Synthesis and Structure of Sulfur Derivatives from 2-Aminobenzimidazole

The reactions of the benzimidazole nitrogen atoms and the exocyclic amino group of 2-aminobenzimidazole with CS2 in NaOH basic medium followed by methylation with methyl iodide was explored. With careful control of the stoichiometric quantities and addition sequences, this set of reactions allows the selective functionalization of the benzimidazole ring with N-dithiocarbamate, S-methyldithiocarbamate or dimethyl- dithiocarboimidate groups. The products were characterized by 1H-, 13C-NMR spectroscopy and three of them by X-ray diffraction analysis. The preferred isomers, tautomers and conformers were established.


Introduction
We are currently investigating the structures of biologically active benzofused nitrogen heterocycles such as 2-aminobenzazoles [1][2][3][4]. They are versatile from the structural point of view because of their free lone pairs, labile hydrogen atoms, and planar delocalized acyclic groups. The delocalized 10-π electronic system and the extended electronic conjugation with the amino group, make these heterocycles have amphoteric character. Moreover, 2-aminobenzazoles [5,6] occur in broad spectrum of drugs and pharmacological agents with anticancer, antibacterial, antiviral, analgesic, antidiabetic

OPEN ACCESS
properties. Thus, several 2-aminobenzimidazole-derived drugs are registered around the world. For example, mebendazole represents a big group of antiparasitic drugs, and astemizole represents an antihistaminic group II generation drug with selective activity toward H1 receptors.
In this context, we have reported a detailed study and characterization of the intermediates involved in the synthesis of dimethyl benzo[d]thiazol-2-carbonodithioimidate (2) [7], by the reaction of 2-aminobenzothiazole (1) with carbon disulfide in basic media, following the procedure reported by Merchand et al. [8] (Scheme 1). Compound 2 reacts with ortho-XH substituted anilines in refluxing DMF to give NH-bisbenzazoles [9][10][11] due to the facility with which HSMe molecules are displaced. We used this method to prepare chiral 2-iminobenzothiazole heterocycles derived from ephedrine [12]. On this basis, we reported a series of sulfur compounds such as thiourea, isothiourea, dithiocarbamate, dithiocarboimine, dimethyldithiocarbamate, methyldithiocarbamate, S-methyl and O-alkyl thiocarbamic esters derived from 2-aminobenzothiazole [7]. These new compounds are versatile because they have very reactive functional groups, and thus they can be used as intermediates for the synthesis of more complex molecules. Besides, they possess rigid frameworks and several lone pairs available for coordination and then they are potentially interesting ligands for metallic coordinating compounds. On the other hand, we have also recently reported a synthetic method to access symmetric and non-symmetric 2-(N,N'-disubstituted)-guanidinebenzothiazoles [13] from the reaction of ammonia, methylamine, pyrrolidine and aniline with compound 2, isolating isothioureas as intermediates [14].

Scheme 1. Synthesis of dimethyl benzo[d]thiazol-2-carbonodithioimidate (2).
The presence of amine groups of different orders in 2-aminobenzimidazole enables the synthesis of various structural derivatives. In this case, we are interested in the functionalization of amino groups in 2-aminobenzimidazole (3) with sodium hydroxide, carbon disulfide and methyl iodide to give sulfur derivatives.

