Derivatives of phenyl tribromomethyl sulfone as novel compounds with potential pesticidal activity

Article abstract of DOI:10.3762/bjoc.8.27

A halogenmethylsulfonyl moiety is incorporated in numerous active herbicides and fungicides. The synthesis of tribromomethyl phenyl sulfone derivatives as novel potential pesticides is reported. The title sulfone was obtained by following three different synthetic routes, starting from 4-chlorothiophenol or 4-halogenphenyl methyl sulfone. Products of its subsequent nitration were subjected to the SNAr reactions with ammonia, amines, hydrazines and phenolates to give 2-nitroaniline, 2-nitrophenylhydrazine and diphenyl ether derivatives. Reduction of the nitro group of 4-tribromomethylsulfonyl-2- nitroaniline yielded the corresponding o-phenylenediamine substrate for preparation of structurally varied benzimidazoles.

Full text of DOI:10.3762/bjoc.8.27

Derivatives of phenyl tribromomethyl sulfone as
novel compounds with potential pesticidal activity
Krzysztof M. Borys, Maciej D. Korzyński and Zbigniew Ochal*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 259–265.
Faculty of Chemistry, Warsaw University of Technology,
Noakowskiego 3, Warsaw 00-664, Poland
doi:10.3762/bjoc.8.27
Received: 10 November 2011
Accepted: 30 January 2012
Published: 15 February 2012
Email:
Zbigniew Ochal* - zbigniew.ochal.pw@gmail.com
* Corresponding author
Associate Editor: J. A. Porco Jr.
Keywords:
© 2012 Borys et al; licensee Beilstein-Institut.
License and terms: see end of document.
2-nitroaniline derivatives; phenylhydrazones; pesticides; SNAr
reaction; tribromomethyl sulfone derivatives
Abstract
A halogenmethylsulfonyl moiety is incorporated in numerous active herbicides and fungicides. The synthesis of tribromomethyl
phenyl sulfone derivatives as novel potential pesticides is reported. The title sulfone was obtained by following three different syn-
thetic routes, starting from 4-chlorothiophenol or 4-halogenphenyl methyl sulfone. Products of its subsequent nitration were
subjected to the SNAr reactions with ammonia, amines, hydrazines and phenolates to give 2-nitroaniline, 2-nitrophenylhydrazine
and diphenyl ether derivatives. Reduction of the nitro group of 4-tribromomethylsulfonyl-2-nitroaniline yielded the corresponding
o-phenylenediamine substrate for preparation of structurally varied benzimidazoles.
Introduction
The rapid growth of the world population results in a continous groups in some nitroaniline and benzimidazole derivatives was
increase in the demand for food. At the same time, about 35% beneficial to their herbicidal and fungicidal activity [6,8,9].
of the global crops around the world are being destroyed due to Moreover, some 2-nitroaniline and 2,6-dinitroaniline deriva-
a diverse range of diseases as well as a wide variety of pests and tives belong to the group of commonly applied herbicides [10].
weeds [1]. Both of these factors are nowadays the reason for the
growing interest in the development of new, selective and effi- Herein we report the synthesis of novel aromatic compounds
cient pesticides. Maintaining our investigations into the prepar- containing a tribromomethylsulfonyl group, including deriva-
ation of novel pesticidal agents, we turned our attention to com- tives of nitroaniline, nitrophenylhydrazine, diphenyl ether and
pounds possessing a halogenmethylsulfonyl group. Aromatic benzimidazole (Scheme 1). All the target molecules are derived
compounds featuring this moiety has been reported to exhibit from a common precursor, namely 4-halogenphenyl tribro-
the desired biological activity [2-7]. The results of our previous momethyl sulfone, efficiently synthesized from inexpensive
research revealed that the presence of halogenmethylsulfonyl 4-halogenthiophenol. The development of an effective method
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Beilstein J. Org. Chem. 2012, 8, 259–265.
Scheme 1: Retrosynthetic analysis of the designed target molecules.
for the preparation of the title compounds allowed an evalua- The first approach utilized the method for trihalogenmethyl
tion of their biological activity against certain fungi to be sulfone synthesis developed by Farrar [11] (Scheme 2, method
carried out.
A). Reaction of 4-chlorothiophenol (2) with sodium hydroxide
and sodium chloroacetate (obtained in situ by neutralization of
chloroacetic acid with NaOH solution) afforded 2-(4-
