Sodium hypochlorite pentahydrate (NaOCl·5H2O) crystals; An effective re-oxidant for TEMPO oxidation

Article abstract of DOI:10.1016/j.tet.2016.03.064

The novel oxidant of sodium hypochlorite pentahydrate (NaOCl·5H₂O), which is now available for industrial and laboratory use has several advantageous properties. The crystalline material has 44% of NaOCl, contains minimal sodium hydroxide and sodium chloride, and the aqueous solution indicates pH 11-12. Herein, NaOCl·5H₂O crystals are examined for use as an oxidant for primary and secondary alcohols, with or without nitroxyl radicals, in the presence or absence of phase-transfer catalysts. The pentahydrate crystals alone (without nitroxyl radicals) demonstrate a powerful oxidizing ability, converting secondary alcohols to the corresponding ketones. In the presence of TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl) or 1-Me-AZADO (1-methyl-2-azaadamantane N-oxy radical), sterically hindered secondary alcohols are oxidized without pH adjustment. A proposed mechanism for the oxidation is discussed.

Full text of DOI:10.1016/j.tet.2016.03.064

Accepted Manuscript
Sodium hypochlorite pentahydrate (NaOCl·5H O) crystals; An effective re-oxidant for
2
TEMPO oxidation
Tomohide Okada, Tomotake Asawa, Yukihiro Sugiyama, Toshiaki Iwai, Masayuki
Kirihara, Yoshikazu Kimura
PII:
S0040-4020(16)30194-6
10.1016/j.tet.2016.03.064
TET 27604
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 1 December 2015
Revised Date: 18 March 2016
Accepted Date: 20 March 2016
Please cite this article as: Okada T, Asawa T, Sugiyama Y, Iwai T, Kirihara M, Kimura Y, Sodium
hypochlorite pentahydrate (NaOCl·5H O) crystals; An effective re-oxidant for TEMPO oxidation,
2
Tetrahedron (2016), doi: 10.1016/j.tet.2016.03.064.
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ACCEPTED MANUSCRIPT
Graphical Abstract
5
mol% Bu NHSO4
4
OH
1 mol% TEMPO or
-Me-AZADO
O
NaOCl·5H O
2
1
crystals
+
R2
(1.1-1.8 eq)
R1
1
2
CH Cl or EtOAc
R
R
2
2
without pH adjustment
N
O
N
1
-Me-AZADO
TEMPO
O

ACCEPTED MANUSCRIPT
Sodium hypochlorite pentahydrate (NaOCl·5H O) crystals;
2
An effective re-oxidant for TEMPO oxidation
a
a
b
c
Tomohide Okada, Tomotake Asawa, Yukihiro Sugiyama, Toshiaki Iwai, Masayuki
c,
d
Kirihara, * Yoshikazu Kimura
a
R&D Department of Chemicals, Nippon Light Metal Company, Ltd., Kambara, Shimizu-ku, Shizuoka 421-3203, Japan
b
Market Development Department, Nippon Light Metal Company, Ltd., Higashi-shinagawa, Shinagawa-ku, Tokyo 140-8628, Japan
c
,
Department of Materials and Life Science, Shizuoka Institute of Science and Technology, Fukuroi, Shizuoka 437-8555 Japan
d
Research and Development Department, Iharanikkei Chemical Industry Co. Ltd., Kambara, Shimizu-ku, Shizuoka 421-3203, Japan
*kirihara@ms.sist.ac.jp
ABSTRACT
The novel oxidant of sodium hypochlorite pentahydrate (NaOCl·5H O), which is now available for
2
industrial and laboratory use has several advantageous properties. The crystalline material has 44%
of NaOCl, contains minimal sodium hydroxide and sodium chloride, and the aqueous solution
indicates pH 11-12. Herein, NaOCl·5H O crystals are examined for use as an oxidant for primary
2
and secondary alcohols, with or without nitroxyl radicals, in the presence or absence of
phase-transfer catalysts. The pentahydrate crystals alone (without nitroxyl radicals) demonstrate a
powerful oxidizing ability, converting secondary alcohols to the corresponding ketones. In the
presence
of
TEMPO
(2,2,6,6-tetramethylpiperidine
1-oxyl)
or
1-Me-AZADO
(1-methyl-2-azaadamantane N-oxy radical), sterically hindered secondary alcohols are oxidized
without pH adjustment. A proposed mechanism for the oxidation is discussed.
Keywords
TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl); 1-Me-AZADO (1-methyl-2-azaadamantane N-
oxyl); sodium hypochlorite pentahydrate (NaOCl·5H O) crystals; l-menthol; oxidation; aldehyde;
2
ketone
1
. Introduction
Oxidations of primary and secondary alcohols to the corresponding carbonyl
compounds have been among the most important reactions in organic synthesis; and
1
therefore, a large number of methods have been reported. However, most of the
existing reactions have serious problems such as using toxic or explosive oxidants and
producing large amounts of undesirable waste after the reactions. To alleviate these
2
drawbacks, catalytic oxidations using molecular oxygen (O ), diluted aqueous
2
3
4
hydrogen peroxide (H O ), or sodium hypochlorite (NaOCl) as a co-oxidant have been
2
2
1

ACCEPTED MANUSCRIPT
developed, because the post-oxidation waste is harmless, nontoxic water (H O) and/or
2
sodium chloride (NaCl). Nitroxyl radical-catalyzed oxidation using aqueous NaOCl as a
5
co-oxidant with TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl) or AZADO
6
(
2-azaadamantane N-oxyl) compounds is such valuable and useful method, because
this oxidation is metal-free, NaOCl is inexpensive, and commercial aqueous solutions
are non-explosive. For the oxidation of sterically hindered secondary alcohols, TEMPO
is not an effective catalyst, and AZADO is required to obtain the desired alcohols in
6
high yields.
Although this method has been frequently applied in organic synthesis, there are
some drawbacks for using commercial aqueous NaOCl. The process has inherently poor
volume efficiency because the concentration of conventional aqueous NaOCl solution is
7
only 8~13% (higher concentrations of the NaOCl solution are known to be unstable).
Moreover, at the pH of conventional NaOCl (~13; as adjusted with free NaOH to
maintain stability) reactions are very slow, and the pH must be lowered in order to speed
5
b
up the rate. In nitroxyl radical-catalyzed oxidations, the aqueous NaOCl must be
adjusted to pH 8-9 with aqueous sodium hydrogen carbonate, resulting in an event
larger reaction media volume.
We recently developed a new manufacturing process for sodium hypochlorite
8
pentahydrate (NaOCl·5H O) crystals (Figure 1). Notable features of NaOCl·5H O
2
2
include: (1) NaOCl content is about 44 wt% (the followings express as %; 3-4 times that
available from conventional NaOCl solution), (2) simple stoichiometric calculations and
easy, accurate mass determination due to the crystalline nature of the compound, (3) the
pH of aqueous solutions is ~11-12 since the solution contains less than 0.04~0.08%
NaOH, and (4) the crystals are stable for 1 year below 7 °C. Currently, NaOCl·5H O
2
9
crystals are commercially available from several companies including us.
mp
25-27 °C
NaOH 0.04~0.08%
NaCl 0.1~0.5%
pH
11-12 (for the aqueous solution)
Figure 1 NaOCl·5H O crystals
2
Recently we have reported the TEMPO-catalyzed oxidation of alcohols with
1
0
NaOCl·5H O crystals as a communication. In the presence of TEMPO or
2
2

