S -Methyl-(- N -aryl and - N -alkyl)isothioureas derived from 2-aminobenzothiazole

S-Methylisothioureas, 2-N ― H, -N ― alkyl and -N ― aryl are synthesized from the reaction of ammonia or the corresponding aromatic amines with benzothiazole dithiomethylcarboimidate. The reaction with pyrrolidine and piperazine are reported. Compounds were characterized by 1 H and 13 C NMR spectroscopy and the X-ray molecular structure of S -methy- N - benzothiazolelisothiourea derivative is reported.


Introduction
Recently, the guanidine group has attracted considerable attention, since it has been found in a wide array of natural and synthetic biologically active compounds. 1These molecules are basic enough (pKa of their conjugate acids is around 12.5) to get the capacity to form intermolecular contacts mediated by H-bonding interactions. 2Its positive charge, resulting from protonation in a wide range of pH values, creates a base for specific intermolecular interactions comprising keysteps of many biological reactions, including enzyme-mediated processes and interaction of hormones with their receptors. 3Guanidinium moiety interacts with functional groups present in enzymes or receptors on the basis of hydrogen bonds and electrostatic interactions.Thus, they are useful pharmacophores in medicinal chemistry. 4They are also studied because of their ability to form intermolecular associations.On the other hand, molecules containing this group are interesting because of their nitrogen atoms bearing lone pairs and labile NH hydrogen atoms reactivity are feasible to obtain coordinating compounds.
It has been demonstrated that the introduction of the guanidine group instead of an existing amino group significantly increases the potency and/or selectivity of biologically active compounds. 5By this, in our currently investigations about biologically active 2aminobenzothiazoles, 6 we are interested in the functionalization of these aromatic heterocycles to get guanidine derivatives, where the nitrogen atoms can be bonded to hydrogen, alkyl or aryl groups and one or two nitrogen atoms are part of five or six membered heterocycles.Herein we report the preparation and 1 H and 13 C NMR structural study of a series of Smethylisothioureas 3, scheme 1, obtained from 2-aminobenzothiazole 1 through dithiomethyl carboimidate 2 as intermediate compound 7 .S-methylisothioureas are interesting intermediates because they have a very reactive S-methyl functional group that can be used for the synthesis of combined guanidines 4. X-ray diffraction structure of N-benzothiazolyl-S-methylisothiourea 3 (R 1 = R 2 = H) is also analysed.

Results and Discussion
The intermediate dithiomethylcarboimidate benzothiazole 2 was obtained from 2aminobenzothiazole by reaction with carbon disulfide in basic media (20 M NaOH) using DMF as solvent (Merchant, et al.) 7 .A detailed study and characterization of the intermediates involved in this reaction have been reported 6 .It has been demonstrated that the reactivity of compound 2 is due to the facility to displace two molecules of HSMe, as leaving group, when it reacts with o-XH substituted anilines in refluxing DMF to get NH-bisbenzazoles 4 8 , scheme 2. The reaction should proceed through the intermediacy of isothiourea derivatives 3a-c, which have not been isolated.