Results and Discussion
Our initial synthetic efforts were aimed at the preparation of the chlorophenylthio)acetic acid (3). Oxidative bromination of 3
starting compound 4-halogenphenyl tribromomethyl sulfone with sodium hypobromite gave sulfone 1 in moderate (57%)
(where halogen stands for chlorine or bromine). 4-Chlorophenyl overall yield, the second step being particularly time-consuming
tribromomethyl sulfone (1) was obtained by following three (80 h). These significant drawbacks led us search for other
different synthetic methods (Scheme 2).
preparation methods. We considered that the readily available
Scheme 2: Synthetic routes for 4-chlorophenyl tribromomethyl sulfone (1).
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Beilstein J. Org. Chem. 2012, 8, 259–265.
methylsulfone 4 may serve as an intermediate in the synthesis
of 1 (Scheme 2, methods B and C). It was obtained by
S-methylation of 4-chlorothiophenol (2) with dimethyl sulfate,
followed by treatment of the resulting product 5 with hydrogen
peroxide and glacial acetic acid. Next, bromination of the
methyl group of 4 was achieved by using either sodium hypo-
bromite (Scheme 2, method B) or bromine chloride (Scheme 2,
method C), both of which have been extensively researched by
us as halogenating agents. The overall yields of tribromomethyl
sulfone 1 obtained by this pathway amounted to 86% and 85%
(starting from 2) for the NaOBr and BrCl method of bro-
mination, respectively.
The next step in the functionalization of sulfone 1 was its nitra-
tion, carried out by standard means of a mixture of concen-
trated nitric and sulfuric acids (Scheme 3) [12].
As pesticides are chemicals produced most commonly in
considerable quantities, optimization of the synthetic process is
highly desirable. Bearing in mind that the obtained nitro com-
pound is the key intermediate for all further transformations, we
decided to check whether the use of bromine-substituted
aromatic methylsulfone 4' would prove to offer higher yields in
the halogenation/nitration sequence. Bromination of 4' with
BrCl afforded tribromomethyl sulfone 1' in 90% yield
(compared to 94% for chlorine analogue 1), while the subse-
quent nitration of 6' resulted in 94% yield (compared to 96%
for analogue 6). With these results at hand, we ultimately
picked chlorine-containing nitrosulfone 6 as the substrate for
the subsequent synthetic steps.
A range of SNAr reactions of 6 with various N- and O-nucleo-
philes was carried out (Scheme 4).
First, aniline derivative 7a (by treatment of 6 with aqueous
ammonia) and phenylhydrazine derivative 7b (by treatment of 6
with hydrazine hydrate and triethylamine as a coproduced HCl
Scheme 4: SNAr transformations of sulfone 6.
acceptor) were prepared. Sulfone 6 was also reacted with ali- resulting compounds being obtained in >85% yields (Table 1;
phatic amines (products 7c–7h), aromatic primary amines see Supporting Information File 1 for further details on prod-
(products 7i–7k) and phenols (products 7l–7o), with all the ucts 7a–7o).
Scheme 3: Halogenation/nitration sequence for 4-halogenphenyl methyl sulfones 4 and 4'.
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Beilstein J. Org. Chem. 2012, 8, 259–265.
of phenylhydrazones possessing various substituents (Table 2;
see Supporting Information File 1 for further details on prod-
ucts 8a–8l).
Table 1: Derivatives of 2-nitroaniline, 2-nitrophenylhydrazine and
diphenyl ether.
Table 2: 2-Nitro-4-tribromomethylsulfonylphenylhydrazones.
product
substituent (R)
yielda (%)
7a
7b
7c
7d
7e
7f
NH2
NHNH2
93
94
95
87
92
94
94
92
NHCH3
compound
substituent (R)
yielda (%)
96
NHC6H11
NHCH2CH2CH3
NHCH2CH(CH3)2
N(C2H5)2
8a
7g
7h
N(CH2CH(CH3)2)2
7i
7j
96
88
86
91
92
8b
8c
87
89
7k
7l
8d
8e
8f
93
90
92
7m
7n
92
90
7o
8g
8h
85
89
aIsolated yield.
At this point, two groups of the designed target molecules
remained to be synthesized: Phenylhydrazones and benzimida-
zoles. The acid-catalyzed reaction of phenylhydrazine deriva-
tive 7b with aldehydes or ketones (Scheme 5) afforded a series
8i
91
8j
88
92
8k
8l
94
aIsolated yield.
Scheme 5: Preparation of phenylhydrazones 8a–8l.
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Beilstein J. Org. Chem. 2012, 8, 259–265.
The two-step synthesis of benzimidazoles featured aniline
Table 3: 5-Tribromomethylsulfonylbenzimidazole derivatives.
derivative 7a as the starting material (Scheme 6).