ACCEPTED MANUSCRIPT
1
-Me-AZADO (1-methyl-2-azaadamantane N-oxyl), several alcohols (including
sterically hindered secondary alcohols) can be oxidized without pH adjustment, and
several advantages were found over conventional oxidation procedure using aqueous
NaOCl. In this article, the detailed manufacturing process for production of
NaOCl·5H O and its use in the oxidation of alcohols are described.
2
2
. Commercial synthesis of sodium hypochlorite pentahydrate (NaOCl·5H O)
2
crystals
Several preparation methods for sodium hypochlorite pentahydrate have been
proposed hitherto. Almost of them involve preparing a solution or slurry of sodium
hypochlorite pentahydrate, which is then diluted to give a 13% NaOCl solution
11
containing less sodium chloride. However an industrial-scale process has remained
elusive. We have recently established an original method for manufacturing sodium
hypochlorite pentahydrate crystals (Scheme 1) and have been supplying this product to
the market. Chlorine gas is added to a 45~48% of NaOH solution to prepare a high
concentration NaOCl solution. After precipitated NaCl is removed by filtration, the
filtrate is cooled to around 15 °C to precipitate NaOCl·5H O crystals, which are
2
collected by centrifugal filtration. Analysis shows that the product is contained with
only 0.1~0.5% of NaCl and 0.04~0.08% of NaOH. That is, the crystals prepared using
this new method contain less free NaOH as well as less NaCl than the product prepared
using other methods. In addition, an aqueous solution of this product has more ideal pH
of 11-12 compared to pH 13 conventional aqueous 13% NaOCl solution (and at lower
pH, oxidations are faster; vide infra). Furthermore, these NaOCl·5H O crystals, which
2
contain 44% of NaOCl, are stable for 1 year at 7 °C. For example, crystals of
NaOCl·5H O (44.2%) became 43.7% after 360 days, and this means that almost 99% of
2
NaOCl was unchanged. This is in sharp contrast to a conventional aqueous NaOCl
solution, whose concentration gradually drops, even at 7 °C. A conventional aqueous
1
3.6% NaOCl solution became 11.3% NaOCl solution. This means that the
concentration of NaOCl became 83% of the original solution. Thus, these NaOCl·5H O
2
crystals are ideally suited for use as an oxidant in organic synthesis.
3

ACCEPTED MANUSCRIPT
Scheme 1 Process for preparation of NaOCl·5H O crystals
2
Table 1 Stability of NaOCl·5H O crystals and conventional aq. NaOCl
2
Original
concentration
44.2%
Concentration of 1 yr. later
a
NaOCl·5H O
43.7% (98.9% of the original concentration)
2
b
aq. NaOCl
13.6%
11.3% (83.1% of the original concentration)
a
b
3
60 days later.
361 days later.
3
. Oxidation of alcohols with NaOCl·5H O
2
As is discussed above, the TEMPO-catalyzed oxidation of alcohols with aqueous
NaOCl is one of the most attractive methods for the preparation of aldehydes and
ketones. Therefore, the reaction of alcohols with NaOCl·5H O in the presence of
2
nitroxyl radicals (TEMPO or AZADO) was examined.
3
-1. Oxidation of 2-octanol with NaOCl·5H O crystals: small-scale experiments to
2
optimize reaction conditions
In order to examine the oxidative ability of the NaOCl·5H O crystals, oxidation of
2
2
-octanol (1) was performed under a variety of reaction conditions (Table 2). First, 10
mmol of 1 was stirred with 1.2 equiv. of NaOCl·5H O crystals in the presence of
2
tetrabutylammonium hydrogensulfate (Bu NHSO ; 5 mol%) in dichloromethane at 5 °C
4
4
for 24 h (without use of TEMPO). GC analysis using an internal standard revealed the
product 2-octanone (2) in 78% yield. (run 1) A control experiment with conventional
1
3% of NaOCl solution (1.2 equiv.) gave 2 in only 9% yield. (run 2). Next, catalytic
ability of TEMPO was examined under the same conditions. Addition of TEMPO (0.1
mol%) resulted in a dramatic acceleration for the oxidation of 1, giving 2 in 97% yield
within 1 h. (run 3). The quantity of TEMPO was successfully limited to 0.1 mol% (run
6
). Notably, TEMPO showed no catalytic acceleration with conventional NaOCl
solution (run 4). All reactions in Table 1 were conducted with NaOCl·5H O crystals
2
or aqueous NaOCl solution without pH adjustment.
Then, catalytic ability of 1-Me-AZADO was examined, and 1-Me-AZADO was also
effective for the oxidation of 1 with NaOCl·5H O crystals in the presence of the phase
2
transfer catalyst (Bu NHSO ) (run 7). Interestingly, 1-Me-AZADO exhibited catalytic
4
4
4

ACCEPTED MANUSCRIPT
effect for conventional NaOCl solution, however the reaction rate was slow (run 8).
Table 2 Comparison of NaOCl·5H O crystals and conventional aqueous NaOCl
2
O
OH
Bu NHSO4
4
NaOCl·5H O
or aq. NaOCl
5 mol%
2
+
4
4
nitroxyl radical
1.2 equiv.
2
in CH Cl2 5 °C
1
2
Yield of 2 (%)b
0.5h 1h 2h 3h
NaOCl·5H O
crystals (equiv.)
aq. NaOCl
solutiona
2
Run
nitroxyl radical
24h
78
(
equiv.)
1
2
--
--
1.2
--
--
--
--
3
1
22 28
1.2 (13.2%)c
1
2
--
2
9(27h)
3
4
5
6
7
8
TEMPO
1.2
--
94 97 --
--
--
1
mol%
TEMPO
mol%
TEMPO
-
-
1.2 (13.5%)c
--
1
2
11(22h)
--
1
1.2
1.2
1.2
--
87 99 -- --
-- 79 96 99
-- 100 -- --
-- 14 29 45
0
.5 mol%
TEMPO
--
--
--
0
.1 mol%
-Me-AZADO
mol%
-Me-AZADO
mol%
1
--
1
1
1.2 (13.2%)c
99
1
a
b
c
aq. NaOCl : conventional aqueous NaOCl (ca. 13% solution) containing NaOH and NaCl
Yields were determined by GC using an internal standard method.
Concentrations were determined via titrations.
Encouraged by these results, additional experimental parameters were examined
Table 3). The efficacy of quaternary ammonium salts as phase-transfer catalysts in the
(
presence of 1 mol% (0.01 equiv.) of TEMPO was evaluated. The use of Bu NBr or
4
Bu NCl instead of Bu NHSO afforded poor results, even with the use of NaOCl·5H O
4
4
4
2
crystals (runs 3 and 4). Since Bu NHSO is more acidic than Bu NBr and Bu NCl, it
4
4
4
4
can be neutralize free NaOH in the NaOCl·5H O crystals. The rest of the Bu NHSO
4
2
4
appears to react with NaOCl to form HOCl. Actually, as shown in Table 4, addition of
Bu NHSO to 13% aq. NaOCl (prepared from NaOCl·5H O) dramatically reduced the
4
4
2
pH value (11.3 to 9.6). On the other hand, addition of Bu NBr or Bu NCl did not affect
4
4
5

