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Review
Sodium Hypochlorite Pentahydrate Crystals (NaOCl·5HO): Convenient
2
and Environmentally Benign Oxidant for Organic Synthesis

Masayuki Kirihara, Tomohide Okada, Yukihiro Sugiyama,
Miyako Akiyoshi, Takehiro Matsunaga, and Yoshikazu Kimura
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00288 • Publication Date (Web): 23 Oct 2017
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Page 1 of 43 Organic Process Research & Development
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8 Sodium Hypochlorite Pentahydrate Crystals
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12 (NaOCl·5H2O): Convenient and Environmentally
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16 Benign Oxidant for Organic Synthesis
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21 Masayuki Kirihara, a* Tomohide Okada,b Yukihiro Sugiyama,b Miyako Akiyoshi,c Takehiro
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23 Matsunaga,c Yoshikazu Kimura d *
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26 a
Department of Materials and Life Science, Shizuoka Institute of Science and Technology,
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2200-2 Toyosawa, Fukuroi, Shizuoka 437-8555, Japan.
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30 b
31 R&D Department of Chemicals, Nippon Light Metal Company, Ltd., 480 Kambara,
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33 Shimizu-ku, Shizuoka 421-3203, Japan
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35 c
Research Center for Explosion Safety, National Institute of Advanced Industrial Science
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37 and Technology, 1-1-1 Higashi, Tsukuba-shi, Ibaraki 305-8565, Japan
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39 d
40 Research and Development Department, Iharanikkei Chemical Industry Co. Ltd., 5700-1
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42 Kambara, Shimizu-ku, Shizuoka 421-3203, Japan
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46 Corresponding Authors
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*E-mail (Masayuki Kirihara): [email protected]
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51 *E-mail (Yoshikazu Kimura): [email protected]
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Organic Process Research & Development Page 2 of 43
1
2
3 TOC graphic
4
5
6 O
7 O O
8 S S
OH R R' R R'
9 O O
O S
10 R R' R R' S
11 R Cl
R R' cat. TEMPO
12
13 S R
14 R SH R S
RCH2OH
15
16 cat. TEMPO NaOCl5H 2O
Ts NaBr
17 O N OH O O
18 S
R H R R Br
19 R H CO2H
20 Ts O
21 N
O
22 R O O
R H
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1
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3 KEYWORDS
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5 Sodium hypochlorite pentahydrate (NaOCl·5H2O) crystals; Sodium hypochlorite; Oxidation;
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7
Alcohol; TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl); Organosulfur compounds
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9
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11 ABSTRACT The novel oxidant of sodium hypochlorite pentahydrate (NaOCl·5H2O)
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13 crystals is now available for industrial and laboratory use. It is superior to conventional
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16 aqueous sodium hypochlorite solutions (aq. NaOCl). The crystalline material is 44% NaOCl,
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18 contains minimal amounts of sodium hydroxide and sodium chloride, and the aqueous
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20 solution, which is prepared from NaOCl·5H2O and water, has a pH of 11~12. Examples of
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22 the selective organic synthesis using NaOCl·5H2O involve the oxidations of primary and
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secondary alcohols, selective oxidations to sulfoxide and sulfone, oxidative cleavage of
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27 disulfide to sulfonyl chloride and bromide, oxaziridine synthesis, and oxidative
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29 dearomatization of phenols.
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36 1. Introduction
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In this review, novel production on a commercial basis of sodium hypochlorite
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42 pentahydrate (NaOCl·5H2O) and its application for organic syntheses is described. Although
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44 NaOCl·5H2O itself has been known since 1919 in the literature,1a nobody has been supplied
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46 on an industrial scale. In 2013, Nippon Light Metal Co. in Japan was the first to put sodium
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48 hypochlorite pentahydrate (NaOCl·5H2O) crystals on the market in the world.2,3 As the
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51 organic synthesis using NaOCl·5H2O as an oxidant has never been reported, we examined the
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53 performance of the NaOCl·5H2O compared to a conventional aqueous NaOCl solution (aq.
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55 NaOCl).
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3
1
2
3 Oxidation using aq. NaOCl4 is one of the most promising methods in process chemistry,
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5 because diluted aq. NaOCl is non-explosive, inexpensive, and the post-oxidation waste is
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harmless and nontoxic sodium chloride (NaCl). However, there are still some drawbacks
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10 when using the conventional aq. NaOCl as an oxidant of organic compounds. The process has
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12 an inherently poor volume efficiency because the concentration of conventional aq. NaOCl is
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14 only 8~13% (higher concentrations of the NaOCl solution are known to be unstable).
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16 Moreover, the pH of conventional aq. NaOCl is very high (~13; as adjusted with free NaOH
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19 to maintain stability), and the pH must sometimes be adjusted lower in order to speed up the
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21 rate or prevent decomposing the starting materials and/or products. Furthermore,
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23 conventional aq. NaOCl is not stable enough and the deteriorated NaOCl sometimes produces
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25 unsuccessful synthetic reactions.
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We expected that NaOCl·5H2O is a superior substitute of aq. NaOCl, and found several
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30 new types of oxidation reactions of organic molecules which had not been successful using
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32 conventional aq. NaOCl. In addition, a high volume efficiency of reactions, good stability in
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34 storage, and unnecessity pH adjustment prior to use, afforded simple methods for organic
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36 synthesis.
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39 Several oxidation reactions were found to occur as shown below.
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41 O
O O
42 S
S
43 OH R R' R R'
44 O S O O
R R' R R' S
45
R Cl
46 R R' cat. TEMPO
47
48 S R
R SH R S
49 RCH2OH
50 cat. TEMPO NaOCl5H 2O NaBr
51 Ts OH O O
O N
52 S
53 R H R R Br
R H CO2H
54
55 Ts O
N
56 O
R O O
57 R H
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4
1
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3 Scheme 1 Synthetic applications of NaOCl·5H2O
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6 2. Sodium hypochlorite pentahydrate (NaOCl·5H2O)2,5
7
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9 As shown in Figure 1, NaOCl·5H2O is pale yellow crystals having the melting point of
10
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12 25−27 °C. Notable features of NaOCl·5H2O include: (1) the NaOCl content is about 44 wt%
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14 (the following expressed as %; 3-4 times higher concentration versus conventional aq.
15
16 NaOCl), (2) simple stoichiometric calculations, easy and accurate mass determination due to
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the crystalline nature of the compound, (3) the pH of aqueous solutions is ~11-12 since the
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21 solution contains less than 0.04~0.08% NaOH, and (4) the crystals are stable for 1 year below
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23 7 °C. Currently, NaOCl·5H2O crystals are commercially available from several companies
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25 including us.3
26
27
28 m.p. 25−27 °C
29 NaOH 0.04−0.08 wt%
30 NaCl 0.1−0.5 wt%
31
pH 11−12 (for the aqueous solution)
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34
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36 Figure 1 NaOCl·5H2O crystals. Reproduced with permission
37 from reference 5. Copyright 2016 Elsevier.
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3. Commercial synthesis of sodium hypochlorite pentahydrate (NaOCl·5H2O) crystals2,5
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44 3-1. Development of the industrial preparation of NaOCl·5H2O
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46 Several preparation methods for NaOCl·5H2O have already been proposed,1 however,
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48 industrial applicable methods to prepare high purity NaOCl·5H2O crystals are unknown. We
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have recently found specified crystallization conditions for high-purity NaOCl·5H2O crystals
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53 based on the NaCl-NaOCl-H2O ternary phase diagram. Based on these findings, we have
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55 established an original method for manufacturing NaOCl·5H2O (Scheme 2) 2 and have been
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57 supplying this product to the market. Chlorine gas is added to a 45~48% NaOH solution to
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5
1
2
3 prepare a highly concentrated NaOCl solution. After removing of the precipitated NaCl by
4
5 filtration, the filtrate is cooled to around 15 °C to precipitate the NaOCl·5H2O crystals, which
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7
are collected by centrifugal filtration.
