Synthesis and Antioxidant Activity of 1 , 4-[ Bis ( 3-arylmethanesulfonyl pyrrolyl and pyrazolyl ) ] benzenes

Uma variedade de (1,4-fenileno)bis(arilmetanossulfonilpirrois e pirazois) foram preparados através da cicloadição de reagentes 1,3-dipolares (isocianeto de tosilmetila e diazometano) com 1,4-bis(E)-2-[(arilmetanossulfonil)vinil]benzenos, como receptores de Michael. Todos os compostos sintetizados foram avaliados como antioxidantes. Entre os compostos testados, um deles exibiu excelente atividade seqüestradora de radicais nos três métodos avaliados, quando comparado com o ácido ascórbico padrão. Por outro lado, os 1,4-[bis(3-arilmetanossulfonil)1H-pirazol-4-il]benzenos exibiram, comparativamente, maior atividade antioxidante do que os 1,4-[bis (3-arilmetanossulfonil)-1H-pirrol-4-il]benzenos. Em geral, foi observado que compostos que possuem um substituinte metoxila no anel aromático, exibem maior atividade antioxidante do que os outros substituintes.


Introduction
The chemistry of activated olefins has gained importance because of their utility as valuable intermediates in a variety of synthetic transformations and useful as building blocks in the synthesis of biologically potent heterocycles. 1The α,βunsaturated sulfones possess many biological properties including anticancer, 2 antimalarial, 3 anti-inflammatory, 4 antioxidant, 5 antibacterial, anti-HIV, 6 and antifungal. 7They are also excellent leading skeletons for modification of drug design and development.Pyrroles and their derivatives represent one of the most pharmaceutically important class of N-heterocyclic compounds because of their remarkable antibacterial, antiviral, anti-inflammatory, antitumoral, and antioxidant activities. 8Apart from these, pyrroles are the core units of many natural products and serve as building blocks for porphyrin synthesis. 9Besides the Paal- Knorr 10 type condensation reaction, various synthetic methods have been developed to synthesize pyrroles, including Hantzsch synthesis, 11 [3+2] cycloaddition of 1,3-dipolar reagents to alkynes, 12 and olefin cross-metathesis. 13Pyrazole and its derivatives have been attracting a great deal of interest due to their various pharmaceutical applications. 14yrazoles display antimicrobial, 15 antidepressant, 16 immunosuppressive, 17 anticonvulsant, 18 antitumor, 19 and anti-inflammatory 20 activities.In fact, various pyrazoles were used as molecular scaffolds in several drugs such as metamizole, 21 difenamizole, 22 lonazolac, 23 phenidone, 24 and mepirizole. 25The general methods for the synthesis of pyrazoles are Pechmann synthesis 26 of 1,3-dipolar cycloaddition of diazo compounds to alkenes 27 or alkynes 28 and the Knorr synthesis 29 between hydrazines and 1,3-difunctional compounds.We have reported the 1,3-dipolar cycloaddition of dipolar reagents to a variety of activated mono and bis(olefins) and studied their antimicrobial and antioxidant activities. 30,31With this background and in our continued interest on the synthesis of biologically potent heterocycles, it was thought of exploiting the Michael acceptor, 1,4-bis(E)-2-((arylmethanesulfonyl) vinyl)benzene to build pyrrole and pyrazole rings and to investigate their antioxidant potentiality.

Results and Discussion
The synthetic pathway to achieve the target molecules is depicted in schemes 1 and 2. The Michael acceptor, 1,4-bis(E)-2-((arylmethanesulfonyl)vinyl)benzenes (5a-d) were prepared by the Knoevenagel reaction of arylmethanesulfonylacetic acids (3a-d) with terephthaldehyde (4).The compounds 3a-d were obtained by the treatment of arylmethane chloride with thioglycolic acid followed by oxidation with hydrogen peroxide and glacial acetic acid.The 1 H NMR spectrum of compound 5a displayed a singlet at 4.55 ppm due to methylene protons and two doublets at 7.52, and 7.48 ppm due to olefin protons H A and H B, respectively.The coupling constant value J AB = 15.5 Hz indicated that they are in trans geometry (Scheme 1).
The olefin functional group present in compounds 5a-d was utilized to develop pyrrole and pyrazole rings.Treatment of compounds 5a-d with tosylmethyl isocyanide in the presence of sodium hydride in a solvent mixture of dimethylsulfoxide and ether gave 1,4-(bis(3arylmethanesulfonyl)-1H-pyrrol-4-yl)benzenes (6a-d).The 1 H NMR spectrum of 6a exhibited a singlet at 4.23 ppm due to methylene protons.However, the singlets corresponding to 2CH of pyrrole ring were merged with aromatic protons and appeared as a multiplet.In addition to these, a broad singlet was observed at 11.85 ppm due to NH which disappeared on deuteration.Furthermore, the 1,3-dipolar cycloaddition of diazomethane to compounds 5a-d at -20 o C to -15 o C in the presence of triethylamine in ether produced 1,4-(bis(3-arylmethanesulfonyl)-4,5dihydro-(1H-pyrazol-4-yl))benzenes (7a-d).The 1 H NMR spectrum of compound 7a showed an AMX splitting pattern for methine and methylene protons of pyrazoline ring.The three double doublets observed at 4.46, 4.17, and 3.75 ppm were assigned to H A , H M and H X , respectively.The coupling constant J AM 12.2, J Mx 11.6, and J Ax 6.4 Hz indicated that H A , H M are cis, H A , H X are trans and H M , H X are geminal.The compound 7a was also exhibited a singlet at 4.09 ppm for methylene protons.Apart from these, a broad singlet was observed at 6.53 ppm due to NH which disappeared on deuteration.Thus, in the 1 H NMR spectrum of 7a the two pyrazoline ring protons displayed signals in the same region indicating that the molecule is highly symmetric.This was further evidenced by the appearance of 10 carbon signals in its 13 C NMR spectrum.The reaction of compounds 7a-d with chloranil in xylene resulted in aromatized compounds 1,4-(bis(3-arylmethanesulfonyl)-1H-pyrazol-4-yl)benzenes (8a-d) (Scheme 2).The absence of an AMX splitting pattern in the 1 H NMR spectrum of 8a confirmed its formation.Moreover in 8a, a singlet at 4.62 ppm, and another singlet at 6.92 ppm were observed due to methylene and CH protons, respectively.A broad singlet due to NH was also appeared at 10.40 ppm, and disappeared when D 2 O was added.The structures of the compounds were further established by IR, 13 C NMR spectra and elemental analyses.

