Tert-Butylnitrite as a convenient and easy-removable oxidant for the conversion of benzylic alcohols to ketones and aldehydes

Article abstract of DOI:10.1016/j.tetlet.2011.12.006

The oxidation of primary and secondary benzylic alcohols was achieved by using tert-butyl nitrite (t-BuONO) as a stoichiometric oxidant. Various substrates were effectively converted into the corresponding ketones or aldehydes in good to excellent yields. The reaction presumably proceeded by a nitrosyl exchange and a subsequent thermal decomposition of benzylic nitrites. This process would realize an oxidation of alcohols with oxygen in theory by combining with a reproduction of alkyl nitrites from NO and alcohols under an O₂ atmosphere. In addition, almost pure oxidized products were readily obtained by simple evaporation of the reaction mixtures since t-BuONO produced only volatile side products.

Full text of DOI:10.1016/j.tetlet.2011.12.006

Tetrahedron Letters 53 (2012) 811–814
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Tetrahedron Letters
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tert-Butylnitrite as a convenient and easy-removable oxidant for the
conversion of benzylic alcohols to ketones and aldehydes
Akiyuki Hamasaki a, Hideyuki Kuwada a, Makoto Tokunaga a,b,
⇑
a Department of Chemistry, Graduate School of Sciences, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan
b International Research Center for Molecular Systems (IRCMS), Kyushu University, Moto-oka 744, Nishi-ku, Fukuoka 819-0395, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The oxidation of primary and secondary benzylic alcohols was achieved by using tert-butyl nitrite
(t-BuONO) as a stoichiometric oxidant. Various substrates were effectively converted into the corre-
sponding ketones or aldehydes in good to excellent yields. The reaction presumably proceeded by a nitro-
syl exchange and a subsequent thermal decomposition of benzylic nitrites. This process would realize an
oxidation of alcohols with oxygen in theory by combining with a reproduction of alkyl nitrites from NO
and alcohols under an O2 atmosphere. In addition, almost pure oxidized products were readily obtained
by simple evaporation of the reaction mixtures since t-BuONO produced only volatile side products.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 21 October 2011
Revised 1 December 2011
Accepted 2 December 2011
Available online 8 December 2011
Keywords:
tert-Butylnitrite
Oxidation
Easy work-up
Green chemistry
Alkyl nitrites and sodium nitrite are frequently employed for
several organic transformations including nitrosation and diazoti-
zation reactions.1 In most cases, they act as a source of NO or nitrous
acid in the reaction system. Although many reactions effectively
progress by the solo use of alkyl nitrites, combinations with palla-
dium or N-hydroxyphthalimide (NHPI) catalysts are employed for
the production of industrially important materials such as dibuty-
loxalate2 or nitrosocycloalkanes.3 Alkyl nitrites and sodium nitrite
are also used for the oxidation of primary and secondary alcohols
to corresponding aldehydes, ketones, and carboxylic acids with
2,2,6,6-tetramethylpiperidines (TEMPO) and/or halogenated com-
pounds.4 These procedures are obviously more environment-
friendly than the classical methods using stoichiometric amounts
of heavy metal based reagents. With the growing concern about
green chemistry, developments of environmentally benign proce-
dures are important issues. This time, we have found a novel feature
of tert-butyl nitrite (t-BuONO) as a stoichiometric oxidant for ben-
zylic alcohols. This procedure required neither metal based reagents
nor organic catalysts. An evolution of NO gas during the reaction
course might be a controversial matter, but several alkyl nitrites
are industrially produced from the corresponding alcohols and gas-
eous NO under an O2 atmosphere5 (Eq. 1). Ube Industries have
translated a scheme of Pd/nitrites oxidation and reproduction of ni-
trites into practical applications to achieve a substantive oxygen
oxidation process.2,5a Thus, t-BuONO would realize an environmen-
tally benign oxidation of alcohols by combining with the alkyl
nitrite reproduction from the evolved NO. Additionally, since t-
BuONO formed only volatile residual products, such as t-BuOH
and gaseous NO, almost pure oxidized products were readily
obtained by simple evaporation of the reaction mixtures. It was a
meaningful advantage especially in the case of large scale reactions.
2 NO þ 2 ROH þ 0:5 O2 ! 2 RONO þ H2O
ð1Þ
Table 1
Optimization of the reaction conditions for the oxidation of 1-phenylethanola
t-BuONO
OH
Me
O
(X equiv.)
COOH
+
Me
Solvent (0.5 mL)
Temp., Time
1a
2a
3a
Entry
X
Solvent
Temp (°C)
Time (h)
Yieldb (%)
2a
3a
1
2
3
4
5
6
7
8
1.5
1.5
1.5
1.5
1.5
1.5
1.5
3
Toluene
t-BuOH
1,2-Dichloroethane
DME
DMSO
Chlorobenzene
None
None
120
110
110
120
120
120
110
110
16
24
24
17
17
17
24
10
99
74
36
96
26
44
82
45
Trace
6
19
4
15
36
18
46
a
⇑
Corresponding author.
E-mail address: mtok@chem.kyushu-univ.jp (M. Tokunaga).
The reaction was conducted on 1 mmol scale in a sealed tube.
GC yield.
b
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.006