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9
10
11 Cl2
12 aq. NaOCl
13 45-48% aq. NaOCl cooling filtration NaOCl5H2 O
aq. NaOH + NaCl crystals
14 + NaOH
+ NaOH filtration
15
16
17 NaCl Soln. containing
18 NaOH
19 Scheme 2 Industrial preparation of NaOCl·5H2O
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22 3-2 Property of NaOCl·5H2O
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24
25
Analysis shows that the prepared NaOCl·5H2O contains only 0.1-0.5% NaCl and 0.04-0.08%
26
27 NaOH. That is, the crystals prepared using this new method contain less free NaOH as well
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29 as less NaCl than the conventional aq. NaOCl. In addition, an aqueous solution of this
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31 product has a more ideal pH of 11-12 whereas that of the conventional aq. NaOCl is pH 13
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33
and oxidations are faster due to the lower pH; vide infra.
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35
36 Stability of the product was evaluated at several temperature (Figure 3). These NaOCl·5H2O
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38 crystals, which contain 44% of NaOCl, are stable at lower temperature. However, the product
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40 gradually decomposed under an ambient temperature.
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56 Figure 2 Stability of NaOCl·5H2O at several temperatures
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6
1
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3 Further evaluation revealed that the NaOCl·5H2O crystals are quite stable in refrigerator.
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5 The concentration of NaOCl of the crystals is almost unchanged (44.2% →43.7%) even
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7
after 360 days at 7 °C (Figure 2). This means that 99% of the NaOCl was maintained (Table
8
9
10 1). This is in sharp contrast to the conventional aqueous NaOCl solution, whose
11
12 concentration gradually drops to 11.3% from 13.6% of original concentration under the same
13
14 condition. This means that 17% of NaOCl content decomposed during storage.
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17
Table 1 Stability of NaOCl·5H2O crystals and conventional aq. NaOCl at 7 °C
18
19
20 Substance Original Concentration 1 yr. later
21 concentration
22 NaOCl·5H2O 44.2% 43.7%a (98.9% of the original concentration)
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24 aq. NaOCl 13.6% 11.3%b (83.1% of the original concentration)
25 a
26 360 days later. b 361 days later. Reproduced with permission from reference 5.
27 Copyright 2016 Elsevier.
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30 Due to the instability of the conventional aq. NaOCl, titration is required to determine the
31
32 exact concentration before use. On the contrary, the accurate mass of NaOCl·5H2O can be
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easily measured using a balance (Figure 3).
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36
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38 NaOCl・5H 2O Crystals
39 （No need for titration）
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42
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44 Stable
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48 Conventional aqueous NaOCｌ
NaOCｌ
49 (Need for titration)
50 Figure 3 Advantage of NaOCl·5H2O crystals on conventional aqueous NaOCl
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3 3-3. Safety assessment of NaOCl·5H2O6
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6 According to the testing method of explosives based on the Japanese Industrial Standards
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(JIS K 4810), the BAM friction test and the drop hammer test have been applied to the
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11 product (NaOCl·5H2O) (Table 2). The results of both tests were negative at classification 7
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13 for the BAM friction test, and 8 for the drop hammer test. This means that NaOCl·5H2O is
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15 not an explosive compound under typical conditions.
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18 Table 2 Sensitivity test of NaOCl·5H2O based on JIS K 4810
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Test Condition Result JIS grade
23 Friction Limiting load: 353 N Negative Class 7
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25 Drop hammer Limiting impact energy: 24.5 J Negative Class 8
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30 Differential scanning calorimetry (DSC) has been done at a heating rate of 5 °C/min
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32 contacting with several materials [stainless (SUS304H), titanium, low density polyethylene
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34 (LD-PE), high density polyethylene (HD-PE) and polypropylene (PP)] in glass ampoule, and
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36 the results are shown in Figures 4 and 5.
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40 The sharp peak was observed at 100 °C in DSC measurement with SUS304H. This result
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42 means that stainless steel reacts with NaOCl·5H2O, thus stainless vessels cannot be used as
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44 reactors. On the other hand, titanium did not react with NaOCl·5H2O, thus the reaction of
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46 NaOCl·5H2O can be performed in titanium vessels as well as glass wares.
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8
1
2
3
4
5
(NaOCl·5H2O)
6 367 J/g 342 J/g
7 55
5
102 397 447
29
8 17 69 284
9
287 J/g
10 31
11
12 (NaOCl·5H2O+SUS304H)
Heat flow (W/g)

13 100
14 53 423 J/g
217 J/g
15 256 425
29
16 17 93 179
17 268 J/g
18 31
19 (NaOCl·5H2O+Ti) 334 J/g
20 29 56 110 321 J/g 392 437
21 18 69 271
22
30 274 J/g
23
24 0 100 200 300 400 500
25 Temperature (℃）
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27
Figure 4 DSC data with SUS304H and titanium
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30
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32 The DSC data of NaOCl·5H2O with these resins (LD-PE, HD-PE and PP) showed that all of
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34 them were not affected by NaOCl·5H2O at ambient temperatures.
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9
1
2
3
(NaOCl·5H2O)
4 342 J/g
367 J/g
5
5 55 447
102 397
29
6 17 69 284
7
8 31 287 J/g
9
10
(NaOCl·5H2O+LD-PE)
11 376
58 297 J/g 133 J/g
12 107 207
30
13
Heat flow (W/g)
17 72 165 262 1006 J/g
14
264 J/g
15 32
16 (NaOCl·5H2O+HD-PE) 396
17 55 308 J/g 123 J/g
18 29 104 138 209
19 16 71 132 178 265 1297 J/g
10 J/g
20 264 J/g
21 31
22 (NaOCl·5H2O+PP)
23 54 460 J/g 393
29 107 193
24
25 18 73 166 263 1008 J/g
26 139 J/g
27 31 275 J/g
28 0 100 200 300 400 500
29 Temperature (℃)
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31 Figure 5 DCS data with resins
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35 4. Oxidation of alcohols with NaOCl·5H2O5,7
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37
The synthesis of aldehydes or ketones by oxidation of the corresponding primary or
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40 secondary alcohols is one of the most important reactions in organic synthesis, and a high
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42 number of methods has been reported. 8 However, there are only a few methods that can be
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44 industrially applied, because most of the existing oxidations have serious drawbacks such as
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46 toxic or explosive property of the oxidants.
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48
49
50 The oxidation of alcohols using conventional aq. NaOCl catalyzed by TEMPO (2,2,6,6-
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52 tetramethylpiperidine 1-oxyl)9 or AZADO (2-azaadamantane N-oxyl)10 have been reported.
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54 They appear to be economically and environmentally benign methods without the use of a
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56 metal catalyst.
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10
1
2
3 However, the process has an inherently poor volume efficiency because the concentration
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5 of the conventional aq. NaOCl solution is up to only 13%. Moreover, at the pH of the
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conventional aq. NaOCl (about 13), the reactions are very slow, thus the pH must be lowered
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10 (pH 8-9) with aqueous sodium hydrogen carbonate (aq. NaHCO3) in order to increase the
11
12 rate.9b NaOCl·5H2O is expected to overcome these mentioned drawbacks.
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18 4-1. Optimization of the reaction conditions
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21
The oxidations of 2-octanol were initially examined using NaOCl·5H2O crystals or the
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23
24 conventional aq. 13% NaOCl in dichloromethane (CH2Cl2) in the presence of 5 mol%
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26 tetrabutylammonium hydrogen sulfate (Bu4NHSO4) without pH adjustment with aq. NaHCO3
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28 in the presence or absence of TEMPO or 1-Me-AZADO. The results are summarized in
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30 Table 4-1. In all cases, the NaOCl·5H2O crystals (runs 1, 3 and 7) showed more excellent
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32
33 results than those of the aq. 13% NaOCl (runs 2, 4 and 8).
34
35
36 Table 3 Comparison with NaOCl·5H2O crystals and conventional aqueous NaOCl
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38 Bu 4NHSO4
39 OH 5 mol% O
40 + 1.2 eq. NaOCl
41 Nitroxyl radical
4 in CH 2Cl2 5 °C 4
42
43
44
45 Run NaOCl Nitroxyl radical (mol%) Time (h) Yield (%)a
46 1 NaOCl·5H2O - 24 78
47
2 aq. 13% NaOCl - 27 9
48
49 3 NaOCl·5H2O TEMPO (1) 1 97
50 4 aq. 13% NaOCl TEMPO (1) 22 11
51 5 NaOCl·5H2O TEMPO (0.1) 3 99
52
6 NaOCl·5H2O 1-Me-AZADO (1) 1 100
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54 7 aq. 13% NaOCl 1-Me-AZADO (1) 24 99
a
55 Determined by GC analysis using internal standard method.
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60
11
1
2
3 We first postulated that the role of Bu4NHSO4 was as a phase transfer catalyst, however, it
4
5 turned out to act as an acid based on the results shown in Tables 4 and 5. As shown in Table 4,
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7
the addition of Bu4NHSO4 to the 13% aq NaOCl (prepared from NaOCl·5H2O) dramatically
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10 reduced the pH value (9.6).
