A simple and efficient synthesis of trihalomethyl and dihalonitromethyl aryl sulfones

Article abstract of DOI:10.1016/j.tetlet.2012.09.121

A method for the preparation of aryl trihalomethyl sulfones - active biocidal agents - with identical or different halogens is presented. The synthesis is based on the reaction of aryl methyl, aryl halomethyl, or aryl nitromethyl sulfones with sodium hypohalite. The method is simple in implementation, does not necessarily require the use of organic solvents, and selectively affords the products in good to excellent yields. Notably, it allows the preparation of the hitherto unknown phenyl trihalomethyl sulfone with three different halogens: fluorine, chlorine, and bromine.

Full text of DOI:10.1016/j.tetlet.2012.09.121

Tetrahedron Letters 53 (2012) 6606–6610
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Tetrahedron Letters
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A simple and efficient synthesis of trihalomethyl and dihalonitromethyl aryl
sulfones
⇑
´
Krzysztof M. Borys, Maciej D. Korzynski, Zbigniew Ochal
Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
A method for the preparation of aryl trihalomethyl sulfones—active biocidal agents—with identical or dif-
ferent halogens is presented. The synthesis is based on the reaction of aryl methyl, aryl halomethyl, or
aryl nitromethyl sulfones with sodium hypohalite. The method is simple in implementation, does not
necessarily require the use of organic solvents, and selectively affords the products in good to excellent
yields. Notably, it allows the preparation of the hitherto unknown phenyl trihalomethyl sulfone with
three different halogens: fluorine, chlorine, and bromine.
Received 1 August 2012
Revised 15 September 2012
Accepted 26 September 2012
Available online 2 October 2012
Keywords:
Sulfone
Ó 2012 Elsevier Ltd. All rights reserved.
Halogenation
Hypohalite
Biocide
The introduction of a trihalomethylsulfonyl group (particularly
with two different halogens) into aromatic compounds has gained
attention due to the application of such compounds in agricultural
chemistry (primarily as biocides) and organic chemistry (as syn-
thetic intermediates). Concerning their biological properties, they
were found to be useful in preventing aquatic organisms from
attaching to fishing nets and ship hulls,1 as well as having diverse
herbicidal,2–4 bactericidal,5 antifungal,3,6,7 algicidal,8 and insecti-
cidal9 types of activity. In organic synthesis, the aforementioned
sulfones were utilized as reagents for the introduction of difluoro-
methyl or phenylsulfonyldifluoromethyl groups into different clas-
ses of organic compounds.10–14 Moreover, their potential to act as
carbene precursors was shown by performing O- and N-difluorom-
ethylations with chlorodifluoromethyl phenyl sulfone.10 Trichloro-
methyl sulfones were reported to undergo a Ramberg–Bäcklund
rearrangement with the formation of dichloromethylene
products.15 The reaction of tribromomethyl phenyl sulfone with
terminal olefins utilizing a mercury lamp yielded phenyl 1,1,3-trib-
romoalkyl sulfones.16 Dehalogenation of the title compounds was
also investigated by performing reduction of phenyl trichloro-
methyl sulfones with iron(II) chloride.17
starting materials, while the target halomethyl sulfone is obtained
by oxidation with hydrogen peroxide and acetic acid.20 Fluorom-
ethyl halides are known to be ozone-depleting substances, there-
fore their manufacture and use have been strictly regulated.
Procedures involving them require special apparatus, and the
product yields vary widely. When the procedures do not make
use of halomethanes, they are inconvenient. As an example, the
preparation of chlorodifluoromethyl phenyl sulfone requires chlo-
rination of difluoromethyl phenyl sulfone with N-chlorosuccini-
mide in the presence of lithium hexamethyldisilazide (LiHMDS)
in THF at À78 °C.10 Another approach, starting from thioanisole, in-
cluded chlorination with elemental chlorine, fluorination with
Olah’s reagent (a mixture of hydrogen fluoride and pyridine), and
oxidation with sodium periodate.10 Farrar’s method for the synthe-
sis of trichloro- and tribromomethyl phenyl sulfones,22 featuring
the reaction of phenylthioacetic acid with sodium hypohalite, suf-
fers from the very long time needed for product formation as well
as from the fact that the products are significantly contaminated.
Finally, none of the methods reported can be utilized for the prep-
aration of trihalomethyl aryl sulfones containing three different
halogens.
Although several approaches toward the synthesis of trihalom-
ethyl phenyl sulfones have been developed, they all suffer from se-
vere drawbacks. Most use halofluoromethanes such as CF2Br2,18,19
CF2BrCl,19 CFBr3 and CFCl3,20 or CF3I21 as the trihalomethyl group
bearing substrates. The reactions feature thiols or disulfides as
In this work we present a simple and efficient method for the
synthesis of trihalomethyl and dihalonitromethyl aryl sulfones
using commercially available sodium hypochlorite or readily
obtainable sodium hypobromite as halogenating agents. Structur-
ally varied substrates were used for the reaction: methyl phenyl
sulfones, halomethyl phenyl sulfones, nitromethyl phenyl sulfones,
as well as halomethyl benzimidazolyl or benzothiazolyl sulfones
containing one or two unsubstituted hydrogen atoms on the
methyl group (Scheme 1 and Table 1).
⇑
Corresponding author. Tel.: +48 22 234 73 27; fax: +48 22 628 27 41.
E-mail address: zbigniew.ochal.pw@gmail.com (Z. Ochal).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.121

