Next Article in Journal
Second Order Kinetic Modeling of Headspace Solid Phase Microextraction of Flavors Released from Selected Food Model Systems
Previous Article in Journal
Tyrosine Kinase Inhibitors as Reversal Agents for ABC Transporter Mediated Drug Resistance
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Synthesis and Structure of Sulfur Derivatives from 2-Aminobenzimidazole

Instituto Politécnico Nacional-UPIBI, Departamento de Ciencias Básicas, Av. Acueducto s/n Barrio la Laguna Ticomán, 07340 México, D.F., Mexico
*
Author to whom correspondence should be addressed.
Molecules 2014, 19(9), 13878-13893; https://doi.org/10.3390/molecules190913878
Submission received: 11 June 2014 / Revised: 14 August 2014 / Accepted: 14 August 2014 / Published: 4 September 2014
(This article belongs to the Section Organic Chemistry)

Abstract

:
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.

Graphical Abstract

1. 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 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).
Scheme 1. Synthesis of dimethyl benzo[d]thiazol-2-carbonodithioimidate (2).
Molecules 19 13878 g007
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.

2. Results and Discussion

2.1. 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 1H-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%). The remaining 2-aminobenzimidazole traps the generated HI to give the iodide salt of 2-ammoniumbenzimidazole (30%), as side product.
Scheme 2. Methylation reactions of 2-aminobenzimidazole (3).
Scheme 2. Methylation reactions of 2-aminobenzimidazole (3).
Molecules 19 13878 g008
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 1H- and 13C-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.
Scheme 3. Reaction of 2-aminobenzimidazole (3) with CS2 and methyl iodide in basic media.
Scheme 3. Reaction of 2-aminobenzimidazole (3) with CS2 and methyl iodide in basic media.
Molecules 19 13878 g009
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.
Scheme 4. Mechanistic pathway to obtain compound 7.
Scheme 4. Mechanistic pathway to obtain compound 7.
Molecules 19 13878 g010
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.
Scheme 5. Synthetic method to get compounds 912.
Scheme 5. Synthetic method to get compounds 912.
Molecules 19 13878 g011
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 corresponded to dimethyl 1H-benzo[d]imidazol-2-ylcarbonodithioimidate (13, Scheme 6). The reaction proceeded through the intermediacy of the exocyclic sodium amide VII whose formation is favored by heating.
Scheme 6. Synthetic pathway to access to compounds 1317.
Scheme 6. Synthetic pathway to access to compounds 1317.
Molecules 19 13878 g012
When three molar equivalents of methyl iodide were used in the methylation reaction to obtain 13, the hydroiodide salt of dimethyl 1-methyl-1H-benzo[d]imidazol-2-ylcarbonodithioimidate (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].
In order to obtain (1,3-dihydrobenzoimidazol-2-ylidene)-dithiocarbamic acid methyl ester (16), the intermediate VIII was prepared in situ and then methylated with one molar equivalent of CH3I, to afford compound 16 in mixture with the iodide salt of 2-(bis(methylthio)methyleneamino)-1H-benzo[d]imidazol-3-ium (17) which was separated as a precipitate from ethanol solution.

