A Facile and Efficient Procedure for the Synthesis of New Benzimidazole-2-thione Derivatives

A series of benzimidazole-2-thione derivatives was synthesized using a reaction between the macrocyclic aminal 16H,13H-5:12,7:14-dimethanedibenzo[d,i]-[1,3,6,8] tetraazecine (DMDBTA, 5) and various nucleophiles in the presence of carbon disulfide. A full chemical characterization using IR, 1H-, 13C-NMR and GC-MS analyses of the new compounds is provided. These compounds were separated from the reaction mixture by column chromatography (CC) in highly pure form in 15%–51.4% yield.

As shown in Table 1, the results reveal that the yield of the reaction depends on the size of the nucleophile. Consequently, the use of t-butanol under the same reaction conditions afforded complex mixtures, from which we were unable to isolate the expected benzimidazole-2-thione and 1-H-benzimidazole derivatives. According to these results, in the presence of an adequate nucleophile, the reactions efficiently proceed to provide the ring opening of the benzoaminal. Thus, the first step of the reaction between 5 and CS 2 might be fast, and the second step, involving the nucleophilic attack of the dithiocarbamate salt, is slower and consequently should be the rate-limiting step. The onset of the reaction is indicated by the evolution of hydrogen sulphide, whose odour was noticeable during the reaction. Based on these results, we propose a possible pathway for the formation of the products (Scheme 2).

Scheme 2.
Proposed pathway for the formation of 7a-f and 8a-f. We assumed that carbon disulfide first reacts with 5 to form the expected dithiocarbamate salt 9 as a very active intermediate. This intermediate then reacts with one equivalent of the nucleophile, a reaction that includes a proton shift, to produce a second intermediate 10 that is able to form S-H···N intramolecular hydrogen bonds. This intramolecular interaction in this intermediate decreases the relative stability of the intermediate and induces the attack of a second equivalent of nucleophile to give a 1-substituted-3-aryl-2,3,4,5-tetrahydro-1H-1,3,5-benzotriazepine intermediate 11, in which a proton transfer induces an intramolecular rearrangement to give 12. The presence of a positive charge on the 1H-benzimidazole ring of 12 makes this adduct fairly labile, and the central NCH 2 N moiety in 12 undergoes a regioselective cleavage involving the preferential attack by a third equivalent of nucleophile to give 13 and 14. Then, the benzimidazole-2-thiones 7a-f are obtained by cyclisation of the acyclic intermediate 13 with the elimination of a molecule of H 2 S. Monosubstituted-benzimidazolines 14a-f, the other products formed from 12 under these reaction conditions, smoothly undergo oxidation in air to yield the 1-(alkoxymethyl)-1,3-dihydro-2H-benzimidazole derivatives 8a-f, as observed previously for other benzimidazoline derivatives [27]. Alcohols and cyclic ethers are good solvents for this oxidative process [28][29][30].

General
Melting points were determined on an Electrothermal 9100 melting point apparatus and are uncorrected. Chemicals were used without further purification. FT-IR spectra were recorded in potassium bromide pellets using Thermo Nicolet IS10 spectrophotometer. 1 H-NMR and 13 C-NMR spectra were recorded in CDCl 3 using a Bruker Avance AV-400 MHz spectrometer operates at 400 MHz for 1 H and 100 MHz for 13 C. Elemental analyses (C, H, N) were determined in a Thermo Scientific Flash 2000. Combined GC-MS analysis was performed on a Hewlett-Packard 5973 mass spectrometer at 70 eV coupled to a Hewlett-Packard 6890 gas chromatograph.
General procedure for the reaction of DMDBTA with CS 2 in alcohols: Following the general procedure described in the literature [25], carbon disulfide (0.95 mmol, 0.07 mL) was added dropwise over 30 min to a shaking solution of DMDBTA (0.95 mmol) in the desired alcohol (30 mL). This yellow solution was stirred at room temperature in the dark until the DMDBTA had dissolved completely. The reaction was monitored by TLC. The removal of the solvent at reduced pressure (50 mmHg) resulted in the collection of a resinous solid that was then purified via column chromatography on silica gel (elution using benzene:ethyl acetate in a 9:1 mixture).
Procedure for the reaction of DMDBTA with benzotriazole and CS 2 : A mixture of DMDBTA (0.95 mmol, 0.25 g), 1H-benzotriazole (2.85 mmol, 0.34 g) and carbon disulfide (0.95 mmol, 0.07 mL) was stirred in 1,4-dioxane (30 mL) for 24 h. at room temperature in the dark yielding a resinous solid. The precipitated solid was collected and purified via column chromatography on silica gel (elution using benzene: ethyl acetate in a 9:1 mixture).
Procedure for the reaction of DMDBTA with cyanide anion and CS 2 : To a solution of DMDBTA (0.95 mmol, 0.25 g) and carbon disulfide (0.95 mmol, 0.07 mL) in acetonitrile (15 mL), an excess of hydrogen cyanide was bubbled in slowly. The reaction mixture was stirred at room temperature in the dark for 24 h. The removal of the solvent at reduced pressure (50 mmHg) resulted in the collection of a resinous product that was then purified via column chromatography on silica gel (elution using benzene:ethyl acetate in a 9:1 mixture).

Conclusions
In conclusion, the reported synthesis is reasonably efficient, direct, and operationally simple. We believe that the methodology presented herein can have wide applications for the development of synthetically useful benzimidazole-2-thiones that were previously inaccessible by other routes.