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12
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14 Table 4 Effect for quaternary ammonium salts and acid in the presence of TEMPOa
15
16 OH O
17 NaOCl5H 2O (1.2 equiv.)
18
19 4 TEMPO (0.01 equiv.) 4
20 Bu4NX (0.005~0.05 equiv.)
2-Octanol CH2Cl2, 5°C 2-Octanone
21
22
X Yield of 2-Octanone (%) b
23 Run Additive
24 (equiv.) 0.5 h 1h 2h 3h 21 h
25
26 1 — — — 0.1 0.1 0.1 0.2 (23 h)
27 HSO4
28 2 — — 40 73 98 —
0.005
29
Br
30 3 — — 6 14 25 87 (22 h)
0.05
31
32 Cl
4 — — 3 10 10 73
33 0.05
34 Cl
35 5 NaHSO 4H 2O 0.05 equiv. — 19 25 — 69
0.05
36
37 Cl NaHSO 4H 2O 0.05 equiv.
6 97 99 — — —
38 0.05 +H2O 0.2 mL
39 NaHSO 4H 2O 0.05 equiv.
40 7 — 46 98 — — —
+H2O 0.2 mL
41 a 1 (10 mmol), NaOCl5H2O (12 mmol), TEMPO (0.1 mmol),Bu4 NX (0.05~0.5 mmol), CH2 Cl2 (30 mL)
42 b
Yields were determined by GC using an internal standard method.
43
44
45
46
47 Table 5 pH of 13% aq. NaOCl (prepared from NaOCl·5H2O)
48 with quaternary ammonium salts
49
50 13% aq. NaOCl* Quaternary ammonium salt pH
51
52 50 mmol None 11.3
53 50 mmol Bu4NHSO4 (2.5 mmol) 9.6
54
55 50 mmol Bu4NBr (2.5 mmol) 11.4
56
57
50 mmol Bu4NCl (2.5 mmol) 11.2
58 * Prepared from NaOCl·5H2O and ion-exchanged water
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12
1
2
3 Based on the results, the oxidation effectively occurred below pH 10. As mentioned below,
4
5 the use of NaHSO4 in place of Bu4NHSO4 gave excellent results for the oxidation of 2-
6
7
octanol.
8
9
10
11
12 NaOH NaOCl5H2O
13 0.08 wt% = 0.4 mol%
14
15 Bu4NHSO4
16 or NaHSO4
17
18
neutralize 5 mol%
19
20
Na2SO4
21
22
23 H2O HOCl HCl
24
25 aqueous phase
26
27 TEMPO
28 organic phase
1 mol%
29 R1
30 OH R1 O
31
2
32 R R2
33
34
35 Scheme 3 Proposed mechanism for the TEMPO-catalyzed oxidation of alcohols with NaOCl·5H2O
36 Reproduced with permission from reference 5. Copyright 2016 Elsevier.
37
38
39
40 Next, we examined the reaction with concentrated aq. NaOCl which can be prepared by
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42 dissolving NaOCl·5H2O crystals with water. We also confirmed that the concentration of a
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44
NaOCl solution higher than 20% is stable for a few days for the reaction. However, almost no
45
46
47 concentration effect was observed at 13, 20, and 31% NaOCl·5H2O. On the other hand, the
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49 use of the solid NaOCl·5H2O crystals dramatically increased the oxidation (Figure 4-1). The
50
51 precise reason is not clear, but it may appear that a high concentration of the primary oxidant
52
53 HOCl forms on the surface of the crystalline solid.
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60
13
1
2
3
4
5
6
7
8
9
10
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12
13
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18
19
20
21
22
Figure 6 Reaction of 2-octanol with several concentrations of
23 aqueous NaOCl prepared from NaOCl·5H2O crystals and water;
24 NaOCl·5H2O crystals (○); aq. 31% NaOCl (△); aq. 20% NaOCl (□);
25 aq. 13% NaOCl (◇) ; conventional aq. 13% NaOCl (×).
26 * 2-Octanol (10 mmol), NaOCl·5H2O (12 mmol), Bu4NHSO4 (0.5
27 mmol), TEMPO (0.1 mmol), CH2Cl2 (30 mL), and appropriate water.
28
29
30 The solvent effects were examined (Table 6) and ethyl acetate was found to be as good a
31
32 reaction solvent as dichloromethane.
33
34 Table 6 Results for the oxidation of 2-octanol in several solvents
35
36
37 OH O
NaOCl5H 2O (1.2 equiv.)
38
39 4 TEMPO (0.01 equiv.) 4
40 Bu4NHSO4 (0.05 equiv.)
2-Octanol a solvent (30 mL)
2-Octanone
41
42
43 Temperature Yield of 2-Octanone (%) b
Solvent (°C)
44 1h 2h 3h 4h
45
46 CH2 Cl2 5 97 — — —
47 EtOAc 5 61 97 — —
48
49 C6 H 5CH3 5 38 90 98 —
50 C6 H5 CF3 5 30 55 87 95
51
CH 3CN 5 53 54 53 52
52
53 AcOH r.t. 18 78 90 90
54
55 a
56 2-Octanol (10 mmol)
57 b
Yields were determined by GC using an internal standard method.
58
59
60
14
1
2
3 A large-scale (26.0 g of 2-octanol, 0.2 mol) example of the oxidation of 2-octanol was
4
5 examined in ethyl acetate (Scheme 4). To maintain the reaction temperature below 20 °C, 2-
6
7
octanol was dropwise added for 15 min to a mixture of all reagents cooling in an ice-water
8
9
10 bath. After stirring for 45 min at 0~20 °C, the reaction mixture was quenched with aqueous
11
12 Na2SO3 followed by extraction with ethyl acetate, and distillation of the residue to produce 2-
13
14 octanone (23.2 g, 91% yield).
15
16
17
OH NaOCl・5H2O(1.2 eq., 39.5 g) O
18
19 TEMPO (0.01eq., 0.312 g)
20 4 Bu4NHSO4 (0.05 eq., 3.4 g)
4
21 26.0 g 23.2 g
EtOAc(80 mL),0-20°C, 1 h
22 (200 mmol) Isolated yield 91%
23
24 200 ml
25 NaOCl・・5H2O ⇒Add 2-Octanol to the flask
26 TEMPO, Bu4NHSO4 （Reaction temp. is controled at 0～20℃）
27 in EtOAc
28 ⇒Distilled yield 91%　　　　　　　　
29
30
31
Easy to scale-up using EtOAc
32
33
34 Scheme 4 Large scale oxidation of 2-octanol in ethyl acetate
35
36
37 As an improved method, NaHSO4 was used instead of Bu4NHSO4. In method A, 2-octanol
38
39
was dropwise added to the reaction mixture. In Method B, 30% NaOCl prepared from
40
41
42 NaOCl·5H2O was dropwise added to the mixture. Both methods gave high yields of the
43
44 desired 2-octanone within 1 h (Scheme 5). NaOCl·5H2O can be used in a slurry or highly
45
46 concentrated solution.