2.2. Molecular Structure in Solution by NMR

A complete list of 1H and 13C-NMR data of compounds 7 and 914 and 1617 is given in Table 1 and Table 2, respectively, to support the proposed structures.
Table 1. 1H-NMR chemical shifts of compounds 7, 914, 16 and 17. Molecules 19 13878 i001
Table 1. 1H-NMR chemical shifts of compounds 7, 914, 16 and 17. Molecules 19 13878 i001
Comp.H4H5H6H7NHNCH3SCH3
7 b7.827.437.549.002.80
9 a7.587.467.317.249.33.672.91
10 b6.857.196.988.107.33.412.78
11 a7.597.417.317.619.13.71, 3.102.96
12 b6.776.937.118.123.40, 3.252.71
13 b7.507.107.117.3212.22.57
14 a7.787.477.457.608.63.77 2.73
167.247.497.497.2413.02.44
177.107.407.407.102.55
a DMSO-d6; b CDCl3, LP = Lone pair.
Table 2. 13C-NMR chemical shifts of compounds 7, 914, 16 and 17.
Table 2. 13C-NMR chemical shifts of compounds 7, 914, 16 and 17.
Comp.C2C4C5C6C7C8C9C10C11NCH3SCH3
7 a172.3127.9120.4125.8118.0131.8142.4182.8172.414.3
9 b148.6125.6111.9124.8111.6129.4131.0200.330.622.8
10 a151.5125.9122.3121.4118.9129.1132.7201.628.520.4
11 a149.0125.7124.8111.3111.3129.7131.1201.431.6, 31.323.0
12 b145.5124.4120.1112.5106.3131.0134.5203.336.0, 29.821.5
13 a153.2118.9121.8118.9111.1133.0143.0173.516.1
14 a149.2114.7125.3125.8114.7130.8132.1185.830.716.7
16 b151.2112.8124.2124.2112.8129.1129.1205.618.6
17 a152.9114.8121.8121.8114.8138.0138.0173.415.9
a DMSO-d6; b CDCl3.
The chemical shift of H7 in compounds 7 and 912, 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).
Figure 1. Endo conformers of compounds 10 and 12 and exo ones of compounds 9 and 11.
Figure 1. Endo conformers of compounds 10 and 12 and exo ones of compounds 9 and 11.
Molecules 19 13878 g001
Scheme 7. Isomerization of 11-exo in DMSO-d6 solution. nOes are represented by double headed curved arrows.
Scheme 7. Isomerization of 11-exo in DMSO-d6 solution. nOes are represented by double headed curved arrows.
Molecules 19 13878 g013
In order to confirm the stereochemistry of compound 11, nOe experiments were carried out. Irradiation of the NH gave a nOe on both N-CH3 groups (Figure 2b) and the irradiation of the N3-CH3 protons gave a nOe on both the CH3 and NH protons of the exocylic C=N group (Figure 2c), in DMSO-d6 solution. After the irradiation of the N3-CH3 signal, nOe was observed only on the NH signal in CDCl3 solution (Figure 2e). In every case, the nOe was not observed on the SCH3 signal. These findings can be explained due to an isomerization process mediated by the participation of the lone pair of electrons on N3 (Scheme 7). In DMSO-d6 solution both E and Z isomers are in a fast equilibrium in the 1H-NMR time scale, whereas in CDCl3 solution the last isomer is the preferred.
Figure 2. (a) 1H-NMR spectrum of compound 11 in DMSO-d6; (b) After irradiation of the NH signal, nOes on both CH3 groups are observed; (c) nOe on the NH, exocyclic NCH3 and H4 after irradiation of the N3-CH3 signal; (d) 1H-NMR spectrum of compound 11 in CDCl3; (e) Irradiation of N3-CH3 gave a nOe on NCH3 in CDCl3.
Figure 2. (a) 1H-NMR spectrum of compound 11 in DMSO-d6; (b) After irradiation of the NH signal, nOes on both CH3 groups are observed; (c) nOe on the NH, exocyclic NCH3 and H4 after irradiation of the N3-CH3 signal; (d) 1H-NMR spectrum of compound 11 in CDCl3; (e) Irradiation of N3-CH3 gave a nOe on NCH3 in CDCl3.
Molecules 19 13878 g002
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 1H-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.
Figure 3. (a) 1H-NMR spectrum of compound 12 in CDCl3; (b) After irradiation of the SCH3 signal, nOe on H7 was observed.
Figure 3. (a) 1H-NMR spectrum of compound 12 in CDCl3; (b) After irradiation of the SCH3 signal, nOe on H7 was observed.
Molecules 19 13878 g003
Scheme 8. Endo-exo equilibrium in compound (E)-12. Expected nOes are represented by double headed curved arrows in E (a) and Z (b) isomers of compound 12.
Scheme 8. Endo-exo equilibrium in compound (E)-12. Expected nOes are represented by double headed curved arrows in E (a) and Z (b) isomers of compound 12.
Molecules 19 13878 g014