812
A. Hamasaki et al. / Tetrahedron Letters 53 (2012) 811–814
Oxidation of 1-phenylethanol (1a) was examined under several
The oxidation of various primary benzylic alcohols was exam-
ined (Table 4). All substrates gave corresponding aldehydes in good
yields. The substrates bearing an electron withdrawing group
exclusively afforded aldehydes 5 (Table 4, entries 2, 4, and 6). In
the cases of electron rich substrates, over-oxidized products were
obtained (Table 4, entries 1, 3, and 5). Heteroaromatic substrates
were also suitable for the reaction (Table 4, entries 7 and 8).
To investigate the mechanism of the reaction, 1-phenylethanol
(1a) and acetophenone (2a) were treated with gaseous NO (Scheme
1). The reaction started from 1a gave a small amount of 2a and 3a
through NO oxidation. On the other hand, oxidation of 2a to 3a
smoothly proceeded with atmospheric NO in a 66% yield. These re-
sults suggested that 3a was formed from 2a and this over-oxidation
step was assumed by NO, but not t-BuONO itself. The solvent effect
on the over-oxidation observed in Table 1 may be explained by the
solubility of NO in each solvent,6 but no specific relationship was
found between them.
conditions (Table 1). The various solvents could be used for the
reaction, especially, toluene was found to be the most suitable of
the tested solvents (Table 1, entries 1–6). The reaction efficiency
was low in halogenated solvents (Table 1, entries 3 and 6), alluding
to an involvement of a radical species. When the reaction was con-
ducted without solvent, the amount of over-oxidized product 3a
was increased (Table 1, entry 7). A large excess of t-BuONO predict-
ably gave a significant amount of 3a (Table 1, entry 8).
With the optimal condition in hand, the substrate scope of the
reaction was examined (Table 2). All 1-phenylethanol derivatives
were smoothly oxidized to give the corresponding acetophenone
derivatives in good to excellent yields (Table 2, entries 1–4). How-
ever, in the case of an electron rich substrate, the low selectivity
was observed because of the over-oxidation (Table 2, entry 4).
The substrates bearing a longer alkyl chain also gave good results
(Table 2, entries 5 and 6). Diphenylmethanol was exclusively trans-
formed into ketone product 2h (Table 2, entry 7).
Next, we turned our attention to primary benzylic alcohols
(Table 3). Under the optimal condition for the secondary alcohols,
benzyl alcohol (4a) gave an almost 1:1 mixture of benzaldehyde
(5a) and benzoic acid (3a) (Table 3, entry 1). The amount of 3a
was decreased under a diluted condition in 1 mL of toluene
(Table 3, entry 2). Switching the solvent to DME and a lower reac-
tion temperature of 100 °C dramatically improved the yield of 5a
(Table 3, entries 3 and 4). A more diluted condition did not show
further improvement of the yield (Table 3, entry 5).
Next, acetophenone (2a) and dodecanophenone (2g) were trea-
ted with 3 equiv of t-BuONO (Scheme 2). The formation of 3a
suggested that gaseous NO was provided from t-BuONO. As an
Table 4
Evaluation of the substrate in the oxidation of primary benzylic alcoholsa
t-BuONO
(1.5 equiv.)
+
Ar
OH
Ar CHO
Ar COOH
DME (1 mL)
4
5
3
Table 2
Evaluation of the substrate in the oxidation of secondary benzylic alcoholsa
Entry Substrate
Temp
(°C)
Time
(h)
Aldehyde
product
Yieldb (%)
5
3
OH
R2
O
t-BuONO
OH
COOH
(1.5 equiv.)
R2
1
100
100
10
15
10
5b
5c
5d
74
26
+
Me
toluene (0.5 mL)
120 °C
R1
R1
R1
OH
1
2
3
2
74 Trace
Cl
Entry
R1
R2
Time (h)
Ketone product
Yieldb (%)
OH
3
120
100
120
120
71
28
2
3
MeO
1
2
3
4
5
6
7
Me
CF3
Cl
OMe
H
Me
Me
Me
Me
Et
17
16
16
16
16
16
20
2b
2c
2d
2e
2f
99
89
82
80
82
94
99
Trace
Trace
Trace
13
OH
4
12
8
5e
5f
72 Trace
F3C
OH
OH
6
4
0
5
80
17
H
H
Pr
Ph
2g
2h
t-Bu
6
10
5g
72 Trace
a
The reaction was conducted on 1 mmol scale in a sealed tube.
GC yield.
O2N
b
S
OH
OH
7
8
100
100
13
17
5h
5i
82
17
N
71 Trace
Table 3
Optimization of the reaction conditions for the oxidation of benzylalcohola
a
The reaction was conducted on 1 mmol scale in a sealed tube.
GC yield.
b
t-BuONO
CHO
+
COOH
(1.5 equiv.)
OH
Solvent
Temp., Time
4a
5a
3a
OH
Me
O
COOH
Yieldb (%)
NO (1 atm)
Me
Entry
Solvent (mL)
Temp (°C)
Time (h)
+
no solvent
5a
3a
110 °C, 10 h
1a
O
2a, 3%
3a, trace
1
2
3
4
5
Toluene (0.5)
Toluene (1)
DME (1)
DME (1)
DME (1.5)
120
120
120
100
100
10
8
6
17
18
30
34
50
89
58
37
15
7
7
7
COOH
NO (1 atm)
Me
no solvent
110 °C, 8 h
2a
3a, 66%
a
The reaction was conducted on 1 mmol scale in a sealed tube.
GC yield.
Scheme 1. Oxidation of 1-phenylethanol (1a) and acetophenone (2a) with gaseous
NO.
b