47
48
49
50
51
52
53
54
55
56
57
58
59
60
15
1
2
3 OH NaOCl・ 5H 2 O (1.2 eq., 19.8 g) O
4 TEMPO (0.01 eq., 0.156 g)
5 NaHSO4 (0.05 eq., 1.7 g)
6 4 4
13.0 g (100 mmol) 0-20°C, 1 h
7
8
Method A (NaOCl・5H2O slurry) Method B (aq. 30% NaOCl)
9
10
11 Added to 2-Octanol Added to aq. NaOCl
12
13 Yield 96% Yield 97%
14
15 2-Octanol 30% aq. NaOCl
16 (from NaOCl・5H2O)
17
18 NaOCl・5H2O
19 2-Octanol
+ water (slurry)
20 TEMPO TEMPO
21
NaHSO4・H2O NaHSO4・H2O
22
23 Scheme 5 Solvent free oxidation of 2-octanol catalyzed by NaHSO4·H2O
24
25
26
27
28
29 4-2. TEMPO-catalyzed oxidation of several alcohols with NaOCl·5H2O
30
31 The optimized TEMPO-catalyzed oxidation with NaOCl·5H2O was applied to various
32
33 primary alcohols (10 mmol) (Table 7). Use of an equimolar amount of NaOCl·5H2O gave the
34
35
36 corresponding aldehydes in good yields. This optimized method using NaOCl·5H2O gives
37
38 encouraging results with TEMPO. It is notable that the reaction of primary alcohols having a
39
40 heteroaromatic moiety (pyridine, thiophene) effectively produced the desired aldehydes.
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
16
1
2
3 Table 7 Selective syntheses of aldehydes from primary alcoholsa
4 5 mol% Bu4 NHSO4
5 1 mol% TEMPO O
6 R OH + NaOCl5H 2O
7 CH2Cl2 R H
8 NaOCl5H2O CH2Cl2 Temp. Time Yield
9 Substrate
(equiv.) (mL) (°C) (h) (%) b
10
11 OH 1.1 30 5 1 91
12 5
13 OH
14 1.1 30 5 1 99
15
16
OH
17 1.2 30 5 2 96
18 MeO
19
20 O OH 1.2 30 5 6 96
21 1.2 15 15 1 97
22 O
23 1.4 30 5 4 67
24 OH 1.4 30 5 3 82 c
25 1.2 30 5 3
26 87 d
1.4 30 5 2
27 85 d
28 OH
29 1.1 30 5 0.5 93
30 Cl
31 OH
32 1.1 30 5 0.5 98
33 NO2
34 OH
35 1.1 30 5 0.5 94
36 N
37 S
38 1.4 30 5 3 79
OH
39
40
a Substrate : 10 mmol
41 b Yields were determined by GC using an internal method
42 c TEMPO 10 mol%
43 d 1-Me-AZADO was used instead of TEMPO
44
45
46
47
48 The oxidations of secondary alcohols were then examined (Table 8). Both the TEMPO- and
49
50 1-Me-AZADO-catalyzed oxidations of sterically-hindered secondary alcohols were reported
51
52 to give poor yields of the ketones using the conventional aq. NaOCl without pH adjustment
53
54 using aq. NaHCO3. In contrast, the optimized method using NaOCl·5H2O gave excellent
55
56
57
58
59
60
17
1
2
3 results with TEMPO even in the reaction of sterically-hindered alcohols (menthol and 2,6-
4
5 dimethyl-4-heptanol). Notably, the cheap TEMPO is useful as a catalyst for the oxidations.
6
7
8
9
10 Table 8 Results for the oxidation of secondary alcoholsa
11
12 5 mol% Bu4NHSO4
13 OH 1 mol% Nitroxyl radical O
14 + NaOCl
15 R1 R2 CH2Cl2 R1 R2
16
17 CH2Cl2 Temp.
Substrate Nitroxyl Time Yield
18 NaOCl (eq.)
radical (mL) (°C) (h) (%) b
19
20
OH
21
TEMPO NaOCl5H2O (1.2) 10 5 0.5 (95)
22
4
23
24
OH
25 TEMPO NaOCl5H2O (1.2) 30 5 1 97
26 TEMPO NaOCl5H2O (1.2) 10 15 0.67 (96)
3
27
28
29 NaOCl5H2O (1.2) 30 5 24 98
30 OH 12% aq. NaOCl (1.2) 30 5 24 2
31 NaOCl5H2O (1.6) 10 15 2 96
32 TEMPO
NaOCl5H2O (1.6) 8 15 2.25 (92)
33 TEMPO
NaOCl5H2O (1.4) 30 rt 0.5 98
34 1-Me-AZADO
35
36 OH TEMPO NaOCl5H2O (1.8) 10 15 6 88
37
1-Me-AZADO NaOCl5H2O (1.4) 30 rt 0.5 95
38
39
a
40 All the reactions were performed without pH adjustment using aq. NaHCO3.
41 b Yields were determined by GC using an internal standard method.
42 Numbers in parentheses refer to isolated yields.
43
44
45
46
47
For the oxidation of alcohols using the conventional aq. NaOCl catalyzed by TEMPO,
48
49 primary alcohols are known to be easier and faster oxidized than secondary alcohols.9
50
51 Actually, the oxidation of an equimolar mixture of a primary alcohol (1-nonanol) and a
52
53 secondary alcohol (2-nonanol) using the conventional aq. NaOCl catalyzed by 4-MeO-
54
55
TEMPO was reported to afford 90% nonanal and 10% 2-nonanone in the literature.9b
56
57
58
59
60
18
1
2
3 Conversely, the reaction of an equimolar mixture of 1-octanol and 2-octanol with
4
5 NaOCl·5H2O in the presence of TEMPO provided octanal in 47% yield and 2-octanone in
6
7
44% yield after 0.5 h. The 4-MeO-TEMPO catalyzed reaction exhibited a similar result
8
9
10 (Table 9). Thus, the oxidation rates for primary and secondary alcohols under these
11
12 conditions are not very different.
13
14
15
16 Table 9 Oxidation of an equimolar mixture of 1-octanol
17
and 2-octanol with NaOCl·5H2O catalyzed by a nitroxyl
18
19 radical
20 O
OH NaOCl. 5H2 O
21 5
(5 mmol) 5 H
22 1-Octanol
5.0 mmol Nitroxyl radical Octanal
23
(0.1 mmol)
24 + +
25 OH Bu 4NHSO4 O
26 (0.5 mmol)
27 4 CH 2Cl2, 5 °C
4
28
29 2-Octanol 2-Octanone
30 5.0 mmol
31
32 Time
Nitroxyl Radical Octanal 2-Octanone
(h)
33
34 47% 44%
TEMPO 0.5
35 (2.35 mmol) (2.20 mmol)
36 48% 37%
37 4-MeO-TEMPO 1.0
(2.40 mmol) (1.85 mmol)
38
* Yields were determined by GC using an internal standard method.
39
40
41
42
43 These results suggest that the reaction-mechanism of the nitroxyl radical catalyzed oxidation
44
45 of alcohols using NaOCl·5H2O is different from the oxidation using the conventional aq.
46
47 NaOCl. The oxidation of alcohols with NaOCl·5H2O/TEMPO/Bu4NHSO4 occurs under
48
49
50 acidic to neutral conditions (Scheme 3 vide supra).5 We proposed a plausible mechanism
51
52 involving intermediate C with hydride transfer (Scheme 6)5 based on the mechanism which
53
54 was reported by Bobbitt et al. as an alternative for the TEMPO oxidation of alcohols under
55
56 neutral or acidic conditions.11 Taking intermediate C into account, steric hindrance of the
57
58
59
60
19
1
2
3 bulky secondary alcohols is likely relaxed, permitting the oxidation to occur. The interaction
4
5 between the lone pair of the nitrogen atom and the hydrogen atom of the hydroxyl group in
6
7
the alcohol plays an important role in this reaction mechanism.
8
9
10
11
12
[O] N [O]
13 O
14 TEMPO
15
16
X
17
18 N N
19 OH O
20 A
R HO R
21 O
R' -HX H R'
22
X
23
24 H O
25 N R
O H
26 R'
27 C
28
29
30
Scheme 6 The plausible reaction mechanism
31
32
33
34 5. Oxidation of organosulfur compounds
35
36 5-1. Selective oxidation of sulfides to sulfoxides12
37
38 Sulfoxides are important and useful compounds in organic synthesis, because they are
39
40
41 frequently used as the intermediates for the construction of several important organic
42
43 molecules. In addition to this, there are many biologically-important compounds containing a
44
45 sulfoxide moiety. They are mainly prepared by the oxidation of the corresponding sulfides;
46
47 however, it is sometimes difficult to stop the oxidation at the sulfoxide stage. Consequently,
48
49
50
several selective sulfide oxidations have been developed to more effectively synthesize
51
52 sulfoxides.13 Although they provide the desired sulfoxides in high yields, some are
53
54 accompanied by large amounts of undesirable waste derived from the oxidants.