In vitro antioxidant activity
The compounds 5a-d-8a-d were evaluated for antioxidant property by 2,2'-diphenyl-1-picrylhydrazyl (DPPH), 32,33 nitric oxide (NO), 34,35 and hydrogen peroxide (H 2 O 2 ) 36 methods.The observed data on the antioxidant activity of the compounds and control drug are shown in Table 1 and Figure 1.The aim of this study is to identify Scheme 1.
Synthesis and Antioxidant Activity of 1,4-[bis(3-arylmethanesulfonylpyrrolyl and pyrazolyl)]benzenes J. Braz.Chem.Soc.1202 the potential heterocyclic compound for antioxidant activity.Amongst the tested compounds 1,4-bis(E)-2-((arylmethanesulfonyl)-vinyl)benzenes (5a-d) were found to be potential antioxidant agents.This may be due to effective conjugation.On the other hand, the 1,4-(bis(3arylmethanesulfonyl)-1H-pyrazol-4-yl)benzenes (8a-d) exhibited comparatively higher antioxidant activity than 1,4-(bis(3-arylmethanesulfonyl)-1H-pyrrol-4-yl)benzenes (6a-d).The presence of methoxy substitutent on the aromatic ring enhanced the activity which may be due to +M effect.This was evidenced that the compounds 5d and 8d showed excellent radical scavenging activity in all the three methods evaluated when compared with the standard ascorbic acid.It was also perceived that the compounds 5b, 6d, and 8b exhibited good activity.However, the compound 7d displayed least activity, whereas compounds 7a-c showed no activity.The IC 50 value of the standard drug ascorbic acid in DPPH method was found to be 59.65 at 100 µg mL -1 whereas IC 50 values of the compounds 5d and 8d were found to be 56.45 and 57.08 µg mL -1 , respectively (Table 2).Besides, the perusal of Table 1 and Figure 1 indicated that radical scavenging activity in all the three

Experimental
Melting points were determined in open capillaries on a Mel-Temp apparatus and are uncorrected.The purity of the compounds was checked by TLC (silica gel H, BDH, ethyl acetate/hexane, 1:3).The IR spectra were recorded on a Thermo Nicolet IR 200 FT-IR spectrometer as KBr pellets and the wave numbers were given in cm -1 .The 1 H NMR spectra were recorded in DMSO-d 6 on a Bruker-400 spectrometer (400 MHz).The 13 C NMR spectra were recorded in DMSO-d 6 on a Bruker spectrometer operating at 100 MHz.All chemical shifts are reported in d (ppm) using TMS as an internal standard.The elemental analyses were carried out on a Perkin-Elmer 240C elemental analyzer.The antioxidant property was performed by using Shimadzu UV-2450 spectrophotometer.The arylmethanesulfonylacetic acids (3a-d) were prepared as per the literature procedure. 37neral procedure for the synthesis of 1,4-bis(E)-2-((arylmethanesulfonyl)vinyl)benzenes (5a-d) To a solution of arylmethanesulfonylacetic acids (3a-d) (2 mmol) in glacial acetic acid (10 mL -1 ), terephthaldehyde (4) (1 mmol) followed by a catalytic amount of benzylamine (0.20 mL) were added and refluxed for 6-8 h.The reaction mixture was cooled, treated with dry ether (50 mL -1 ) and left overnight in a refrigerator.The separated solid was collected and washed with methanol.The filtrate was diluted with ether and washed successively with a saturated solution of sodium bicarbonate, sodium bisulfite, dilute hydrochloric acid and water.The organic layer was dried over anhydrous sodium sulfate.In many cases, a solid product was obtained on removal of ether under reduced pressure.However, in some instances a syrupy substance was obtained which was solidified on treatment with 2-propanol.
Then, it was treated with 5% sodium hydroxide solution.The organic extract was separated, repeatedly washed with water and dried anhydrous sodium sulfate.The solvent was removed in vaccuo.The resultant solid was recrystallized from 2-propanol.

Antioxidant testing
The compounds 5a-d-8a-d were tested for antioxidant property by DPPH, NO, and H 2 O 2 methods.

Table 2 .
The IC 50 of compounds 5a
Figure1.The in-vitro antioxidant activity of compounds 5a-d-8a-d in all three methods.