2.3. Molecular Structure of Compounds 7, 13 and 14 by X-Ray Diffraction

Analysis of the X-ray diffraction structure of compound 7 (Figure 4) shows the new fusioned heterocycle in the same plane of the benzimidazole ring. The values of the torsion angles N(10)–C(11)–S(12)–C(13) of 2.0(2)° and N(10)–C(2)–N(1)–C(13) of 2.4(4)°, are representative of this condition. These molecular arrangement, explains the interaction of the phenyl hydrogen with the sulfur atom whose geometric parameters are: H(7)∙∙∙S(13) of 2.68 Å and C(7)–H(7)∙∙∙S(13) of 121°; this interaction is responsible for the high frequency shift of the phenyl H7 observed in the 1H NMR spectrum. The bond distances N(3)―C(2) of 1.301(3) Å and N(10)–C(2) of 1.355(3) Å are of intermediate value for single and double bond character, whereas the N(1)–C(2) and N(10)–C(11) distances of 1.433(3) Å and 1.286(4) Å, are characteristics for a single and a double bonds, respectively. The bond distances and angles are in agreement with the proposed structure.
Figure 4. Molecular structure of compound 7. Selected bond lengths (Å) and angles (°): S(12)–C(11) 1.760(2), S(12)–C(13) 1.744(2), S(13)–C(13) 1.629(2), S(14)–C(11) 1.739(2), S(14)–C(15) 1.796(3), N(3)–C(2) 1.301(3), N(3)–C(9) 1.394(3), N(1)–C(2) 1.433(3), N(1)–C(13) 1.372(3), N(10)–C(2) 1.355(3), N(10)–C(11) 1.286(4), C(11)–S(12)–C(13) 103.77(12), C(11)–S(14)–C(15) 101.18(13), C(2)–N(1)–C(13) 126.11(19), C(2)–N(10)–C(11) 121.6(2), N(1)–C(2)–N(3) 112.31(18), S(12)–C(11)–N(10) 126.27(16), N(10)–C(2)–N(1)–C(13) 2.4(4), N(1)–C(2)–N(10)–C(11) −4.1(3), C(7)–C(8)–N(1)–C(13) −3.0(4), N(10)–C(11)–S(12)–C(13) 2.0(2), N(10)–C(11)–S(14)–C(15)–6.1(2).
Figure 4. Molecular structure of compound 7. Selected bond lengths (Å) and angles (°): S(12)–C(11) 1.760(2), S(12)–C(13) 1.744(2), S(13)–C(13) 1.629(2), S(14)–C(11) 1.739(2), S(14)–C(15) 1.796(3), N(3)–C(2) 1.301(3), N(3)–C(9) 1.394(3), N(1)–C(2) 1.433(3), N(1)–C(13) 1.372(3), N(10)–C(2) 1.355(3), N(10)–C(11) 1.286(4), C(11)–S(12)–C(13) 103.77(12), C(11)–S(14)–C(15) 101.18(13), C(2)–N(1)–C(13) 126.11(19), C(2)–N(10)–C(11) 121.6(2), N(1)–C(2)–N(3) 112.31(18), S(12)–C(11)–N(10) 126.27(16), N(10)–C(2)–N(1)–C(13) 2.4(4), N(1)–C(2)–N(10)–C(11) −4.1(3), C(7)–C(8)–N(1)–C(13) −3.0(4), N(10)–C(11)–S(12)–C(13) 2.0(2), N(10)–C(11)–S(14)–C(15)–6.1(2).