55
56 As we emphasized in the introduction, NaOCl has several merits as an environmentally-
57
58
59
60
20
1
2
3 benign oxidant. Despite these merits, NaOCl has seldom been used for the synthesis of
4
5 sulfoxides from sulfides, because it is difficult to selectively obtain the desired sulfoxides
6
7
without producing the over-oxidized sulfone. The use of TEMPO as a catalyst has been
8
9
10 required to obtain the sulfoxides in high yields.14 We expected that the oxidation of sulfides
11
12 with NaOCl·5H2O might be an excellent method for the selective preparation of sulfoxides.
13
14
15
16 5-1-1. Optimization of the reaction conditions
17
18 The reactions of thioanisole with 1.1 equiv. of NaOCl (conventional 12 wt% aq. NaOCl
19
20 solution or NaOCl·5H2O crystals) in acetonitrile were examined in the absence of a catalyst
21
22
23
(Scheme 7). In the case of the NaOCl·5H2O crystals, the desired sulfoxide was selectively
24
25 obtained in 18 min. Conversely, the conventional aq. NaOCl reacted more slowly with the
26
27 sulfide to produce the sulfoxide in 79% yield accompanied by a certain amount of the
28
29 overoxidized sulfone.
30
31
32
33
34 12% aq. NaOCl O O O
35 (1.1 equiv.) + S + S
S Ph CH3 Ph CH3
36 Ph CH3
CH 3CN, r.t., 4 h 5% a
37 79% a 16% a
38
S
39 Ph CH 3
NaOCl5H 2 O O O O
40
(1.1 equiv.) + S
41 S Ph CH3
42 Sulfide CH3CN/H2 O (5:1 v/v) Ph CH3
43 r.t., 18 min 98% b 2%b
44
45 Sulfoxide Sulfone
46
a Based on 1H NMR signal ratio (CH3 protons)
47
b
48 Isolated yields
49
50 Scheme 7 Reaction of thioanisole with NaOCl
51
52
53
54
55 As we described in the previous chapters, the main difference between NaOCl·5H2O and
56
57 aq.NaOCl is their pH values. Therefore, the reactivities of NaOCl·5H2O and conventional aq.
58
59
60
21
1
2
3 NaOCl were compared while altering the pH with HCl or NaOH (Table 10). At pH 11, the
4
5 reaction rapidly proceeded to selectively afford the desired sulfoxide (runs 1, 2). At pH 13, on
6
7
the other hand, the reaction was not complete after 4 h, and a significant amount of over-
8
9
10 oxidized sulfone was produced along with the desired sulfoxide (runs 3, 4). As we had
11
12 surmised, the selectivity of this reaction depends on the basicity of the reaction mixture.
13
14 These results show that the ideal pH range for the selective production of the sulfoxide is
15
16
10−11.
17
18
19
20
21 Table 10 Reactivity of NaOCl·5H2O and conventional aqueous NaOCl solutions
22
23 12% aq. NaOCl
24 (1.1 equiv.) O O O
S
25 Ph CH3 S + S
CH3 CN, r.t. Ph CH3 Ph CH3
26
27 Sulfide Sulfoxide Sulfone
28
29 1H NMR ratios (%) (CH3 protons)
30 Run NaOCl pH Time
31 Sulfide Sulfoxide Sulfone
32
1 Prepared from NaOCl5H 2O 11 20 min 1 99 0
33
34 3
2 Conventional aqueous solution + HCl 11 20 min 0 97
35
36 3 Prepared from NaOCl5H 2O + NaOH 13 4h 18 66 16
37
38 4 Conventional aqueous solution 13 4h 5 79 16
39
40 5 Prepared from NaOCl5H 2O + HCl 10 20 min 1 98 1
41
42 6 Prepared from NaOCl5H 2O + HCl 9 20 min 8 88 4
43
44 7 Prepared from NaOCl5H 2O + HCl 8 4h 37 8 55
45
8 Prepared from NaOCl5H 2O + HCl 7 4h 38 7 55
46
47
48
49
50 Although the conventional aqueous NaOCl adjusted to pH 11 with HCl can provide the
51
52 desired sulfoxide in high yield, as a practical oxidant, it has some drawbacks (low
53
54 concentration, unstable, etc.) as we mentioned in the earlier chapters. In addition, it is very
55
56 important to add the correct amount of oxidant in order to prevent over-oxidation during the
57
58
59
60
22
1
2
3 selective oxidation of sulfides to the corresponding sulfoxides. However, during storage of
4
5 the conventional aq. NaOCl, the NaOCl concentration gradually decreases, even when it is
6
7
stored in a refrigerator. Therefore, titration is required to determine the exact concentration
8
9
10 before use. If a higher concentration of the NaOCl solution is desired (e.g., 20wt % NaOCl,
11
12 as demonstrated in Table 13 entry 2, for gram-scale synthesis), it can be prepared from
13
14 crystalline NaOCl·5H2O and water. This would be useful in large-scale syntheses due to the
15
16 need for a high volume efficiency and reduced waste water. Consequently, NaOCl·5H2O is
17
18
19 much more convenient than aqueous NaOCl for such applications.
20
21 The survey of the solvent effects on the reaction of thioanisole with NaOCl·5H2O revealed
22
23 that acetonitrile is appropriate solvent for this reaction. It selectively provided the sulfoxide in
24
25 high yield with a shorter reaction time (run 1) among the several experimental conditions as
26
27
shown in Table 11.
28
29
30
31
32 Table 11 Reaction of thioanisole (sulfide) with NaOCl·5H2O
33 in a mixture of various organic solvents and water
34 12% aq. NaOCl (1.1 equiv.) O O O
35 S prepared from NaOCl・5H 2O + S
36 Ph CH3 S Ph CH3
Ph CH3
37 solvent/H 2O (5:1 v/v), r.t.
Sulfide Sulfoxide Sulfone
38
39 1
Time H NMR ratios (%) (CH3 protons)
40 Run Solvent
(h) Sulfone
41 Sulfide Sulfoxide
42
1 CH3CN 0.3 0 98 2
43
44 2 CH2Cl2 24 50 43 7
45
46 3 CH2Cl2 + 5 mol% Bu 4HSO4 3.5 13 68 19
47 4 EtOAc 24 8 69 23
48
49 5 EtOAc + 5 mol% Bu4NHSO4 3 13 68 19
50 6 toluene 24 42 4 54
51
52 7 toluene + 5 mol% Bu4NHSO4 4 38 7 55
53
54
55
56
57
58
59
60
23
1
2
3 The acetonitrile/water ratios were variable to afford similar results between 5:1 and 50:1
4
5 (Table 12). In the absence of water (run 5), the reaction did not reach completion even after
6
7
20 h affording the sulfoxide in an unsatisfactory yield accompanied by a significant
8
9
10 amount of the sulfone. Since NaOCl·5H2O crystals are hard to dissolve in pure acetonitrile,
11
12 the reaction proceeds very slowly.
13
14 Table 12 Optimization for the ratio of acetonitrile to water
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37 5-1-3. Selective synthesis of sulfoxides from the reaction of sulfides with NaOCl·5H2O
38
39 The optimized oxidation of sulfides with 1.1 equiv. of NaOCl·5H2O in aqueous acetonitrile
40
41
42 was used for the synthesis of various sulfoxides (Table 13). The desired sulfoxides were
43
44 selectively obtained in high yields in all cases. It is notable that an alkene moiety (entry 6)
45
46 and a pyridine ring (entry 12) were inert under these reaction conditions.
47
48
49
50
51
52
53
54
55
56
57
58
59
60
24
1
2
3 Table 13 Reaction of sulfides with NaOCl·5H2O in aqueous acetonitrile
4 NaOCl5H 2O
5 S (1.1 equiv.) O O O
R1 R2 + S 2
6 S 1
CH3CN/H2O R1 R2 R R
7
Sulfide (5:1 v/v )a, r.t.
