An efficient method for the preparation of sulfonyl chlorides: Reaction of disulfides or thiols with sodium hypochlorite pentahydrate (NaOCl·5H2O) crystals

Article abstract of DOI:10.1246/cl.140899

The reaction of disulfides or thiols with sodium hypochlorite pentahydrate in acetic acid efficiently provided the corresponding sulfonyl chlorides in high yields.

Full text of DOI:10.1246/cl.140899

Received: September 26, 2014 | Accepted: November 7, 2014 | Web Released: November 18, 2014
CL-140899
An Efficient Method for the Preparation of Sulfonyl Chlorides:
Reaction of Disulfides or Thiols with Sodium Hypochlorite
Pentahydrate (NaOCl¢5H2O) Crystals
Tomohide Okada,1 Hiroaki Matsumuro,2 Toshiaki Iwai,2 Saori Kitagawa,2 Kento Yamazaki,2 Tomomi Akiyama,2
Tomotake Asawa,1 Yukihiro Sugiyama,3 Yoshikazu Kimura,4 and Masayuki Kirihara*2
1R&D Department of Chemicals, Nippon Light Metal Company, Ltd., 480 Kambara, Shimizu-ku, Shizuoka 421-3203
2Department of Materials and Life Science, Shizuoka Institute of Science and Technology,
2200-2 Toyosawa, Fukuroi, Shizuoka 437-8555
3Market Development Department, Nippon Light Metal Company, Ltd.,
2-2-20 Higashi-shinagawa, Shinagawa-ku, Tokyo 140-8628
4Research and Development Department, Iharanikkei Chemical Industry Co., Ltd.,
5700-1 Kambara, Shimizu-ku, Shizuoka 421-3203
(E-mail: kirihara@ms.sist.ac.jp)
O
O
The reaction of disulfides or thiols with sodium hypochlorite
pentahydrate in acetic acid efficiently provided the correspond-
ing sulfonyl chlorides in high yields.
OH
NaOCl 5H2O (1.1−1.6 equiv)
R
R
H
R
R
H
TEMPO (1 mol%),
Bu4NHSO4 (5 mol%)
OH
CH2Cl2, 5 °C−rt
R'
R'
Sulfonyl chlorides are very important compounds in organic
synthesis as precursors to sulfonic esters, sulfonamides, sulfonic
anhydrides, sulfonic hydrazide, sufonyl azide, etc. One of the
most practical methods for the preparation of sulfonyl chlorides
is the oxidative chlorination of disulfides or thiols, and several
reactions have been developed using a variety of chlorinating
agents: chlorine-acetic acid,1 aqueous chlorine,2 potassium
nitrate-sulfuryl chloride,3 hydrochloric acid-chlorine,4 hydro-
chloric acid-N-chlorosuccinimide,5 hydrogen peroxide-zirco-
nium tetrachloride,6 hydrogen peroxide-thionyl chloride,7
OxoneTM-thionyl chloride,8 potassium nitrate-chlorotrimethyl-
silane,9 trichlorocyanuric acid-benzyltrimethylammonium chlo-
ride,10 N-chlorosuccinimide-tetra-t-butylammonium chloride,11
and N-chlorosuccinimide.12 Although these reagents are useful,
some are toxic and hazardous (chlorine, sulfuryl chloride,
bromine, and thionyl chloride), explosive (potassium nitrate and
hydrogen peroxide), or relatively expensive (N-chlorosuccin-
imide, cyanuric chloride, chlorotrimethylsilane, trichlorocyanu-
ric acid, and benzyltrimethylammonium chloride). An environ-
mentally benign and economical preparation method of sulfonyl
chloride is therefore in great demand.