Molecules 19 13878 g004
Figure 5. Molecular structure of compound 13. Selected bond lengths (Å) and angles (°): S(12)–C(11) 1.745(2), S(12)–C(13) 1.786(3), S(14)–C(11) 1.748(2), S(14)–C(15) 1.795(3), N(1)–C(2) 1.338(3), N(1)–C(8) 1.383(3), N(3)–C(2) 1.335(3), N(3)–C(9) 1.388(3), N(10)–C(2) 1.383(3), N(10)–C(11) 1.273(3), C(11)–S(12)–C(13) 101.10(14), C(11)–S(14)–C(15) 104.73(16), C(2)–N(10)–C(11) 121.95(18), N(1)–C(2)–N(3) 113.69(17), N(1)–C(2)–N(10) 125.16(19), N(3)–C(2)–N(10) 120.78(19), S(12)–C(11)–S(14) 117.10(15), S(12)–C(11)–N(10) 120.23(17), S(14)–C(11)–N(10) 122.67(17), N(1)–C(2)–N(10)–C(11) −71.3(3), N(3)–C(2)–N(10)–C(11) 116.2(2), N(10)–C(11)–S(12)–C(13) −1.0(2), S(12)–C(11)–S(14)–C(15) 7.4(2), N(10)–C(11)–S(14)–C(15) −173.0(2), S(12)–C(11)–N(10)–C(2) 179.93(18), S(14)–C(11)–N(10)–C(2) 0.4(3).
Figure 5. Molecular structure of compound 13. Selected bond lengths (Å) and angles (°): S(12)–C(11) 1.745(2), S(12)–C(13) 1.786(3), S(14)–C(11) 1.748(2), S(14)–C(15) 1.795(3), N(1)–C(2) 1.338(3), N(1)–C(8) 1.383(3), N(3)–C(2) 1.335(3), N(3)–C(9) 1.388(3), N(10)–C(2) 1.383(3), N(10)–C(11) 1.273(3), C(11)–S(12)–C(13) 101.10(14), C(11)–S(14)–C(15) 104.73(16), C(2)–N(10)–C(11) 121.95(18), N(1)–C(2)–N(3) 113.69(17), N(1)–C(2)–N(10) 125.16(19), N(3)–C(2)–N(10) 120.78(19), S(12)–C(11)–S(14) 117.10(15), S(12)–C(11)–N(10) 120.23(17), S(14)–C(11)–N(10) 122.67(17), N(1)–C(2)–N(10)–C(11) −71.3(3), N(3)–C(2)–N(10)–C(11) 116.2(2), N(10)–C(11)–S(12)–C(13) −1.0(2), S(12)–C(11)–S(14)–C(15) 7.4(2), N(10)–C(11)–S(14)–C(15) −173.0(2), S(12)–C(11)–N(10)–C(2) 179.93(18), S(14)–C(11)–N(10)–C(2) 0.4(3).
Molecules 19 13878 g005
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]. The N(1)–(2), N(3)–(2) and N(10)–(2) distance values of 1.338(3), 1.335(3) and 1.383(3) Å, are intermediate between single and a double bond character, compared with N(10)–C(11) of 1.273(3) Å, which has a double bond character.