8 Sulfoxide Sulfone
(2 mmol) Catalyst Free
9
10 Isolated yield (%)
11 Time
Entry R1 R2 (min)
13
14 1 Ph CH3 18 98 2
15
2b Ph CH3 20 96 3
16
17 3 4-MeOC 6H 4 CH3 6 99 1
18
19 4 4-ClC6H 4 CH3 11 93 5
20 5 4-O2 NC6H 4 CH3 10 83 7
21
22 6 Ph CH2CH=CH 2 8 86 2
23 7 Ph Bn 7 86 trace
24
25 8 Bn Bn 10 89 trace
26 9 Bn CH3 39 0
76
27
28 10 CH3 (CH 2) 9 CH3 9 quant. 0
29
11 Ph Ph 25 95 5
30
31 12 2-Py CH3 23 84 7
32
S
33
34 13 c 24 86 6
35
36 a
CH3CN (10 mL) and H2O (2 mL) were used.
37 b
Thioanisole (2.48 g, 20 mmol), aqueous 20.6% NaOCl (7.59 g, 21 mmol) from NaOCl5H2O and CH3CN
38 (100 mL) were used. A water bath (ca. 20°C) was used to control the reaction temperature for a
39 gram-scale synthesis.
40 c
Dichloromethane was added to dissolve 1 in the solvent. Bu4 NHSO4 (0.05 equiv.) was also added.
41
42
43
44
45 5-2. Efficient synthesis of sulfones from sulfides15
46
47 Synthetic studies of the sulfone by the oxidation of sulfides with NaOCl·5H2O and
48
49 conventional aq. NaOCl were examined. Under the similar condition to sulfoxide synthesis
50
51 using 2.4 eq. NaOCl·5H2O gave the desired sulfone in 78% yield along with α-chlorinated
52
53
54 compounds. After solvent survey, aromatic hydrocarbons were found to be optimal solvents
55
56 to give excellent results as shown in Table 14.
57
58
59
60
25
1
2
3 Table 14 Solvent effect for the oxidation of thioanisole by NaOCla
4
5 13 wt% aq. NaOCl (2.4 eq.) O O
6 prepaed from NaOCl5H2O O O O O
S + +
7 Ph CH3 S S S Cl + S Cl
Solvent, 20 °C Ph CH3 Ph CH3 Ph Ph
8
9 (0.33 M)
10 GC area %b
Time
11 Run Solvent Chloromethyl- Chloromethyl-
(h) Sufoxide Sulfone
12 sulfoxide sulfone
13
14 1 Acetonitrile 6 8 78 5 9
15
16 2 Toluene 6 0 99 <1 <1
17
18 3c Toluene 3 3 94 0 2
19
20 4 Chlorobenzene 4 0 99 <1 <1
21
22 5 2-Chlorotoluene 2 0 98 0 1
23
24
6 Dichloromethane 6 36 62 1 <1
25
7 Ethyl acetate 2 0 63 36 1
26
27
28 a
Thioanisole (10 mmol), solvent (30 mL).
29 b
Main impurities are chloromethylphenyl sulfoxide and chloromethylphenyl sulfone, which
30 were identified by GC-MS.
31 c
1 mol% of (C8~10)3NMeCl was added.
32
33
34
35 The reaction of several sulfides with 13 wt% NaOCl prepared from NaOCl·5H2O and water
36
37 in toluene produced the desired sulfones in good yields in most cases (Table 15).
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
26
1
2
3 Table 15 Synthesis of sulfones from sulfides
4
5 13 wt% aq. NaOCl (2.4 eq.) O O
6 S prepared from NaOCl5H 2O S
7 R R' R R'
8 toluene, additive , 20 °C
Yield (Time)
9
10 O O
O O O O
11 S
12 CH3 N S S
CH3
13
14
15 99%*, 98%** (6 h) a 97%*, 90%** (8 h) a,c
99%*, 98%** (2 h) b 98%*, 97%** (6 h) a
16
17
18 O O O O O O
19
C 4H 9 S C 4 H9 PhH 2C
S
CH3 C 10H21
S
CH 3
20
21 99%*, 96%** (10 h) a 76%*, 73%** (6 h) a 57%*, 32%** (24 h) a,c,d
22
23
24 a
Sulfide (10 mmol), toluene (30 mL)
25 b
26 Sulfide (10 mmol), toluene (10 mL)
c
27 1 mol% of (C8~10)3NMeCl was used
d
28 Accompanied with the sulfoxide (partially oxidized compound) (41%).
*
29 GC yield by using an internal standard
**
30 Isolated yield
31
32
33 A plausible reaction mechanism is shown below (Scheme 8). The sulfur atom of sulfide is
34
35
36 chlorinated by hypochloric acid, and the chlorine atom of A is substituted for oxygen to form
37
38 the sulfoxide. The sulfur atom of the sulfoxide is similarly oxidized to produce the sulfone. In
39
40 polar solvents, alkali species readily dissolve in the reaction mixture, and cause α-
41
42
deprotonation of sulfoxides and/or sulfones. The resulting α-carbanions react with
43
44
45 hypochloric acid to form the chlorinated by-products. On the other hand, alkali species are
46
47 hard to dissolve in non-polar organic phase containing reactants and products, therefore
48
49 productions of the chlorinated by-products are suppressed.
50
51
52
53
54
55
56
57
58
59
60
27
1
2
3 Cl OH H OH 2
4 Cl O
5 S S S
6 R CH2 R' R CH2R' R CH2 R'
7 OH
Sulfide
8
A B
9
10
HO Cl O O OH
11 -HCl O O
12 S S S
R CH2 R' R CH2 R'
13 R CH2R' Cl
15 C
-
16 1) OH 1) OH -
17 2) HOCl 2) HOCl
18
19 O O O
HOCl
20 S S
R CHClR' R CHClR'
21
22
23 Scheme 8 Plausible reaction mechanism for the oxidation of sulfides
24 to sulfoxides and sulfones
25
26
27 5-3. Synthesis of sulfonyl chlorides from disulfides or thiols16
28
29
Sulfonyl chlorides are very important compounds in organic synthesis as precursors to
30
31
32 sulfonic esters, sulfonamides, sulfonic anhydrides, sulfonic hydrazide, sulfonyl azide, etc.
33
34 The representative method for the preparation of sulfonyl chlorides is the oxidative
35
36 chlorination of disulfides or thiols. 17 Many reagents are proposed though there are some
37
38 issues such as being toxic, hazardous, explosive or relatively expensive.
39
40
41 An environmentally-benign and economical preparation method of sulfonyl chloride is
42
43 therefore in great demand. We expected that NaOCl·5H2O could oxidize and chlorinate
44
45 disulfides or thiols to effectively form the corresponding sulfonyl chlorides. 18
46
47
48
49
50
5-3-1. Optimization of the reaction conditions
51
52
A search for the appropriate solvent found only acetic acid (Table 16). In order to
53
54
55 occur the oxidative chlorination from disulfide to sulfonyl chloride, 5 equiv. of HOCl are
56
57
58
59
60
28
1
2
3 necessary based on following experiment. The mechanism is assumed in the original
4
5 document. 16
6
7
8
9
10 Table 16 Reaction of di-p-tolyl disulfide with NaOCl·5H2O in several solvents
11
12 O O
NaOCl5H2O 2
13 S p-Tol S
p-Tol S solvent p-Tol X
14
15 0°C to r.t. X=Cl, OCH 3, OC 2H 5
16
17 NaOCl5H 2O Time Yield
Run Solvent
(equiv.) (h) (%)
18
19 1 CH3OH 8.5 3.0 35 (X=OCH 3 )a
20
21 2 C 2H 5OH 18.5 7.7 13 (X=OC 2 H 5) a
22 3 t-BuOH 6.5 0.5 33 (X=Cl)a,b
23
24 4 CH3CN 6.5 1.0 14 (X=Cl)a
25 5 AcOH 5.0 1.1 80 (X=Cl)a,c
26
6 CH2Cl2 6.5 16.7 27 (X=Cl)d
27
28 7 toluene 6.5 16.7 29 (X=Cl)d
29 a The starting material completely disappeared, and no other product was obtained.