A. Hamasaki et al. / Tetrahedron Letters 53 (2012) 811–814
813
additional evidence for the evolution of NO, a brown fume was ob-
served when the sealed vessel was opened in air after the reaction.
In the case of 2g, a generation of undecanenitrile (6) was observed
along with 3a. This result indicated the C–C bond between car-
bonyl and the adjacent alkyl carbons was cleaved by the over-oxi-
dation step.
On the basis of the above experimental results and the previous
reports on the character of alkyl nitrites,7–10 the following mecha-
nism was proposed (Scheme 3). A treatment of benzylic alcohol with
t-BuONO resulted in a nitrosyl exchange.7 The formation of nitrosat-
ed intermediate was confirmed by an NMR experiment at 20 °C
(Fig. 1). A thermal decomposition of alkyl nitrites takes place under
heated conditions, but simple aliphatic nitrites generally requires a
high temperature to attain sufficient reaction rates.8 According to
Kornblum’s report, 2-octyl nitrite needed 8 days for a complete
decomposition at 100 °C.8b On the other hand, benzyl nitrites suffi-
ciently decompose even under a mild temperature below 100 °C.9
Therefore, the formation of a benzyloxy radical was in preference
to that of a t-butoxy radical (Scheme 3, step 1). A subsequent
Figure 1. Observation of nitrosyl exchange between 1a and t-BuONO in toluene-d8.
The spectra of 1a in the presence of 3, 1.5, 1, 0.5, and 0 equiv of t-BuONO from top to
bottom.
a
-hydrogen abstraction from another benzyl nitrite gave the car-
O
bonyl product, NO, and starting alcohol (Scheme 3, step 2). An
over-oxidation of theproductwas attributedto NOfrom thereaction
course and a partial decomposition of t-BuONO.10 The exact mecha-
nism of over-oxidation was unclear, but the products and the partic-
t-BuONO
COOH
(3 equiv.)
Me
no solvent
110 °C, 3 days
2a
O
3a, 55%
ipation of NO were reminiscent of a nitrosation of a
-position11 and
t-BuONO
(3 equiv.)
n-C10H21
COOH
subsequent Beckmann type fragmentation.12 (Scheme 3, step 3).
According to the above reaction mechanism, at least 2 equiv of
t-BuONO were necessary for the complete consumption of alco-
hols. Therefore, an involvement of other reaction paths should be
considered since the reaction effectively proceeded with 1.5 equiv
of t-BuONO. The thermal decomposition of nitrites generally gives
an excess amount of oxidized products over alcohols,9b,9c but not
+
NC n-C10H21
6, 22%
no solvent
110 °C, 3 days
2g
3a, 39%
Scheme 2. Oxidation of acetophenone (2a) and dodecanophenone (2g) with
t-BuONO.
the equal amount presumed from Scheme 3, step 2. The inequality
Step 1: Nitrosyl exchange and thermal decomposition of nitrites
9b,9c
arose from a reduction of NO to HNO (Eq. 2 and 3),
and this
OH
nitrosyl
exchange
ONO
reduction step likely participated in the reaction system. Another
possibility including the formation of a methyl or phenyl radical
from benzyloxy radicals8a,9b,9c contradicted quantitative yields of
the products. A direct rearrangement from benzyloxy radicals to