Compound 14 crystalized with one molecule of water (Figure 6). The intramolecular N(3)–H(3)∙∙∙S(12) hydrogen bonding interaction gives shape to a six membered ring with a N(3)∙∙∙S(12) distance of 3.081(6) Å and N(3)–H(3)∙∙∙S(12) angle of 120° which forces the planarity of the molecule. The angles N(1)–C(2)–N(10)–C(11) of 179.8(7)° and N(3)–C(2)–N(10)–C(11) of −0.8(14)° confirm the planarity of the N=C(SMe)2 an the value of N(10)–C(2) bond length of 1.342(10) Å, the strengthening of this bond. There is an intermolecular O1∙∙∙S12 interaction of 3.302(9) Å, instead of the S∙∙∙S interaction observed in the crystal structure of the neutral compound 15 [15].
Figure 6. Molecular structure of the iodide salt 14 at 30% of probability. Selected bond lengths (Å) and angles (°): S(12)–C(11) 1.743(9), S(12)–C(13) 1.791(8), S(14)–C(11) 1.731(8), S(14)–C(15) 1.794(10), N(1)–C(2) 1.356(10), N(1)–C(8) 1.378(9), N(1)–C(16) 1.458(12), N(3)–C(2) 1.345(10), N(3)–C(9) 1.382(9), N(10)–C(2) 1.342(10), N(10)–C(11) 1.289(10), C(4)–C(5) 1.391(11), C(2)–N(1)–C(16) 125.3(6), C(2)–N(10)–C(11) 129.2(7), N(1)–C(2)–N(3) 107.9(6), N(1)–C(2)–N(10) 118.4(7), N(3)–C(2)–N(10) 133.8(7), S(12)–C(11)–S(14) 116.9(4), S(12)–C(11)–N(10) 123.7(6), S(14)–C(11)–N(10) 119.5(6), N(1)–C(2)–N(10)–C(11) 179.8(7), N(3)–C(2)–N(10)–C(11) −0.8(14), N(10)–C(11)–S(12)–C(13) −177.8(7), S(12)–C(11)–S(14)–C(15) 176.5(5), N(10)–C(11)–S(14)–C(15) −3.5(7), S(12)–C(11)–N(10)–C(2) 1.5(11), S(14)–C(11)–N(10)–(2) −178.5(6).
Figure 6. Molecular structure of the iodide salt 14 at 30% of probability. Selected bond lengths (Å) and angles (°): S(12)–C(11) 1.743(9), S(12)–C(13) 1.791(8), S(14)–C(11) 1.731(8), S(14)–C(15) 1.794(10), N(1)–C(2) 1.356(10), N(1)–C(8) 1.378(9), N(1)–C(16) 1.458(12), N(3)–C(2) 1.345(10), N(3)–C(9) 1.382(9), N(10)–C(2) 1.342(10), N(10)–C(11) 1.289(10), C(4)–C(5) 1.391(11), C(2)–N(1)–C(16) 125.3(6), C(2)–N(10)–C(11) 129.2(7), N(1)–C(2)–N(3) 107.9(6), N(1)–C(2)–N(10) 118.4(7), N(3)–C(2)–N(10) 133.8(7), S(12)–C(11)–S(14) 116.9(4), S(12)–C(11)–N(10) 123.7(6), S(14)–C(11)–N(10) 119.5(6), N(1)–C(2)–N(10)–C(11) 179.8(7), N(3)–C(2)–N(10)–C(11) −0.8(14), N(10)–C(11)–S(12)–C(13) −177.8(7), S(12)–C(11)–S(14)–C(15) 176.5(5), N(10)–C(11)–S(14)–C(15) −3.5(7), S(12)–C(11)–N(10)–C(2) 1.5(11), S(14)–C(11)–N(10)–(2) −178.5(6).
Molecules 19 13878 g006

