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Sodium Hypochlorite Pentahydrate Crystals (NaOCl·5H2O): A

Convenient and Environmentally Benign Oxidant for Organic
Synthesis
Masayuki Kirihara,*,† Tomohide Okada,‡ Yukihiro Sugiyama,‡ Miyako Akiyoshi,§ Takehiro Matsunaga,§
and Yoshikazu Kimura*,∥
†
Department of Materials and Life Science, Shizuoka Institute of Science and Technology, 2200-2 Toyosawa, Fukuroi, Shizuoka
437-8555, Japan
‡
R&D Department of Chemicals, Nippon Light Metal Company, Ltd., 480 Kambara, Shimizu-ku, Shizuoka 421-3203, Japan
§
Research Center for Explosion Safety, National Institute of Advanced Industrial Science and Technology, 1-1-1 Higashi, Tsukuba-shi,
Ibaraki 305-8565, Japan
∥
Research and Development Department, Iharanikkei Chemical Industry Co. Ltd., 5700-1 Kambara, Shimizu-ku, Shizuoka 421-3203,
Japan
*
S Supporting Information

ABSTRACT: The novel oxidant of sodium hypochlorite pentahydrate (NaOCl·5H2O) crystals is now available for industrial
and laboratory use. It is superior to conventional aqueous sodium hypochlorite solutions (aq. NaOCl). The crystalline material is
44% NaOCl and contains minimal amounts of sodium hydroxide and sodium chloride, and the aqueous solution, which is
prepared from NaOCl·5H2O and water, has a pH of 11−12. Examples of the selective organic synthesis using NaOCl·5H2O
involve the oxidations of primary and secondary alcohols, selective oxidations to sulfoxide and sulfone, oxidative cleavage of
disulfide to sulfonyl chloride and bromide, oxaziridine synthesis, and oxidative dearomatization of phenols.

1. INTRODUCTION We expected that NaOCl·5H2O is a superior substitute of aq.

In this review, novel production on a commercial basis of
sodium hypochlorite pentahydrate (NaOCl·5H2O) and its
application for organic syntheses is described. Although
NaOCl·5H2O itself has been known since 1919 in the
literature,1 nothing has been supplied on an industrial scale.
In 2013, Nippon Light Metal Co. in Japan was the first to put
sodium hypochlorite pentahydrate (NaOCl·5H2O) crystals on
the market in the world.2,3 As the organic synthesis using
NaOCl·5H2O as an oxidant has never been reported, we
examined the performance of the NaOCl·5H2O compared to a
conventional aqueous NaOCl solution (aq. NaOCl).
Oxidation using aq. NaOCl4 is one of the most promising
methods in process chemistry, because diluted aq. NaOCl is
nonexplosive and inexpensive, and the postoxidation waste is
harmless and nontoxic sodium chloride (NaCl). However,
there are still some drawbacks when using the conventional aq.
NaOCl as an oxidant of organic compounds. The process has
an inherently poor volume efficiency because the concentration
of conventional aq. NaOCl is only 8−13% (higher concen-
trations of the NaOCl solution are known to be unstable).
Moreover, the pH of conventional aq. NaOCl is very high
(∼13; as adjusted with free NaOH to maintain stability), and
the pH must sometimes be adjusted lower to speed up the rate
or prevent decomposing the starting materials and/or products.
Furthermore, conventional aq. NaOCl is not stable enough,
and the deteriorated NaOCl sometimes produces unsuccessful
synthetic reactions.
NaOCl and found several new types of oxidation reactions of
organic molecules which had not been successful using
conventional aq. NaOCl. In addition, a high volume efficiency
of reactions, good stability in storage, and unnecessity pH
adjustment prior to use afforded simple methods for organic
synthesis.
Several oxidation reactions were found to occur as shown in
Scheme 1.
2. SODIUM HYPOCHLORITE PENTAHYDRATE
(NaOCl·5H2O)2,5
As shown in Figure 1, NaOCl·5H2O consists of pale yellow
crystals having the melting point of 25−27 °C. Notable features
of NaOCl·5H2O include: (1) the NaOCl content is about 44
wt % (the following expressed as %; 3−4 times higher
concentration versus conventional aq. NaOCl), (2) simple
stoichiometric calculations, easy and accurate mass determi-
nation 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·5H2O crystals are
commercially available from several companies including us.3
Received: September 1, 2017
Published: October 23, 2017

