HETEROCYCLES

Short Paper | Regular issue | Vol. 91, No. 8, 2015, pp. 1645-1653
Received, 25th May, 2015, Accepted, 29th June, 2015, Published online, 15th July, 2015.
DOI: 10.3987/COM-15-13254

■ Simple and Efficient Synthesis of Some Novel Triazoles Sulfonamides

Maha Hachicha, Monaem Balti,* Hédi Mrabet, and Mohamed Lotfi El Efrit

Department of Chemistry, Faculty of Sciences of Tunis-Tunisia, El Manar-B.P. 94 Poste Romena, 1068, Tunisia

Abstract

Reaction of iminoesters 1 with sulfonyl isocyanates gave the corresponding sulphonamide imidates 2. The cyclocondensation of the latter with a series of hydrazine in methanol affords new functionalized triazoles in high yields.

Simple nitrogen-containing heterocycles attached to sulfonamido moieties have received a large amount of attention in the literature, as a consequence of their exciting biological properties and their role as pharmacophores of considerable historical importance. Heterocyclic sulfonamides are used as carbonic anhydrase inhibitors,1-3 antibacterial agents,4 anticancer, anti-inflammatory and analgesic agents,5 β3-adrenergic receptor agonists,6 PC-1 inhibitors,7 antifungal agents,8 and antiviral agents.9 Triazole derivatives have consistently attracted scientific and practical interest because of their widely varying chemical properties, synthetic versatility, and pharmacological activities, such as antibacterial,10-12 antifungal,13-15 antitubercular,16-18 analgesic,19,20 anti-inflammatory,20-22 anticancer,23,24 anticonvulsant,25 antiviral,26 insecticidal,27 and antidepressant,28 antiviral properties. Moreover, the triazole compounds carrying sulfone moiety have been reported as antibacterial and antifungal, antihypertensive, analgesic, anti-inflammatory, or antitumoral agents.29-31 For these vast biological activities and in continuation of our work on the synthesis of novel nitrogen heterocyclic compounds containing a sulfamide group,32 we

undertook the synthesis of a new series of compounds incorporating the abovementioned biologically active moieties in one molecule. The scheme 1 depicts the discovery of a practical and high yielding method for the efficient one-pot synthesis of diverse triazole sulfonamides starting from a wide range of imidates.

Some studies reported on the synthesis of 1,3,5-triazoles bearing specific functionalities or substituents using N-acylamidrazone as an intermediate.33 In the same context, we performed the synthesis of N-sulfonamide imidates by condensation of iminoesters 1 with sulfonyl isocyanates 2 (Scheme 2) and we next focused our efforts to investigate their behavior towards the synthesis of some novel triazoles.

The reaction is thought to proceed via nucleophilic attack of the NH group of iminoesters on the carbonyl group of sulfonyl isocyanates giving rise to an imidate. The structures of the title compounds were established on the basis of their spectral data. It was shown that no peak duplication is observed suggesting that these compounds were obtained as E isomer. Moreover, a study conducted using RX in our laboratory34 on the N-functionalized iminoesters confirm this finding. In 1H-NMR spectra, we observed essentially the total disappearance of the signal of the NH group and the appearance of a new signal around 11 ppm characteristic of the protons of the amide group. 13C-NMR chemical shifts of different types of atoms are consistent with the structure of the synthesized compounds. Analysis of the 13C-NMR spectra shows the appearance of a new signal around 160 ppm attributed to the carbonyl of the amide group.
The imidates 3 possess several reagent sites in particular in position 1,3. The bis electrophilic character of imidates 3 would allow to postulate that their reaction with the hydrazine derivatives could constitute an easy access to new series of triazole 4. Effectively, good yields of triazole sulfonamides 4 have been obtained by the reaction of N-sulfonamide imidates 3 with a series of hydrazine in methanol at room temperature (Scheme 3). In order to demonstrate the efficiency and generality of this protocol, we examined the reactions of various imidates and substituted hydrazine (Table 2). All substrates react to give the corresponding triazole sulfonamides in good to excellent yields.