ACCEPTED MANUSCRIPT
the pH values of the aqueous solution. Combination of Bu NCl and NaHSO ·H O with
4
4
2
a small amount of water, which exhibited a catalytic acceleration (run 6), supports this
theory. Surprisingly, the use of 5 mol% of NaHSO ·H O and a small amount of water in
4
2
the absence of a phase-transfer catalyst was found to give an excellent result (run 7).
This means that the oxidation reaction involves minimal anion-transfer, but rather,
HOCl is the real oxidant. (Scheme 2)
Table 3 Effect for quaternaly annmonium salts and acid in the presence of TEMPOa
O
OH
Bu NX 5 mol%
4
+
NaOCl·5H
O
2
4
1
.2 equiv.
TEMPO 1 mol%
4
in CH Cl 5 °C
2
2
2
1
Yield of 2 (%)b
.5h 1h 2h 3h 21h
Run
1
X
Additive
0
HSO4
--
--
94 97 --
--
--
--
2
3
HSO (0.5 mol%)
-- 40 73 98
4
Br
Cl
Cl
--
--
--
--
6 14 25 87(22h)
3 10 10 73
4
5
NaHSO ·H O 5 mol%
-- 19 25 -- 69
4
2
NaHSO ·H O 5 mol%
6
7
4
2
9
7
99 -- --
--
--
Cl
+
H O 0.2 mL
2
NaHSO ·H O 5 mol%
--
4
2
46 98 -- --
+
H O 0.2 mL
2
a
1
(10 mmol), NaOCl·5H O (12 mmol), Bu NX (0.5 mmol), TEMPO (0.1 mmol), CH Cl (30 mL)
2 4 2 2
b
Yields were determined by GC using an internal standard method.
6

ACCEPTED MANUSCRIPT
Table 4 pH of 13% aq. NaOCl (prepared from NaOCl·5H O)
2
with a phase transfer catalyst
*
1
3% aq. NaOCl
Phase Transfer
none
pH
11.3
9.6
5
5
5
5
0 mmol
0 mmol
0 mmol
0 mmol
Bu NHSO (2.5 mmol)
4
4
Bu NBr (2.5 mmol)
11.4
11.2
4
Bu NCl (2.5 mmol)
4
*
prepared from NaOCl·5H O and ion-exchanged water
2
Thus, the role of Bu NHSO as an acid is both neutralize the free NaOH and to react
4
4
with NaOCl to form HOCl, which again, is likely the genuine oxidant. As the oxidation
proceeds, HCl is generated, which reacts with NaOCl to form additional HOCl (Scheme
2
). If HOCl is the true oxidant, a quaternary ammonium salt as a phase-transfer catalyst
for anion transfer is not necessary. This is supported by the reaction of 2-octanol with
NaOCl·5H O/TEMPO in the presence of NaHSO instead of Bu NHSO affording a
2
4
4
4
comparable yield of 2-octanone (Table 2, run 7). NaHSO is also an acid which acts to
4
neutralize the free NaOH in NaOCl·5H O.
2
NaOH
NaOCl·5H O
2
0
.08 wt% = 0.4 mol%
Bu NHSO
4
4
or NaHSO4
5 mol%
neutralize
Na SO
2
4
H O
2
HCl
HOCl
aqueous phase
organic phase
TEMPO
mol%
1
R1
R2
R1
R2
OH
O
Scheme 2 Proposed mechanism for the TEMPO-catalyzed oxidation of alcohols with
NaOCl·5H O
2
7

ACCEPTED MANUSCRIPT
Next, the relationship between the oxidation rate and the concentrations of NaOCl
(
prepared from NaOCl·5H O crystals and water) was evaluated. The results are shown
2
in Figure 2. Almost no concentration effect is observed at 13, 20, and 31% of
NaOCl·5H O solution. However, the use of the solid NaOCl·5H O crystals speeds up
2
2
the oxidation dramatically. The precise reason is not clear, but it appears that a high
concentration of the primary oxidant HOCl forms at the surface of the crystalline solid.
Figure 2 Reaction* of 1 with several concentration of aqueous
NaOCl prepared from NaOCl·5H O crystals and water ;
2
NaOCl·5H O crystals (○); aq. 31% NaOCl (△); aq. 20% NaOCl (□);
2
aq. 13% NaOCl (
◇
) ; conventional aq. 13% NaOCl (×).
*
1 (10 mmol), NaOCl·5H O (12 mmol), Bu NHSO (0.5 mmol),
2
4
4
TEMPO (0.1 mmol), CH Cl (30 mL), and appropriate water.
2
2
For large scale syntheses, the use of dichloromethane should be avoided for
environmental reasons. Thus, the small-scale (10 mmol) oxidation was examined in
various solvents (Table 5). Ethyl acetate was found to be as good reaction solvent as
dichloromethane, and toluene, acetic acid and trifluoromethylbenzene were nearly as
8

ACCEPTED MANUSCRIPT
effective, albeit with a slightly extended reaction time.
Table 5 Results for oxidationof 1 in several solventsa
NaOCl·5H O
OH
2
O
1.2 equiv.
5
mol% Bu NHSO
4
4
4
1
mol% TEMPO
4
2
1
solvent (30 mL)
Yield of 2 (%)b
1h 2h 3h 4h
Temperature
°C)
Solvent
CH Cl
(
5
5
5
5
5
rt
97 --
61 97
--
--
--
--
2
2
EtOAc
C H CH
38 90 98 --
30 55 87 95
53 54 53 52
18 78 90 90
6
5
3
C H CF
6
5
3
CH CN
3
AcOH
a
1
(10 mmol)
b
Yields were determined by GC using an internal standard
To further evaluate this, a large-scale (26.0 g of
was attempted using ethyl acetate as the solvent (Scheme 3). To be maintained the
reaction temperature, was added dropwise for 15 min to a mixture of NaOCl·5H O
crystals, TEMPO, and Bu NHSO in ethyl acetate being controlled below 20 °C in an
1, 0.2 mol) example of the oxidation
of
1
1
2
4
4
ice-water bath, and then continued to be stirred for 45 min within 0~20 °C. The
reaction mixture was quenched with aqueous Na SO followed by extraction with
2
3
EtOAc, washed with water, and dried over MgSO . Distillation of the residue gave
2
4
in 91% yield.
9