© 2017 American Chemical Society 1925 DOI: 10.1021/acs.oprd.7b00288

Org. Process Res. Dev. 2017, 21, 1925−1937
Organic Process Research & Development
Scheme 1. Synthetic Applications of NaOCl·5H2O
Figure 1. NaOCl·5H2O crystals. Reproduced with permission from ref
5. Copyright 2016 Elsevier.
3. COMMERCIAL SYNTHESIS OF SODIUM
HYPOCHLORITE PENTAHYDRATE (NaOCl·5H2O)
CRYSTALS2,5
3.1. Development of the Industrial Preparation of
NaOCl·5H2O. Several preparation methods for NaOCl·5H2O
have already been proposed;1 however, industrial applicable
methods to prepare high-purity NaOCl·5H2O crystals are
unknown. We have recently found specified crystallization
conditions for high-purity NaOCl·5H2O crystals based on the
NaCl−NaOCl−H2O ternary phase diagram. On the basis of
these findings, we have established an original method for
manufacturing NaOCl·5H2O (Scheme 2)2 and have been
supplying this product to the market. Chlorine gas is added to a
45−48% NaOH solution to prepare a highly concentrated
NaOCl solution. After removing of the precipitated NaCl by
filtration, the filtrate is cooled to around 12 °C to precipitate
the NaOCl·5H2O crystals, which are collected by centrifugal
filtration.
3.2. Property of NaOCl·5H2O. Analysis shows that the
prepared NaOCl·5H2O contains only 0.1−0.5% NaCl and
0.04−0.08% NaOH. That is, the crystals prepared using this
new method contain less free NaOH as well as less NaCl than
the conventional aq. NaOCl. In addition, an aqueous solution
of this product has a more ideal pH of 11−12, whereas that of
Scheme 2. Industrial Preparation of NaOCl·5H2O
1926
Review
the conventional aq. NaOCl is pH 13 and oxidations are faster
due to the lower pH, vide infra.
The stability of the product was evaluated at several
temperatures (Figure 2). These NaOCl·5H2O crystals, which
contain 44% of NaOCl, are stable at lower temperatures.
However, the product gradually decomposed under an ambient
temperature.
Further evaluation revealed that the NaOCl·5H2O crystals
are quite stable in refrigerator. The concentration of NaOCl of
the crystals is almost unchanged (44.2% → 43.7%) even after
360 days at 7 °C (Figure 2). This means that 99% of the
NaOCl was maintained (Table 1). This is in sharp contrast to
the conventional aqueous NaOCl solution, whose concen-
tration gradually drops to 11.3% from 13.6% of original
concentration under the same condition. This means that 17%
of NaOCl content decomposed during storage.
Because of the instability of the conventional aq. NaOCl,
titration is required to determine the exact concentration before
use. On the contrary, the accurate mass of NaOCl·5H2O can be
easily measured using a balance (Figure 3).
3.3. Safety Assessment of NaOCl·5H2O.6 According to
the testing method of explosives based on the Japanese
Industrial Standards (JIS K 4810), the BAM friction test and
the drop hammer test have been applied to the product
(NaOCl·5H2O) (Table 2). The results of both tests were
negative at classification 7 for the BAM friction test and 8 for
the drop hammer test. This means that NaOCl·5H2O is not an
explosive compound under typical conditions.
Differential scanning calorimetry (DSC) has been done at a
heating rate of 5 °C/min contacting with several materials
[stainless (SUS304H), titanium, low-density polyethylene (LD-
PE), high-density polyethylene (HD-PE), and polypropylene
(PP)] in glass ampule, and the results are shown in Figures 4
and 5.
DOI: 10.1021/acs.oprd.7b00288
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Figure 2. Stability of NaOCl·5H2O at several temperatures.

Table 1. Stability of NaOCl·5H2O Crystals and Conventional Table 2. Sensitivity Test of NaOCl·5H2O Based on JIS K
Aq. NaOCl at 7 °C 4810
original test condition result JIS grade
substance concentration concentration 1 year later
friction limiting load: 353 N negative Class 7
NaOCl·5H2O 44.2% 43.7%a (98.9% of the original drop hammer limiting impact energy: 24.5 J negative Class 8
concentration)
aq. NaOCl 13.6% 11.3%b (83.1% of the original
concentration)
a
360 days later. b361 days later. Data are from ref 5.

The sharp peak was observed at 100 °C in DSC

measurement with SUS304H. This result means that stainless
steel reacts with NaOCl·5H2O; thus, stainless vessels cannot be
used as reactors. On the other hand, titanium did not react with
NaOCl·5H2O, and thus the reaction of NaOCl·5H2O can be
performed in titanium vessels as well as glass wares.
The DSC data of NaOCl·5H2O with these resins (LD-PE,
HD-PE, and PP) showed that all of them were not affected by
NaOCl·5H2O at ambient temperatures.

4. OXIDATION OF ALCOHOLS5,7
The synthesis of aldehydes or ketones by oxidation of the
corresponding primary or secondary alcohols is one of the most
important reactions in organic synthesis, and a high number of
methods has been reported.8 However, there are only a few
methods that can be industrially applied, because most of the
existing oxidations have serious drawbacks such as toxic or Figure 4. DSC data with SUS304H and titanium.
explosive property of the oxidants.
The oxidation of alcohols using conventional aq. NaOCl
catalyzed by TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl)9 or They appear to be economically and environmentally benign
AZADO (2-azaadamantane N-oxyl)10 have been reported. methods without the use of a metal catalyst.

Figure 3. Advantage of NaOCl·5H2O crystals on conventional aqueous NaOCl.

1927 DOI: 10.1021/acs.oprd.7b00288

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Table 3. Comparison with NaOCl·5H2O Crystals and

Conventional Aqueous NaOCl

run NaOCl nitroxyl radical (mol %) time (h) yield (%)a

1 NaOCl·5H2O 24 78
2 aq. 13% NaOCl 27 9
3 NaOCl·5H2O TEMPO (1) 1 97
4 aq. 13% NaOCl TEMPO (1) 22 11
5 NaOCl·5H2O TEMPO (0.1) 3 99
6 NaOCl·5H2O 1-Me-AZADO (1) 1 100
7 aq. 13% NaOCl 1-Me-AZADO (1) 24 99
a
Determined by GC analysis using an internal standard method.