K. M. Borys et al. / Tetrahedron Letters 53 (2012) 6606–6610
6607
ArSO2CH3
ArSO2CX3
The methodology developed made it possible to synthesize the
hitherto unknown bromochlorofluoromethyl 4-chlorophenyl sul-
fone (34), bearing three different halogen atoms on the methyl
group (Scheme 2).
NaOX
ArSO2CH2NO2
ArSO2CH(3-n)Yn
ArSO2CX2NO2
ArSO2CX(3-n)Yn
The commercially available, inexpensive, 4-chlorothiophenol
was utilized as the starting material. Its reaction with
formaldehyde and hydrochloric acid yielded the corresponding
monochloromethyl thioether.36 The second step of the synthesis,
fluorination of chloromethyl phenyl sulfide with tetra-n-butylam-
monium dihydrotrifluoride, was carried out according to the pat-
ented procedure which constitutes a general method for the
preparation of fluorohalomethyl aryl sulfides.23 The resulting chlo-
rofluoromethyl sulfide was oxygenated with a mixture of hydrogen
peroxide and acetic acid, the procedure being a standard method
for the synthesis of aryl methyl sulfones.37 Finally, the target
bromochlorofluoromethyl sulfone 34 was obtained by bromination
with sodium hypobromite (the bromination step proceeded in 85%
yield (Scheme 2).
Another structurally interesting product obtained via hypoha-
lite halogenation was 2,5-bis(trichloromethylsulfonyl)benzimid-
azole (44), a heterocyclic compound possessing two trihalomethy
lsulfonyl groups. Chlorination with sodium hypochlorite was exe-
cuted on 5-[(chloromethyl)sulfonyl]-2-(methylsulfanyl)benzimid-
azole (20), synthesized from the corresponding thiol33 by
methylation with methyl iodide. Notably, the hypochlorite played
a double role in this transformation: first it acted as an oxidizing
agent, converting the thioether into the sulfone, and then as a hal-
ogenating agent (Scheme 3).
Scheme 1. Scope of the substrates utilized along with the obtained products (Ar, X,
and Y are given in Table 1).
The reaction yielded exclusively halomethyl sulfones fully hal-
ogenated on the methyl group. Notably, when methyl phenyl sulf-
ones were used as substrates, no isolation of intermediates (i.e.
mono- and dihalomethyl sulfones) was observed. Halogenation of
mononitromethyl phenyl sulfones also led to the fully halogenated,
dihalomethyl derivatives. These observations indicate that the
halogenation is very fast. For sulfones, chlorination using technical
grade commercial sodium hypochlorite (NaOCl) was employed. In
the case of bromination, sodium hypobromite was freshly prepared
by dropwise addition of bromine to a cold aqueous solution of
sodium hydroxide. The hypohalites were usually used in threefold
molar excess, up to a maximum of five equivalents of hypohalite
when the volume of the mixture had to be increased in order to
facilitate stirring. The process was carried out within 3–6 h at
75 °C (reactions performed at higher temperatures resulted in low-
er yields due to apparent decomposition of the hypohalites), the
crude product being easily isolated by filtration. A significant
advantage of this method is that there is no need for the use of or-
ganic solvents. Moreover, addition of an organic solvent—toluene,
xylene, dichloromethane, or trichloromethane—and carrying out
the reaction in a biphasic (aqueous-organic) system did not lead
to the formation of the products (or resulted in only trace
amounts), even when phase-transfer catalysts (PTC) such as trieth-
ylbenzylammonium chloride, tetra-n-butylammonium bromide, or
Aliquat 336 were applied.
The compounds synthesized were tested for their biological
activity (see Supplementary data, Tables 2 and 3, for detailed
information). The evaluation of fungicidal activity was carried
out by determining the percentage inhibition of mycelium growth
on agar medium under the influence of the tested compound
compared with the control. Phytocidal activity was evaluated
(n-Bu)4N H2F3
(CH2O)n
Cl
SH
Cl
S
CH2Cl
Cl
Cl
S CHClF
HCl
H2O2
CH3COOH
NaOBr
Cl
SO2CBrClF
34
SO2CHClF
13
Scheme 2. Synthesis of bromochlorofluoromethyl sulfone 34.
H
N
H
N
H
NaOCl
N
N
CH3I
SO2CH3
SH
S
N
Cl3CO2S
N
ClH2CO2S
ClH2CO2S
20
NaOCl
H
N
SO2CCl3
N
Cl3CO2S
44
Scheme 3. Preparation of 2,5-bis(trichloromethylsulfonyl)benzimidazole (44).