product
substituent (R)
yielda (%)
11a
11b
11c
CH3
CF3
86
93
57
CH2C6H5
Scheme 6: Products of the nitro group reduction of sulfone 7a.
11d
81
The first transformation, i.e., the reduction of the nitro group,
was initially intended to be completed with stannous chloride in
concentrated hydrochloric acid as a reducing agent. However,
this method proceeded solely to debromination, and 4-dibromo-
methylsulfonyl-1,2-diamine (10) was isolated exclusively.
Bromine cleavage in phenyl tribromomethyl sulfones was
previously observed also by Fields and Shechter [13], who
investigated the addition of phenyl tribromomethyl sulfone to
olefins. Fortunately we found out that conducting the reduction
with SnCl2/HCl in ethanol provided the desired diamine 9,
although along with up to 40% yield of the debrominated di-
amine 10. The reaction work-up involved treatment of the
resulting chlorostannic acid–diamine complexes with sodium
hydroxide, the particular products being later successfully
isolated by recrystallization.
11e
77
11f
11g
11h
C6H5
C6H4-4-Cl
SH
79
65
80
11i
92
76
11j
aIsolated yield.
With diamine 9 at hand, we proceeded to the synthesis of benz- chloric acid successfully afforded 2-substituted benzimidazoles
imidazole scaffolds (Scheme 7, Table 3; see Supporting Infor- 11a–11e in moderate to high yields.
mation File 1 for further details on products 11a–11j).
It is worth noting that we encountered significant difficulties
The cyclization was carried out according to the well-estab- while applying the Philips method for the cyclization of di-
lished Philips method [14,15], based on treatment of the appro- amine 9 with benzoic acid and 4-chlorobenzoic acid. The
priate substrates with hydrochloric acid. Reactions of diamine, expected benzimidazole was not formed, and only the substrates
as well as its alpha-functionalized derivatives, with hydro- were isolated from the reaction mixture. Therefore we made an
Scheme 7: Synthesis of benzimidazole derivatives 11a–11g.
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Beilstein J. Org. Chem. 2012, 8, 259–265.
attempt at synthesizing 2-arylbenzimidazole 11f and 11g Conclusions
according to our patented method [16]. The cyclization of di- In conclusion, we designed and synthesized a series of tri-
amine 9 with benzoic acids was run in anhydrous xylene with bromomethylsulfonyl bearing derivatives of 2-nitroaniline,
titanium tetrachloride as a catalyst (Scheme 7).
2-nitrophenylhydrazine, diphenyl ethers and benzimidazole.
Unexpected difficulties experienced during the synthesis were
2-Mercaptobenzimidazole 11h was obtained by the reaction of successfully circumvented utilizing, among other things, our
diamine 9 with carbon disulfide (Scheme 8) [17]. Moreover, patented methodologies. The outcome of biological screening
11h was subjected to the reaction with aromatic isocyanates to showed that some of the obtained compounds exhibit fungi-
give benzimidazolthiocarbamates 11i and 11j.
cidal activity.
The synthesized compounds were tested for their fungicidal
activity. The evaluation 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 pan. It was found that compounds 7a, 7m, 7n and 7i ex-
hibit high or moderate activity against some fungal pathogens
(Table 4).
Supporting Information
Supporting Information File 1
Experimental procedures and characterization data.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-27-S1.pdf]
Scheme 8: Preparation and further transformation of 2-mercaptobenzimidazole 11h.
Table 4: Fungicidal activity of the active compoundsa.
A. alternata
B. cinerea
F. culmorum
200 μg/mL
20 μg/mL
P. cactorum
R. solani
B. graminis
100 μg/mL
1000 μg/mL
80
50
80
60
80
60
100
80
7a
7m
7n
7i
70
80
60
50
50
55
50
35
80
40
60
0
100
20
100
30
40
0
80
60
100
80
100
60
80
50
80
20
70
20
90
40
aThe results of biological evaluation are expressed as the values of percentage inhibition of colony growth of the fungi, derived from the following
formula: I = 100 (C − T)/C, where I = percentage inhibition of colony growth of the fungi, 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 compound in the sample.
264

Beilstein J. Org. Chem. 2012, 8, 259–265.
Acknowledgements
This work was financially supported by Warsaw University of
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This is an Open Access article under the terms of the
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