ACCEPTED MANUSCRIPT
Scheme 3 Large scale oxidation of
1 in ethyl acetate.
The 0.10 mol scaled oxidation was also demonstrated without solvent via two
methods using NaHSO instead of Bu NHSO . In method A, was added dropwise into
a mixture of NaOCl·5H O and water, with catalytic amounts of NaHSO ·H O and
1
4
4
4
2
4
2
TEMPO in an ice-water bath. In Method B, 32% NaOCl prepared from NaOCl·5H O
2
and water was added dropwise to a mixture of
ice-water bath. Both methods gave high yields of
1, NaHSO ·H O, and TEMPO in an
4 2
2
within 1 h (Scheme 4).
Method A
1
(13.0 g)
1 h
1
5
.2 equiv. NaOCl-5H O (19.7 g)
2
1
mol% TEMPO (0.16 g)
2
mol% NaHSO -H O (0.69 g)
4
2
5~18 °C
97.0% by GC
H O (13.2 g)
2
Method B
3
2% NaOCl (28.2 g, 1.2 equiv.)
prep. from NaOCl-5H O and H O
2
2
1
(13.0 g)
mol% TEMPO (0.16 g)
mol% NaHSO -H O (0.69 g)
1 h
1
2
5
4
2
0
~12 °C
95.7% by GC
Scheme 4 Solvent free oxidation of
1 catalyzed by NaHSO ·H O.
4 2
3
-2. TEMPO-catalyzed oxidation of several alcohols with NaOCl·5H O
2
The optimized TEMPO-catalyzed oxidation with NaOCl·5H O was applied to
2
various primary and secondary alcohols. Table 4 shows the results for primary alcohols
10 mmol). Use of an equimolar amount of NaOCl·5H O gave the corresponding
(
2
aldehydes in good yield. The oxidations of secondary alcohols are summarized in Table
. Both TEMPO- and 1-Me-AZADO-catalyzed oxidations of sterically hindered
5
secondary alcohols gave poor yields of the ketones with the conventional aqueous
NaOCl without pH adjustment. In contrast, this optimized method using NaOCl·5H O,
2
gives encouraging results with TEMPO, even absent pH adjustment.
1
0

ACCEPTED MANUSCRIPT
Table 6 Selective syntheses of aldehydes from primary alcoholsa
5
1
mol% Bu NHSO
4 4
O
mol% TEMPO
CH Cl
+
NaOCl·5H O
2
R
OH
2
2
R
H
NaOCl·5H O CH Cl
Temp.
(°C)
Time
(h)
Yield
2
2
2
Substrate
(equiv.)
(mL)
%)b
(
1
.1
30
30
5
1
1
91
99
OH
OH
5
1.1
5
5
OH
1.2
30
2
96
MeO
O
OH
OH
OH
1.2
.2
30
15
5
15
6
1
96
97
1
O
1
1
1
1
.4
.4
.2
.4
30
30
30
30
5
5
5
5
4
3
3
2
67
c
d
d
8
2
8
7
8
5
1.1
30
5
0.5
93
98
Cl
OH
1.1
30
5
0.5
O N
2
OH
1
.1
30
30
5
5
0.5
3
94
79
N
S
1.4
OH
a
b
c
d
Substrate : 10 mmol
Yields were determined by GC using an internal method
TEMPO 10 mol%
1-Me-AZADO was used instead of TEMPO
11

ACCEPTED MANUSCRIPT
Table 7 Results for the oxidation of secondary alcoholsa
5
mol% Bu NHSO
4 4
OH
O
1
mol% nitroxyl radical
+
NaOCl·5H O
2
R1
R2
CH Cl
R1
R2
2
2
nitroxyl NaOCl·5H Oaq. NaOCl CH Cl Temp. Time Yield
2
2
2
Substrate
equiv.)b (mL)
c
(
(%)
radical
(equiv.)
(°C) (h)
OH
TEMPO
1.2
--
10
5
0.5 (95)
4
OH
TEMPO
TEMPO
1.2
1.2
--
--
30
10 15
5
1
97
0.67 (96)
3
-
-
-
-
1.2
--
1.6
1.6
1.4
1.4
--
1.2
--
--
--
--
--
30
30
10
8
10
30
30
5
5
15
15
rt
rt
rt
24
24
2
98
2
96
OH
TEMPO
TEMPO
TEMPO
TEMPO
2.25 (92)
4
4
0.5
95
88
98
1
-Me-AZADO 1.4
OH
TEMPO
-Me-AZADO 1.4
1.8
--
--
10 15
30 rt
6
0.5
88
95
1
a
b
c
All the reactions were performed without pH adjustment for NaOCl. See experimental section
aq NaOCl: 12.1 wt% of conventional aqueous solution
Yields were determined by GC using an internal standard method.
Numbers in parentheses refer to isolated yields.
1
2

ACCEPTED MANUSCRIPT
3
-3. Oxidation of an equimolar mixture of 1-octanol and 2-octanol.
In order to be elucidated the mechanism for the oxidation of alcohols with
NaOCl·5H O, a mixture of 1-octanol (5 mmol) and 2-octanol (5 mmol) was oxidized
2
in dichloromethane with NaOCl·5H O (5 mmol) in the presence of TEMPO (or
2
4
-MeO-TEMPO) (0.1 mmol) and Bu NHSO (0.5 mmol) at 5 °C (Table 8). The reaction
4 4
mixture was analyzed by GC, and found that octanal was produced from 1-octanol in
7% yield and 2-octanone was provided from 2-octanol in 44% yield after 0.5 h, in the
4
case of TEMPO. The 4-MeO-TEMPO catalyzed reaction exhibited the similar result.
Thus, the oxidation rates for primary and secondary alcohols under these conditions are
not large different.
On the contrast, oxidation of an equimolar mixture of 1-nonanol and 2-nonanol with
aqueous NaOCl catalyzed by 4-MeO-TEMPO was reported to afford 90% of nonanal
5
b
and 10% of 2-nonanone in a literature.
Table 8 Oxidation of an equimolar mixture of 1-octanol
and 2-octanol with NaOCl·5H O catalyzed by a nitroxyl
2
radical
.
O
.
NaOCl 5H O
2
(
5 mmol)
Nitroxyl radical
(0.1 mmol)
OH
H
5
5
1
-octanol
octanal
5
+
.0 mmol
+
OH
Bu
0.5 mmol)
CH Cl , 5 °C
4
NHSO
4
O
(
2
2
4
4
2
-octanol
.0 mmol
2
-octanone
5
Nitroxyl Radical Time (h) Octanal
2-Octanone
44%
TEMPO 0.5 47%
(2.35 mmol)
(2.20 mmol)
4
*
-MeO-TEMPO 1.0
48%
37%
(1.85 mmol)
(2.40 mmol)
Yields were determined by GC using an internal standard method.
1
3

ACCEPTED MANUSCRIPT
4
. Mechanism
A number of mechanistic studies have been published for TEMPO-catalyzed alcohol
1
2
oxidations. The explanation involves key intermediate
B
, as shown in Scheme 6.
In
general to be said, the TEMPO-catalyzed oxidation of bulky secondary alcohols gives
poor results due to steric hindrance caused by the four methyl groups neighboring the
nitroxyl center preventing the formation of the intermediate B.
H
R
O
R'
H
X
[O]
N
N
-HX
O
O
TEMPO
A
O
[O]
N
O
R
R'
B
H
N
HO
R
O
R'
1
2
Scheme 5 Reported mechanism under basic conditions
For the oxidation of bulky secondary alcohols such as l-menthol, AZADO and the
related nitroxyl catalysts developed by Iwabuchi and co-workers, which have less steric
hindrance around the nitroxyl radical, are required to obtain the desired ketones.
Since it has been shown in Table 7, however, bulky secondary alcohols can be oxidized
smoothly to the corresponding ketones with NaOCl·5H O/TEMPO, an alternative
2
mechanism must be at work.
To be cleared the mechanism for alcohol oxidation with NaOCl·5H O, it must
2
acknowledge the following: 1) oxidation rates for primary and secondary alcohols are
almost equal (Table 8), 2) a benzyl alcohol having an electron withdrawing group
1
4