We have recently developed a new manufacturing process
for sodium hypochlorite pentahydrate (NaOCl¢5H2O) crystals,
whose use in chemical reactions has several advantages over
the conventional aqueous NaOCl solution (ca. 12 wt % NaOCl,
pH 13): (1) the available chlorine content is about 42%, (2) the
pH upon dissolution is around 11 (the solution contains less than
0.08 wt % hydroxide ions), (3) the crystals are much more stable
than aqueous NaOCl below ambient temperature,13 and (4) the
simple weighting of the desired amount of reagent is possible
because of the crystals. Nowadays, NaOCl¢5H2O is commer-
cially available from several companies.14 For an example of
application to organic synthesis using NaOCl¢5H2O, we have
explored that primary and secondary alcohols could be oxidized
to the corresponding aldehydes and ketones with NaOCl¢5H2O
in the presence of catalytic amounts of TEMPO (2,2,6,6-
tetramethylpiperidinium oxy radical) and tetrabutylammonium
Scheme 1. Oxidation of alcohols with NaOCl¢5H2O catalyzed by
TEMPO and Bu4NHSO4.
O
O
NaOCl 5H2O
S
R
or
SH
R
S
R
S
R
Cl
Scheme 2. Our attempts to synthesize sulfonyl chlorides from
reactions of disulfides or thiols with NaOCl¢5H2O.
hydrogen sulfate (Scheme 1).15 This method does not require pH
adjustment and is applicable to sterically hindered secondary
alcohols.
Based on this, we have expected that NaOCl¢5H2O could
oxidize and chlorinate disulfides or thiols to effectively form the
corresponding sulfonyl chlorides (Scheme 2).
At first, solvent effects have been investigated by the
reaction of di-p-tolylsulfide (1a) with NaOCl¢5H2O in several
relatively polar solvents. After the disulfides disappeared from
the thin layer chromatography (TLC), saturated aqueous sodium
thiosulfate was added, and the products were extracted with
dichloromethane (Table 1, Runs 1-5). The desired sulfonyl
chloride 2a was provided in t-butanol, acetonitrile, and acetic
acid (AcOH) (Runs 3-5). Except for the case of AcOH,
the yields of 2a were relatively low (less than 50%). The
corresponding sulfonyl esters (2¤a and 2¤¤a) were obtained in
methanol or ethanol in low yields (Runs 1 and 2). Interestingly,
the sulfonyl chloride or sulfonyl esters were the sole products,
and any other compounds, including the starting material 1a,
were not obtained at all. It is estimated that another compounds
which were produced from the reaction of 1a with NaOCl¢5H2O
are soluble in water and hard to be extracted with dichloro-
methane.
In less polar solvents such as dichloromethane or toluene,
the reaction proceeded very slowly, and parts of the unreacted 1a
remained after 16 h (Runs 6 and 7).
Chem. Lett. 2015, 44, 185–187 | doi:10.1246/cl.140899
© 2015 The Chemical Society of Japan | 185

Table 1. Reaction of 1a with NaOCl¢5H2O in several solvents
Table 3. Reaction of disulfides with NaOCl¢5H2O in AcOH
O
O
2a (X=Cl)
2'a (X=OCH3)
2"a (X=OC2H5)
O
O
NaOCl 5H2O
2
Solvent
S
p-Tol
(5.0 equiv)
S
R
NaOCl 5H2O
AcOH, r.t.
Isolated
p-Tol
S
S
2
S
R
S
p-Tol
X
1a
R
Cl
1
0 °C
r.t.
2
NaOCl¢5H2O
/equiv
Time
/h
Product
Isolated yield/%
Time
/h
Time Isolated
/h
R
R
Run
Solvent
yield/%
yield/%
1
2
3
4
5
6
7
CH3OH
C2H5OH
t-BuOH
CH3CN
AcOH
8.5
18.5
6.5
6.5
5.0
3.0
7.7
0.5
1.0
1.1
35 (X = OCH3)a
13 (X = OC2H5)a
33 (X = Cl)a
14 (X = Cl)a
80 (X = Cl)a
27 (X = Cl)b
29 (X = Cl)b
1.1
0.6
80
0.3
74
Me
Cl
63
84
0.4
0.2
75
97
CH2Cl2
toluene
6.5
6.5
16.7
16.7
0.5
MeO
aThe starting material 1a was completely disappeared, and no other
product was obtained. Parts of the starting material 1a remained.
b
O
S
2nd
Cl
S
Cl OH
+
HOCl
+ H
1st
- HCl
R
S
R
R
S
R
S
Table 2. Reaction of 1b with “NaOCl” in several conditions
+
R
S
R
- HCl
- H O
2
- H
B
1
A
Disulfide
O
O
"NaOCl" (5 equiv)
2
Solvent, r.t.