6608
K. M. Borys et al. / Tetrahedron Letters 53 (2012) 6606–6610
Table 1
Reaction of sulfones with sodium hypohalites
Entry
1
Substrate
Ref.a
24
Hypohalite
NaOCl
Product
Yieldb (%)
93
Time (h)
4
Cl
SO2CH3
SO2CH2Cl
SO2CHCl2
SO2CH3
Cl
SO2CCl3
SO2CCl3
SO2CCl3
SO2CCl3
1
2
21
21
21
22
Cl
Cl
Br
Cl
Cl
Br
2
25
25
31
26
27
28
28
28
29
35
24
25
28
25
28
28
23
30
30
NaOCl
NaOCl
NaOCl
NaOCl
NaOCl
NaOCl
NaOCl
NaOCl
NaOCl
NaOBr
NaOBr
NaOBr
NaOBr
NaOBr
NaOBr
NaOBr
NaOBr
NaOCl
NaOBr
94
93
88
92
87
78
88
88
91
72
96
83
84
88
87
83
85
88
86
3
3
4
4
4
4
4
4
6
5
3
3
3
3
4
4
4
6
5
3
3
4
4
Cl
Cl
Cl
SO2CH2Br
SO2CHBr2
SO2CH2F
Cl
Cl
Cl
SO2CCl2Br
SO2CClBr2
SO2CCl2F
5
5
6
7
23
24
25
6
7
SO2CHF2
SO2CClF2
8
8
26
Cl
SO2CHF2
Cl
Cl
SO2CClF2
9
27
28
9
Cl
SO2CH2I
SO2CCl2I
10
11
12
13
14
15
16
17
18
19
20
10
SO2CH3
SO2CBr3
11
29
Cl
SO2CH3
Cl
Cl
Cl
Cl
SO2CBr3
1
2
30
24
31
Cl
Cl
Cl
SO2CH2Cl
SO2CH2F
SO2CHCl2
SO2ClBr2
SO2CBr2F
12
3
SO2CCl2Br
23
SO2CF2Br
SO2CHF2
8
32
Cl
SO2CHF2
Cl
Cl
Cl
Cl
SO2CF2Br
33
34
35
36
9
Cl
Cl
Cl
SO2CHClF
SO2CBrClF
SO2CCl2NO2
SO2CBr2NO2
13
14
14
SO2CH2NO2
SO2CH2NO2