The reaction was assumed to proceed by the substitution of the methoxy group of imidates 3 by the NH2 group of hydrazine giving an intermediate which then immediately yielded via a heterocyclization the correspondent triazole sulfonamides. It has been shown that in the case of methylhydrazine, reaction lead to the formation of two triazole isomers (4f’ and 4f’’ in 75/25 ratio). Methoxy group of imidates 3 can be substituted indifferently by the two nitrogen atoms of methylhydrazine. One of these nitrogen atoms is less sterically hindered (Me-NH-NH2) so we have obtained 4f’ as major regioisomer in accordance with the literature.35-38

Triazole sulfonamides 4a-k were characterized by their spectroscopic data of IR, NMR and by satisfactory HRMS. Examination of the 13C-NMR spectra of the products 4a-k shows the disappearance of the signal at 50 ppm relative to methoxy carbon and the appearance of new signal around 157 ppm attributable to the endocyclic imine carbon. The 1H-NMR spectra are consistent with the literature data for closely related compounds.
In conclusion, we have developed a convenient method for the synthesis of some new triazole sulfonamide derivatives in high yields from corresponding substituted hydrazine and N-sulfonamide imidates. This procedure offers significant advantages over prior reports, such as efficiency, and mild reaction conditions.

EXPERIMENTAL
Melting points were measured with a Kofler hot-staged apparatus and are uncorrected. 1H, 31P and 13C NMR spectra were recorded with CDCl3 as the solvent, on a Bruker-300 spectrometer. The chemical shifts are reported in ppm relative to TMS (internal reference) for 1H and 13C-NMR and relative to 85% H3PO4 (external reference) for 31P-NMR. The coupling constants are reported in Hz. For the 1H-NMR, the multiplicities of signals are indicated by the following abbreviations: s: singlet, m: multiplet. Mass spectra were determined on a VOYAGER DE STR spectrometer under MALDI ionization conditions. IR spectra were recorded on a Nicolet IR200 spectrometer. The progress of the reactions was monitored by TLC. The starting materials (iminoesters 1 and phosphorylated hydrazine) were prepared according to reported procedures.39,40

General procedure for the preparation of imidates (3a-e).
To a well-stirred solution of iminoester 1 (1 mmol) in dry Et2O (20 mL) was added aroxysulfonyl isocyanate 2 dropwise over 2 min at 0 °C. The reaction mixture was stirred for 2 h. Resulting precipitate was filtered of in satisfactory purity.

3a: White solid; mp 180 °C, Yield: 96%. IR (KBr, cm-1): 3257 (NH), 3087 (CHarom), 1680 (C=O), 1346, 1154 (SO2). 1H-NMR (CDCl3): 3.9 (s, OCH3), 11.5 (br s, NH), 7.1-7.95 (m, 10H, Ar-H). 13C-NMR (75 MHz, CDCl3): 52.13, 122.04-149.60 (Carom), 153.60, 161.56.

3b: White solid; mp 183 °C, Yield: 94%. IR (KBr, cm-1): 3274 (NH), 3053 (CHarom), 1688 (C=O), 1370, 1156 (SO2). 1H-NMR (CDCl3): 2.35 (s, CH3), 3.5 (s, OCH3), 11.09 (s, NH), 7.01-7.96 (m, 9H, Ar-H). 13C-NMR (75 MHz, CDCl3): 21.50, 52.13, 123.55-138.77 (Carom), 152.50, 161.41.

3c: Yellow solid; mp 175 °C, Yield: 96%. IR (KBr, cm-1): 3273 (NH), 3067 (CHarom), 1693 (C=O), 1347, 1130 (SO2). 1H-NMR (CDCl3): 2.5 (s, CH3), 3.49 (s, CH2), 3.8 (s, OCH3), 11.23 (br s, NH), 6.96-7.93 (m, 9H, Ar-H). 13C-NMR (75 MHz, CDCl3): 21.65, 43.70, 52.13, 124.11-136.87 (Carom), 154.20, 162.36.

3d: White solid; mp 178 °C, Yield: 96%. IR (KBr, cm-1): 3267 (NH), 3051 (CHarom), 1710 (C=O), 1339, 1158 (SO2). 1H-NMR (CDCl3): 1.1 (m, 6H), 2.4 (s, CH3), 2.6 (m, 1H), 3.5 (s, OCH3), 11.15 (br s, NH), 7.11-7.86 (m, 4H, Ar-H). 13C-NMR (75 MHz, CDCl3): 18.66, 21.54, 32.48, 52.82, 128.3-137.60 (Carom), 151.30, 162.7.