OH
2
S
Ph
O
Ph
S
Cl OH
4th
O
S
O
Path A
Ph
Cl
S
1b
-H O
2
2
Cl
OH
2b
O
O
R
Cl
S
E
3rd
2
R
OH
+
+
Cl
Time GC-Yielda
+H
-H O
S
R
S
R
-H
Sulfonyl Chloride
R
S
S
Run Solvent “NaOCl”
Additive
2
R
- H
/h
/%
+
C
H O
2
O
O
- HCl
O
Cl OH
5th
+H
-H O
Cl
1
2
3
AcOH
AcOH
BTF
NaOCl¢5H2O
aq. 12% NaOCl
NaOCl¢5H2O
®
®
0.5
0.5
0.5
80
80
87
O
+
S
Cl
Cl
OH
S
R
R
2
AcOH
F
2
Path B
(6.75 equiv)
®
Cl OH
4th
-
O
O
BTF
BTF
NaOCl¢5H2O
NaOCl¢5H2O
5
1
2b
43c
Cl
Cl
O
4
5
+
- HCl
S
R
S
+ H
R
S
S
Bu4NBr
Cl
+
R
S
+
- H
R
Cl
- H O
R
Cl
2
+H
-H O
G
(0.05 equiv)
Bu4NHSO4
(0.05 equiv)
Bu4NBr
H
Cl
HO
3rd
D
Cl OH
5th
2
OH
+
2
6
7
BTF
BTF
NaOCl¢5H2O
0.5
0.5
47c
17c
+
O
O
S
O
+ H
- HCl
+
- H O
2
S
2
2
- H
OH
aq. 12% NaOCl
2
R
Cl
R
Cl
(0.05 equiv)
Cl
Sulfonyl Chloride
aGC-yield using an internal standard. bMost of 1b was unreacted.
cSodium benzenesulfonate was accompanied as the by-product.
Scheme 3. A plausible reaction mechanism of 1 with NaOCl¢5H2O
in AcOH.
To investigate the effect of acetic acid on this reaction,
diphenyl disulfide (1b) was reacted with 5 equiv of either
NaOCl¢5H2O or aqueous NaOCl (12 w/w%) under a variety of
conditions as shown in Table 2. Both NaOCl¢5H2O and aqueous
NaOCl are equally effective in the synthesis of benzene sulfonyl
chloride when acetic acid is used as the solvent at room
temperature (Runs 1 and 2). The reaction of 1b with NaOCl¢
5H2O in (trifluoromethyl)benzene (benzotrifluoride, BTF) in the
presence of acetic acid (6.75 equiv) also efficiently produced the
desired product in high yield (Run 3). Conversely, the reaction
did not proceed in BTF in the absence of acetic acid because of
the solubility problem of NaOCl¢5H2O (Run 4). Therefore, we
then examined the reactions of NaOCl¢5H2O in BTF without
AcOH in the presence of a phase-transfer catalyst (tetrabutyl-
ammonium bromide or tetrabutylammonium hydrogen sulfate)
(Runs 5-7). Although the reaction went to completion in 0.5-
1 h, 2b was obtained in less than 50% yield accompanied by
sodium benzenesulfonate as the by-product.16
Although both NaOCl¢5H2O and aqueous NaOCl solution
are equally available for the synthesis of sulfonyl chlorides,
NaOCl¢5H2O is easier to use than aqueous NaOCl. As a
chemical property, the process using NaOCl¢5H2O has inher-
ently volume efficiency than that of aqueous NaOCl (available
chlorine contents: 42% vs 12%), which might be an important
factor in large-scale synthesis. Secondly, since aqueous NaOCl
is not particularly stable, it is difficult to be certain of the exact
concentration in absent from titration. On the other hand,
because NaOCl¢5H2O is crystalline, simply weighting the
desired amount of the reagent is possible.
Therefore, the reaction of several disulfides with precisely
5 equiv of NaOCl¢5H2O in acetic acid at room temperature was
undertaken next, and the corresponding sulfonyl chlorides were
obtained in high yields in all cases (Table 3).17
A plausible reaction mechanism is shown in Scheme 3.
