A novel method for the synthesis of aryl trihalomethyl sulfones and their derivatization: The search for new sulfone fungicides

Article abstract of DOI:10.1016/j.tetlet.2013.12.012

A novel method for the preparation of bioactive aryl trihalomethyl sulfones is reported. An iodination reaction with iodine bromide is applied for the synthesis of difluoroiodomethyl aryl sulfones. A series of difluoroiodomethylsulfonyl group bearing derivatives is afforded, including nitroanilines and benzimidazoles. Biological studies show high fungicidal activity for a number of the synthesized sulfones.

Full text of DOI:10.1016/j.tetlet.2013.12.012

Tetrahedron Letters 55 (2014) 745–748
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Tetrahedron Letters
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A novel method for the synthesis of aryl trihalomethyl sulfones
and their derivatization: the search for new sulfone fungicides
⇑
´
Maciej D. Korzynski, Krzysztof M. Borys, Justyna Białek, 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 novel method for the preparation of bioactive aryl trihalomethyl sulfones is reported. An iodination
reaction with iodine bromide is applied for the synthesis of difluoroiodomethyl aryl sulfones. A series
of difluoroiodomethylsulfonyl group bearing derivatives is afforded, including nitroanilines and benzim-
idazoles. Biological studies show high fungicidal activity for a number of the synthesized sulfones.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 17 September 2013
Revised 5 November 2013
Accepted 5 December 2013
Available online 12 December 2013
Keywords:
Difluoroiodomethyl sulfone
Iodine bromide
SNAr reaction
Sulfone fungicides
Many iodine-containing aryl halomethyl sulfones show high
fungicidal activity against certain plant pathogens and are the sub-
ject of a number of reports, mainly patents.1–4 Diiodomethyl p-to-
lyl sulfone was proposed as
a veterinary medicine for the
treatment of fungal diseases in domestic animals.2 Moreover,
many other para-substituted aryl diiodomethyl sulfones exhibit
fungicidal activity toward pathogenic fungi.3,4 In the context of
applications in organic synthesis, difluoroiodomethyl phenyl sul-
fone has been utilized as a reagent in the radical (phenylsulfo-
nyl)difluoromethylation of terminal alkenes.5
Scheme 1. Iodination of the starting aryl halomethyl sulfones with iodine bromide
(the substituents are identified in Table 1).
A known method for the preparation of aryl iodomethyl sulf-
ones containing no other halogen in the halomethylsulfonyl group
is based on the iodination of arylsulfonylacetic acids with molecu-
lar iodine in alkaline solution.6 The major disadvantage of this
method is that it is necessary to prepare an appropriate starting
arylsulfonylacetic acid, most often via a multistep synthesis. There
are only a few methods for the preparation of aryl trihalomethyl
sulfones which also contain halogens other than iodine. Aryl iod-
odifluoromethyl sulfones were synthesized by coupling the mer-
cury salts of arylsulfinyldifluoroacetic acids with iodine followed
by oxidation with MCPBA.7 Difluoroiodomethyl phenyl sulfone
was obtained from the reaction of difluoromethyl phenyl sulfone
with iodine and potassium tert-butoxide in DMF at low (ꢀ30 to
ꢀ20 °C) temperature.8 Alternatively, it was obtained by treatment
of difluoro(trimethylsilyl)methyl phenyl sulfone with copper(I) io-
dide and cesium fluoride in DMF (ꢀ30 °C, then 0 °C).9
Table 1
Iodine-containing aryl trihalomethyl sulfones 1–5
Entry
Product
R1
R2
R3 (substrate)
R3 (product)
Yielda (%)
1
2
3
4
5
1
2
3
4
5
H
H
H
H
NO2
H
CHF2
CHCl2
CHF2
CHF2
CH2F
CF2I
CCl2I
CF2I
CF2I
CFI2
92
82
94
74
66
Cl
Cl
Cl
Cl
a
Isolated yield.
⇑
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 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.12.012