3. Experimental Section

3.1. 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. 1H- and 13C-NMR spectra were recorded on a Varian Mercury 300 MHz (1H, 300.08; 13C, 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.
Table 3. Complementary data of compounds 6, 7, 914, 16, 17.
Table 3. Complementary data of compounds 6, 7, 914, 16, 17.
Comp.Yield (%)Physical AppearanceM.p. (°C)(cm−1)m/z (%M+)Elemental AnalysisFound (Calculated)
CHN
695white crystals263–2643273, 1647 37.73
(37.40)
4.33
(4.18)
13.96
(14.54)
740yellow crystals134–1351607, 1542265(70)46.30
(45.26)
2.72
(2.66)
15.20
(15.83)
980yellow powder198–1993273, 3206, 1647237+HI(61)32.95
(32.87)
3.39
(3.28)
11.29
(11.50)
1090yellow powder66–67 237(61)49.93
(50.60)
4.78
(4.67)
17.29
(17.70)
1192yellow powder148–1503276, 3114 1646 34.25
(34.83)
3.79
(3.69)
10.66
(11.08)
1286yellow powder85–86 53.05
(52.58)
5.12
(5.18)
16.15
(16.73)
1325white crystals179–1803469, 1624 1554237(30)50.51
(50.63)
4.76
(4.64)
17.28
(17.72)
1490white crystals 46.82
(34.83)
4.77
(3.69)
19.48
(11.08)
1642white powder198–200
1740white crystals215–2163129, 1616, 1573, 1543 48.25
(48.40)
4.07
(4.06)
18.37
(18.82)
Table 4. X-ray crystal data of compounds 7, 13 and 14.
Table 4. X-ray crystal data of compounds 7, 13 and 14.
Compound71314
Unit Cell Information
Cell axes [Å] a15.8405(4)10.0640(20)7.4895(7)
B4.5179(1)8.9376(18)10.3023(9)
C18.8892(6)13.4110(30)11.2194(10)
Cell angles [deg] α90.0090.00110.270(1)
Β126.546(2)107.480(30)95.492(2)
Γ90.0090.00104.655(1)
Crystal systemMonoclinicMonoclinicTriclinic
Space groupP 21/cP 21/cP-1
Molecular FormulaC10H7N3S3C10H11N3S2C11H16N3OS2I
Density [g cm−1]1.621.371.71
Formula weight265.4237.3397.3
No. Form. Units Z442
Reflection Data
No. Meas.10175106277445
No. Uniq.217320232706
No. Obs.197118962301
Current Refinement
No. Refln.217320232706
No. Param.147136166
Delta-rho [eÅ−3] max, min0.361, −0.5180.392, −0.3321.012, −1.134
R_all, R_obs0.045, 0.0420.045, 0.0430.079, 0.065
wR2_all, wR2_obs0.117, 0.1130.122, 0.1200.130, 0.125

3.2. Procedures to Obtain 2-Aminobenzimidazole Sulfur Derivatives

3.2.1. 1,3-Dimethyl-1,3-dihydrobenzimidazol-2-ylideneammonium Iodide (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. 1H-NMR [δ, ppm, DMSO-d6]: 8.72 (b, 2H, +NH2), 7.55 (m, 2H, Ar) and 7.35 (m, 2H, Ar) 3.67 (s, 6H, N-CH3) 13C-NMR [δ, ppm, DMSO-d6]: 150.73 (s, C2), 130.68 (s, C8, C9), 124.05 (s, C5, C6), 110.81(s, C4, C7).

3.2.2. 2-Methylthio-4H-[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.

3.2.3. 2-Aminobenzimidazole-1-carbodithioic Acid Methyl Ester (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.

3.2.4. 1-Methyl-3-(methylthiocarbonothioyl)-1H-benzo[d]imidazol-2(3H)-iminium Iodide (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.

3.2.5. 2-Imino-3-methyl-2,3-dihydrobenzimidazol-1-carbodithioic Acid Methyl Ester (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.

3.2.6. N-(1-Methyl-3-(methylthiocarbonothioyl)-1H-benzo[d]imidazol-2(3H)-ylidene)methanaminium Iodide (11)

In 100 mL round-bottom flask a solution of compound 10 (1.0 g, 4.2 mmol) in DMF (6 mL) and methyl iodide (0.26 mL, 4.2 mmol) were successively added. The mixture was stirred for 24 h at room temperature and cold water (100 mL) was then added to the mixture. The precipitated solid was filtered off and washed with water. After air drying, 1.08 g of yellow powder (67.5%) were obtained.

3.2.7. (E)-3-Methyl-2-methylimino-2,3-dihydrobenzimidazole-1-carbodithioic Acid Methyl Ester (12)

Compound 11 (1.0 g, 2.63 mmol) was reacted with aqueous sodium hydroxide solution (5.3 mL, 0.5 M). The resulting precipitate was washed with enough water to give 0.48 g (72.7%) of a yellow powder.

3.2.8. 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.

3.2.9. 2-(Bis(methyltio)methyleneamino)-1-methyl-1H-benzo[d]imidazol-3-ium Iodide (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.