ACCEPTED MANUSCRIPT
(4-nitrobenzyl alcohol) is oxidized much faster than that one having an electron
donating group (4-methoxybenzyl alcohol) (Table 6), and 3) sterically hindered
secondary alcohols having bulky groups are successfully oxidized in the presence of
TEMPO (Table 7).
6,12
The Scheme 5 mechanism has been proposed involving weakly basic conditions.
However, the oxidation of alcohols with NaOCl·5H O/TEMPO/Bu NHSO occurs
2
4
4
under acidic to neutral conditions (Scheme 2 vide supra). Bobbitt et.al. proposed an
alternative mechanism for the TEMPO oxidation of alcohols involving intermediate
C
1
2e,f
with hydride transfer under neutral or acidic conditions (Scheme 6).
intermediate
Taking
C
into account, steric hindrance of bulky secondary alcohols is likely
relaxed, permitting the oxidation to proceed. The interaction between the lone pair of
nitrogen atom and the hydrogen atom of hydroxyl group in the alcohol plays an
important role of this reaction mechanism. Therefore, more acidic alcohols (such as
4
-nitrobenzyl alcohol having an electron withdrawing group) reacted faster than less
acidic alcohols (such as 4-methoxybenzyl alcohols having an electron donating group)
did. These features suggest that the oxidation using NaOCl·5H O/TEMPO/Bu NHSO
2
4
involves intermediate
C as shown Scheme 6.
X
[O]
N
N
O
O
TEMPO
A
X
H
O
N
R
O
H
C
[O]
R'
-HX
N
OH
R
O
R'
Scheme 6 Proposed mechanism under neutral or acidic conditions
1
5

ACCEPTED MANUSCRIPT
5
. Conclusions
In this articles, a novel manufacturing process for NaOCl·5H
application of this reagent in the oxidation of alcohols were explored.
2
O and the
T
he
ready availability, high volume efficiency, wide applicability, and high
activity make this a very attractive oxidation reagent and method for
laboratory and industrial use.
6
. Experimental
All melting points were determined with a Buchi melting point apparatus (model
1
B-545) and are uncorrected. NMR spectra were recorded with a JEOL, JNM-EX400
spectrometer in CDCl using tetramethylsilane (TMS) as a reference. GC-mass spectra
3
were recorded with a Shimadzu GCMS-QP2010 SE using a DB-5 column (0.32 mm ID
×
30 m, df=0.50µm) or a Shimadzu GC-17A/GCMS-QP5050A using an InertCap1
column (0.25 mm ID × 60 m, df=0.4 µm). GC analyses were run on a Shimadzu
GC-2014 instrument with flame-ionization detectors, equipped with an NB-1 (0.25 mm
×
60 m, df=0.4 µm) GC column using helium as the carrier gas.
Unless stated otherwise, all reagents and chemicals were obtained commercially and
used without further purification.
The sodium hypochlorite pentahydrate (NaOCl·5H O) crystals were manufactured
2
by the Nippon Light Metal Co. Ltd. using the process developed by us. The reagent can
be purchased from Wako Pure Chemical Industries, Ltd., Tokyo Chemical Industry Co.
Ltd. Junsei Chemical Co. Ltd., TCI America, and TCI Europe for laboratory use.
Manufacturing process for sodium hypochlorite pentahydrate (NaOCl·5H O)
2
crystals (Method of Nippon Light Metal Co. Ltd.)
Chlorine gas (193 kg/h, 2.7 kmol/h) was added to a 45% NaOH solution (500 kg/h,
5
.6 kmol/h) at 25~30°C for 6 h average residence time to give sodium hypochlorite.
Precipitated sodium chloride crystals (151 kg/h, 2.6 kmol/h) were separated from the
slurry, giving a sodium hypochlorite solution (542 kg/h, NaOCl: 30.8%). After the
sodium hypochlorite solution was cooled to 12°C, seed crystals of NaOCl·5H O (170 g)
2
were added, and the mixture was stirred for 13 h average residence time. The
precipitated NaOCl·5H O crystals (172 kg/h) were collected by centrifugal filtration.
2
Analysis shows the product contains 0.1~0.5% of NaCl and 0.04~0.08% of NaOH
(representative values).
1
6

ACCEPTED MANUSCRIPT
Analytical methods.
odium hypochlorite concentration:
Ion-exchanged water (20 mL) was added to ca. 0.1 g weighed of NaOCl·5H O
S
2
crystals in a conical beaker. Two grams of potassium iodide and 10 mL of 50% aqueous
acetic acid were added to the stirred solution. Iodine liberated from the solution was
titrated with 0.1 M sodium thiosulfate for volumetric analysis (the liquid goes from
brown to colorless).
Free sodium chloride:
I
on-exchanged water (2 mL) was added to ca. 0.1 g of NaOCl·5H O crystals in a
2
weighed in a conical beaker. Aqueous ~30% of hydrogen peroxide was added to the
stirred solution until bubbling ceased, and ion-exchanged water (20 mL) was added. A
few drops of phenolphthalein solution were added to the colorless solution, and if the
color of the solution became pink (basic), nitric acid (2%) was added until it become
colorless. To the mixture was added 0.2 mL of potassium chromate (5%), and the
solution was titrated with 0.1 M of silver nitrate solution for volumetric analysis (the
solution turned slightly orange from yellow).
Free [NaCl] = [total chlorine concentration] titrated above – [sodium hypochlorite
concentration]
Free sodium hydroxide:
Ion-exchanged water (20 mL) was added to 10 g of NaOCl·5H O crystals weighed
2
in conical beaker. About 30% of hydrogen peroxide was added to the stirred solution
until bubbling ceased. A few drops of phenolphthalein solution were added to the
solution, which was then titrated with 0.1 M hydrochloric acid for volumetric analysis
(the color of the solution went from pink to colorless).
Conventional aqueous NaOCl solution manufactured by the Nippon Light Metal
Co. Ltd.
Representative values;
NaOCl 12.6~13.6%: NaCl 12~13%: NaOH 0.6~0.8%: pH was 13, determined using a
pH meter.
An aqueous 13% NaOCl solution prepared from NaOCl·5H O:
2
An aqueous 13% NaOCl (110.9 g) was prepared from NaOCl·5H O (32.7 g) and
2
1
7