Table 4. Effect for Quaternary Ammonium Salts and Acid in

the Presence of TEMPOa

yield of 2-octanone (%)b

X
run (equiv) additive 0.5 h 1h 2h 3h 21 h
Figure 5. DSC data with resins.
1 0.1 0.1 0.1 0.2
(23 h)
However, the process has an inherently poor volume 2 HSO4 40 73 98
efficiency because the concentration of the conventional aq. 0.005
NaOCl solution is up to only 13%. Moreover, at the pH of the 3 Br 0.05 6 14 25 87
conventional aq. NaOCl (about 13), the reactions are very (22 h)
slow; thus, the pH must be lowered (pH 8−9) with aqueous 4 Cl 0.05 3 10 10 73
5 Cl 0.05 NaHSO4·H2O, 19 25 69
sodium hydrogen carbonate (aq. NaHCO3) to increase the 0.05 equiv
rate.9b NaOCl·5H2O is expected to overcome these mentioned 6 Cl 0.05 NaHSO4·H2O, 97 99
drawbacks. 0.05 equiv +
4.1. Optimization of the Reaction Conditions. The H2O, 0.2 mL
oxidations of 2-octanol were initially examined using NaOCl· 7 NaHSO4·H2O, 46 98
0.05 equiv +
5H2O crystals or the conventional aq. 13% NaOCl in H2O, 0.2 mL
dichloromethane (CH2Cl2) in the presence of 5 mol % a
2-octanol (10 mmol), NaOCl·5H2O (12 mmol), TEMPO (0.1
tetrabutylammonium hydrogen sulfate (Bu4NHSO4) without mmol), Bu4NX (0.05−0.5 mmol), CH2Cl2 (30 mL). bYields were
pH adjustment with aq. NaHCO3 in the presence or absence of determined by GC using an internal standard method.
TEMPO or 1-Me-AZADO. The results are summarized in
Table 3. In all cases, the NaOCl·5H2O crystals (runs 1, 3, 5, Table 5. pH of 13% aq. NaOCl (Prepared from NaOCl·
and 6) showed more excellent results than those of the aq. 13% 5H2O) with Quaternary Ammonium Salts
NaOCl (runs 2, 4, and 7).
We first postulated that the role of Bu4NHSO4 was as a 13% aq. NaOCla quaternary ammonium salt pH
phase transfer catalyst; however, it turned out to act as an acid 50 mmol none 11.3
based on the results shown in Tables 4 and 5. As shown in 50 mmol Bu4NHSO4 (2.5 mmol) 9.6
Table 5, the addition of Bu4NHSO4 to the 13% aq NaOCl 50 mmol Bu4NBr (2.5 mmol) 11.4
(prepared from NaOCl·5H2O) dramatically reduced the pH 50 mmol Bu4NCl (2.5 mmol) 11.2
value (9.6). a
Prepared from NaOCl·5H2O and ion-exchanged water.
On the basis of the results, the oxidation effectively occurred
below pH 10. As mentioned below, the use of NaHSO4 in place
of Bu4NHSO4 gave excellent results for the oxidation of 2-
octanol (Scheme 3). use of the solid NaOCl·5H2O crystals dramatically increased
Next, we examined the reaction with concentrated aq. the oxidation (Figure 6). The precise reason is not clear, but it
NaOCl which can be prepared by dissolving NaOCl·5H2O may appear that a high concentration of the primary oxidant
crystals with water. We also confirmed that the concentration of HOCl forms on the surface of the crystalline solid.
a NaOCl solution higher than 20% is stable for a few days for The solvent effects were examined (Table 6), and ethyl
the reaction. However, almost no concentration effect was acetate was found to be as good of a reaction solvent as
observed at 13, 20, and 31% aq. NaOCl. On the other hand, the dichloromethane.
1928 DOI: 10.1021/acs.oprd.7b00288
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Scheme 3. Proposed Mechanism for the TEMPO-Catalyzed Na2SO3 followed by extraction with ethyl acetate and
Oxidation of Alcohols with NaOCl·5H2O (Reproduced with distillation of the residue to produce 2-octanone (23.2 g, 91%
Permission from Ref 5. Copyright 2016 Elsevier) yield).
As an improved method, NaHSO4 was used instead of
Bu4NHSO4. In method A, 2-octanol was dropwise added to the
reaction mixture. In method B, 30% NaOCl prepared from
NaOCl·5H2O was dropwise added to the mixture. Both
methods gave high yields of the desired 2-octanone within 1
h (Scheme 5). NaOCl·5H2O can be used in a slurry or highly
concentrated solution.
4.2. TEMPO-Catalyzed Oxidation of Several Alcohols
with NaOCl·5H2O. The optimized TEMPO-catalyzed oxida-
tion with NaOCl·5H2O was applied to various primary alcohols
(10 mmol) (Table 7). Use of an equimolar amount of NaOCl·
5H2O gave the corresponding aldehydes in good yields. This
optimized method using NaOCl·5H2O gives encouraging
results with TEMPO. It is notable that the reaction of primary
alcohols having a heteroaromatic moiety (pyridine, thiophene)
effectively produced the desired aldehydes.
The oxidations of secondary alcohols were then examined
(Table 8). Both the TEMPO- and 1-Me-AZADO-catalyzed
oxidations of sterically hindered secondary alcohols were
reported to give poor yields of the ketones using the
conventional aq. NaOCl without pH adjustment using aq.
NaHCO3. In contrast, the optimized method using NaOCl·
5H2O gave excellent results with TEMPO even in the reaction
of sterically hindered alcohols (menthol and 2,6-dimethyl-4-
heptanol). Notably, the cheap TEMPO is useful as a catalyst for
the oxidations.
For the oxidation of alcohols using the conventional aq.
NaOCl catalyzed by TEMPO, primary alcohols are known to
be easier and faster oxidized than secondary alcohols.9 Actually,
Figure 6. Reaction of 2-octanol with several concentrations of aqueous the oxidation of an equimolar mixture of a primary alcohol (1-
NaOCl prepared from NaOCl·5H2O crystals and water; NaOCl·5H2O nonanol) and a secondary alcohol (2-nonanol) using the
crystals (○); aq. 31% NaOCl (△); aq. 20% NaOCl (□); aq. 13% conventional aq. NaOCl catalyzed by 4-MeO-TEMPO was
NaOCl (◇) ; conventional aq. 13% NaOCl (×). 2-Octanol (10
mmol), NaOCl·5H2O (12 mmol), Bu4NHSO4 (0.5 mmol), TEMPO
reported to afford 90% nonanal and 10% 2-nonanone in the
(0.1 mmol), CH2Cl2 (30 mL), and appropriate water. literature.9b
Conversely, the reaction of an equimolar mixture of 1-
Table 6. Results for the Oxidation of 2-Octanol in Several octanol and 2-octanol with NaOCl·5H2O in the presence of
