Synthesis and Crystal Structure of Novel Sulfone Derivatives Containing 1,2,4-Triazole Moieties

Some 3-(Substituted methylthio)-4-phenyl-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazole derivatives were synthesized in six steps starting from easily accessible gallic acid. The resulting sulfides were then catalytically oxidized to the title sulfones with H2O2. The products were obtained in high yield under mild conditions and practically devoid of any by-products. The structures were confirmed by elemental analysis, IR, 1H- and 13C-NMR spectral data. Furthermore, a detailed X-ray crystallography structural analysis of model triazole 7g was carried out.


Chemistry
3,4,5-Trimethoxybenzhydrazide (3) was synthesized from the starting material gallic acid through etherification, esterification and hydrazidation. The compound 3 was then converted into 4 by reaction with 1-isothiocyanatobenzene in ethanol. Cyclization of this intermediate with sodium hydroxide under reflux conditions afforded 4-phenyl-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazole-3-thiol (5). Subsequently, this triazole analogue was converted to the thioether derivatives 6 in a thioetherification reaction with suitable halides (RX) catalyzed by indium or indium trichloride [16]. Treatment of the sulfides with H 2 O 2 catalyzed by sodium tungstate finally produced the title heterocyclic sulfone derivatives 7. Although the electron rich thioether can be oxidized to sulfone by a variety of agents such as m-CPBA [17], CH 3 CO 3 H [18], halogen derivatives NaClO [19], H 5 IO 6 [20], transition metal derivatives e.g., manganese (iv) oxide [21] and KMnO 4 [22], none of them seem to match the advantages offered by aqueous hydrogen peroxide, which is an ideal environmentally-friendly wasteavoiding oxidant with water being the only theoretical by-product of the reaction. Moreover, due to its high solubility in water and many organic solvents, it is very attractive as an oxidant for solution-phase reactions. Compared to other reagents, aqueous hydrogen peroxide is readily available, cheap, and is associated with easy handling, storage and transportation. This prompted us to compare the efficacy of H 2 O 2 against other agents e.g. NaClO, KMnO 4 , m-CPBA, and the results are provided in Table 1. It could be easily observed that amongst all the oxidizing agents, H 2 O 2 afforded the highest yield of the product (Table 1, Entries 4-6). Since some Lewis acid metal catalysts possessing vacant orbitals e.g. Sc(OTf) 3 [23], Fe(III)-and Mn(III)-meso-tetraarylporphyrin [24], (NH 4 ) 2 MoO 4 [25] and methyltrioxorhenium(VII) (CH 3 ReO 3 , abbreviated as MTO) [26] are known to catalyze certain oxidative reactions, the role of catalysts Al 2 O 3 , (NH 4 ) 2 MoO 4 , and Na 2 WO 4 ·2H 2 O was studied in selected cases. The yield of sulfone was found to be considerably lower with the oxidant m-CPBA in the presence of the catalyst (NH 4 ) 2 MoO 4 (Entry 1) and practically negligible for the uncatalyzed reactions using oxidants KMnO 4 and NaClO, respectively (Entries 2 and 3). When the oxidation with hydrogen peroxide was executed in the presence of catalysts Al 2 O 3 and Na 2 WO 4 ·2H 2 O, the later exhibited much superior activity compared to the former (Entries 4 and 6). This is indeed in line with the observation noted by Sato et al. [27] who reported an effective conversion of diaryl sulfides into sulfones by the oxidant hydrogen peroxide in the presence of the catalyst sodium tungstate. Having established the role of the oxidant H 2 O 2 and the catalyst Na 2 WO 4 ·2H 2 O, a systematic study of the effect of reaction parameters e.g., reaction temperature, time, solvent, molar ratio (substrate: oxidant) and the amount of catalyst was undertaken for optimization of the reaction. The results for the synthesis of 7a are summarized in Table 2.
First, the effect of amount of the oxidant was studied. As the molar ratio of the reagents (substrate: hydrogen peroxide) was varied at 55 °C ( Table 2, Entries 1-4), a maximum yield of 88% was noticed with a molar ratio of 1:6 (Table 2, Entry 2). On increasing the temperature from 45 °C to 50 °C and then 55 °C, the corresponding yields obtained were 77.0%, 84% and 88% (Table 2, Entries 5, 6, and 2) respectively. When the temperature was further increased to 60 °C and 70 °C, no improvement but rather a slight lowering in the yield (Table 2, Entries 7-8) was observed. Next, in order to obtain ideal reaction time, the reaction was also carried out for 40 min and 70 min (Entries 9 and 10), but the most suitable time was found to be 50 min (Entry 2). Amongst the different solvents examined, yields were found to be significantly lower in N,N-dimethylformamide (DMF), acetonitrile and toluene as compared to glacial acetic acid, while practically no product was observed in acetone and ethanol (Table 2, Entries 2 and 11-15). The ability of glacial acetic acid to serve both as a proton donor and a miscible cosolvent for organic/aqueous phase might account for this observation. Based on these results, the optimal conditions for the synthesis of sulfone are established with a molar ratio of (substrate:oxidant) 1:6 in glacial acetic acid at 55 °C for 50 min. As may be seen from Table 3, using optimal conditions, the compounds 7a-7i were obtained in high yields (80-92%).

