by GC analysis using biphenyl as internal standard.
e H2O was not added.
Having gotten the optimal reaction conditions, a number of secondary aliphatic alcohols were
examined firstly and the results are summarized in Table 2. Because of our initial efforts to acquire
high conversion and selectivity of unactivated alcohol oxidation, cyclic alcohols, such as cyclopentanol
(1b), cycloheptanol (1c) could be fully converted into cyclopentanone (2b) and cycloheptanone (2c) in
good isolated yields (entries 1 and 2). What’s more, the end point of reaction time could be determined
conveniently by observation of the vessel pressure through a barometer. As expected, o-, m-,
p-methylcyclohexanol were smoothly oxidized into their corresponding ketones (2d, 2e and 2f) in 2-2.5
h with excellent selectivity (entries 4-6). 3,3-Dimethylcyclohexanone (2g) could be obtained in 98%
isolated yield when 3,3-dimethylcyclohexanol (1g) was used as the substrate (entry 7). However,
2-octanol (1h) was less reactive under the optimal reaction conditions, the conversion was only 66% in
5 h. A full conversion of 1h with 99% selectivity and 90% yield of 2-octanone (2h) was achieved by
increasing the amount of both TBN and KPF6 to 6 mol% (entry 8). Moreover, the substrate containing a
phenyl group (1i) almost quantitatively afforded 2i in 99% isolated yield (entry 9).20

Table 2.
Oxidation of Secondary Unactivated Alcohols a
Entry Substrate
Product
Time Conv.b
Select.b Yieldc
(%)
(h)
(%)
1
2
1.5
99
99
99
85
83
1a
1b
2a
2b
3.5
2
97
99
3
4
99
98
96
90
1c
2c
2.5
99
1d
2d
5
2
99
99
99
99
99
99
99
98
91
96
98
90
1e
1f
2e
2f
6
2
7
2
1g
1h
2g
2h
8d
3.5
9
3
>99
99
99
1i
2i
o
a 1 (30 mmol), ABNO (6 mol%), TBN (5 mol%), KPF6 (4 mol%), water (10 mL), 60 C (oil bath), O2 (0.5
MPa).
b Conversion and selectivity were determined by GC with area normalization method.
c Isolated yield.
d TBN (6 mol%), KPF6 (6 mol%)
.
With these results in hand, we then focused our studies on the application ABNO/TBN/KPF6/O2
system to a variety of activated alcohols in water. The results are summarized in Table 3. As expected,
secondary benzylic alcohols are more reactive compared with secondary aliphatic alcohols.
Acetophenone (4a) could be transformed from 1-phenylethanol (3a) smoothly when we reduced the
amount of ABNO and KPF6 to 2 mol% and oxygen pressure to 0.3 MPa.21 Two secondary benzylic
alcohols, 3b and 3c, bearing electron-donating groups were oxidized to the corresponding ketones (4b

and 4c) efficiently. Moreover, the oxidation of secondary
benzylic alcohols with
electron-withdrawing groups, such as 1-(4-fluorophenyl)ethanol (3d), 1-(4-bromophenyl)ethanol (3e)
and 1-(4-chlorophenyl)ethanol (3f), furnished the expected products (4d, 4e and 4f) with excellent
yields in 2-2.5 h. 1-(3-Chlorophenyl)ethanone (4g) was also obtained in 98% isolated yield. However,
sterically hindered substrate 3h containing 2-Cl on phenyl ring showed lower reactivity, only 68%
conversion was achieved in 5 h. Notably, 93% isolated yield could be achieved in the case of
increasing both loading of ABNO and KPF6 to 3 mol%. 1-Phenylpropan-1-ol (3i) and
1-p-tolylpropan-1-ol (3j) were transformed smoothly, and almost quantitatively afforded their
corresponding ketones (4i and 4j) in 98-99% isolated yields. When 1-(4-chlorophenyl)propan-1-ol (3k)
was chosen as the substrate, only 31% conversion was obtained in 5 h in the same reaction conditions.
To our delight, 93% isolated yield could be achieved (4k) with 6 mol% ABNO, 5 mol% TBN, 4 mol%
KPF6 under 0.5 MPa of oxygen pressure in 80 oC. The conversion of 1-phenylbutan-1-ol (3l) was 74%
in 6.5 h, but it could be improved to more than 99% by increasing loading of ABNO and KPF6 to 3
mol%. When 2-methyl-1-phenylpropan-1-ol (3m) was used as the substrate, the isolated yield of 4m
could be reached to 90% under the optimal reaction conditions of unactivated alcohols. Several other
benzylic
secondary
alcohols
including
2,3-dihydro-1H-inden-1-ol
(3n),
1,2,3,4-tetrahydronaphthalen-1-ol (3o), diphenylmethanol (3p) and 1-(naphthalen-2-yl)ethanol (3q)
were also tested for the aerobic oxidation in water. It was found that 3o could quantitatively converted
to 4o. High yields of ketones 4n, 4p and 4q were achieved by enhancing the reaction conditions
slightly. However, 1-(thiophen-2-yl)ethanol (3r) was difficult to be transformed to