ACCEPTED MANUSCRIPT
ion-exchanged water (78.2 g). The pH was 11.3, determined using a pH meter.
Determination of pH for NaOCl·5H O with tetrabutylannmonium salts:
2
Bu NHSO Bu NBr, or Bu NCl (2.5 mmol) was added to 13% NaOCl (28.5 g, 50
4
4,
4
4
mmol) prepared from NaOCl·5H O and ion-exchanged water. The pH of the resulting
2
solutions were determined using a pH meter.
Typical example for small scale oxidation of 2-octanol (Tables 2, run 3):
NaOCl·5H O crystals (1.97 g, 12.0 mmol) were added in one portion to a mixture of
2
Bu NHSO (0.170 g, 0.50 mmol), TEMPO (15.5 mg, 0.10 mmol), and
1 (1.30 g, 10.0
4
4
mmol) in dichloromethane (30 mL) at 5 °C. After stirring for 1 h, exact 0.5 mL of the
organic layer and 0.03 g weighed of 4-chloro-trifluoromethylbenzene (PCBTF) as an
internal standard were added to 1 mL of CH Cl . Yield of the product
2 (97%) was
2
2
determined by GC. GCMS analysis of the product was identical to an authentic sample.
+
GCMS: m/z =128 (M , relative intensity 3%), 113 (3%), 85 (3%), 71(6%), 58(54%), 43
(base peak)
Small scale oxidation of primary alcohols for Table 6: (general procedure)
NaOCl·5H O crystals (11.0~14.0 mmol) were added in one portion to a mixture of
2
Bu NHSO (0.170 g, 0.50 mmol), TEMPO (15.6 g, 0.10 mmol), alcohols (10.0 mmol),
4
4
and 0.2 g of PCBTF (an internal standard) in dichloromethane (15 or 30 mL) at 5 or
1
1
5 °C. After stirring for an appropriate time, 0.5 mL of the organic layer was added to
mL of CH Cl for GC analysis. GCMS analyses of the products were identical with
2
2
authentic samples.
Oxidation of 1-octanol
NaOCl·5H O crystals (1.81 g, 11.0 mmol) were added in one portion to a mixture of
2
Bu NHSO (0.170g, 0.50 mmol), TEMPO (15.6 mg, 0.10 mmol), 1-octanol (1.31 g,
4
4
1
0.1 mmol), in dichloromethane (30 mL) at 5°C. After stirring for 1 h, 0.5 mL of the
organic layer and 0.03 g weighed of PCBTF as an internal standard were added to 2 mL
of CH Cl . Octanal was determined in 91% yield for GC analysis. GCMS analysis of
2
2
+
the product was identical with authentic sample. GCMS: m/z =128 (M , relative
intensity 0.2%), 110 (5%), 100 (10%), 84(61%), 69(31%), 56 (48%), 43 (base peak), 41
(99%)
Oxidation of benzyl alcohol
NaOCl·5H O crystals (1.81 g, 11.0 mmol) were added in one portion to a mixture of
2
Bu NHSO (0.170g, 0.50 mmol), TEMPO (15.6 mg, 0.10 mmol), benzyl alcohol (1.10 g,
4
4
1
8

ACCEPTED MANUSCRIPT
1
0.2 mmol), in dichloromethane (30 mL) at 5°C. After stirring for 1 h, 0.5 mL of the
organic layer and 0.03 g weighed of 1, 3-dichlorobenzene as an internal standard were
added to 2 mL of CH Cl . Benzaldehyde was determined in 99% yield for GC analysis.
2
2
GCMS analysis of the product was identical with authentic sample. GCMS: m/z =106
+
(
M , relative intensity 74%), 105 (74%), 85 (0.4%), 77(base peak), 63(2%), 51 (27%),
39 (8%)
Oxidation of 4-methoxybenzyl alcohol
4
-Methoxybenzaldehyde was prepared from 4-methoxybenzyl alcohol in 96% yield.
+
GCMS: m/z =136 (M , relative intensity 72%), 135 (base peak), 119 (1%), 107(25%),
9
2(20%), 77 (31%), 65 (11%), 51 (14%), 39 (23%)
Oxidation of piperonyl alcohol
,3-Benzodioxole-5-carbaldehyde (piperonal) was prepared from 1,3-benzodioxole
1
-
5-ylmethanol
(
piperonyl alcohol), under a variety of different conditions as described in
+
Table 4, in 96~97% yield. GCMS: m/z =150 (M , relative intensity 92%), 149 (base
peak), 121 (32%), 91(10%), 77(3%), 65 (16%), 63 (26%), 53 (7%), 39 (7%)
Oxidation of cinnamyl alcohol
Cinnamaldehyde was prepared from cinnamyl alcohol, under a variety of different
+
conditions as described in Table 4, in 67~87% yield. GCMS: m/z =132 (M , relative
intensity 60%), 131 (base peak), 115 (1%), 103 (69%), 91 (2%), 77 (32%), 63 (7%), 51
(
48%), 39 (12%)
Oxidation of 4-chlorobenzyl alcohol
-Chlorobenzaldehyde was prepared from 4-chlorobenzyl alcohol in 93% yield.
4
+
+
GCMS: m/z =142 (M +2, relative intensity 22%), 141 (37%), 140 (M , 68%), 139 (base
peak), 113 (19%), 111 (60%), 91 (2%), 85 (4%), 77 (18%), 75 (32%), 61 (4%), 50
(31%), 38 (8%)
Oxidation of 4-nitrobenzyl alcohol
4
-Nitrobenzaldehyde was prepared from 4-nitrobenzyl alcohol in 98% yield.
+
GCMS: m/z =151 (M , relative intensity 92%), 150 (base peak), 135 (2%), 120 (7%),
1
05 (22%), 92 (12%), 77 (72%), 65 (12%), 51 (85%), 39 (8%)
Oxidation of 3-pyridinemethanol
3
-Pyridinecarboxaldehyde was prepared from 3-pyridinemethanol in 94% yield.
+
GCMS: m/z =107 (M , base peak), 106 (relative intensity 53%), 78 (45%), 61 (1%),
5
1(60%)
Oxidation of 2-thiophenemethanol
Thiophene-2-carbaldehyde was prepared from 2-thiophenemethanol in 79% yield.
+
GCMS: m/z =112 (M , relative intensity 93%), 114 (5%), 113 (11%), 111 (base peak),
1
9