3e: White solid; mp 185°C, Yield: 97%. IR (KBr, cm-1): 3227 (NH), 3023 (CHarom), 1697 (C=O), 1351, 1155 (SO2). 1H-NMR (CDCl3): 0.92 (m, CH3), 1.44 (m, CH2), 1.61 (m, CH2), 2.36 (CH3), 3.5 (s, OCH3), 11.29 (br s, NH), 7.40-7.80 (m, 4H, Ar-H). 13C-NMR (75 MHz, CDCl3): 13.16, 14.87, 19.03, 37.25, 52.79, 128.19-140.60 (Carom), 154.10, 161.71.

General synthetic procedure for triazole sulfonamides (4a-k).
To a solution of sulfonamide imidates 3 (1 mmol) in MeOH (10 mL) were added hydrazine derivatives (1 mmol). The mixture was stirred for 2-6 h at room temperature. The precipitate thus formed was collected by filtration, washed with MeOH (10 mL), dried and recrystallized from petroleum ether. The crude product 4f was purified using flash chromatography (silica gel:EtOAc/hexane) to give pure compounds 4f’ and 4f’’.

4a: Pink solid; mp 230 °C, Yield: 90%. IR (KBr, cm-1): 3273, 3178 (NH), 3053 (CHarom), 1604 (C=N), 1345, 1154 (SO2). 1H-NMR (DMSO-d6): 7.01-8.06 (m, 10H, Ar-H), 7.95 (br s, NH). 13C-NMR (DMSO-d6): 121.5-145.17 (Carom), 156.6, 161.68. HRMS (EI): m/z calculated for C14H12N4O3S (M+H)+: 317.07; found 317.18.

4b: White solid; mp 250 °C, Yield: 88%. IR (KBr, cm-1): 3278, 3130 (NH), 3097 (CHarom), 1588 (C=N), 1394, 1186 (SO2). 1H-NMR (DMSO-d6): 2.36 (s, CH3), 7.29 (br s, NH), 6.96-7.93 (m, 9H, Ar-H). 13C-NMR (DMSO-d6): 20.84, 124.71-136.81 (Carom), 157.33, 161.32. HRMS (EI): m/z calculated for C15H14N4O2S (M+H)+: 315.09; found 315.13.

4c: White solid; mp 230 °C, Yield: 89%. IR (KBr, cm-1): 3301, 3125 (NH), 3105 (CHarom), 1591 (C=N), 1371, 1174 (SO2). 1H-NMR (DMSO-d6): 2.34 (s, CH3), 3.56 (s, CH2), 7.16-7.73 (m, 9H, Ar-H) 7.52 (br s, NH). 13C-NMR (DMSO-d6): 21.15, 33.2, 125.3-138.1 (Carom), 157.2, 161.2. HRMS (EI): m/z calculated for C16H16N4O2S (M+H)+: 329.10; found 329.16.

4d: White solid; mp 251 °C, Yield: 88%. IR (KBr, cm-1): 3337, 3143 (NH), 3022 (CHarom), 1604 (C=N), 1357, 1176 (SO2). 1H-NMR (DMSO-d6): 2.38 (s, CH3), 7.99 (br s, NH), 7.41-8.05 (m, 14H, Ar-H). 13C-NMR (DMSO-d6): 19.94, 127.62-137.4 (Carom), 154.3, 160.98. HRMS (EI): m/z calculated for C21H18N4O2S (M+H)+: 391.12; found 391.16.

4e: White solid; mp 245 °C, Yield: 88%. IR (KBr, cm-1): 3276, 3123 (NH), 3066 (CHarom), 1583 (C=N), 1363, 1188 (SO2). 1H-NMR (DMSO-d6): 2.33 (s, CH3), 3.64 (s, CH2), 7.22-8.12 (m, 14H, Ar-H), 7.40 (br s, NH). 13C-NMR (DMSO-d6): 19.39, 32.90, 123.62-139.14 (Carom), 155.31, 161.87. HRMS (EI): m/z calculated for C22H20N4O2S (M+H)+: 405.13; found 405.19.

4f’: White solid; mp 255 °C, Yield: 72%. IR (KBr, cm-1): 3224, 3157 (NH), 3056 (CHarom), 1612 (C=N), 1384, 1159 (SO2). 1H-NMR (DMSO-d6): 2.34 (s, CH3), 3.89 (s, CH3), 7.13-7.95 (m, 9H, Ar-H), 7.83 (br s, NH). 13C-NMR (DMSO-d6): 20.3, 31.21, 122.12-137.31 (Carom), 158.3, 162.4. HRMS (EI): m/z calculated for C16H16N4O2S (M+H)+: 329.10; found 329.12.

