Synthesis of New Active Sulfones in the 5-Nitroimidazole Series

Abstract

We describe here the preparation of new 5-nitroimidazoles which are known to have an efficacy against metronidazole-susceptible and -resistant Giarda, Trichomonas, and Entamoeba spp. The multi-step synthesis uses electron transfer methodology.

Introduction

Nitroimidazole drugs have been used for over 20 years, not only as major antimicrobial drugs but also as sensitizers of hypoxic tumors in conjunction with radiotherapy, thus possessing a wider spectrum of useful clinical activity than any other antibiotic. These compounds have various substitutions on the imidazole ring either on the nitrogen at position 1 or on the carbon at position 2. The more common are metronidazole, ornidazole, tinidazole and dimetridazole. Our program directed toward electron transfer reactions in nitroheterocyclic series and in particular the 5-nitroimidazole series led us to synthesize more new active compounds [1]. Among them, we describe in this report the preparation of a series of 5-nitroimidazoles with an allylic-sulfone chain at the 2 position. Moreover, these compounds have shown efficacy against metronidazole-susceptible and -resistant Giarda, Trichomonas, and Entamoeba spp [2].

Results and Discussion

The starting material, 2-(3-chloro-2-chloromethylpropenyl)-1-methyl-5-nitro-1H-imidazole (2), was obtained in three steps by the previously described procedure starting from 1-methyl-2-chloromethyl-5-nitro-1H-imidazole (1) [3,4]. The reaction of 2 with sodium p-toluenesulfinate furnished the allylic-sulfone 3 as an unseparated mixture of E and Z isomers (1:2) in 70% yield. Under phase-transfer conditions (40% tetrabutylammonium hydroxide in water and toluene as solvent) and under S_RN1 reaction conditions (inert atmosphere, light catalysis), derivative 3 was treated with 2-nitropropane to give the C-alkylation derivative 4 as the sole product. After purification by chromatography, we have obtained the E isomer in 40% yield and the Z isomer in 20% yield (Scheme 1).

Scheme 1.

Scheme 1.

The formation of 4 constitutes a new example of the LD S_RN1 mechanism (S_RN1 at long distance from the nitro group) in the 5-nitroimidazole series [1]. As the site of metronidazole activation in the anaerobic protozoa is the membrane-localized electron transport pathway [2], the high antiprotozoal activity of 4 may be linked to the side chains that are more hydrophobic than those of metronidazole.

Conclusions

We have reported here a facile route for the formation of new sulfones in the 5-nitroimidazole series by an electron transfer methodology. Moreover, these 5-nitroimidazoles have displayed antiprotozoal activity against metronidazole-susceptible and –resistant species.

Experimental

General

Melting points were determined on Büchi B-540 and are uncorrected. Elemental analyses were performed by the Centre de Microanalyses of the University of Aix-Marseille 3. Both ¹H- and ¹³C-NMR spectra were determined on Bruker ARX 200 spectrometer. The ¹H chemical shifts were reported as parts per million downfield from tetramethylsilane (Me₄Si), and the ¹³C chemical shifts were referenced to the CDCl₃solvent peak (76.9 ppm). Silica gel 60 (Merck, 230-400 mesh) was used for column chromatography. Thin-layer chromatography was performed with silica gel Merck 60F-254 (0.25 mm layer thickness). 2-(3-Chloro-2-chloromethylpropenyl)-1-methyl-5-nitro-1H-imidazole (2) was prepared as previously described from 2-chloromethyl-1-methyl-5-nitro-1H-imidazole (1) [3,4].

Synthesis of 2-[3-chloro-2-(toluene-4-sulfonylmethyl)propenyl]-1-methyl-5-nitro-1H-imidazole (3). A solution of sodium 4-methylbenzenesulfinate (0.2 g, 2 mmol) in dimethylsulfoxide (4 mL) was added dropwise to a solution of dichloride 2 (0.5 g, 2 mmol) in dimethylsulfoxide (5 mL) and stirred under inert atmosphere for 12 h. The reaction mixture was poured into cold water and a precipitate was thus formed. After filtration, the crude product was dissolved in dichloromethane (10 mL), washed twice with water (2 x 20 mL), dried over MgSO₄ and the solvent removed under reduced pressure. Purification by chromatography on a silica gel column eluting with dichloromethane-ethyl acetate (95/5) and recrystallization from ethanol gave 0.52 g (70% yield) of 2-[3-chloro-2-(toluene-4-sulfonylmethyl)propenyl]-1-methyl-5-nitro-1H-imidazole (3) (E:Z, 1:2): Brown solid, mp 134 °C (ethanol). Anal. Calcd for C₁₅H₁₆N₃O₄SCl : C, 48.72; H, 4.36; N, 11.36; Cl, 9.59; S, 8.67; Found : C, 48.71; H, 4.39; N, 11.34; Cl, 9.70; S, 8.60.

E isomer

¹H-NMR (CDCl₃) δ: 2.49 (s, 3H, CH₃), 3.88 (s, 3H, NCH₃), 4.14 (s, 2H, CH₂Cl), 4.89 (s, 2H, CH₂SO₂), 6.31 (s, 1H, CH=C), 7.41 (d, 2H, J = 8.2 Hz, CH_Ar), 7.81 (d, 2H, J = 8.2 Hz, CH_Ar), 8.02 (s, 1H, CH_Imid); ¹³C-NMR (CDCl₃) δ: 22.3 (CH₃), 33.8 (NCH₃), 42.8 (CH₂Cl), 62.0 (CH₂SO₂), 121.1 (CH=C), 129.1 (2 x CH_Ar), 130.8 (2 x CH_Ar), 133.8 (CH_Imid), 136.8 (Cq), 139.0 (Cq), 146.2 (Cq), 146.6 (Cq).