ACCEPTED MANUSCRIPT
8
3 (8%), 58 (7%), 45 (15%), 39 (28%), 77 (72%), 65 (12%), 51 (85%), 39 (8%). As a
by-product it was assigned 5-chlorothiophene-2-carbaldehyde (8.5 GC%). GCMS
+
analysis of the product was identical with authentic sample. GCMS: m/z =148 (M +2,
+
relative intensity 29%), 147 (45%), 146 (M , 86%), 145 (base peak), 117 (20%), 82
(8%), 73 (19%), 57 (12%), 45 (20%)
Small scale oxidation of secondary alcohols for Table 7:( general procedure)
NaOCl·5H O crystals (12.0~18.0 mmol) were added in one portion to a mixture of
2
Bu NHSO (0.170 g, 0.50 mmol), TEMPO (15.6 mg, 0.10 mmol), and alcohols (10.0
4
4
mmol) in dichloromethane (10 mL or 30 mL) at several temperature. After stirring for
an appropriate time, 0.5 mL of the organic layer and 0.03 g weighed of PCBTF as an
internal standard were added to 1~2 mL of CH Cl for GC analysis. GCMS analyses of
2
2
the products were identical with authentic samples.
Oxidation of 3-octanol
+
3
-Octanone was prepared from 3-octanol in 97% yield. GCMS: m/z =128 (M ,
relative intensity 4%), 99 (29%), 72 (23%), 71 (21%), 57 (53%), 43 (base peak).
Oxidation of l-menthol
l
-menthone was prepared from
l
-menthol in 88~98% yield, with several conditions
+
described in Table 5. GCMS: m/z =154 (M , relative intensity 36%), 139 (52%), 112
(base peak), 97 (40%), 83 (28%), 69 (75%), 55 (62%), 41 (61%)
Oxidation of 2,6-dimethyl-4-heptanol
2
,6-Dimethyl-4-heptanone was prepared from 2,6-dimethyl-4-heptanol in 88~95%
+
yield, with several conditions described in Table 5. GCMS: m/z =142 (M , relative
intensity 12%), 127 (5%), 100 (3%), 85 (74%), 71 (1%), 57 (base peak), 43 (12%),
4
1(25%)
Preparative examples
Oxidation of 2-octanol
NaOCl·5H O crystals (2.0 g, 12.2 mmol) were added in one portion to a mixture of
2
Bu NHSO (0.17 g, 0.50 mmol), TEMPO (21 mg, 0.13 mmol), and
1
(1.30 g, 10.0
mmol) in dichloromethane (10 mL) at 5 °C. After 15 min, GC monitoring showed that
all of the starting material had been consumed. The reaction was stopped after 0.5 h
4
4
1
by quenching with aqueous saturated sodium sulfite solution (20 mL). The organic layer
was separated and the aqueous layer was extracted with dichloromethane (30 mL).
The combined organic layers were washed with water (30 mL), dried over Na SO , and
2
4
concentrated to give
2 as colorless oil (1.27 g, crude yield of 99.2%, GC analysis
2
0

ACCEPTED MANUSCRIPT
showed the product to be 96.8% pure). A 0.42 g portion of the crude
2
was purified by
bulb-to-bulb distillation (6 kPa, 120
g, 95%).
−130 °C bath temperature) to afford pure 2 (0.40
Oxidation of 3-octanol
NaOCl·5H O crystals (2.0 g, 12.0 mmol) were added in one portion to a mixture of
2
Bu NHSO (0.16 g, 0.47 mmol), TEMPO (20.0 mg, 0.13 mmol), 3-octanol (1.30 g, 10.0
4
4
mmol), and water (0.2 mL) in dichloromethane (10 mL) at 8 °C. The reaction was
stopped after 0.5 h by quenching with aqueous saturated sodium sulfite solution (20
mL). The organic layer was separated and the aqueous layer was extracted with
dichloromethane (30 mL). The combined organic layers were washed with water (30
mL), dried over Na SO , and concentrated to give 3-octanone as a colorless oil (1.30 g).
2
4
A 0.40 g portion of the crude
3
was purified by bulb-to-bulb distillation (8.7 kPa,
(0.38 g, 96%, GC purity 99.7%).
1
30 140 °C bath temperature) to afford pure 3
−
Oxidation of l-menthol
NaOCl·5H O (658.0 mg, 4 mmol) was added in one portion to a mixture of
2
Bu NHSO (44.5 mg, 0.131 mmol), TEMPO (3.4 mg, 0.022 mmol), and
l
-menthol
391.5 mg, 2.5 mmol) in dichloromethane (8 mL) at 15 °C. The mixture was stirred at
5 °C for 2.25 h, and then the reaction was quenched by treatment with saturated
4
4
(
1
aqueous sodium sulfite solution (5 mL). The aqueous layer was extracted with
dichloromethane (10 mL × 3). The combined organic layers were washed with saturated
brine, dried over anhydrous Na SO , and concentrated to give
l
-menthone as a colorless
2
4
oil (475.7 mg), which was purified by column chromatography (Hexane : AcOEt = 10 :
2
5
1
) on silica gel to give pure
l
-menthone (355.3 mg, 92%). [
α]D
=
−
28.1° (c=0.0156,
1
0d
1
EtOH) (lit. , [
.6, 2.3 Hz, 1H), 2.18
d, J = 6.8 Hz, 3H), 0.85 (d, J = 6.8 Hz, 3H).
α
] =
−
28.6°). H NMR (400 MHz, CDCl3): δ＝ 2.35 (ddd, J = 13.1,
D
3
−1.80 (m, 6H), 1.43−1.29 (m, 2H), 1.01 (d, J = 6.4 Hz, 3H), 0.91
(
Large scale oxidation of 2-octanol in ethyl acetate:
A mixture of NaOCl·5H O (39.5 g, 0.24 mol) and ethyl acetate (70 mL) was cooled
2
to 3 °C in a 200 mL of 4-necked flask with stirring . Bu NHSO (3.4 g , 0.010 mol) and
4
4
TEMPO (0.31 g , 0.002 mol) were added to the mixture, and then 2-octanol (26.0 g ,
.20 mol) was added over a period of 15 min via a dropping funnel. The temperature of
0
2
1

ACCEPTED MANUSCRIPT
the reaction mixture reached a maximum of 18 °C during the addition, and was 12 °C at
the end of the 2-octanol addition. The dropping funnel was washed with 10 mL of
AcOEt and the stirring was continued for a further 45 min. The temperature of the
reaction mixture was 2 °C. The mixture was quenched with satd. Na SO (30 mL),
2
3
extracted with AcOEt (20 mL × 3), washed with brine (20 mL × 1) and water (20 mL ×
), and dried over MgSO . After filtration, the organic layer was concentrated in vacuo
2
4
and distilled (bp 130 °C /26.6-25.5 kPa) to give 2-octanone (23.2 g, 90.5% yield). GC
and GCMS analyses of the product were identical with authentic sample and indicated
9
9.3% purity.
Solvent free oxidation of 2-octanol with NaHSO ·H O
4
2
Method A
To NaOCl·5H O (19.7 g, 0.12 mol) and water (13.2 g) were added NaHSO ·H O
2
4
2
(0.69 g, 5.0 mmol) and TEMPO (0.16 g, 1.0 mmol) in ice-water bath with stirring.
Thirteen grams of 2-octanol (0.10 mol) were added at 5~18 °C over a period of 1 h. The
pH of the reaction mixture was measured to be 9.5~10.3 during this period. Point one
mL of the organic layer was measured out to 10 mL of CH Cl and 0.17 g weighed of
2
2
PCBTF as an internal standard was added for GC analysis. The yield of 2-octanone was
7.0%.
9
Method B
A 30% NaOCl solution (28.2 g, 0.12 mol) prepared from NaOCl·5H O and water was
2
added dropwised to a mixture of 2-octanol (13.0 g, 0.10 mol), NaHSO ·H O (0.69 g, 5.0
4
2
mmol) and TEMPO (0.16 g, 1.0 mmol) for 1 h at 0~12 °C with stirring. The pH was
3
~8 for the first 0.5 h and 8~10 for the next 0.5 h. Point one mL of the organic layer and
.17 g weighed of PCBTF as an internal standard were added to 10 mL of CH Cl for
0
2
2
GC analysis. The yield of 2-octanone was 95.7%.
6
. References
1
. (a) Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 16, 2647-2650; (b) Corey, E. J.; Schmidt, G.
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1
978, 43, 2480-2482; (d) Corey, E. J.; Kim, C. U. J. Am. Chem. Soc. 1972, 94, 7586-7587; (e)
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Fudesaka, M.; Kodama, S.; Node, M. Tetrahedron Lett. 2002, 43, 5177-5179; (g) Griffith, W. P.;
Ley, S. V.; Whitcombe, G. P.; White, A. D. J. Chem. Soc., Chem. Commun. 1987, 1625-1627; (h)
2
2