NaOCl in AcOH is converted to hypochloric acid (HOCl),
which chlorinates a disulfide-sulfur atom. Water attacks the
sulfur atom of sulfonium ion (A) to form the thiosulfinate (B)
with HCl elimination.
These results suggest that the generation of hypochloric acid
(HOCl) from NaOCl and acetic acid is crucial for the production
of sulfonyl chlorides from disulfides with a satisfactory isolated
yield.
A second hypochloric acid then reacts with B via a similar
mechanism to produce an equilibrium mixture of the disulfoxide
186 | Chem. Lett. 2015, 44, 185–187 | doi:10.1246/cl.140899
© 2015 The Chemical Society of Japan

Table 4. Reaction of thiols with NaOCl¢5H2O in AcOH
References and Notes
1
2
3
a) I. Douglass, B. Farah, J. Org. Chem. 1958, 23, 330. b) I. B.
Douglass, B. S. Farah, E. G. Thomas, J. Org. Chem. 1961, 26, 1996.
R. J. Watson, D. Batty, A. D. Baxter, D. R. Hannah, D. A. Owen, J. G.
Montana, Tetrahedron Lett. 2002, 43, 683.
a) Y. J. Park, H. H. Shin, Y. H. Kim, Chem. Lett. 1992, 1483. b) Y.
Gareau, J. Pellicelli, S. Laliberté, D. Gauvreau, Tetrahedron Lett.
2003, 44, 7821.
O
O
NaOCl 5H2O (4.0 equiv)
r.t.
S
R
SH
R
Cl
AcOH,
3
2
Time
/min
Isolated
yield/%
Time Isolated
R
R
/min
yield/%
86
79
90
1
1
1
4
A. Meinzer, A. Breckel, B. A. Thaher, N. Manicone, H.-H. Otto, Helv.
Chim. Acta 2004, 87, 90.
Me
Cl
5
6
7
8
A. Nishiguchi, K. Maeda, S. Miki, Synthesis 2006, 4131.
K. Bahrami, M. M. Khodaei, M. Soheilizada, Synlett 2009, 2773.
J. Humljan, S. Gobec, Tetrahedron Lett. 2005, 46, 4069.
a) R. N. Reddie, Synth. Commun. 1987, 17, 1129. b) L. Kværnø, M.
Werder, H. Hauser, E. M. Carreira, Org. Lett. 2005, 7, 1145.
G. K. S. Prakash, T. Mathew, C. Panja, G. A. Olah, J. Org. Chem.
2007, 72, 5847.
1
1
71
95
1
97
MeO
9
10 H. Veisi, A. Sedrpoushan, S. Hemmati, D. Kordestani, Phosphorus,
Sulfur Silicon Relat. Elem. 2012, 187, 769.
11 H. Veisi, R. Ghorbani-Vaghei, S. Hemmati, J. Mahmoodi, Synlett
2011, 2315.
O
O
S
p-Tol
S
p-Tol
S
p-Tol
Cl
NaOCl 5H2O
(11.4 mmol)
1.0 mmol
81% (3.24 mmol)
12 M. Kirihara, S. Naito, Y. Nishimura, Y. Ishizuka, T. Iwai, H.
Takeuchi, T. Ogata, H. Hanai, Y. Kinoshita, M. Kishida, K. Yamazaki,
T. Noguchi, S. Yamashoji, Tetrahedron 2014, 70, 2464.
p-Tol SH
2.0 mmol
S
p-Tol
AcOH, 1 min
rt
p-Tol
S
trace
13 T. Asawa, T. Tsuneizumi, Y. Iwasaki, JP 4211130, 2008.
14 NaOCl¢5H2O is commercially available from Wako Pure Chemical
Industries and Junsei Chemical Co. Large quantity of NaOCl¢5H2O
can be directly supplied by Nippon Light Metal Company.
15 T. Okada, T. Asawa, Y. Sugiyama, M. Kirihara, T. Iwai, Y. Kimura,
Synlett 2014, 25, 596.
Scheme 4. A reaction of NaOCl¢5H2O with a mixture of 1a and 3a.