Solvents TEMPO provided octanal in 47% yield and 2-octanone in 44%
yield after 0.5 h. The 4-MeO-TEMPO catalyzed reaction
exhibited a similar result (Table 9). Thus, the oxidation rates
for primary and secondary alcohols under these conditions are
not very different.
These results suggest that the reaction mechanism of the
yieldb of 2-octanone (%)
nitroxyl radical catalyzed oxidation of alcohols using NaOCl·
5H2O is different from the oxidation using the conventional aq.
solvent temperature (°C) 1h 2h 3h 4h NaOCl. The oxidation of alcohols with NaOCl·5H2O/
CH2Cl2 5 97 TEMPO/Bu4NHSO4 occurs under acidic to neutral conditions
EtOAc 5 61 97 (Scheme 3 vide supra).5 We proposed a plausible mechanism
C6H5CH3 5 38 90 98 involving intermediate B with hydride transfer (Scheme 6)5
C6H5CF3 5 30 55 87 95 based on the mechanism which was reported by Bobbitt et al.
CH3CN 5 53 54 53 52 as an alternative for the TEMPO oxidation of alcohols under
AcOH r.t. 18 78 90 90 neutral or acidic conditions.11 Taking intermediate B into
a
2-Octanol (10 mmol). bYields were determined by GC using an account, steric hindrance of the bulky secondary alcohols is
internal standard method. likely relaxed, permitting the oxidation to occur. The
interaction between the lone pair of the nitrogen atom and
A large-scale (26.0 g of 2-octanol, 0.2 mol) example of the the hydrogen atom of the hydroxyl group in the alcohol plays
oxidation of 2-octanol was examined in ethyl acetate (Scheme an important role in this reaction mechanism.
4). To maintain the reaction temperature below 20 °C, 2-
octanol was dropwise added for 15 min to a mixture of all 5. OXIDATION OF ORGANOSULFUR COMPOUNDS
reagents cooling in an ice−water bath. After stirring for 45 min 5.1. Selective Oxidation of Sulfides to Sulfoxides.12
at 0−20 °C, the reaction mixture was quenched with aqueous Sulfoxides are important and useful compounds in organic
1929 DOI: 10.1021/acs.oprd.7b00288
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Organic Process Research & Development
Scheme 4. Large-Scale Oxidation of 2-Octanol in Ethyl Acetate
Scheme 5. Solvent-Free Oxidation of 2-Octanol Catalyzed by NaHSO4·H2O
synthesis, because they are frequently used as the intermediates
for the construction of several important organic molecules. In
addition to this, there are many biologically important
compounds containing a sulfoxide moiety. They are mainly
prepared by the oxidation of the corresponding sulfides;
however, it is sometimes difficult to stop the oxidation at the
sulfoxide stage. Consequently, several selective sulfide oxida-
tions have been developed to more effectively synthesize
sulfoxides.13 Although they provide the desired sulfoxides in
high yields, some are accompanied by large amounts of
undesirable waste derived from the oxidants.
As we emphasized in the introduction, NaOCl has several
merits as an environmentally benign oxidant. Despite these
merits, NaOCl has seldom been used for the synthesis of
sulfoxides from sulfides, because it is difficult to selectively
obtain the desired sulfoxides without producing the over-
oxidized sulfone. The use of TEMPO as a catalyst has been
required to obtain the sulfoxides in high yields.14 We expected
that the oxidation of sulfides with NaOCl·5H2O might be an
excellent method for the selective preparation of sulfoxides.
5.1.1. Optimization of the Reaction Conditions. The
reactions of thioanisole with 1.1 equiv of NaOCl (conventional
12 wt % aq. NaOCl solution or NaOCl·5H2O crystals) in
acetonitrile were examined in the absence of a catalyst (Scheme
7). In the case of the NaOCl·5H2O crystals, the desired
sulfoxide was selectively obtained in 18 min. Conversely, the
conventional aq. NaOCl reacted more slowly with the sulfide to
produce the sulfoxide in 79% yield accompanied by a certain
amount of the overoxidized sulfone.
1930
Review
As we described in the previous chapters, the main difference
between NaOCl·5H2O and aq. NaOCl is their pH values.
Therefore, the reactivities of NaOCl·5H2O and conventional
aq. NaOCl were compared while altering the pH with HCl or
NaOH (Table 10). At pH 11, the reaction rapidly proceeded to
selectively afford the desired sulfoxide (runs 1, 2). At pH 13, on
the other hand, the reaction was not complete after 4 h, and a
significant amount of overoxidized sulfone was produced along
with the desired sulfoxide (runs 3, 4). As we had surmised, the
selectivity of this reaction depends on the basicity of the
reaction mixture. These results show that the ideal pH range for
the selective production of the sulfoxide is 10−11.
Although the conventional aqueous NaOCl adjusted to pH
11 with HCl can provide the desired sulfoxide in high yield, as a
practical oxidant, it has some drawbacks (low concentration,
unstable, etc.) as we mentioned in the earlier chapters. In
addition, it is very important to add the correct amount of
oxidant in order to prevent overoxidation during the selective
oxidation of sulfides to the corresponding sulfoxides. However,
during storage of the conventional aq. NaOCl, the NaOCl
concentration gradually decreases, even when it is stored in a
refrigerator. Therefore, titration is required to determine the
exact concentration before use. If a higher concentration of the
NaOCl solution is desired (e.g., 20 wt % NaOCl, as
demonstrated in Table 13 entry 2, for gram-scale synthesis),
it can be prepared from crystalline NaOCl·5H2O and water.
This would be useful in large-scale syntheses due to the need
for a high volume efficiency and reduced wastewater.
DOI: 10.1021/acs.oprd.7b00288
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Table 7. Selective Syntheses of Aldehydes from Primary Table 9. Oxidation of an Equimolar Mixture of 1-Octanol
Alcoholsa and 2-Octanol with NaOCl·5H2O Catalyzed by a Nitroxyl
Radicala