Synthesis
To investigate the nitrogen nucleophilicity, we reacted 2-aminobenzimidazole with methyl iodide (MeI) in ethanol as solvent (Scheme 2). If one molar equivalent of MeI was added, a mixture of the iodide salts: 1-methyl-2-ammoniumbenzimidazole (4, 30%), 1,3-dimethyl-2-ammoniumbenzimidazole (6, 30%) and 2-ammoniobenzimidazole (30%) were observed in the 1 H-NMR spectrum. To explain this result, we propose that 2-aminobenzimidazole is methylated to produce the iodide salt of the N-methylated compound 4A as intermediate, which is immediately transformed into the more stable tautomer 4B. When two molar equivalents of methyl iodide were used, the basic imidazolic nitrogen atom of the iodide salt 4B is methylated to give the dimethylated iodide salt 6 (60% In order to isolate the N-methylbenzimidazole 5, we reacted 2-aminobenzimidazole (3) with one molar equivalent of sodium hydroxide using as DMF solvent, followed by one molar equivalent of MeI, as depicted in Scheme 2. Under these conditions, the reaction afforded a 1:1:1 mixture of 5, the dimethylated iodide salt 6 and unreacted 3. The same reaction with two molar equivalents of MeI affords 6 as the only product in 90% yield.
On these bases, a detailed study and the characterization of the compounds derived from the reaction of 2-aminobenzimidazole (3) with carbon disulfide in basic media followed by methylation with methyl iodide, using DMF as solvent were performed. When 3 was reacted with CS2 and CH3I in basic (NaOH) medium, following the reported procedure for the synthesis of compound 2 [8], the reaction failed to give the analogous compound, and instead a 1:3 mixture of compounds 7 and 8 were observed in the 1 Hand 13 C-NMR spectra (Scheme 3). With separation purposes, this mixture was dissolved in ethanol. 2-Methylthio-4H- [1,3,5]thiadiazino [3,4-a]benzimidazole-4-thione (7) was isolated from the mixture as an insoluble yellow solid and after recrystallization from chloroform, it was obtained as yellow crystals in 15% yield. 2-Aminobenzimidazole-1-carbodithioic acid methyl ester (8) precipitated from the ethanol solution, as yellow crystals in 40% yield as the previously described polymorph [15]. In this reaction, the small quantity of compound 7 is formed from 8 because CH3I, NaOH and CS2 were added in 20% molar excess. Compounds 7 and 8 were obtained in 40% and 66% yield, respectively, when the reactions were carried out in stoichiometric quantities. These results are in agreement with the stronger acidic character of the imidazolic hydrogen atom than that of the exocyclic 2-amino group.  The formation of compounds 7 and 8 can be explained by assuming that the benzimidazolate I, obtained from the reaction of 3 with NaOH, which reacts with one molar equivalent of CS2 to give the thiocarbamate II that, after methylation, affords compound 8. The intermediate III, formed by a second molar equivalent of NaOH, reacts with a second molar equivalent of CS2 to produce the dithiocarbamate dianion IV. The subsequent methylation of IV with two molar equivalents of MeI, affords the proposed intermediate compound V, which is finally cyclized to give the heterocyclic compound 7. This mechanistic proposal is depicted in Scheme 4. In order to obtain the compound 10, we reacted 2-aminobenzimidazole (3) with exactly one molar equivalent of NaOH and one molar equivalent of CS2 followed by the addition of two molar equivalents of MeI. Under these conditions, the iminium iodide salt 9 was formed. Compound 9 was neutralized with NaOH to give 2-imino-3-methyl-2,3-dihydro-benzimidazol-1-carbodithioic acid methyl ester (10). Subsequent methylation at the imine nitrogen of compound 10 was performed to give N-(1-methyl-3-(methylthiocarbonothioyl)-1H-benzo[d]imidazol-2(3H)-ylidene)methanaminium iodide (11). 3-Methyl-2-methylimino-2,3-dihydro-benzoimidazole-1-carbodithioic acid methyl ester (12) was obtained by deprotonating 11 with NaOH. The sequence of reactions is depicted in Scheme 5.
The reaction of 2-aminobenzimidazole with NaOH and CS2 in an equimolar ratio, in refluxing DMF by 8 h was carried out, then one molar equivalent of NaOH and two molar equivalents of CH3I were subsequently added. Under these conditions, a white solid precipitates from the aqueous-DMF solution. The solid compound was purified by recrystallization in ethanol and white crystals were obtained in 25% yield. This compound was characterized by NMR and X-ray diffraction analysis and the structure imidazol-2-ylcarbonodithioimidate (13, Scheme 6). The reaction proceeded through the intermediacy of the exocyclic sodium amide VII whose formation is favored by heating.  (14) precipitated from the aqueous-DMF solution and was crystallized from ethanol. The structure of this compound was analyzed by X-ray diffraction (vide infra). After neutralization of 14 with one equivalent of NaOH, dimethyl 1-methyl-1H-benzo[d]imidazol-2-ylcarbonodithioimidate (15) was obtained quantitatively as a white solid. This compound has already been obtained from 1-methyl-2-aminobenzimidazole whose NMR data and X-ray diffraction structure has been reported elsewhere [16].