4f’’: White solid; mp 255 °C, Yield: 24%. IR (KBr, cm-1): 3228, 3152 (NH), 3076 (CHarom), 1608 (C=N), 1392, 1189 (SO2). 1H-NMR (DMSO-d6): 2.35 (s, CH3), 3.87 (s, CH3), 7.13-7.95 (m, 9H, Ar-H), 7.8 (br s, NH). 13C-NMR (DMSO-d6): 20.55, 29.87, 12.12-138.09 (Carom), 158.43, 162.49. HRMS (EI): m/z calculated for C16H16N4O3S (M+H)+: 329.10; found 329.13.

4g: White solid; mp 261 °C, Yield: 85%. IR (KBr, cm-1): 3297, 3144 (NH), 3036 (CHarom), 1579 (C=N), 1391, 1184 (SO2). 1H-NMR (DMSO-d6): 2.34 (s, CH3), 3.21 (m, CH2), 5.19 (m, CH2), 7.34-8.08 (m, 9H, Ar-H), 7.94 (br s, NH). 13C-NMR (DMSO-d6): 15.65, 20.3, 41.1, 118.9, 125.62-136.32 (Carom), 157.12, 161.73. HRMS (EI): m/z calculated for C18H17N5O2S (M+H)+: 368.11; found 368.14.

4h: Hygroscopic yellow solid; mp 279 °C, Yield: 82%. IR (KBr, cm-1): 3283, 3171 (NH), 3010 (CHarom), 1622 (C=N), 1363, 1147 (SO2), 1253 (P=O). 1H-NMR (DMSO-d6): 1.29 (m, CH3), 2.34 (s, CH3), 4.01 (m, CH2), 7.13-8.02 (m, 9H, Ar-H), 7.2 (br s, NH). 13C-NMR (DMSO-d6): 16.55, 21.3, 59.1, 124.76-137.23 (Carom), 158.3, 160.22. 31P NMR (DMSO-d6): 1.43. HRMS (EI): m/z calculated for C19H23N4O5PS (M+H)+: 451.12; found 451.19.

4i: Hygroscopic yellow solid; mp 281 °C, Yield: 85%. IR (KBr, cm-1): 33337, 3181 (NH), 3050 (CHarom), 1587 (C=N), 1361, 1167 (SO2), 1270 (P=S). 1H-NMR (DMSO-d6): 1.17 (m, CH3), 2.39 (s, CH3), 3.87 (m, CH2), 7.23-7.78 (m, 9H, Ar-H), 7.42 (s, NH). 13C-NMR (DMSO-d6): 17.12, 23.11, 57.32, 123.57-135.96 (Carom), 156.44, 163.08. 31P NMR (DMSO-d6): 23.16.HRMS (EI): m/z calculated for C19H23N4O4PS2 (M+H)+: 467.09; found 467.17.

4j: White solid; mp 251 °C, Yield: 90%. IR (KBr, cm-1): 3265, 3154 (NH), 3020 (CHarom), 1624 (C=N), 1377, 1123 (SO2). 1H-NMR: (DMSO-d6): 1.15 (m, CH3), 1.69 (m, CH2) 2.36 (s, CH3), 2.89 (m, CH2), 7.39 (br s, NH), 7.12-7.85 (m, 4H, Ar-H). 13C-NMR (DMSO-d6): 16.31, 20.37, 22.09, 30.1, 127.19-139.43 (Carom), 157.43, 163.71. HRMS (EI): m/z calculated for C12H16N4O2S (M+H)+: 281.10; found 281.18.

4k: White solid; mp 251 °C, Yield: 90%. IR (KBr, cm-1): 3312, 3123 (NH), 3072 (CHarom), 1593 (C=N), 1352, 1145 (SO2). 1H-NMR: (DMSO-d6): 1.23 (m, 6H), 2.36 (s, CH3), 3.17 (m, 1H), 7.93 (br s, NH), 7.11-7.97 (m, 4H, Ar-H). 13C-NMR (DMSO-d6): 21.1, 21.4, 30.1, 128.9-138.2 (Carom), 154.5, 162.12. HRMS (EI): m/z calculated for C12H16N4O2S (M+H)+: 281.10; found 281.23.

ACKNOWLEDGMENTS
The financial assistant from Tunisian Ministry of Higher Education and Scientific Research is acknowledged with thanks. Thanks are due to Dr. Mohamed Abed Rahmen Sanhouri (Department of Chemistry, Faculty of Sciences of Tunisia) for valuable discussions.

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