nitroxyl radical time (h) octanal 2-octanone

TEMPO 0.5 47% (2.35 mmol) 44% (2.20 mmol)
4-MeO-TEMPO 1.0 48% (2.40 mmol) 37% (1.85 mmol)
a
Yields were determined by GC using an internal standard method.

Scheme 6. Plausible Reaction Mechanism

a
Substrate: 10 mmol. bYields were determined by GC using an
internal standard method. cTEMPO 10 mol %. d1-Me-AZADO was
used instead of TEMPO.

Consequently, NaOCl·5H2O is much more convenient than
aqueous NaOCl for such applications.
The survey of the solvent effects on the reaction of
thioanisole with NaOCl·5H2O revealed that acetonitrile is
appropriate solvent for this reaction. It selectively provided the
sulfoxide in high yield with a shorter reaction time (run 1)
among the several experimental conditions as shown in Table
11.
The acetonitrile/water ratios were variable to afford similar
results between 5:1 and 50:1 (Table 12). In the absence of

Table 8. Results for the Oxidation of Secondary Alcoholsa

a
All the reactions were performed without pH adjustment using aq. NaHCO3. bYields were determined by GC using an internal standard method.
Numbers in parentheses refer to isolated yields.

1931 DOI: 10.1021/acs.oprd.7b00288

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Scheme 7. Reaction of Thioanisole with NaOCl Table 11. Reaction of Thioanisole (Sulfide) with NaOCl·
5H2O in a Mixture of Various Organic Solvents and Water

1
H NMR ratios (%)
(CH3 protons)
time
run solvent (h) sulfide sulfoxide sulfone
1 CH3CN 0.3 0 98 2
2 CH2Cl2 24 50 43 7
3 CH2Cl2 + 5 mol % Bu4HSO4 3.5 13 68 19
4 EtOAc 24 8 69 23
water (run 5), the reaction did not reach completion even after 5 EtOAc + 5 mol % Bu4NHSO4 3 13 68 19
20 h affording the sulfoxide in an unsatisfactory yield 6 toluene 24 42 4 54
accompanied by a significant amount of the sulfone. Since 7 toluene + 5 mol % Bu4NHSO4 4 38 7 55
NaOCl·5H2O crystals are hard to dissolve in pure acetonitrile,
the reaction proceeds very slowly. Table 12. Optimization for the Ratio of Acetonitrile to
5.1.2. Selective Synthesis of Sulfoxides from the Reaction Water
of Sulfides with NaOCl·5H2O. The optimized oxidation of
sulfides with 1.1 equiv of NaOCl·5H2O in aqueous acetonitrile
was used for the synthesis of various sulfoxides (Table 13). The
desired sulfoxides were selectively obtained in high yields in all
cases. It is notable that an alkene moiety (entry 6) and a
pyridine ring (entry 12) were inert under these reaction 1
H NMR ratios (%)
conditions. (CH3 protons)
5.2. Efficient Synthesis of Sulfones from Sulfides.15 run CH3CN:H2O (v/v) time sulfide sulfoxide sulfone
Synthetic studies of the sulfone by the oxidation of sulfides with
1 5:1 15 min 0 98 2
NaOCl·5H2O and conventional aq. NaOCl were examined.
2 10:1 15 min 3 96 1
Under similar conditions to sulfoxide synthesis, using 2.4 equiv
3 20:1 15 min 2 97 1
of NaOCl·5H2O gave the desired sulfone in 78% yield along
4 50:1 15 min 3 96 1
with α-chlorinated compounds. After the solvent survey, 5 100:0 20.5 h 20 72 8
aromatic hydrocarbons were found to be optimal solvents to
give excellent results as shown in Table 14.
The reaction of several sulfides with 13 wt % NaOCl with hypochloric acid to form the chlorinated byproducts. On
prepared from NaOCl·5H2O and water in toluene produced the other hand, alkali species are hard to dissolve in nonpolar
the desired sulfones in good yields in most cases (Table 15). organic phase containing reactants and products; therefore,
A plausible reaction mechanism is shown in Scheme 8. The productions of the chlorinated byproducts are suppressed.
sulfur atom of sulfide is chlorinated by hypochloric acid, and 5.3. Synthesis of Sulfonyl Chlorides from Disulfides or
the chlorine atom of A is substituted for oxygen to form the Thiols.16 Sulfonyl chlorides are very important compounds in
sulfoxide. The sulfur atom of the sulfoxide is similarly oxidized organic synthesis as precursors to sulfonic esters, sulfonamides,
to produce the sulfone. In polar solvents, alkali species readily sulfonic anhydrides, sulfonic hydrazide, sulfonyl azide, and so
dissolve in the reaction mixture and cause α-deprotonation of forth. The representative method for the preparation of sulfonyl
sulfoxides and/or sulfones. The resulting α-carbanions react chlorides is the oxidative chlorination of disulfides or thiols.17

Table 10. Reactivity of NaOCl·5H2O and Conventional Aqueous NaOCl Solutions

1
H NMR ratios (%) (CH3 protons)
run NaOCl pH time sulfide sulfoxide sulfone
1 prepared from NaOCl·5H2O 11 20 min 1 99 0
2 conventional aqueous solution + HCl 11 20 min 0 97 3
3 prepared from NaOCl·5H2O + NaOH 13 4h 18 66 16
4 conventional aqueous solution 13 4h 5 79 16
5 prepared from NaOCl·5H2O + HCl 10 20 min 1 98 1
6 prepared from NaOCl·5H2O + HCl 9 20 min 8 88 4
7 prepared from NaOCl·5H2O + HCl 8 4h 37 8 55
8 prepared from NaOCl·5H2O + HCl 7 4h 38 7 55

1932 DOI: 10.1021/acs.oprd.7b00288

Org. Process Res. Dev. 2017, 21, 1925−1937
Organic Process Research & Development Review

Table 13. Reaction of Sulfides with NaOCl·5H2O in Table 15. Synthesis of Sulfones from Sulfides
Aqueous Acetonitrile

a
Sulfide (10 mmol), toluene (30 mL). bSulfide (10 mmol), toluene
(10 mL). c1 mol % of (C8−10)3NMeCl was used. dAccompanied with
the sulfoxide (partially oxidized compound) (41%). eGC yield by using
an internal standard. fIsolated yield.

