Bulgarian Chemical Communications, Volume 45, Number 3 (332 335) 2013

Design and synthesis of two sulfathiazole derivatives using a three-component system

L. Figueroa-Valverde^1*, F. Díaz-Cedillo², E. García-Cervera¹, E. Pool Gómez¹, M. Rosas-Nexticapa³, M. López-Ramos<sup>1

1</sup>Laboratory of Pharmaco-Chemistry at the Faculty of Chemical Biological Sciences of the University Autonomous of Campeche, Av. Agustín Melgar s/n, Col Buenavista C.P.24039 Campeche Cam., México.
²Escuela Nacional de Ciencias Biológicas del Instituto Politécnico Nacional. Prol. Carpio y Plan de Ayala s/n Col. Santo Tomas, México, D.F. C.P. 11340.

³Facultad de Nutrición, Universidad Veracruzana, Médicos y Odontologos s/n C.P. 91010, Unidad del Bosque Xalapa Veracruz, México

Received June 2, 2012; Revised November 5, 2012

Two sulfonamide derivatives were synthetized using a three-component system; in the first stage the compound 4-[(2-hydroxy-naphtalen-1-yl)-phenyl-methyl]-amino-N-thiazol-2-yl-benzenesulfonamide (4) was obtained by the reaction of β-naphtol, benzaldehyde and sulfathiazole (3) in ethanol. The second stage was achieved by the reaction of 3 with 1-hexyne and benzaldehyde using cupric chloride as a catalyst to form 4(hex-1-ynyl-phenyl-amino)-N-thiazol-2-yl-benzenesulfonamide (6). The structure of the compounds obtained was confirmed by elemental analysis, spectroscopy and spectrometry data. The proposed method offers some advantages such as good yields, simple procedure, low cost, and ease of workup.

Introduction

Since many years sulfonamide derivatives have been synthetized; for example, a sulfonamide derivative was prepared by the reaction of sulfonic acid salts with amines and alcohols using the reagent triphenylphosphine ditriflate [1]. There are other reports on the synthesis of 1-[4-(N-pyrimidin-2-yl-sulfamoyl)phenyl]-1,11-dihydro-11-oxo-4-methylpyrimido[4',5':4,5]selenolo[2,3-b]quinolone by the reaction of an iminoether with 4-amino-N-pyrimidin-2-ylbenzenesulfonamide under reflux in glacial acetic acid [2]. Other studies described the obtaining of 4-(1,2,3,4-tetrahydro-4,4,6-trimethyl-2-thioxo-1-pyrimidinyl)-N-(2-thiazolyl)-bezene sulfonamide using sulfathiazole and 4-methyl-4-isothiocyanato-2-pentanone [3]. The synthesis of N-(2-anilinopyridin-3-yl)-4-methylbenzenesulfona- mide by the reaction of N²-phenylpyridine-2,3-diamine with 4-methylbenzenesulfonyl chloride [4] is also reported.

* To whom all correspondence should be sent:
E-mail: : lauro_1999@yahoo.com


© 2013 Bulgarian Academy of Sciences, Union of Chemists in Bulgaria

The sulfamethoxazolato anion is obtained by the reaction of sulfamethoxazole with Ph₃PAuCl and AgCl in methanol/triethylamine [5]. 4-(1,2,3,4-Tetrahydro-4,4,6-trimethyl-2-thioxo-1-pyrimidi-nyl)-N-(2-thiazolyl)-bezenesulfonamide is synthe-tized by the reaction of sulfathiazole with 4-isothiocyanato-2-pentanone under reflux [6]. The procedures for synthesis of sulfonamide derivatives described in the literature require, however, expensive reagents and special conditions. Therefore, in this study two new sulfonamide derivatives were synthetized using a three-component system.

Material and methods

The compounds used in this study were purchased from Sigma-Aldrich Co., Ltd. The melting points of the different compounds were determined on an Electrothermal (900 model) apparatus. Infrared (IR) spectra were recorded on a Perkin Elmer Lambda 40 spectrometer using KBr pellets. ¹H and ¹³C NMR spectra were recorded on a Varian VXR-300/5 FT NMR spectrometer at 300 and 75.4 MHz in CDCl₃ using TMS as internal standard. EIMS spectra were obtained on a Finnigan Trace GCPolaris Q spectrometer. Elemental analysis data were acquired from a Perkin Elmer Ser. II CHNS/0 2400 elemental analyzer.