Molecular Structure in Solution by NMR
A complete list of 1 H and 13 C-NMR data of compounds 7 and 9-14 and 16-17 is given in Tables 1 and 2, respectively, to support the proposed structures.  The chemical shift of H7 in compounds 7 and 9-12, is sensitive to the conformation of the C=S group. It appears as a doublet at δ 9.0 in compound 7 because of the deshielding effect of the neighbouring thiocarbonyl group. In this context, it is worth noting that the chemical shift of H7 for the neutral compounds 10 and 12, is approximately at 8.1; this shift to higher frequencies suggests that the preferred conformation of the thiocarbonyl group on the NMR time scale is endo ( Figure 1). In contrast, the hydrogen atom on the exocyclic nitrogen atom in imminium compounds 9 and 11, forms a hydrogen bond with the sulfur atom of the thiocarbonyl group. This interaction has the effect to fix the conformation of the thiocarbonyl group in exo disposition, as has been reported for compound 8, [15] shifting H7 to lower frequencies at 7.24 and 7.61 ppm, respectively (Scheme 7).  The shift of this equilibrium to the (E)-11-exo isomer in polar solvents, explains the isolation of the neutral compound 12 with both NCH3 groups in syn disposition and preference for the endo rotamer, on the 1 H-NMR time scale. The stereochemistry of compound (E)-12 was confirmed by nOe experiments (Figure 3). After irradiation of the SCH3 signal, both in DMSO-d6 and CDCl3 solutions, a very small nOe was observed on the H7 proton but not on the exocyclic NCH3, as expected for the (Z)-12-exo isomer (Scheme 8). nOe on N3-CH3 was useless because the close proximity with the chemical shift of the exocyclic N-CH3.

Molecular Structure of Compounds 7, 13 and 14 by X-Ray Diffraction
Analysis of the X-ray diffraction structure of compound 7 (Figure 4   The molecular structure of compound 13 is depicted in Figure 5. Benzimidazole NH prefers to form intermolecular N-H···N, instead of intramolecular hydrogen bonding interactions to give a polymeric supramolecular structure. Thus the N=C(SMe)2 moiety is free for rotation, being located out of the mean benzimidazole ring plane as shown by the values of the torsion angles of −71.3(3)° for N(1)-C(2)-N(10)-C(11) and 116.2(2)° for N(3)-C(2)-N(10)-C (11). This geometric feature contrasts with the planar structure observed for the analogous derivatives of 2-aminobenzothiazole and 2-amino-1-methyl benzimidazole [16].

General Procedures
Melting points were measured on an Electrothermal IA apparatus and are uncorrected. IR spectra were recorded in a film on ZnSe using a Perkin-Elmer 16F PC IR spectrophotometer. 1 H-and 13 C-NMR spectra were recorded on a Varian Mercury 300 MHz ( 1 H, 300.08; 13 C, 75.46 MHz instrument). The spectra were measured with tetramethylsilane as internal reference following standard techniques. Physicochemical data is listed in Table 3. Crystallographic data (excluding structure factors) for the structures in this paper has been deposited in the Cambridge Crystallographic Data Centre as supplementary publication numbers CCDC 7 (1002932), 13 (1002930) and 14 (1002929). A summary of collection and refinement of the X-ray data is listed in Table 4. H atoms were treated as riding atoms, with C-H distances in the range of 0.93-0.96 Å and N-H distances of 0.82 Å. X-ray diffraction cell refinement and data collection: a Bruker SMART APEX Diffractometer and SAINT [17]. The SHELXS-97 programs were used to solve the structures [18]. PLATON [19] and WinGX [20] software was used to prepare material for publication. 2-Aminobenzimidazole (3) was a commercial product.   (6) In a 100 mL round-bottom flask, a solution of sodium hydroxide (0.3 g, 7.52 mmol) in water (0.5 mL), and a solution of 2-aminobenzimidazole (3, 1.0 g, 7.52 mmol) in DMF (6 mL) were successively added. The mixture was cooled on an ice bath and stirring for 30 min, then methyl iodide (0.94 mL, 15.0 mmol) was added and stirring was continued for 24 h. The reaction was quenched by the addition of cold water (100 mL). The precipitated solid was filtered off, washed with water and recrystallized from ethanol. After air drying, 1.95 g (90%) of white crystals were obtained. 1 [1,3,5]thiadiazino [3,4-a]benzimidazole-4-thione (7) In a 100 mL round-bottom flask, a solution of sodium hydroxide (0.4 g, 10 mmol) in water (0.5 mL), and a solution of 2-aminobenzimidazole (3, 1.33 g, 10 mmol) in DMF (6 mL) were successively added. The mixture was cooled on an ice-water bath and stirring for 30 min. Then, the following reactants were successively added: (a) carbon disulfide (0.6 mL, 10 mmol); (b) sodium hydroxide aqueous solution 20 M (0.5 mL 10 mmol); (c) carbon disulfide (0.6 mL, 10 mmol) and (d) methyl iodide (1.25 mL, 20 mmol). Portionwise addition and a delay of 30 min between additions were necessary in order to complete the reaction. Stirring was continued for 24 h and cold water (100 mL) was added to the mixture. The precipitated solid was filtered off, washed with water, and purified by recrystallization from chloroform. After air drying, 1.06 g (40%) of yellow crystals were obtained. (8) The same procedure and quantities as described for 7 were used following the sequence: (a) carbon disulfide (0.6 mL, 10 mmol); (b) methyl iodide (0.63 mL, 10 mmol). Compound 8 was purified by recrystallization from ethanol to obtain 1.47 g (66%) of yellow crystals. (9) The same procedure as described for 8 was used following the sequence: (a) carbon disulfide (0.6 mL, 10 mmol); (b) methyl iodide (1.25 mL, 20 mmol). Compound 9 was purified by recrystallization from ethanol to obtain 2.41 g (66%) of yellow powder. (10) The same procedure as described for 9 was used, adding (c) sodium hydroxide aqueous solution (0.5 mL, 10 mmol). After standing, 1.42 g (60%) of compound 10 precipitated as a yellow powder.