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B.; Movassaghi, M.; Kung, D. W.; Lanman, B. A.; Kwon, S. Tetrahedron Lett. 2000, 41,
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359-1362
2
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3
. (a) Sato, K.; Aoki, M.; Takagi, J.; Noyori, R. J. Am. Chem. Soc. 1997, 119, 12386-12387; (b)
Sato, K.; Aoki, M.; Takagi, J.; Zimmermann, K.; Noyori, R. Bull. Chem. Soc. Jpn. 1999, 72,
2
287-2306
4
. (a) Stevens R.V.; Chapman K.T.; Stubbs, C. A.; Tam, W. W.; Albizati, K. F. Tetrahedron Lett.
1
982, 23, 4647-4650; (b) Stevens, R. V.; Chapman, K. T.; Weller, H. N. J. Org. Chem. 1980, 45,
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2
Mirafzal, G.A.; Lozeva, A. M. Tetrahedron Lett. 1998, 39, 7263-7266
5
6
. (a) deNooy, A. E. J.; Besemer, A. C.; Bekkum, H. V. Synthesis 1996, 1153-1176; (b) Anelli, P.L.;
Biffi, C.; Montanari, F.; Quici, S. J. Org. Chem. 1987, 52, 2559-2562
. (a) Shibuya, M.; Tomizawa, M.; Suzuki, I.; Iwabuchi, Y. J. Am. Chem. Soc. 2006, 128,
8
412−8413; (b) Iwabuchi, Y., J. Synth. Org. Chem. Jpn. 2008, 66, 1076−1084.
7
. Adam, L. C.; Gordon, G. Inorg. Chem. 1999, 38, 1299-1304
8
. Asawa, T.; Tuneizumi, T.; Iwasaki, Y. Japanese Patent 4211130 (2008); JP (Japan Kokai Tokkyo
Koho) 2000-290003, Chem. Abstr. 133, 311496 (2000).
9
. NaOCl·5H O is commercially available from Wako Pure Chemical Industries, Ltd., Tokyo
2
chemical industry Co., Ltd., and Junsei Chemical Co., Ltd. Large quantity of NaOCl·5H O can
2
be directly supplied from Nippon Light Metal Company, Ltd.
1
1
0. Okada, T.; Asawa, T.; Sugiyama, Y.; Kirihara, M.; Iwai, T.; Kimura, Y. Synlett 2014, 25,
5
96-598
1. (a) Applebey, M. P. J. Chem. Soc. Trans. 1919, 115, 1106-1109.; (b) Takimoto, K.; Karasawa, Y.
JP 56-022604 (1981); Chem. Abstr. 1981, 95, 45459.; (c) Duncan, B. L.; Ness, R. C.; WO
9
217399 (1992); Chem. Abstr. 1992, 117, 254363.; (d) Timshina, A. V. ; Rubtsova, S. A.; Kodess,
M. I.; Matochkina, E. G.; Slepukhin, P. A.; Kuchin, A. V. Russian J. Org.Chem. 2008, 44,
043-1048; Chem. Abstr. 2008, 150, 398714.; (e) Cawlfield, D. W.; Morris, R. T.; Ness, R. C.;
Richard, L. L.; Scott, L. L.; Moore, S. H.; Asuru, A. P.; US 2014-0117278 (2014); Chem. Abstr.
014, 160, 638958.; (f) Iwata, T.; Nishiumi, K.; Takimoto, H. JP 2014-169215 (2014); Chem.
Abstr. 2014, 161, 448861.; (g) Fehèr, F.; Hirschfeld, D.; Linke, K. -H. Acta. Crystallographica,
962, 15, 1188-1189; (h) Taguchi, S.; Terao, T.; Yamazaki, K.; Murakami, M. CN 104743514
2015); Chem. Abstr. 2015, 163, 176884.
1
2
1
(
2
3

ACCEPTED MANUSCRIPT
1
2. (a) Golubev. V. A.; Rozantsev, E. G.; Neiman, M. B. Bull. Acad. Sci. USSR, Div. Chem. Sci. 1965,
1
898-1904; (b) Semmelhack, M. F.; Scimid, C. R.; Cortés, D.A. Tetrahedron Lett. 1986, 27,
1119-1122; (c) Ma, Z.; Bobbitt, J. M. J. Org. Chem. 1991, 56, 6110-6114; (d) de Nooy, A. E. J.;
Besemer, A. C. Tetrahedron 1995, 51, 8023-8032; (e) Bobbitt, J. M. TCIMAIL (Tokyo Chemical
Industry Co. Ltd) No 146 (August 2011) pp 2-10; (f) Bailey, W. F.; Bobbitt, J. M.; Wiberg, K. B.
J. Org. Chem. 2007, 72, 4504-4509
2
4

Cl2
aq NaOCl
cooling filtration
NaOCl·5H O
crystals
4
5-48%
aq NaOCl
+ NaOH
2
+
+
NaCl
NaOH
aq NaOH
filtration
NaCl
Soln. containing
NaOH

NaOH
NaOCl·5H O
2
0.08 wt% = 0.4 mol%
Bu NHSO
4
4
or NaHSO4
5 mol%
neutralize
Na SO
2
4
H O
2
HCl
HOCl
aqueous phase
organic phase
TEMPO
mol%
1
R1
R2
R1
R2
OH
O

OH
2
00 mL flask
4
6.0 g
O
2
15 min
1
.2 equiv. NaOCl-5H O (39.5 g)
2
1
mol% TEMPO (0.31 g)
4
5
mol% Bu NHSO (3.40 g)
4
4
<
20 °C
EtOAc (80 mL)
2
3.2 g (Y=91%)
b.p.130 °C/26 kPa
additional 45 min

Method A
1
(13.0 g)
1
h
1
.2 equiv. NaOCl-5H O (19.7 g)
2
1
mol% TEMPO (0.16 g)
2
5
mol% NaHSO -H O (0.69 g)
4
2
5~18 °C
97.0% by GC
H O (13.2 g)
2
Method B
32% NaOCl (28.2 g, 1.2 equiv.)
prep. from NaOCl-5H O and H O
2
2
1
(13.0 g)
mol% TEMPO (0.16 g)
mol% NaHSO -H O (0.69 g)
1 h
1
2
5
4
2
0
~12 °C
95.7% by GC