Z isomer

¹H-NMR (CDCl₃) δ: 2.37 (s, 3H, CH₃), 3.71 (s, 3H, NCH₃), 4.55 (s, 2H, CH₂Cl), 5.05 (s, 2H, CH₂SO₂), 6.54 (s, 1H, CH=C), 7.21 (d, 2H, J = 8.2 Hz, CH_Ar), 7.63 (d, 2H, J = 8.2 Hz, CH_Ar), 7.88 (s, 1H, CH_Imid). ¹³C-NMR (CDCl₃) δ: 22.1 (CH₃), 33.5 (NCH₃), 48.7 (CH₂Cl), 55.8 (CH₂SO₂), 119.2 (CH=C), 129.1 (2 x CH_Ar), 129.7 (2 x CH_Ar), 133.2 (CH_Imid), 136.2 (Cq), 137.7 (Cq), 145.7 (Cq), 146.8 (Cq).

S_RN1 reaction of chloride 3 and 2-nitropropane. Under nitrogen atmosphere, a solution of tetrabutylammonium hydroxide (1.6M/water, 3.6 mL, 5.4 mmol) was treated with 2-nitropropane (0.48 g, 5.4 mmol) for 1 h. A solution of chloride 3 (0.5 g, 1.35 mmol) in toluene (10 mL) was added and the mixture was irradiated with a 300W sun lamp for 8 h. The organic layer was separated and the aqueous layer was extracted with dichloromethane (3 x 10 mL). The combined organic layers were washed twice with water (2 x 30 mL), dried over MgSO₄ and removed under reduced pressure. Purification by chromatography on silica gel eluting with chloroform-ethyl acetate (95/5) and recrystallization from ethanol gave the 3-(1-methyl-5-nitro-1H-imidazol-2-yl)-2-(2-methyl-2-nitropropyl)prop-2-ene-1-sulfinic acid p-tolyl ester (4E) (0.23 g, 40% yield) and (4Z) (0.12 g, 20% yield).

3-(1-methyl-5-nitro-1H-imidazol-2-yl)-2-(2-methyl-2-nitropropyl)prop-2-ene-1-sulfinic acid p-tolyl ester (4E): Yellow solid, mp 115 °C (ethanol). ¹H-NMR (CDCl₃) δ: 1.67 (s, 6H, (CH₃)₂CNO₂), 2.32 (s, 3H, CH₃), 3.17 (s, 2H, CH₂C(CH₃)₂NO₂), 3.57 (s, 3H, NCH₃), 4.90 (s, 2H, CH₂SO₂), 6.03 (s, 1H, CH=C), 7.16 (d, 2H, J = 8.2 Hz, CH_Ar), 7.55 (d, 2H, J = 8.2 Hz, CH_Ar), 7.82 (s, 1H, CH_Imid). ¹³C-NMR (CDCl₃) δ: 22.1 (CH₃), 26.8 (2 x CH₃), 33.4 (NCH₃), 47.7 (CH₂C(CH₃)₂NO₂), 58.9 (CH₂SO₂), 89.4 (C(CH₃)₂NO₂), 121.1 (CH=C), 129.2 (2 x CH_Ar), 129.7 (2 x CH_Ar), 133.1 (CH_Imid), 135.9 (Cq), 136.5 (Cq), 145.6 (Cq), 147.0 (Cq). Anal. Calcd for C₁₈H₂₂N₄O₆S : C, 51.18; H, 5.25; N, 13.26; S, 7.59. Found : C, 51.15; H, 5.21; N, 13.30; S, 7.52.

3-(1-methyl-5-nitro-1H-imidazol-2-yl)-2-(2-methyl-2-nitropropyl)prop-2-ene-1-sulfinic acid p-tolyl ester (4Z): Yellow solid, mp 118 °C (ethanol). ¹H-NMR (CDCl₃) δ: 1.61 (s, 6H, (CH₃)₂CNO₂), 2.48 (s, 3H, CH₃), 3.57 (s, 2H, CH₂C(CH₃)₂NO₂), 3.80 (s, 2H, CH₂SO₂), 3.95 (s, 3H, NCH₃), 6.53 (s, 1H, CH=C), 7.40 (d, 2H, J = 8.2 Hz, CH_Ar), 7.78 (d, 2H, J = 8.2 Hz, CH_Ar), 8.03 (s, 1H, CH_Imid). ¹³C-NMR (CDCl₃) δ: 22.3 (CH₃), 26.6 (2 x CH₃), 33.7 (NCH₃), 41.7 (CH₂C(CH₃)₂NO₂), 63.5 (CH₂SO₂), 89.0 (C(CH₃)₂NO₂), 122.9 (CH=C), 129.0 (2 x CH_Ar), 130.7 (2 x CH_Ar), 133.5 (CH_Imid), 136.2 (Cq), 136.4 (Cq), 139.4 (Cq), 146.1 (Cq), 147.4 (Cq). Anal. Calcd for C₁₈H₂₂N₄O₆S : C, 51.18; H, 5.25; N, 13.26; S, 7.59. Found : C, 51.15; H, 5.30; N, 13.20; S, 7.80.