3.2.10. Dimethyl 1-methyl-1H-benzo[d]imidazol-2-ylcarbonodithioimidate (15)

Compound 14 (1.32 g, 3.48 mmol) was reacted with sodium hydroxide aqueous solution (7.2 mL, of 0.5 M). The resulting precipitate was washed with enough water to give 0.73 g (85%) of white crystals.

3.2.11. (1,3-Dihydrobenzimidazol-2-ylidene)-dithiocarbamic Acid methyl Ester (16) and 2-(bis(methyl- thio)methyleneamino)-1H-benzo[d]imidazol-3-ium Iodide (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.

4. 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.

Acknowledgments

A. Cruz thanks Secretaría de Investigación y Posgrado del Instituto Politécnico Nacional (SIP-IPN), Grant 20140285 for financial support.

Author Contributions

A. C. coordinated the design of the investigation and write the manuscript. I.I.P.-M. was collaborator in the collection and analysis of NMR spectroscopy and also participated in the manuscript writing. E.V.G.-B. participated in collection and analysis of the X-ray diffraction data of structures. G.G.-M. conducted the investigation in the laboratory.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Andrade-López, N.; Ariza-Castolo, A.; Contreras, R.; Vázquez-Olmos, A.; Barba-Behrens, N.; Tlahuext, H. Versatile behaviour of 2-guanidinobenzimidazole nitrogen atoms toward protonation, coordination and methylation. Heteroat. Chem. 1997, 8, 397–410. [Google Scholar] [CrossRef]
  2. Andrade-López, N.; Cartas-Rosado, R.; García-Báez, E.; Contreras, R.; Tlahuext, H. Boron heterocycles derived from 2-guanidinobenzimidazole. Heteroat. Chem. 1998, 9, 399–409. [Google Scholar]
  3. Fialon, M.-P.; Andrade-López, N.; Barba-Behrens, N.; Contreras, R. Organometallic tin complexes derived from 2-guanidinebenzimidazole. Heteroat. Chem. 1998, 9, 637–641. [Google Scholar]
  4. Fialon, M.-P.; García-Baez, E.; Andrade-López, N.; Osorio-Monreal, G.; Canseco-Melchor, V; Velázquez-Montes, I.; Barba-Behrens, N.; Contreras, R. Boron and transition metal compounds derived from 2-uroylbenzimidazole. Heteroat. Chem. 1999, 10, 577–584. [Google Scholar] [CrossRef]
  5. Bansal, Y.; Silakari, O. The therapeutic journey of benzimidazoles: A review. Bioorg. Med. Chem. 2012, 20, 6208–6236. [Google Scholar]
  6. Chaudhary, P.; Sharma, K.P.; Sharma, A.; Varshney, J. Recent advances in pharmacological activity of benzothiazole derivatives. Int. J. Curr. Pharm. Res. 2010, 2, 5–11. [Google Scholar]
  7. Téllez, F.; Cruz, A.; López-Sandoval, H.; Ramos-García, I; Gayosso, M.; Castillo-Sierra, R.N.; Paz-Michel, B.; Nöth, H.; Flores-Parra, A.; Contreras, R. Dithiocarbamates, thiocarbamic esters, dithiocarboimidates, guanidines, thioureas, isothioureas, and tetraaza-thiapentalene derived from 2-aminobenzothiazole. Eur. J. Org. Chem. 2004. [Google Scholar] [CrossRef]
  8. Merchán, F.; Garín, J.; Meléndez, E. A facile synthesis of dimethyl N-(2-benzothiazolyl)-dithiocarbonimidates and methyl N-(2-benzothiazolyl)-dithiocarbamates. Synthesis 1982. [Google Scholar] [CrossRef]