1-(thiophen-2-yl)ethanone (4r), 80% yield of 4r was obtained by increasing loading of ABNO, TBN
and KPF6 to 10 mol% and oxygen pressure to 0.5 MPa.
Table 3.
Oxidation of Secondary Activated Alcohols a
Entry Substrate
Product
Time (h) Conv.b (%) Select.b (%) Yieldc (%)
1
2
>99
97
99
99
98
99
93
95
3a
3b
3c
4a
4b
4c
2
3
4
5
1.5
3.5
99
2
2
99
99
99
96
99
3d
3e
4d
4e
>99
6
2.5
2.5
3
99
99
96
98
93
98
99
3f
3g
3h
3i
4f
4g
4h
4i
7
99
99
8d
9
97
>99
99
2
99
10
4.5
>99
99
3j
4j
11e,f
12d
13e
14d
3.5
5
86
99
99
95
99
84
99
90
97
3k
3l
4k
4l
>99
99
2.5
2.5
3m
3n
4m
4n
99

15
4
4
>99
99
99
96
99
92
3o
3p
4o
4p
16f,g
17e,f
18h
3.5
1.5
99
95
95
90
93
80
3q
3r
4q
4r
o
a 3 (30 mmol), ABNO (2 mol%), TBN (5 mol%), KPF6 (2 mol%), water (10 mL), 60 C (oil bath), O2 (0.3
MPa).
b Conversion and selectivity were determined by GC with area normalization method.
c Isolated yield.
d ABNO (3 mol%), KPF6 (3 mol%).
e ABNO (6 mol%), KPF6 (4 mol%), O2 (0.5 MPa).
f 80 oC.
g ABNO (6 mol%), TBN (6 mol%), KPF6 (6 mol%), O2 (0.5 MPa).
h ABNO (10 mol%), TBN (10 mol%), KPF6 (10 mol%), O2 (0.5 MPa).
In addition, this system was also suitable for the oxidation of primary benzylic alcohols into their
corresponding aldehydes. With the reaction conditions of 1 mol% ABNO, 5 mol% TBN and 1 mol%
o
KPF6 in 10 mL water at 60 C under 0.3 MPa of O2, 4-methoxybenzyl alcohol could be oxidized into
4-methoxybenzaldehyde with 97% isolated yields in 3 h. However, when primary aliphatic alcohol,
such as cyclohexylmethanol was chosen as the substrate under the optimal reaction conditions of
secondary unactivated alcohols, 65% cyclohexanecarbaldehyde along with 34% cyclohexanecarboxylic
acid were obtained.
A plausible overall reaction mechanism for the transformation of secondary alcohol into ketone is
shown in Scheme 2. Under a certain reaction temperature TBN can release NO, which will be easily
oxidized into NO2 by O2. The ABNO is oxidized to ABNO+ by NO2. The alcohol is oxidized to its
corresponding ketone by ABNO+, which is reduced to ABNOH at the same time. Then ABNOH is
oxidized to ABNO+ by NO2, which turns into NO immediately.