Scheme 2. NH-bisbenzazoles from dithiomethylcarboimidate benzothiazole 2 with o-substituted anilines
In a previous work, 6 we tested the reactivity of compound 2 by using methyl-and ipropylamines as nucleophiles to prepare S-methyl, N-methyl and S-methyl, Nisopropylisothioureas, and N,N´-dimethylguanidine derivatives, when the reaction is carried out in refluxing ethanol.However, this reaction was not generalized to isolate the methylisothiourea intermediates when o-, m-, and p-XH-substituted anilines, ammonia, aniline, or cyclic amines are used.
In order to isolate the methylisothiourea derivatives using o-substituted anilines, the reaction was carried out just stirring or refluxing the reaction mixture with solvents of low boiling points like ethanol or chloroform.The reaction with o-aminophenol or o-aminothiophenol afforded, the corresponding bicyclic derivatives 4a or 4b, respectively, whereas o-phenylenediamine led to the corresponding S-methylisothiourea derivative 3c, Figure 1. 1 H NMR spectrum of compound 3c shows a NH signal at 11.9 ppm in CDCl 3 .The high frequency shift of this signal is indicative of an intramolecular hydrogen bonding between the NH proton and the thiazole nitrogen atom, as indicated in figure 1.The SCH 3 signal is present as a singlet at 2.46 ppm, whose integration is 3:8 in relation to the aromatic hydrogen atoms.In 13 C NMR spectrum, 15 signals are present, in agreement with the proposed structure.
These results can be explained in terms of the acidity of both OH and SH groups, which are more acidic in comparison with the NH 2 group.This make phenoxide and thiolate groups more reactive than the o-aniline nitrogen atom, which can be responsible of the stability of intermediate 3c in comparison with the analogous intermediates derived from o-OH or o-SH substituted anilines.On the basis of the last results, m-and p-phenylenediamine isomers were reacted with compound 2 at refluxing ethanol during 16 hours and the corresponding methylisothiourea 3d,e derivatives were obtained, figure 1.In all cases, the 1 H NMR data, showed the expected 8:3 aromatic-aliphatic integral ratio and a broad signal appeared in 11.9 ppm (ortho), 11.8 (meta) and 11.7 (para), which integrated for one bridged N-H proton.The aniline NH 2 protons appear in 4.0 ppm (o-amino group), 4.7 ppm (m-amino group) and 6.34 ppm (p-amino group).The presence of fifteen (o-and m-) and thirteen (p-) signals in 13 C NMR spectra confirm the formation of this intermediates.The intermediate compounds 3c-e possesses an additional -NH 2 group, which can react with a second molecule of compound 2. The reactions were carried out by using 2 molar equivalents of compound 2 and one molar equivalent of the corresponding phenylenediamine.The reaction with the ortho isomer, only produced compound 3c and one equivalent of compound 2 remained without reaction.The reaction with m-and p-isomers afforded the corresponding diisothioureidic derivatives 3f and 3g, figure 2. Thirteen and eleven carbon signals were observed in 13 C NMR spectra for 3f and 3g, respectively.In a previous work, 6 it was reported that the reaction of compound 2 with one and two molar equivalents of methylamine afforded the isothioureidic compound 3h (R 1 = H, R 2 = CH 3 ) and the corresponding guanidine derivative 4h (R 1 = R 3 = H, R 2 = R 4 = CH 3 ) respectively, scheme 1. Characteristic NMR data from which it can be pointed out the chemical shift of C11 in 175.0 ppm in thiocarboimidate compound 2, 172.5 ppm in the respective isothioureidic compound 3h and 174.7 ppm in the corresponding guanidine compound 4h.From these results, we completed the study with aniline, ammonia and cyclic amines as pyrrolidine and piperazine to isolate the isothiourea derivatives.
In the case of the reaction with one molar equivalent of aniline, one S-methyl group of compound 2 is substituted.The 1 H NMR data, showed a 9:3 aromatic-aliphatic integral ratio and a broad signal at 12.4 ppm, assigned to the N-H proton.Thirteen signals in 13 C NMR spectrum are indicative of the presence of the S-methyl-benzothiazolyl-phenylisothiourea compound 3i, figure 3. When one molar equivalent of compound 2 were reacted with 3 molar equivalents of aqueous ammonia in stirring ethanol at room temperature during 48 hours, one molar equivalent of thiomethanol were evolved to get the corresponding isothiourea derivative 3j.The 1 H NMR data, showed a 4:3 aromatic-aliphatic integral ratio and a broad signal, for two NH protons, appeared at 9.27 ppm.This chemical shift compared with the same NH signal of the aniline analogous 3i (12.4 ppm) suggests that this hydrogen atoms are more weakly bridged with the thiazole nitrogen.It is explained because in the case of compound 3i, the electron pairs of the aniline nitrogen atom are conjugated with the aromatic ring and make hydrogen more acid, reinforcing the hydrogen bridge.From a saturated ethanolic solution, S-Methyl-N-benzothiazolylisothiourea 3j was crystallized and its structure analyzed by X-ray diffraction, figure 4.An intramolecular hydrogen bonding interaction between one hydrogen atom of the amine group and the thiazole nitrogen atom to form a six membered ring was observed.The N14H14⋅⋅⋅N3 distance of 2.11 Å and the angle of 128° (2) are in the range for a strong interaction 9 .The formed hydrogen bond is strong enough that forces the nitrogen atom of NH 2 group to be in a planar delocalized π system between N14-C11-N10-C2-N3 atoms which adopt a U conformation.Torsion dihedral angles C11-N10-C2-N3 (0.3º) and C2-N10-C11-N14 (4.  9 .On the other hand, the supramolecular structure, figure 4 (right), is given by intermolecular hydrogen bonds between the second hydrogen atom of the amino group and the N10b of a second molecule with N12-H14⋅⋅⋅N10b distance of 2.36 Å and angle of 148º, forming a polymer.It is interesting to observe that methyl and amino groups are in a syn conformation, N14-C11-S12-C13 torsion angle is 13.03º(19).It is possible this conformation is adopted due to an intermolecular interaction between one hydrogen atom of methyl group and the thiazolic sulfur atom C13-H⋅⋅⋅S1b bond distance of 2.86 Å and angle of 147º.
The reaction with pyrrolidine, was carried out with one and two molar equivalents, with the aim to obtain monosubstituted and disubstituted compounds, respectively, however in both cases only guanidine compound 4k was formed, figure 5.It seems that isothiourea intermediate 3k is not stable enough because of the high basisity of the amine and the lack of N-H itramolecular interaction.A very similar result was obtained when piperazine was used, the reaction give in both molar relations, the diisothiourea derivative 3l, figure 5.Both 1 H and 13 C NMR spectra of compound 3l, showed two signals in 3.94, 2.26 and 47.65 16.68 ppm, respectively, on the aliphatic zone, which is in agreement with the symmetry of compound 3l.