Dimethyl 1H-benzo[d]imidazol-2-ylcarbonimidodithioate (13)
In 500 mL round-bottom flask, a solution of sodium hydroxide (2.0 g, 50 mmol) in water (2.5 mL), and a solution of 2-aminobenzimidazole 3 (6.65 g, 50 mmol) in DMF (30 mL) were successively added. The mixture was cooled on an ice-water bath, stirred for 30 min and carbon disulfide (3.0 mL, 50 mmol) was added. The mixture was refluxed for 4 h, the solution was cooled on an ice bath and the following reactants were successively added: (a) sodium hydroxide aqueous solution 20 M (2.5 mL, 50 mmol); (b) methyl iodide (6.25 mL, 100 mmol). Portionwise addition and a delay of 30 min between additions were necessary in order to complete the reaction. Stirring was continued for 24 h and cold water (500 mL) was added to the mixture. The precipitated solid was filtered off, washed with water and purified by recrystallization in ethanol to obtain 2.96 g (25%) of white crystals. (14) In 100 mL round-bottom flask a solution of compound 13 (1.0 g, 4.2 mmol) in of DMF (6 mL) and methyl iodide (0.3 mL, 4.8 mmol) were added, The mixture was cooled on an ice-water bath and stirring for 12 h and cold water (100 mL) was added to the mixture. The precipitated solid was filtered off, washed with water and purified by recrystallization in ethanol to obtain 1.32 g (85.7%) of white crystals.  (17) The same procedure and quantities as described for 13 were used, but half the amount of methyl iodide (3.13 mL, 50 mmol) was used. The precipitated solid was dissolved in ethanol and 1.2 g of compound 17 precipitated as white crystals. From the ethanol solution, 0.8 g of compound 16 precipitated as a white powder.

Conclusions
We have demonstrated that by a careful control of the stoichiometric quantities and addition sequences as well as the temperature, the reactions of 2-aminobenzimidazole with NaOH, CS2 and CH3I allow the selective functionalization of the benzimidazole ring with N-dithiocarbamate, S-methyldithiocarbamate or dimethyldithiocarboimidate groups. The imidazolic hydrogen atom is more acid than that of the amino group in 2-aminobencimidazole, thus both endocyclic nitrogen atoms are methylated with methyl iodide in neutral or basic media. In the reaction with CS2 at ice-water bath (4 °C) temperature, the endocyclic dithiocarbamate is formed when the first molar equivalent of CS2 is added whereas the exocyclic dithiocarbamate is formed after the second molar equivalent of CS2 is added. The regiochemistry of this reaction is shifted to form the exocyclic dithiocarboimidate as the only product when the reaction is performed in refluxing DMF. The dimethyldithiocarboimidate group of compound 13 is out of the benzimidazole plane, in contrast to the planar structure of the analogous compounds 15 and 2 derived from 2-amino-1-methylbenzimidazole and 2-aminobenzothiazole, respectively. The preferred conformers of iminium salts, compounds 9 and 11, and the corresponding neutral compounds, 10 and 12, were determined. Compound (Z)-11 was observed in CDCl3, whereas a Z-E isomerization occurred in DMSO-d6. Compound (E)-11 is selectively deprotonated to form the free base (E)-12.