Scheme 2. A proposed overall reaction mechanism.
In summary, we have successfully applied the ABNO/TBN/KPF6/O2, a transition-metal free catalytic
oxidation system, for the aerobic oxidation of a variety of secondary alcohols in water. This green
catalytic oxidation system displayed high reaction efficiency. Numerous ketones could be obtained
conveniently in the medium of water.
Acknowledgement: This work was financially supported by the National Natural Science
Foundation of China (21376224, 21206147), the Natural Science Foundation of Zhejiang Province
(LY17B060007), and Hangzhou Qianjiang Distinguished Experts Project.
Supplementary data
1
Supplementary data (experimental details and copies of H NMR and 13C NMR for the products)
associated with this article can be found, in the online version, at http://.

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20. Typical procedure for aerobic oxidation of secondary unactivated alcohols (Table 2, entry 9): A
Teflon-lines 316 L stainless steel autoclave (300 mL) equipped with magnetic stirring bar was
charged with 4.51 g of 4-phenylbutan-2-ol (1i, 30 mmol), 252.0 mg of ABNO (1.8 mmol, 6
mol%), 154.6 mg of TBN (1.5 mmol, 5 mol%), 220.8 mg KPF6 (1.2 mmol, 4 mol%) and 10 mL
deionized water. The autoclave was closed and charged with oxygen to 0.5 MPa. Then the
o
autoclave was placed into a preheated 60 C oil bath. The mixture was then stirred for a certain
time until the the vessel pressure dropped to 0.4 Mpa. The autoclave was taken out from the oil
bath, cooled to room temperature and carefully depressurized. Most product was obtained
directly through simple phase separation. The aqueous phase was extracted with diethyl ether (20
mL×3) , the ether layer was then washed with saturated NaCl, dried over anhydrous Na2SO4 and
concentrated to dryness. A 99% isolated yield of 2i was obtained based on the combined product.
1H NMR (CDCl3) δ 7.31-7.27 (m, 2H), 7.22-7.19 (m, 3H), 2.93-2.91(m, 2H), 2.79-2.76(m, 2H),
2.15 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 207.8, 140.9, 128.4, 128.2, 126.0, 45.1, 30.0, 29.7.
21. Typical procedure for aerobic oxidation of secondary activated alcohols (Table 3, entry 1): A
Teflon-lines 316 L stainless steel autoclave (300 mL) equipped with magnetic stirring bar was
charged with 3.66 g of 1-phenylethanol (3a, 30 mmol), 84.0 mg of ABNO (0.6 mmol, 2 mol%),
154.6 mg of TBN (1.5 mmol, 5 mol%), 110.4 mg of KPF6 (0.6 mmol, 2 mol%) and 10 mL of
deionized water. The autoclave was closed and charged with oxygen to 0.3 MPa. Then the
o
autoclave was placed into a preheated 60 C oil bath. The mixture was then stirred for a certain
time until the the vessel pressure dropped to 0.2 Mpa. The autoclave was taken out from the oil
bath, cooled to room temperature and carefully depressurized. The mixture was extracted with

diethyl ether (20 mL×3). Then the combined organic layer was dried over anhydrous Na2SO4 and
concentrated to dryness, followed by flash column chromatography over silica gel with a mixture
of ethyl acetate/petroleum ether as eluent to afford 99% isolated yield of 4a. 1H NMR (CDCl3) δ
7.92-7.90 (m, 2H), 7.52-7.49 (m,1H), 7.42-7.39 (m, 2H), 2.54 (s, 3H). 13C NMR (125 MHz,
CDCl3) δ 197.8, 136.9, 132.8, 128.3, 128.0, 26.3.

Aerobic oxidation of secondary alcohols in water with ABNO/tert-butyl
nitrite/KPF6 catalytic system
Jiaqi Ma, Chao Hong, Yan Wan, Meichao Li, Xinquan Hu, Weimin Mo, Baoxiang Hu, Nan Sun,
Liqun Jin, Zhenlu Shen*
A green and efficient transition-metal free ABNO/tert-butyl nitrite/KPF6-catalyzed aerobic oxidation
of secondary alcohols in water has been achieved. Under the optimal reaction conditions, a number of
secondary aliphatic alcohols and secondary benzylic alcohols can be converted to their corresponding
ketones in excellent yields (up to 99%).

Highlights
1. Oxidation of secondary alcohols into ketones.
2. ABNO, tert-butyl nitrite and KPF6 as the catalysts and oxygen as the oxidant.
3. Good to excellent yields can be obtained.
4. Water as the green reaction solvent.
5. Metal-free reaction conditions.