K. M. Borys et al. / Tetrahedron Letters 53 (2012) 6606–6610
6609
Table 1 (continued)
Entry
Substrate
Ref.a
32
Hypohalite
NaOCl
Product
Yieldb (%)
Time (h)
N
N
N
N
CF3
CF3
CF3
21
88
5
F2HCO2S
ClF2CO2S
37
15
16
H
H
N
N
N
CF3
22
23
33
32
NaOCl
NaOCl
78
82
5
5
N
ClH2CO2S
F2HCO2S
Cl3CO2S
38
39
N
N
CF3
CF3
N
N
ClF2CO2S
17
17
N
N
N
CF3
CF3
CF3
CF3
24
25
26
27
32
34
32
34
NaOBr
NaOCl
NaOCl
NaOBr
NaOCl
79
77
96
78
81
4
3
3
4
4
N
F2HCO2S
F2HCO2S
F2BrCO2S
ClF2CO2S
40
S
N
S
N
18
41
N
N
N
N
F2HCO2S
F2HCO2S
F2ClCO2S
F2BrCO2S
19
18
42
43
S
N
S
N
CF3
CF3
H
H
N
N
N
N
SCH3
SO2CCl3
28
ClH2CO2S
Cl3CO2S
20
44
a
The references concerned with substrate preparation.
Isolated yields.
b
by calculating the percentage of damage of bioindicator
monocotyledonous and dicotyledonous crop plants under the
influence of the tested compound compared with the control
plants. Some of the trihalomethyl phenyl sulfones exhibited
interesting fungicidal activity: compounds 23, 30, 34, and 44 were
highly or moderately active against certain fungal pathogens. The
trihalomethylsulfonyl-bearing benzimidazole and benzothiazoles
showed phytocidal activity, products 37 and 39 being the most
potent.
The methodology presented for sulfone halogenation with the
use of sodium hypohalites proved to be an efficient way of synthe-
sizing trihalomethyl and dihalonitromethyl aryl sulfones with di-
verse structures. The preparation of trihalomethyl phenyl sulfone
with three different halogens on the methyl group was achieved
and is reported for the first time.
22 and 30). See Supplementary data for the characterization of
the chlorination products obtained.
Sulfone bromination with sodium hypobromite-general
procedure
To a solution of NaOH (15% w/w, 8 mL) cooled to 5 °C, Br2
(0.4 mL, 15 mmol, 3 equiv) was added dropwise while maintaining
the temperature of the mixture below 10 °C. Next, the sulfone
(5 mmol, 1 equiv) was added in one portion. The resulting mixture
was stirred for the given time (Table 1) at 75 °C. The mixture was
cooled to room temperature, and the precipitate filtered off,
washed with H2O, dried in air, and crystallized from 2-PrOH. See
Supplementary data for the characterization of the bromination
products obtained.
Acknowledgment
Sulfone chlorination with sodium hypochlorite-general
procedure
This work was financially supported by the Warsaw University
of Technology.
To an aqueous solution of sodium hypochlorite (12–13 mL of a
technical solution containing 0.10–0.12 g NaClO per 1 mL,
18 mmol, 3 equiv), was added the sulfone substrate (6 mmol,
1 equiv) in one portion and the mixture was stirred for the time gi-
ven (Table 1) at 75 °C. The mixture was cooled to room tempera-
ture and the precipitate was filtered off, washed with H2O, dried
in air, and crystallized from 2-PrOH (EtOH in the case of products
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
09.121.

6610
K. M. Borys et al. / Tetrahedron Letters 53 (2012) 6606–6610
17. Folli, U.; Goldoni, F.; Iarossi, D.; Sbardellati, S.; Taddei, F. J. Chem. Soc., Perkin
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