Scheme 8. Plausible Reaction Mechanism for the Oxidation

of Sulfides to Sulfoxides and Sulfones

a
CH3CN (10 mL) and H2O (2 mL) were used. bThioanisole (2.48 g,
20 mmol), aqueous 20.6% NaOCl (7.59 g, 21 mmol) from NaOCl·
5H2O, and CH3CN (100 mL) were used. A water bath (ca. 20 °C)
was used to control the reaction temperature for a gram-scale
synthesis. cDichloromethane was added to dissolve the sulfide in the
solvent. Bu4NHSO4 (0.05 equiv) was also added.

Many reagents are proposed though there are some issues such
as being toxic, hazardous, explosive, or relatively expensive.
An environmentally benign and economical preparation
method of sulfonyl chloride is therefore in great demand. We
expected that NaOCl·5H2O could oxidize and chlorinate
disulfides or thiols to effectively form the corresponding
sulfonyl chlorides.18
5.3.1. Optimization of the Reaction Conditions. A search chloride, 5 equiv of HOCl is necessary based on the following
for the appropriate solvent found only acetic acid (Table 16). experiment. The mechanism is assumed in the original
To occur the oxidative chlorination from disulfide to sulfonyl document.16

Table 14. Solvent Effect for the Oxidation of Thioanisole by NaOCla

GC area %b
run solvent time (h) sulfoxide sulfone chloromethyl sulfoxide chloromethyl sulfone
1 acetonitrile 6 8 78 5 9
2 toluene 6 0 99 <1 <1
3c toluene 3 3 94 0 2
4 chlorobenzene 4 0 99 <1 <1
5 2-chlorotoluene 2 0 98 0 1
6 dichloromethane 6 36 62 1 <1
7 ethyl acetate 2 0 63 36 1

a
Thioanisole (10 mmol), solvent (30 mL). bMain impurities are chloromethylphenyl sulfoxide and chloromethylphenyl sulfone, which were
identified by GC-MS. c1 mol % of (C8−10)3NMeCl was added.

1933 DOI: 10.1021/acs.oprd.7b00288

Org. Process Res. Dev. 2017, 21, 1925−1937
Organic Process Research & Development Review

Table 16. Reaction of Di-p-tolyl Disulfide with NaOCl·5H2O Table 18. Reaction of Disulfides with NaOCl·5H2O in AcOH
in Several Solvents

entry R time isolated yield (%)

1 p-Tol 1.1 h 80
run solvent NaOCl·5H2O (equiv) time (h) yield (%) 2 p-Tol 1 min 99a
1 CH3OH 8.5 3.0 35 (X = OCH3)a 3 Ph 0.6 h 63
2 C2H5OH 18.5 7.7 13 (X = OC2H5)a 4 p-MeOC6H4 0.5 h 84
3 t-BuOH 6.5 0.5 33 (X = CI)a,b 5 p-ClC6H4 0.3 h 74
4 CH3CN 6.5 1.0 14 (X = CI)a 6 PhCH2 0.4 h 75
5 AcOH 5.0 1.1 80 (X = C1)a,c 7 cyclohexyl 0.2 h 97
a
6 CH2Cl2 6.5 16.7 27 (X = CI)d GC area %.
7 toluene 6.5 16.7 29 (X = CI)d
a
The starting material completely disappeared, and no other product Thus, treatment of the disulfide with NaOCl·5H2O (5 equiv) in
was obtained. bAt 30 °C. cAt room temperature. dPart of the starting acetic acid, which was monitored by GC analysis, revealed that
material remained. the reaction was immediately completed, and 99% of the
disulfide was converted to the corresponding sulfonyl chloride
The generation of hypochloric acid (HOCl) from NaOCl within 1 min (entry 2).
and acetic acid might be crucial for the production of sulfonyl Next, several thiols were treated with NaOCl·5H2O in acetic
chlorides in this reaction based on a further investigation acid at room temperature (Table 19). According to the
(Table 17). Both NaOCl·5H2O and aqueous NaOCl are
Table 19. Reaction of Thiols with NaOCl·5H2O in AcOH
Table 17. Reaction of Diphenyl Disulfide with NaOCl under
Several Conditionsa

entry R isolated yield (%)