Crystal Structure Analysis of 7g
The crystal data and summary of data collection and structure refinement of 7g are given in Table 4. Selected bond lengths and angles are given in Table 5. The molecular structure of compound 7g is shown in Figure 1 and the packing of the molecule in crystal lattice is illustrated in Figure 2.  Table 5. Crystal data and summary of data collection and structure refinement.  From the bond length data it can be observed that the bond length of N(1)-N(2) is 0.1396 nm, which is shorter than the normal single N-N bond length (0.1450 nm). The bond lengths of 0.1376 nm and 0.1367 nm for N(3)-C(10) and N(3)-C(11), respectively, are shorter than normal single N-C bond length (0.1470 nm) and hence indicative of some double bond character. Again, the N(1)-C(10) (0.1312 nm) and the N(2)-C(11) (0.1304 nm) bond lengths are significantly closer to that of a typical C=N bond (0.134 nm). The N-C and N=C bonds near the phenyl ring are longer than the symmetrical bonds present near the sulfone presumably due to the conjugation of the phenyl with the triazole ring. The bond lengths observed in the 1,2,4-tirazole ring are in agreement with those found in other related studies [28][29]. The bond angle of C(10)-N(1)-N(2) is 107.69(14)° and C(11)-N(2)-N(1) is 106.23 (14)°. The bond angle values further confirm the presence of delocalization in the triazole ring.

General
Unless otherwise stated, all the reagents and reactants were purchased from commercial suppliers; melting points were determined on a XT-4 binocular microscope (Beijing Tech Instrument Co., China) and are uncorrected; the 1 H-NMR and 13 C-NMR spectra were recorded on a JEOL ECX 500 NMR spectrometer at room temperature operating at 500 MHz for 1 H-NMR and 125 MHz for 13 C-NMR by using CDCl 3 as the solvent and TMS as an internal standard; infrared spectra were recorded in KBr on a Bruker VECTOR 22 spectrometer; elemental analysis was performed on an Elemental Vario-III CHN analyzer. The course of the reactions was monitored by TLC; analytical TLC was performed on silica gel GF 254 ; column chromatographic purification was carried out using silica gel. The carbothiamide (4) was prepared as described in the literature from gallic acid as the starting material through esterification and hydrazidation [30].

Conclusions
In the present study, a mild and effective method for the preparation of novel sulfone derivatives containing 1,2,4-triazole moieties was undertaken using gallic acid as the starting material. The key step of the oxidation from thioether to the corresponding sulfone was optimized. The method has some salient features such as faster reaction rates, high yields and environmental friendliness. The synthesized compounds were characterized by spectral data ( 1 H-NMR, 13 C-NMR, IR) and elemental analysis. Furthermore, 3-(3-methoxybenzylsulfonyl)-4-phenyl-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4triazole (7g) was investigated by X-ray crystallographic analysis. In the solid state, a three dimensional hydrogen bond network within the molecule presumably imparts stability to the crystal lattice.