´
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M. D. Korzynski et al. / Tetrahedron Letters 55 (2014) 745–748
Scheme 2. Methods for the preparation of nitro derivative 4.
Scheme 3. SNAr transformations of sulfone 4.
Table 2
previously shown to exhibit increased biological activity when
Iodine-containing nitroaryl trihalomethyl sulfones 6a–6i
combined with a halomethylsulfonyl group).10,11 The products
were then investigated in terms of their fungicidal activity. As a re-
sult, several promising new leads for the development of sulfone-
based biocidal agents were obtained.
Our research revealed that a convenient method for the prepa-
ration of aryl trihalomethyl sulfones containing one or two iodine
atoms involved iodination with commercially available iodine bro-
mide. The reactions were carried out with potassium hydroxide in
carbon tetrachloride within the temperature range of 20–60 °C
(Scheme 1 and Table 1).
Entry
Product
R
Yielda (%)
1
2
3
6a
6b
6c
NH2
NHNH2
CH3NH
92
89
86
Notably, in the reaction of 4-chlorophenyl fluoromethyl sulfone
with iodine bromide a diiodo derivative was formed, and no
monoiodinated derivative was observed, despite utilizing iodine
bromide in less than stoichiometric quantity.
4
5
6d
6e
87
95
The substrates: 4-chlorophenyl difluoromethyl sulfone, 4-chlo-
rophenyl fluoromethyl sulfone, and 4-chlorophenyl dichlorometh-
yl sulfone were obtained according to our previous work.12
Application of potassium tert-butoxide as a base resulted in similar
or lower yields, except for the iodination of chlorophenyl 4-fluo-
romethyl sulfone in which the product 5 was obtained in 12% high-
er yield (78% yield with t-BuOK compared to 66% yield with KOH).
The desired products were obtained in very good yields (82–92%).
Analogous reactions carried out with iodine chloride afforded
sulfone 3 in yields ranging from 18% to 26%. With 4-chlorophenyl
dichloromethyl sulfone and 4-chlorophenyl fluoromethyl sulfone,
no products were obtained in the reactions with ICl; instead the
starting substrates were isolated from the reaction mixture.
Bearing in mind the interesting fungicidal activity of aryl iodo-
methyl sulfones, we decided to undertake further synthetic trans-
formations of compound 4 to give derivatives with potentially
6
7
6f
92
87
6g
8
9
6h
6i
92
87
CH3O
a
Isolated yield.
Herein we report a novel method for the synthesis of difluoroi-
odomethyl aryl sulfones, which makes use of simple substrates.
The synthetic procedure is easy to execute, occurs at room or
slightly elevated temperature, and the isolation of the product is
straightforward. Further functionalization of the nitro-substituted
product afforded a series of difluoromethyl sulfone derivatives,
including nitroanilines and benzimidazoles (compounds

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M. D. Korzynski et al. / Tetrahedron Letters 55 (2014) 745–748
Scheme 4. Preparation of benzimidazoles 8a–8d (the substituents are identified in Table 3).
consisted of the reduction of the nitro group using stannous chlo-
ride in concentrated hydrochloric acid, followed by work-up with
aqueous sodium hydroxide (hydrolysis of the resulting chlorostan-
nic acid–diamine complexes). The so-obtained crude nitroanilines
7a and 7b were used directly in the next step. The formation of
the benzimidazole scaffolds was carried out according to the Phi-
lips method,13,14 based on the treatment of an aromatic diamine
with a carboxylic acid and aqueous hydrochloric acid. 2-Substi-
tuted benzimidazoles 8a–8d were obtained in good yields over
the two steps (Table 3).
Table 3
Benzimidazole derivatives 8a–8d
Entry
Product
R1
R2
Yielda (%)
1
2
3
4
8a
8b
8c
8d
H
H
CH3
CH3
CH3
CF3
CH3
CF3
65
72
65
70
The synthesized compounds were tested for their fungicidal
activity (Table 4), which was investigated by inhibition of myce-
lium growth on agar medium, caused by the tested compounds
and compared with the control (untreated mycelium).
a
Isolated yields over two steps (starting from the nitroaniline substrate).
The highest fungicidal activity was exhibited by sulfone 4,
which at both examined concentrations resulted in nearly total
elimination of the five tested fungi. Substitution of the chlorine
atom in sulfone 4 with an amine group (6a) resulted in lower fun-
gicidal activity. Introduction of other substituents at the 1-position
also lowered the fungicidal activity. Interesting activity was
showed by benzimidazole derivatives 8b and 8d containing a tri-
fluoromethyl group at their 2-position, being much more active
than their 2-methyl-substituted analogues.
In conclusion, we have developed a novel, simple method for
the synthesis of aryl difluoroiodomethyl sulfones. The preparation
of derivatives of these compounds, including nitroanilines and
benzimidazoles, has broadened the scope for biological evaluation.
The biological studies showed that some of the investigated spe-
cies present high fungicidal activity and should therefore be fur-
higher biological activity. In the first step, a nitro derivative was
synthesized in two different ways: the first was via nitration of
4-chlorophenyl difluoroiodomethyl sulfone, and the second in-
volved the reaction of 4-chloro-3-nitrophenyl difluoromethyl sul-
fone with iodine bromide (Scheme 2).
Both the nitration and iodination of the sulfones occurred in
satisfactory yields (94% and 74%, respectively). Sulfone 4 was then
used as a substrate for aromatic nucleophilic substitution reactions
with ammonia, hydrazine, and primary and secondary amines
(Scheme 3). In the reaction with sodium methoxide, the chlorine
atom underwent substitution with a methoxy group. The substitu-
tion products were obtained in good to excellent yields (Table 2).
The 2-nitroanilines 6a and 6c were converted into benzimid-
azole derivatives in a two-step synthesis (Scheme 4). The first step
Table 4
Fungicidal activity of the most active compoundsa
Entry
Test substrate
A. alternata
100 g/mL
B. cinerea
F. culmorum
P. cactorum
R. solani
l
200
lg/mL
10 mg/mL
20
lg/mL
1
2
3
4
5
6
7
8
9
4
100
100
100
100
100
100
60
20
60
20
60
40
50
20
80
60
60
20
100
100
100
80
80
80
80
60
80
60
80
60
80
60
100
80
80
100
90
100
80
100
80
80
60
50
20
80
60
80
50
80
60
80
60
100
90
100
80
100
80
80
60
50
30
80
60
50
20
80
60
80
60
100
100
100
80
100
100
80
60
40
0
80
40
40
0
80
60
80
60
5
6a
6b
6f
6g
6h
8b
8d
60
a
The results of biological evaluations as the values of percentage inhibition of colony growth of the fungus, derived from the following formula: I = 100(C ꢀ T)/C, where
I = percentage inhibition of colony growth of the fungus, C = zone of growth of the fungus colony in mm in the control, T = zone of growth of the fungus colony in mm in the
examined sample. The first row of the table contains the names of the utilized fungal pathogens, the second row shows the examined concentration(s) of the test compound
in the sample.