1 p-Tol 86
time GC yieldb 2 Ph 79
run solvent NaOCl additive (h) (%)
3 p-MeOC6H4 97
1 AcOH NaOCl·5H2O 0.5 80 4 p-ClC6H4 90
2 AcOH aq. 12% NaOCI 0.5 80 5 PhCH2 71
3 BTF NaOCl·5H2O AcOH 0.5 87 6 cyclohexyl 95
(6.75 equiv)
4 BTF NaOCl·5H2O 5 2c
5 BTF NaOCl·5H2O Bu4NBr 1 43d
(0.05 equiv) mechanism described in the previously published communica-
6 BTF NaOCl·5H2O Bu4NHSO4 0.5 47d tion, 4 equiv of NaOCl·5H2O was required for the completion
(0.05 equiv)
of the reaction. The exothermic reactions went to completion
7 BTF aq. 12% NaOCI Bu4NBr 0.5 17d
(0.05 equiv) immediately to form the corresponding sulfonyl chloride in
a high yields.19
Diphenyl disulfide (3.0 mmol), NaOCI (15.0 mmol), solvent (33
mL). bGC yield using an internal standard. cMost of the diphenyl
Similar to the reaction of disulfides, hypochloric acid derived
disulfide was unreacted. dSodium benzenesulfonate was accompanied from NaOCl acts as an electrophilic chlorinating agent of sulfur
as a byproduct. atoms.
5.4. Synthesis of Sulfonyl Bromides from Disulfides or
Thiols.20 Our extensive study of the oxidative chlorination was
equally effective for the synthesis of benzenesulfonyl chloride in next attempted for bromination. Sulfonyl bromides may be
acetic acid (runs 1, 2). Acetic acid is not a very favorable solvent favorable reagents for the synthesis of sulfone amides over
for large-scale synthesis; thus, we used a minimum amount of sulfonyl chlorides. It is well-known that hypochlorite (OCl−)
acetic acid in water as an immiscible solvent. The reaction of reacts with the bromoanion (Br−) to produce hypobromite
diphenyl disulfide with NaOCl·5H2O in (trifluoromethyl)- (OBr−).21 On the basis of the plausible reaction mechanism
benzene (benzotrifluoride, BTF) in the presence of acetic acid shown as Scheme 9, it is expected that the reactions of
(6.75 equiv) also efficiently produced the desired product in disulfides or thiols with NaOCl·5H2O in acetic acid in the
high yield (run 3). presence of excess amounts of sodium bromide (NaBr)
Although both NaOCl·5H2O and aq. NaOCl are equally produce the corresponding sulfonyl bromide.
available for the synthesis of sulfonyl chlorides, NaOCl·5H2O is
easier to use than the aqueous NaOCl as we described in the
Scheme 9. Synthesis of Sulfonyl Bromide
previous chapters.
5.3.2. Example for the Reaction of Disulfides or Thiols to
Sulfonyl Chloride. The reaction of several disulfides with
precisely 5 equiv of NaOCl·5H2O in acetic acid at room
temperature was undertaken, and the corresponding sulfonyl
chlorides were obtained in high yields in all cases19 (Table 18).
The oxidative chlorinations were actually quickly completed.
1934 DOI: 10.1021/acs.oprd.7b00288
Org. Process Res. Dev. 2017, 21, 1925−1937
Organic Process Research & Development Review

The addition of several disulfide or thiols to a mixture of crystals as oxidants (Scheme 11).26,28 The reaction of β-(2-
NaOCl·5H2O and NaBr in acetic acid resulted in the formation hydroxyphenyl)-carboxylic acids with 1.1 equiv of NaOCl·
of the corresponding sulfonyl bromides (Tables 20 and 21).22 5H2O provided the desired spirolactones in good yields.

Table 20. Synthesis of Sulfonyl Bromides from Disulfides Scheme 11. Oxidative Dearomatization of Phenols by
NaOCl·5H2O

entry R time (min) yield (%)

1 p-Tol 80 85
2 p-MeOC6H4 30 62
3 p-ClC6H4 40 73 The present method is not limited to only the spirolacto-
4 cyclohexyl 40 92 nization of β-(2-hydroxyphenyl) carboxylic acids. The reaction
5 CH3(CH2)9 10 79 of various phenols gave the corresponding oxidized compounds
in high yields (Scheme 12).
Table 21. Synthesis of Sulfonyl Bromides from Disulfides
Scheme 12. NaOCl·5H2O-Mediated Oxidation of Various
Phenols

entry R time (min) yield (%)

1 Ph 50 quant
2 p-tol 42 91
3 p-MeOC6H4 27 quant
4 p-ClC6H4 40 61
5 cyclohexyl 27 quant

6. MISCELLANEOUS REACTIONS
6.1. Synthesis of Davis Oxaziridines.23 Davis oxazir-
idines (N-sulfonyloxaziridines) are important reagents in
synthetic organic chemistry and can be used as oxidizing and
electrophilic amination reagents.24,25 They are generally
prepared by the oxidation of the corresponding imines, and
several oxidants have been used for this purpose.
We found that Davis oxaziridines can be synthesized by the
oxidation of the corresponding N-sulfonylimines with aq.
NaOCl prepared from NaOCl·5H2O in acetonitrile without any
catalysts.23 In this oxidation, a basic condition (pH = 13) and
excess amount of NaOCl are required to obtain the products in
high yields (Scheme 10).

Scheme 10. Synthesis of Oxaziridines

In this reaction, NaOCl·5H2O provided a better result than

the conventional aq. NaOCl (Table 22). The high chemo-
selectivity of NaOCl·5H2O might be due to its lower pH value.

Table 22. Reaction of Phenol with NaOCl·5H2O or Aq.

NaOCl

6.2. Oxidative Dearomatization of Phenols.26 The

oxidative dearomatization of phenols and their analogues has NaOCl yield (%)
been a useful synthetic method and has been used for the NaOCl·5H2O 92
syntheses of natural products or biologically active com- conventional aq. NaOCl (ca. 10 wt %) 74a
pounds.27 Recently, Ishihara, Uyanik, and colleagues reported
a
the oxidative dearomatization of phenols using NaOCl·5H2O Accompanied with byproducts.

1935 DOI: 10.1021/acs.oprd.7b00288

Org. Process Res. Dev. 2017, 21, 1925−1937
Organic Process Research & Development Review