Conclusions
Primary amines in contrast of the more reactive cycloalkylamines afforded isothiourea derivatives.The acidity of hydrogen atom of o-XH substituted anilines is determinant in the stability of the isothiourea intermediates.The formation of an intramolecular hydrogen bonding between one hydrogen atom of the amine group and the thiazole nitrogen reinforce the stability of isothiourea derivatives.Compounds 3i and 3j were base to assign compounds 3c-g.

Experimental Section
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).The spectra were measured with tetramethylsilane as internal reference following standard techniques.Crystallographic data (excluding structure factors) for the structures in this paper have been deposited in the Cambridge Crystallographic Data Centre as supplementary publication numbers CCDC 3j, (650099).For this compound, H atoms were treated as riding atoms, with C-H distances in the range of 0.93±0.96Å and N-H distances of 0.82 Å. X-ray diffraction cell refinement and data collection: BRUKER SMART APEX Diffractometer and SAINT 10 , programs used to solve structures: SHELXS-97 11 ; software used to prepare material for publication: PLATON 12 and WinGX. 13-Aminobenzothiazole 1 was a commercial product.Benzothiazole dithiomethylcarboimidate 2 was prepared according to a literature procedure 7 .

General procedure
In a 100 mL flask 1.0 g (3.94 mmol) of benzothiazole dithiomethylcarboimidate 2 were dissolved with 20 mL of anhydrous ethanol, three molar equivalents of ammonia, or one molar equivalent of the respective aliphatic or aromatic amine were added and the mixture was refluxed for 16 hours in the case of 3c-e, for 24 hours for compounds 3f,g, and stirring at room temperature for 24 hours in the case of 3l.The solvent was reduced to 10 ml by evaporation and cooled to room temperature, after precipitation the resulting solid was filtered and washed with a mixture 1:1 water-ethanol to give, after drying a white solid.

Figure 4 .
Figure 4. Molecular structure of compound 3j (left) and supramolecular arrangement (right) in b axis direction.