A solution of β-naphtol (100 mg, 0.69 mmol), sulfathiazole (192 mg, 0.69 mmol) and benzaldehyde (70 µl, 71 mmol) in 10 mL of ethanol was stirred for 72 h at room temperature. The reaction mixture was evaporated to a smaller volume. Then, the mixture was diluted with water and extracted with chloroform. The organic phase was evaporated to dryness under reduced pressure, the residue was purified by crystallization from methanol:water (3:1) yielding 60 % of product, m.p. 118-120 ºC; IR (V_max, cm^-1): 3530 (OH), 3450 (C-NH-Ar) and 1325 (S=O); ¹H NMR (300 MHz, CDCl₃) δ_: 5.45 (s, IH), 6.50 (d, 2H, J = 9.0 Hz), 7.06 (broad, 3H), 7.08-7.12 (m, 2H), 7.16 (d, 1H, J = 9.0 Hz), 7.19(m, 1H), 7.21-7.23 (m, 2H), 7.46-7.52 (m, 2H), 7.57 (d, 1H, J = 3.5 Hz), 7.59 (m, 1H), 7.73 (m, 1H), 7.75 (d, 2H, J = 9.0Hz), 7.80 (m, 1H) ppm. ¹³ C NMR (75.4 Hz, CDCl₃) δ_C: 56.68 (C-17), 114.11 (C-20), 116.04(C-14, C-12), 116.50 (C-5), 119.70 (C-18), 120.89 (C-24), 123.80 (C-26), 127.02 (C-25) 127.10 (C-11, C-15), 127.36 (C-22), 127.80 (C-31), 128.50 (C-21), 129.68 (C-27), 129.90 (C-30, C-32), 130.66 (C-29, C-33), 132.90 (C-28), 135.42 (C-4), 137.65 (C-10), 137.70 (C-23), 153.70 (C-19), 154.22 (C-13), 168.02 (C-2) ppm. EI-MS m/z: 487.75 (M⁺, 12), 334.27, 169.21. Anal. Calcd for C₂₆H₂₁N₃O₃S₂: C, 64.04; H, 4.34; N, 8.62; O, 9.84; S, 13.15. Found: C, 64.02; H, 4.33.

A solution of 1-hexyne (80 µl, 0.70 mmol), sulfathiazole (192 mg, 0.69 mmol) benzaldehyde (75 µl, 0.70 mmol) and cupric chloride anhydrous (140 mg, 1.04 mmol) in 10 ml of ethanol was stirred for 72 h at room temperature. The reaction mixture was evaporated to a smaller volume. Then, the mixture was diluted with water and extracted with chloroform. The organic phase was evaporated to dryness under reduced pressure, the residue was purified by crystallization from methanol:water (3:1) yielding 45 % of product, m.p. 178-180 ºC; IR (V_max, cm^–1): 3310 (CC), 1320 (S=O) and 1170 (C-N); ¹H NMR (300 MHz, CDCl₃) δ_: 0.91 (t, J = 6.3 Hz, 3H), 1.47 (m, 4H), 2.21 (t, J= 6.8 Hz, 2H), 6.67 (m, 2H), 6.78 (m, 1H), 7.17 (d, J = 3.4 Hz, 1H), 7.20 (m, 2H), 7.33 (m, 2H), 7.50 (d, J = 3.4 Hz, 1H), 7.88 (m, 2H), 8.98 (broad, 1H) ¹³ C NMR (75.4 Hz, CDCl₃) δ_C: 13.60 (C-28), 16.95 (C-25), 21.98 (C-27), 32.03 (C-26), 61.08 (C-24), 75.02 (C-23), 113.10 (C-18, C-22), 116.26 (C-12, C-14), 116.57 (C-5, 119.60 (C-20), 128.37 (C-15), 128.50 (C-21), 135.32 (C-4), 138.80 (C-10), 147.02(C-17), 152.34 (C-13), 166.98 (C-2). EI-MS m/z (M⁺ 12): 411.15 (M⁺, 12), 218.08(100), 174.24(60), 103.07 (65), 76.15 (78). Anal. Calcd for C₂₁H₂₁N₃O₂S₂: C, 61.29; H, 5.14; N, 10.21; O, 7.78, S, 15.58. Found: C, 61.03; H, 5.11.

In many procedures a three-component system is used for the synthesis of several compounds. The most widely practiced method employs boric acid [7], silica sulfuric acid [8], poly(4-vinylpyridine-co-divinylbenzene)-Cu(II) complex [9], H₂SO₄[10], silica triflate [11] and phosphorus pentoxide [12]. Nevertheless, despite their wide scope, the former protocols suffer from several drawbacks, e.g., limited stability or dangerous preparation of some reagents. In this study we report a straightforward route for the synthesis of 4 using a modification of a method reported by Dabiri and coworkers [13]. According to this procedure, 4 is obtained by reaction of β-naphtol, benzaldehyde and sulfathiazole in ethanol (Figure 1). The ¹H NMR spectrum of 4 shows

signals at 5.40 ppm for methylene bound to both phenyl and amine groups; at 6.50 and 7.75 ppm for phenyl group bound to amine group; at 7.08–7.12 and 7.21-7.23 ppm for protons involved in the phenyl group which is bound to the methylene group; at 7.16 ppm for hydrogen of thiazole ring; at 7.19, 7.46-7.73 and 7.80 ppm for naphtol fragment. Finally, another signal at 7.06 ppm for both amino and hydroxyl groups was found. The ¹³C NMR spectrum contains peaks at chemical shifts of 56.68 ppm for the carbon of the methylene bound to both phenyl and amine groups. Other signals at 116.50, 135.42 and 168.02 ppm for carbons involved in the thiazole ring; at 127.80 and 129.90–132.90 ppm for phenyl group bound to methylene group; at 114.10, 119.70-127.02, 127.36, 128.50-129.68 and 137.70–153.70 ppm for naphtol fragment; 116.04, 127.10, 137.65 and 154.22 ppm for phenyl group bound to amine group were found. Finally, the presence of 4 was confirmed by the mass spectrum which showed a molecular ion at m/z 487.75.

In conclusion, the synthesis of sulfonamide derivatives using a three-component system offers some advantages such as good yields, simple procedure, low cost, and ease of workup.

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