  9. Merchán, F.; Garín, J.; Meléndez, E.; Tejero, T. 2-(2-Benzimidazolylamino)-benzothiazoles and 2-(2-Imidazolidinylidenamino)-benzothiazoles. Synthesis 1982. [Google Scholar] [CrossRef]
  10. Garín, J.; Meléndez, E.; Merchan, F.L.; Ortíz, D.; Tejero, T. Facile synthesis of 8-aryl-aminoand 8-hetarylaminopurines and their 1- and 3-deaza analogs. Synthesis 1985. [Google Scholar] [CrossRef]
  11. Merchan, F.L.; Garín, J.; Meléndez, E.; Tejero, T. A facile synthesis of 2-(2-benzothiazolyl-amino)-1,3-heterazoles. Synthesis 1987. [Google Scholar] [CrossRef]
  12. Cruz, A.; Gayosso, M.; Contreras, R. Syntheses of optically active 2-(2-benzothiazoly-limino)-heterazolidines. Heteroat. Chem. 2001, 12, 586–593. [Google Scholar]
  13. Cruz, A.; Padilla-Martínez, I.I.; García-Báez, E.V. A synthetic method to access symmetric and non-symmetric 2-(N,N'-disubstituted)guanidinebenzothiazoles. Molecules 2012, 17, 10178–10191. [Google Scholar]
  14. Cruz, A.; Padilla-Martínez, I.I.; García-Báez, E.V.; Juárez-Juárez, M. S-Methyl-(-N-aryl and -N-alkyl)isothioureas derived from 2-aminobenzothiazole. ARKIVOC 2007, 2008, 200–209. [Google Scholar]
  15. Esparza-Ruiz, A.; Peña-Hueso, A.; Mijangos, E.; Osorio-Monreal, G.; Nöth, H.; Flores-Parra, A.; Contreras, R.; Barba-Beherens, N. Cobalt(II), Nikel(II) and Zinc(II) coordination compounds derived from aromatic amines. Polyhedron 2011, 30, 2090–2098. [Google Scholar]
  16. Peña-Hueso, A.; Téllez, F.; Vieto-Peña, R.; Esquivel, R.O.; Esparza-Ruiz, A.; Ramos-García, I.; Contreras, R.; Barba-Behrens, N.; Flores-Parra, A. Synthesis and structure of dithiocarbonimidates derived from aromatic heterocycles: Role of weak interactions in the preferred conformation. J. Mol. Struct. 2010, 984, 409–415. [Google Scholar]
  17. Bruker. APEX II, SAINT, SADABS and SHELXTL; Bruker AXS Inc.: Madison, WI, USA, 2004. [Google Scholar]
  18. Sheldrick, G.M. SHELXS97 and SHELXL97; University of Göttingen: Göttingen, Germany, 1997. [Google Scholar]
  19. Spek, A.L. PLATON, Version of March 2002; University of Utrecht: Heidelberglaan, The Netherlands, 2002.
  20. Farrugia, L.J. WinGX suite for small molecule single crystal crystallography. J. Appl. Crystallogr. 1999, 32, 837–838. [Google Scholar]
  • Sample Availability: Samples of the compounds 717 are available from the authors.

Share and Cite

MDPI and ACS Style

Cruz, A.; Padilla-Martínez, I.I.; García-Báez, E.V.; Guerrero-Muñoz, G. Synthesis and Structure of Sulfur Derivatives from 2-Aminobenzimidazole. Molecules 2014, 19, 13878-13893. https://doi.org/10.3390/molecules190913878

AMA Style

Cruz A, Padilla-Martínez II, García-Báez EV, Guerrero-Muñoz G. Synthesis and Structure of Sulfur Derivatives from 2-Aminobenzimidazole. Molecules. 2014; 19(9):13878-13893. https://doi.org/10.3390/molecules190913878

Chicago/Turabian Style

Cruz, Alejandro, Itzia I. Padilla-Martínez, Efrén V. García-Báez, and Gerardo Guerrero-Muñoz. 2014. "Synthesis and Structure of Sulfur Derivatives from 2-Aminobenzimidazole" Molecules 19, no. 9: 13878-13893. https://doi.org/10.3390/molecules190913878

Article Metrics

Back to TopTop