30 b
31 At 30°C. c At room temperature. d Part of the starting material remained.
32
33
34 Generation of hypochloric acid (HOCl) from NaOCl and acetic acid might be crucial for
35
36 the production of sulfonyl chlorides in this reaction based on a further investigation (Table
37
38
39
17). Both NaOCl·5H2O and aqueous NaOCl are equally effective for the synthesis of benzene
40
41 sulfonyl chloride in acetic acid (runs 1, 2). Acetic acid is not a very favorable solvent for
42
43 large scale synthesis, thus we used a minimum amount of acetic acid in water as an
44
45 immiscible solvent. The reaction of diphenyl disulfide with NaOCl·5H2O in
46
47
(trifluoromethyl)benzene (benzotrifluoride, BTF) in the presence of acetic acid (6.75 eq.) also
48
49
50 efficiently produced the desired product in high yield (run 3).
51
52
53
54
55
56
57
58
59
60
29
1
2
3
4
5
6
7
Table 17 Reaction of diphenyl disulfide with NaOCl under several conditionsa
8
9
10 NaOCl (5.0 equiv.) O O
S Ph 2
11 Ph S S
solvent, r.t. Ph Cl
12
13 Time GC yieldb
14 Run Solvent NaOCl Additive
(h) (%)
15
16 1 AcOH NaOCl5H2 O — 0.5 80
17
2 AcOH aq. 12% NaOCl — 0.5 80
18
19 AcOH
3 BTF NaOCl5H2 O 0.5 87
20 (6.75 equiv.)
21
22 4 BTF NaOCl5H2 O — 5 2c
23 Bu4 NBr
5 BTF NaOCl5H2 O 1 43d
24 (0.05 equiv.)
25
Bu4 NHSO4
26 6 BTF NaOCl5H2 O 0.5 47d
(0.05 equiv.)
27
28 Bu4 NBr
7 BTF aq. 12% NaOCl 0.5 17d
29 (0.05 equiv.)
30 a
Diphenyl disulfide (3.0 mmol), NaOCl (15.0 mmol), solvent (33 mL)
31 b GC yield using an internal standard. c Most of the diphenyl disulfide was unreacted.
32 d Sodium benzenesulfonate was accompanied as a by-product.
33
34
35
36
37 Although both NaOCl·5H2O and aq. NaOCl are equally available for the synthesis of
38
39 sulfonyl chlorides, NaOCl·5H2O is easier to use than the aqueous NaOCl as we described in
40
41 the previous chapters.
42
43
44
45
46 5-3-2. Example for the reaction of disulfides or thiols to sulfonyl chloride
47
48
49 The reaction of several disulfides with precisely 5 equiv of NaOCl·5H2O in acetic acid
50
51 at room temperature was undertaken, and the corresponding sulfonyl chlorides were obtained
52
53 in high yields in all cases19 (Table 18). The oxidative-chlorinations were actually quickly
54
55 completed. Thus, treatment of the disulfide with NaOCl·5H2O (5 eq.) in acetic acid, which
56
57
58 was monitored by GC-analysis, revealed that the reaction was immediately completed and
59
60
30
1
2
3 99% of the disulfide was converted to the corresponding sulfonyl chloride within 1 minute
4
5 (entry 2).
6
7
Table 18 Reaction of disulfides with NaOCl·5H2O in AcOH
8
9
10 NaOCl5H2O (5.0 equiv.) O O
S R 2 S
11 R S AcOH, r.t. R Cl
12 Entry R Time Isolated yield (%)
13
14 1 p-Tol 1.1 h 80
15 2 p-Tol 1 min 99a
16
3 Ph 0.6 h 63
17
18 4 p-MeOC6H4 0.5 h 84
19 5 p-ClC6H4 0.3 h 74
20
21 6 PhCH2 0.4 h 75
22 7 Cyclohexyl 0.2 h 97
23 a
GC area%
24
25
26
27
28 Next, several thiols were treated with NaOCl·5H2O in acetic acid at room temperature
29
30 (Table 19). According to the mechanism described in the previously published
31
32 communication, 4 eq. of NaOCl·5H2O was required for completion of the reaction. The
33
34
exothermic reactions went to completion immediately to form the corresponding sulfonyl
35
36
37 chloride in high yields. 19
38
39
40
41
Table 19 Reaction of thiols with NaOCl·5H2O in AcOH
42
NaOCl5H2O (4.0 equiv.) O O
43 SH
R S
44 AcOH, r.t., 1 min R Cl
45 Entry R Isolated yield (%)
46
47 1 p-Tol 86
48 2 Ph 79
49 3 p-MeOC6H4 97
50
51 4 p-ClC6H4 90
52 5 PhCH2 71
53
6 Cyclohexyl 95
54
55
56
57
58
59
60
31
1
2
3 Similar to the reaction of disulfides, hypochloric acid derived from NaOCl acts as an
4
5 electrophilic chlorinating agent of sulfur atoms.
6
7
8
9
10 5-5. Synthesis of sulfonyl bromides from disulfides or thiols20
11
12 Our extensive study of the oxidative chlorination was next attempted for bromination.
13
14 Sulfonyl bromides may be favorable reagents for the synthesis of sulfone amides over
15
16 sulfonyl chlorides. It is well known that hypochlorite (OCl-) reacts with the bromoanion (Br-)
17
18
19 to produce hypobromite (OBr-).21Based on the plausible reaction mechanism shown as
20
21 Scheme 9, it is expected that the reactions of disulfides or thiols with NaOCl·5H2O in acetic
22
23 acid in the presence of excess amounts of sodium bromide (NaBr) produce the corresponding
24
25 sulfonyl bromide.
26
27
28 NaOCl
29 NaBr HOBr
30 AcOH
31
S R
32 1/2 R S O O
33 or S
34 R Br
R SH
35
36 Scheme 9 Synthesis of sulfonyl bromide
37
38
39
40
41 The addition of several disulfide or thiols to a mixture of NaOCl·5H2O and NaBr in acetic
42
43 acid resulted in the formation of the corresponding sulfonyl bromides (Tables 20,21)22
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
32
1
2
3 Table 20 Synthesis of sulfonyl bromides from disulfides
4
NaOCl・5H 2 O (6.5 eq.)
5
NaBr (8 eq.) O O
6 S R 2
R S S
7 AcOH, r.t. R Br
8
9
Time Yield
Entry R
10 ( min ) (%)
11 1 p-tol 80 85
12
13
14 2 p-MeOC 6 H4 30 62
15
16 3 p-ClC6 H 4 40 73
17
18 4 Cyclohexyl 40 92
19
20 CH3(CH 2) 9
5 10 79
21
22
23
24
25 Table 21 Synthesis of sulfonyl bromides from disulfides
26
27
NaOCl5H 2O (6.5 eq.)
28 O O
S NaBr (8 eq.)
29 R H S
30 AcOH, r.t. R Br
31
32 Time Yield
Entry R
33 ( min ) (%)
34
35 1 Ph 50 quant
36 2 p-tol 42 91
37
38 3 p-MeOC 6H 4 27 quant
39 4 p-ClC 6H 4 40 61
40
41 5 Cyclohexyl 27 quant
42
43
44
45
46 6. Miscellaneous reactions
47
48 6-1. Synthesis of Davis oxaziridines23
49
50 Davis oxaziridines (N-sulfonyloxaziridines) are important reagents in synthetic organic
51
52
53
chemistry, and can be used as oxidizing and electrophilic amination reagents.24,25 They are
54
55 generally prepared by the oxidation of the corresponding imines, and several oxidants have
56
57 been used for this purpose.
58
59
60
33
1
2
3 We found that Davis oxaziridines can be synthesized by the oxidation of the corresponding
4
5 N-sulfonylimines with aq. NaOCl prepared from NaOCl·5H2O in acetonitrile without any
6
7
catalysts.23 In this oxidation, a basic condition (pH=13) and excess amount of NaOCl are
8
9
10 required to obtain the products in high yields (Scheme 10).
11
12
13
14
15
pH = 13
16 12% NaOCl aq. (6 eq.)
17 Ts (prepared from NaOCl .5H2O Ts
18 N N
19 and pH 13 buffer) O
20 Ph H Ph H
21 CH3CN
22 0 oC to r.t. 30 min 90%
23
24
25 pH = 13
26 12% NaOCl aq. (6 eq.)