(C) and the thiosulfonate (D). There are two possible reaction
pathways from this mixture (Path A and B). In Path A, a third
acid attacks C to provide the sulfinic acid (E) and sufinyl
chloride (F). Two more equivalents of acid react with E and F to
afford two molecules of the sulfonyl chloride 2. In Path B, the
thiosulfonate (D) reacts with hypochloric acid and chloride ion
(eliminated from A) to produce the sulfinyl chloride (G) and
sulfonyl chloride (2). The reaction of a fourth hypochloric acid
with G provides the sulfinyl chloride (H), and a fifth hypochloric
acid reacts with H to afford the sulfonyl chloride.
Next, several thiols 3 were treated with 4 equiv of
NaOCl¢5H2O in acetic acid at room temperature (Table 4).19
Interestingly, the exothermic reactions went to completion
immediately to form the corresponding sulfonyl chloride 2 in
high yields. In most cases, the yield of the desired sulfonyl
chloride was higher than that obtained from the reaction of the
corresponding disulfide with NaOCl¢5H2O.
Thiols are generally easily oxidized to the corresponding
disulfides; therefore, the corresponding disulfides derived from
thiols with NaOCl are further reacted to produce the sulfonyl
chloride. The reason why thiols reacted with NaOCl¢5H2O
much faster than disulfides did, is due to the heat of the reaction.
Actually, the treatment of a mixture of 1a and 3a with
NaOCl¢5H2O in 1 min at room temperature produced 2a in
high yield (81%) recovered only a trace amount of 1a
(Scheme 4).
In conclusion, the reaction of NaOCl with disulfides or
thiols in acetic acid is an highly effective method for the
preparation of sulfonyl chloride. Further studies and their full
details will be published as a full paper.
16 In the cases of Runs 5 and 6, colorless crystals formed and
precipitated from the BTF solution. It was confirmed that these
crystals contain sodium p-toluenesulfonate by HPLC analysis. In the
case of 7, it was also confirmed that the aqueous phase of the reaction
mixture contains sodium p-toluenesulfonate by HPLC analysis.
17 Representative procedure for the synthesis of sulfonyl chlorides
from the reaction of NaOCl¢5H2O with disulfides: To a solution
of di-p-tolyldisulfide (739.2 mg, 3.0 mmol) in acetic acid (11 mL),
NaOCl¢5H2O (2.47 g, 15.0 mmol) was added and stirred at room
temperature for 65 min. Saturated aqueous sodium thiosulfate (4 mL)
and dichloromethane (15 mL) was added to the reaction mixture. The
organic layer was separated and the aqueous phase was extracted with
dichloromethane (15 mL © 2). The combined extracts were dried over
anhydrous sodium sulfate, and evaporated to afford p-toluenesulfonyl
chloride (915.0 mg, 80%) as colorless crystals. This product is pure
enough without further purifications, and is consistent with the
commercial reagent. mp 70-71 °C (lit18 69-71 °C); 1H NMR (CDCl3):
¤ 2.49 (3H, s), 7.41 (2H, d, J = 8.3 Hz), 7.93 (2H, d, J = 8.3 Hz);
13C NMR (CDCl3): ¤ 21.83, 127.06, 130.23, 141.71, 146.79.
18 The Merck Index, 13th ed., Merck & Co., Inc, Whitehouse Station,
2001, p. 1701.
19 Representative procedure for the synthesis of sulfonyl chlorides
from the reaction of NaOCl¢5H2O with thiols: To a solution of
p-methylbenzenethiol (248.4 mg, 2.0 mmol) in acetic acid (11 mL),
NaOCl¢5H2O (1.32 g, 12.0 mmol) was added and stirred at room
temperature for 1 min. Saturated aqueous sodium thiosulfate (4 mL)
and dichloromethane (20 mL) was added to the reaction mixture. The
organic layer was separated and the aqueous phase was extracted with
dichloromethane (20 mL). The extracts were dried over anhydrous
sodium sulfate, and evaporated to afford p-toluenesulfonyl chloride
(328.9 mg, 86%) as colorless crystals. This product is pure enough
without further purifications, and is consistent with the commercial
reagent.
Supporting Information is available electronically on J-STAGE.
Chem. Lett. 2015, 44, 185–187 | doi:10.1246/cl.140899
© 2015 The Chemical Society of Japan | 187