a benzyl radical species was also experimentally negated.8b,9c
R
R
+ t-BuONO
+ t-BuOH
100–120 °C
slow
100–120 °C
fast
O
t-BuO
+ NO
R
+
NO
RCH2Oꢀ þ NO ! RCH@O þ HNO
2 HNO ! N2O þ H2O
ð2Þ
ð3Þ
Step 2: Formation of carbonyl products via hydrogen abstraction
ONO
O
It was noteworthy that almost pure products were obtained by
simple evaporation since t-BuONO left only volatile side products.
In case of the oxidation of 1-phenylethanol, the crude residue after
evaporation consisted of the compounds derived from the starting
material. If necessary, a further purification could be readily per-
formed by distillation.13 This was a great advantage especially in
large scale synthesis.14
R
R
+
OH
ONO
hydrogen
abstraction
R
R
+
In conclusion, we have found a novel feature of t-BuONO to oxi-
dize benzylic alcohols as a stoichiometric reagent. This method
was environmentally benign since it did not require heavy metal
based reagents or additional catalysts. Furthermore, almost pure
products were obtained by a simple evaporation work-up, since
t-BuONO produced only volatile side products such as t-BuOH
and gaseous NO.
O
R
+ NO
Step 3: Over-oxidation by gaseous NO
O
R
O
R
+
NO (g)
N
OH
Acknowledgments
O
This work was supported by a Grant-in-Aid for Global-COE pro-
gram, ‘Science for Future Molecular Systems’, and Scientific Re-
search (A) (No. 20245014) from the Ministry of Education,
Culture, Science, Sports and Technology of Japan. Appreciation also
gose to Ube Industries, Ltd., for the financial support the company
+
OH
N
C
R
Scheme 3. Plausible reaction mechanism for oxidation of benzylic alcohols with
t-BuONO.

814
A. Hamasaki et al. / Tetrahedron Letters 53 (2012) 811–814
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provided. We gratefully acknowledged Professor Tsutomu Katsuki
of Kyushu University for providing use of a nitric oxide gas cylinder.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.12.006.
References and notes
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mixture of 1-phenylethanol (1a) (121
0.205 mmol, internal standard) and toluene (0.5 mL) in a screw cap tube was
added t-BuONO (Tokyo Chemical Industry Co., Ltd, >90%) (198 L, 1.5 mmol,
lL, 1 mmol), tridecane (50 lL,
l
1.5 equiv) under N2 atmosphere. The solution was stirred at 120 °C for 16 h.
The reaction mixture was analyzed by GC and the product was isolated by
column chromatography (SiO2) for the characterization. The same procedure
was applicable to 10 mmol scale reaction. The almost pure product was readily
obtained by simple evaporation of the reaction mixture, and the further
purification by vacuum distillation gave 2a (968 mg, 81%) as a colorless oil.
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regeneration of nitrites as mentioned in the introduction part. However, a
proper treatment for the evolved NO will be needed in the operation on a lab
scale reactions.
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