7. CONCLUSIONS (6) Unpublished results. The details of the experimental results are
shown in the Supporting Information of this review.
NaOCl·5H2O crystals have several advantages over the (7) Okada, T.; Asawa, T.; Sugiyama, Y.; Kirihara, M.; Iwai, T.;
conventional aq. NaOCl as shown in Table 23. These Kimura, Y. Synlett 2014, 25, 596−598.
advantages can make NaOCl·5H2O a useful oxidant for organic (8) (a) Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 16, 2647−
synthesis as shown in this review. 2650. (b) Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1979, 20, 399−
402. (c) Mancuso, A. J.; Huang, S. L.; Swern, D. J. Org. Chem. 1978,
Table 23. Advantages of NaOCl·5H2O over Conventional 43, 2480−2482. (d) Corey, E. J.; Kim, C. U. J. Am. Chem. Soc. 1972,
aq. NaOCl 94, 7586−7587. (e) Corey, E. J.; Kim, C. U. Tetrahedron Lett. 1973,
14, 919−922. (f) Nishide, K.; Ohsugi, S.; Fudesaka, M.; Kodama, S.;
conventional aq. Node, M. Tetrahedron Lett. 2002, 43, 5177−5179. (g) Griffith, W. P.;
features NaOCl NaOCl·5H2O Ley, S. V.; Whitcombe, G. P.; White, A. D. J. Chem. Soc., Chem.
merit oxidation performance standard strong Commun. 1987, 1625−1627. (h) Keck, G. E.; Knutson, C. E.; Wiles, S.
volumetric efficiency low high (3 times) A. Org. Lett. 2001, 3, 707−710. (i) Myers, A. G.; Zhong, B.;
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wt % (available (9) (a) de Nooy, A. E. J.; Besemer, A. C.; Bekkum, H. V. Synthesis
chlorine wt %) 1996, 1996, 1153−1176. (b) Anelli, P. L.; Biffi, C.; Montanari, F.;
convenience stability suffers from stable during Quici, S. J. Org. Chem. 1987, 52, 2559−2562.
decomposition cold storage (10) (a) Shibuya, M.; Tomizawa, M.; Suzuki, I.; Iwabuchi, Y. J. Am.
(<7 °C)
Chem. Soc. 2006, 128, 8412−8413. (b) Iwabuchi, Y. Yuki Gosei Kagaku
titration before using necessary not required
Kyokaishi 2008, 66, 1076−1084.
hazardous nature nonexplosive nonexplosive (11) (a) Bobbitt, J. M. TCIMAIL; Tokyo Chemical Industry Ltd.,
properties pH 13 11 No. 146, April 2010; pp 2−14. (b) Bailey, W. F.; Bobbitt, J. M.;
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appearance yellow liquid yellow crystals (12) Okada, T.; Matsumuro, H.; Kitagawa, S.; Iwai, T.; Yamazaki, K.;
Kinoshita, Y.; Kimura, Y.; Kirihara, M. Synlett 2015, 26, 2547−2552.

■
(13) (a) Drabowicz, J.; Kielbsinski, P.; Mikolajczyk, M. The Chemistry
of Sulphone and Sulfoxide; Patai, S., Rappoport, Z., Stirling, C., Eds.;
ASSOCIATED CONTENT John Wiley and Sons: New York, 1988. (b) Carreno, M. C. Chem. Rev.
*
S Supporting Information 1995, 95, 1717−1760. (c) Fernandez, I.; Khiar, N. Chem. Rev. 2003,
The Supporting Information is available free of charge on the 103, 3651−3706. (d) Drabowicz, J.; Kielbasinski, P.; Zajac, A.; Wach-
ACS Publications website at DOI: 10.1021/acs.oprd.7b00288. Panfitow, P. Comprehensive Organic Synthesis, 2nd ed.; Knochel, P.,
Experimental details of hazard estimation of sodium Molander, G. A., Eds.; Elsevier: Amsterdam, 2014; Vol. 6, pp 131−
174. (e) Wu, R.; Wu, J.; Yu, M.; Zhu, L. RSC Adv. 2017, 7, 44259−
hypochlorite pentahydrate (PDF)

■
44264. (f) Dai, W.; Shang, S.; Lv, Y.; Li, G.; Li, C.; Gao, S. ACS Catal.
2017, 7, 4890−4895. (g) Li, Z.; Liu, C.; Abroshan, H.; Kauffman, D.
AUTHOR INFORMATION R.; Li, G. ACS Catal. 2017, 7, 3368−3374. (h) Gan, S.; Yin, J.; Yao, Y.;
Corresponding Authors Liu, Y.; Chang, D.; Zhu, D.; Shi, L. Org. Biomol. Chem. 2017, 15,
*E-mail (Masayuki Kirihara): kirihara.masayuki@sist.ac.jp. 2647−2654. (i) Zhang, Z.; Yang, X.; Zhang, Q.; Wang, L.; He, M.;
*E-mail (Yoshikazu Kimura): kimura.yoshikazu@iharanikkei. Chen, Q.; Huang, X. RSC Adv. 2016, 6, 104036−104040. (j) Doherty,
co.jp. S.; Knight, J. G.; Carroll, M. A.; Clemmet, A. R.; Ellison, J. R.;
Backhouse, T.; Holmes, N.; Thompson, L. A.; Bourne, R. A. RSC Adv.
ORCID 2016, 6, 73118−73131. (k) Casado-Sanchez, A.; Gomez-Ballesteros,
Masayuki Kirihara: 0000-0002-3400-6377 R.; Tato, F.; Soriano, F. J.; Pascual-Coca, G.; Cabrera, S.; Aleman, J.
Notes Chem. Commun. 2016, 52, 9137−9140. (l) Baig, N.; Madduluri, V. K.;
The authors declare no competing financial interest. Sah, A. K. RSC Adv. 2016, 6, 28015−28022. (m) Lang, X.; Zhao, J.;

■
Chen, X. Angew. Chem., Int. Ed. 2016, 55, 4697−4700. (n) Zhao, G.;
ACKNOWLEDGMENTS Tan, R.; Zhang, Y.; Luo, X.; Xing, C.; Yin, D. RSC Adv. 2016, 6,
24704−24711. (o) Tabrizian, E.; Amoozadeh, A.; Rahmani, S. RSC
We grateful to Dr. Hideyuki Tsutsui and Mr. Hideo Shimazu Adv. 2016, 6, 21854−21864. (p) Dai, W.; Mi, Y.; Lv, Y.; Chen, B.; Li,
(Nippon Light Metal Co. Ltd.) for their useful suggestions.

■
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1937 DOI: 10.1021/acs.oprd.7b00288

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