27
28 (prepared from NaOCl .5H2O
29 and pH 13 buffer) O
30 N
31
S S N
O O CH3CN
32
33 0 oC to r.t. 30 min O O 66%
34
35 Scheme 10 Synthesis of oxaziridines
36
37
38
39
40 6-2. Oxidative dearomatization of phenols26
41
42 The oxidative dearomatization of phenols and their analogues has been a useful synthetic
43
44 method, and has been used for the syntheses of natural products or biologically-active
45
46 compounds.27 Recently, Ishihara, Uyanik, and colleagues reported the oxidative
47
48
49 dearomatization of phenols using NaOCl·5H2O crystals as oxidants (Scheme 11).26,28 The
50
51 reaction of β-(2-hydroxyphenyl)-carboxylic acids with 1.1 eq. of NaOCl·5H2O provided the
52
53 desired spirolactones in good yields.
54
55
56
57
58
59
60
34
1
2
3 OH O
4 NaOCl・5H2O (1.1 eq.)
5 O
R R O
6 CO2H Method A: EtOAc, -20 oC
7
Method B: EtOAc/H 2O (20:1 v/v), 0 oC 78~99%
8
9
10 Scheme 11 Oxidative dearomatization of phenols by NaOCl·5H2O
11
12
13
14
15 The present method is not limited to only the spirolactonization of β-(2-hydroxyphenyl)
16
17 carboxylic acids. The reaction of various phenols gave the corresponding oxidized
18
19 compounds in high yields (Scheme 12).
20
21 OH O
22 NaOCl5H2O (1.1 eq.)
23 O
24 EtOAc/H2O (30:1 v/v)
25 O
0 oC, 3 h
26 Ph H Ph 76%
27 OH O
28
29 NaOCl5H2O (2 eq.)
30 N
EtOAc/H2O (70:1 v/v)
31 HN Ms
0 oC, 30 min
32 Ph Ms Ph 80%
33 OH O
34
36 EtOAc/H2O (6:1 v/v) 91%
37
38 rt, 3 h OH
39 O
OH
40
41 t-Bu OH NaOCl5H2O (1.1 eq.) t-Bu O
42 98%
43
44 t-Bu 0 oC, 40 min t-Bu
45
46
OH O
47
49 90%
50 o
51 OH 0 C, 20 min
O
52
53 Scheme 12 NaOCl·5H2O-mediated oxidation of various phenols
54
55
56
57
58
59
60
35
1
2
3 In this reaction, NaOCl·5H2O provided a better result than the conventional aq. NaOCl
4
5 (Table 22). The high chemoselectivity of NaOCl·5H2O might be due to its lower pH value.
6
7 OH O
8
NaOCl (1 equiv.)
9 O
10 EtOAc/H2O O
CO2H
11 (79:1 v/v)
12 Ph 0 oC, 2 h Ph
13
14 NaOCl Yield (%)
15
16 NaOCl・5H 2O 92
17
18 conventional aq. NaOCl (ca. 10 wt%) 74*
19
20
21 Table 22 Reaction of phenol with NaOCl·5H2O or aq. NaOCl
22
23 *
Accompanied with by-products.
24
25
26
27
28
29
30 7. Conclusions
31
32 NaOCl·5H2O crystals have several advantages over the conventional aq. NaOCl as shown
33
34 in Table 23. These advantages can make NaOCl·5H2O a useful oxidant for organic synthesis
35
36 as shown in this review.
37
38
39
40
41 Table 23 Advantages of NaOCl·5H2O over conventional aq. NaOCl
42
43
Conventional
44 Features ・5H2O
NaOCl・
45 aq.NaOCl
46 Oxidation
47 Standard Strong
performance
48
49 Volumetric
50
Low High (3 times)
efficiency
51
52 Merit Waste water High Reduce to 1/5
53
54
55 Concentration as
56 NaOCl wt% Under 13%
44% (42%)
57 (available (~12%)
58 chlorine %)
59
60
36
1
2
3
Suffers from Stable during cold storage
4 Stability
5
decomposition (< 7 °C)
6
Titration before
7 Convenience Necessary Not required
8
using
9 Hazardous
10 Non-explosive Non-explosive
11
nature
12
13
pH pH = 13 pH = 11
14
15 Properties Melting point - 25～27 °C
16
17 Appearance Yellow liquid Yellow crystals
18
19
20
21 Acknowledgement
22
23
24 We grateful to Dr. Hideyuki Tsutsui and Mr. Hideo Shimazu (Nippon Light Metal Co. Ltd.)
25
26 for their useful suggestions.
27
28
29
30
31
32
33 Supporting Information
34
35
36 Experimental details of hazard estimation of sodium hypochlorite pentahydrate.
37
38
39
40
41
42 References and Notes
43
44
45
(1) Applebey, M. P. J. Chem. Soc. Trans. 1919, 115, 1106-1109.
46
47
48
49 (2) Asawa, T.; Tuneizumi, T.; Iwasaki, Y. Japanese Patent 4,211,130, 2008; JP (Japan Kokai
50
51 Tokkyo Koho) 2000-290003, Chem. Abstr. 2000, 133, 311496.
52
53
54 (3) NaOCl·5H2O is commercially available from Wako Pure Chemical Industries, Ltd.,
55
56 Tokyo Chemical Industry Co. Ltd., and Junsei Chemical Co., Ltd. in Japan. TCI America
57
58
59
60
37
1
2
3 and TCI Europe also provide NaOCl·5H2O as a reagent. Large quantity of NaOCl·5H2O
4
5 can be directly supplied from Nippon Light Metal Company, Ltd. under the trade name of
6
7
“SHC5”.
8
9
10
11 (4) Galvin, J. M.; Jacobsen, E. N.; Palucki, M.; Frederick, M. O. e-EROS 2013, NaOCl, DOI:
12
13 10.1002/047084289X.rs084.pub3 and references cited therein.
14
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16 (5) Okada, T.; Asawa, T.; Sugiyama, Y.; Iwai, T.; Kirihara, M.; Kimura, Y. Tetrahedron
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18 2016, 72, 2818-2827.
19
20
21
(6) Unpublished results. The details of the experimental results are shown in the supporting
22
23
24 information of this review.
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26
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13 (14) Siedlecka, R.; Skarżewski, J. Synthesis 1994, 401-404.
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(16) Okada, T.; Matsumuro, H.; Iwai, T.; Kitagawa, S.; Yamazaki, K.; Akiyama, T.;
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56 2471.
57
58
59
60
40
1
2
3 (18) A synthesis of alkanesulfonyl chlorides via aq. NaOCl-mediated oxidative
4
5 chlorosulfonation of S-alkyl isothiourea salts was reported: Yang, Z.; Zhou, B.; Xu, J.
6
7
Synthesis 2014, 46, 225–229.
8
9
10
11 (19) In the preliminary communication (ref. 16), the representative procedures for the
12
13 synthesis of sulfonyl chlorides from disulfides or thiols are the cases of p-toluenesulfonyl
14
15 chloride, and saturated aqueous sodium thiosulfate (sat. aq. Na2S2O3) was added to
16
17 quench the reaction. We recently found that sat. aq. Na2S2O3 sometimes promotes the
18
19
20
decomposition of the products (sulfonyl chlorides), therefore, addition of the same
21
22 volume of water instead of sat. aq. Na2S2O3 is recommended; Kirihara, M.; Okada T.;
23
24 unpublished results.
25
26
27 (20) Kirihara, M.; Odagiri, T.; Asawa, T. JP (Japan Kokai Tokkyo Koho) 2017-52728;
28
29 Chem. Abstr. 2017, 166, 304950.
30
31
32
33 (21) Farkas, L.; Lewin, M.; Bloch, R. J. Am. Chem. Soc. 1949, 71, 1988-1991.
34
35
36 (22) It is crucial that OCl- must be completely converted to OBr- prior to the reaction with
37
38 disulfides or thiols. If OCl- remained, the corresponding sulfonyl chlorides would also be
39
40 produced.
41
42
43
(23) Kirihara, M.; Takizawa, S.; Odagiri, T.; Asawa, T. JP (Japan Kokai Tokkyo Koho)
44
45
46 2017-52729; Chem. Abstr. 2017, 166, 339575.
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53 25-26; (c) Davis, F. A.; Stringer, O. D. J. Org. Chem. 1982, 47, 1774-1775; (d) Davis, F.
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59
60
41
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