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M. D. Korzynski et al. / Tetrahedron Letters 55 (2014) 745–748
748
2. Smith, R. A. Topical Treatment of Fungal or Yeast Infections Using p-Tolyl
Diiodomethyl Sulfone. U.S. Patent US 4185120, Jan 22, 1980; Chem. Abstr. 1980,
92, 203585.
ther investigated in terms of their application in crop protection
against phytopathogenic fungi.
3. Crovetti, A. J. 40-[(Diiodomethyl)Sulfonyl] Acetanilide. U.S. Patent US 3855253,
Dec 17, 1974; Chem. Abstr. 1977, 87, 584216.
Acknowledgements
4. Crovetti, A. J.; Germann, R. P.; Blank, A. Process for Producing Iodomethyl
Sulfones. U.S. Patent US 3657353, Apr 18, 1972; Chem. Abstr. 1976, 84, 135301.
5. Li, Y.; Liu, J.; Zhang, L.; Zhu, L.; Hu, J. J. Org. Chem. 2007, 72, 5824.
6. Ammo, T.; Yamagishi, M.; Kouchiwa, S.; Ukai, S.; Hayashi, H.; Tobari, Y. Novel
Diiodomethyl Sulfones. Japanese Patent JP 43006609, Mar 12, 1968; Chem.
Abstr. 1968, 69, 496242.
This work was financially supported by the Polish State Com-
mittee for Scientific Research, Grant No. N N209 119937 and War-
saw University of Technology.
7. Yagupolskii, L. V.; Matsnev, A. V. Mendeleev Commun. 2006, 16, 132.
8. Surya Prakash, G. K.; Hu, J.; Wang, Y.; Olah, G. A. Org. Lett. 2004, 6, 4315.
9. Zhu, J.; Wang, F.; Huang, W.; Zhao, Y.; Ye, W.; Hu, J. Synlett 2011, 899.
10. Bakuniak, E.; Ptaszkowska, J.; Zimin´ ska, Z.; Ejmocki, Z.; Ochal, Z.; Tippe, A.
Preparation of Trihalomethyl 3-Nitrophenyl Sulfones. Polish Patent PL 172321,
Sep 30, 1997; Chem. Abstr. 1998, 128, 62633.
11. Ochal, Z.; Mizerski, A.; Załecki, S. Preparation of Novel Benzimidazole
Derivatives as Herbicides. Polish Patent PL 194478, Jun 29, 2007; Chem.
Abstr. 2008, 148, 594265.
Supplementary data
Supplementary data (experimental procedures and character-
ization data) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tetlet.2013.12.012.
´
12. Borys, K. M.; Korzynski, M. D.; Ochal, Z. Tetrahedron Lett. 2012, 53, 6606.
References and notes
13. Philips, M. A. J. Chem. Soc. 1928, 2393.
14. Wright, J. B. Chem. Rev. 1951, 48, 397.
1. Malichenko, B. F.; Kornienko, R. A.; Yagupolskii, L. M. Ukr. Khim. Zh. 1968, 34,
486.