On the selective methylation of benzoyl and furoylthiocarbamates

The methylation reaction of alkyl N -acylthiocarbamates in DMF with dimethyl sulfate in the presence of potassium carbonate takes place with high selectivity affording the S -methylated derivative as the principal reaction product. No isomeric reaction products derived from the N - or the O -methylation were isolable. The new carbonimidothioates 3a-g synthesised were fully characterized by spectroscopic methods. The experimental findings are supported by X-ray and theoretical studies at the B3LYP/6-311G(d.p) level .


Introduction
Polydentate systems have received considerable attention due to their use as chelating ligands of multivalent metal ions and by the attempt to justify and to predict the major reaction products from compounds with several reaction sites.So, effort has been made to study the alkylation reaction of systems exhibiting multiple reaction sites, in which the different alternative reaction routes present very small free energy differences. 1hiocarbamate derivatives are well-known systems that have received a lot of attention due to their interesting technological 2 and biological applications. 3Most notably, thiocarbamate derivatives are used as elastase inhibitors, 4 and they can exhibit antineoplastic 5 and antiinflammatory 6 effects.In addition, recent paper have reported the studies of new acylthiocarbamates as potent non-nucleoside HIV-1 reverse transcriptase inhibitors. 7-Alkyl-N-acylthiocarbamate derivatives have been proposed as intermediates for regio-and chemoselective deoxygenation of primary and secondary aliphatic alcohols. 8In addition, Oalkyl-N-aroylthiocarbamates are useful as sequestering substances of heavy metal ions in aqueous solutions. 9Furthermore, it has also been reported that N-benzoylthiocarbamic-Oalkylesters are weak monoprotic acids which behave as fairly stable and versatile bidentate (O,S)-chelating ligands towards multivalent metal ions like Ni(II), Cu(II) and Pb(II). 10These derivatives are also employed in liquid-liquid extractions of silver(I) ions. 11Moreover, the use of bis(O-alkyl-N-benzoylthiocarbamate) in the formation of nickel(II) complexes has also been studied. 124][15][16][17][18] The crystal structures of some derivatives such as those of O-isopropyl-N-(2-furoyl)thiocarbamate, 13 O-benzyl-N-(2-furoyl)thiocarbamate, 14 O,Odiethyl-N,N-(p-phenylenedicarbonyl)-bis(thiocarbamate), 15 and O,O-dimethyl-N,N-(mphenylenedicarbonyl)-bis(thiocarbamate), have also been reported in the literature. 16Nacylthiocarbamates have also been employed as starting compounds to obtain a variety of different heterocyclic compounds such as aminothiazoles, thietanes, aminotetrazoles, thiadiazoles, or thiadiazolines. 19s part of our studies on the behaviour of polydentate molecules, in previous work we have reported the highly selective S-alkylation of benzoyl and furoylthioureas and these results were supported by means of NMR experiments, X-ray studies and semiempirical theoretical calculations. 20In a previous work, we have reported the synthesis of new alkyl Nacylthiocarbamates and the crystalline structure of isopropyl N-furoylthiocarbamate and determined that the molecule exists in the E,Z´ conformation which is stabilised because of the presence of an intramolecular hydrogen bonding between the furan oxygen and the N-H of the amide group. 21n continuation of our interest in the chemistry of multiple site reactive systems, in this paper we describe the X-ray crystallographic study of butyl N-benzoylthiocarbamate and the methylation reaction of various alkyl N-furoyl-and alkyl N-benzoylthiocarbamates in order to account for the selectivity observed in the reactivity of these multiple site reactive systems.The methylation was carried out by treatment of a solution of the corresponding alkyl Nacylthiocarbamates in DMF with dimethyl sulfate in the presence of potassium carbonate.In addition, justification of the obtained experimental results has been carried out by X-ray studies.

Results and Discussion
Alkyl N-acylthiocarbamates 1 afford anions 2 in the presence of weak bases and, consequently, the alkylation reaction of compounds 1 could take place on any of their three heteroatoms leading to a mixture of three different isomeric products 3, 4 or 5 resulting from the S-, N-and O-methylation, respectively (Scheme 1).The thiocarbamates 1 were prepared according to the procedure described previously 21 by using acid chlorides and ammonium thiocyanate in acetone.The intermediate isothiocyanate reacts in situ with the corresponding alcohol affording 1.
The addition of potassium carbonate to a solution of different compounds 1 in dimethylformamide resulted in a fast decoloration of the solution, which could indicate the formation of the respective anionic species 2. Further addition of the alkylating reagent, Me2SO4, led to the S-methylated compounds 3 as the only isolable reaction product.As expected, the behavior of a variety of differently substituted compounds 1 in the methylation reactions is quite similar and the S-methyl derivatives 3a-g are thus obtained in good yields (see Table 1).The formation of the N-and O-methylated derivatives 4 and 5 were only detected by HPLC. Figure 2 shows the analytical HPLC chromatogram of the reaction mixture for the synthesis of 3e, chosen as a reaction model.At 13.10 min.(87% yield) the signal corresponding to the Smethylated 3e is observed.At 9.13 and 11.42 min.two signals are found that could be reasonably assigned to the N-and O-methylated products which are found in minor amounts (6-7%).Structures of the novel compounds 3 were established by their 1 H and 13 C NMR spectroscopic data.Thus, the signal at  2.3 ppm in the 1 H-NMR spectra of compounds 3 was assigned to the -SCH3 group and 13 C-NMR spectra of 3 showed two signals at 173.8 and 163.3 ppm corresponding to the C=N and C=O groups, respectively, and no signal at  188 ppm (C=S group) was detected.In addition, the IR spectra of compounds 3 were also in agreement with the proposed structures and no C=S band was observed.
In order to explain the high predominance of S-alkylation, we analysed the structure of the alkyl N-acylthiocarbamates 1.It has been established that N-acyl-O-alkylthiocarbamates exist in four possible conformations 9 as shown in Figure 3.
Z, E' In this work we have determined the X-ray molecular structure of butyl Nbenzoylthiocarbamate 1 and calculated its preferential conformation by B3LYP/6-311G(d.p)(See Figure 4).Table 2 shows geometrical data calculated for butyl N-benzoylthiocarbamate B3LYP/6-311G(d.p)as well as those determined by X-ray.
X-ray analysis shows that moiety S1=C8-N-C7=O is in a nearly planar conformation with torsion angle S1-C8-N-C7 = -14.5(4)o and O1-C7-N-C8 = -0.5(4)o .These values indicate that both carbonyl and thiocarbonyl groups are on the same side of the molecule showing a Z,Z' conformation, which is in agreement with previously reported results for these types of compounds. 15,16,22This conformation is particularly stabilized by three intramolecular hydrogen bond, N atom and H5 from the phenyl ring [N ….C5: 2.864( 5) Å], the oxygen from the carbonyl group and the H1 from the phenyl ring [C1 ….O1: 2.769( 6) Å] and H11 (from the methylene group) and the O2 atom [C11 ….O2: 2.987 (7) Å] (see Table 3).The thioamide group O1-C7-N-C8-S is deviated of the planarity with respect to the plane formed by the benzene rings C1-C2-C3-C4-C5-C6, showing angle of 16.8(2) o .The Z,Z´ conformation between the C7=O1 and C8=S groups (two donors sites rich in electron density) of the thiourea fragment, can also be explained by the existence of the intermolecular N-H …. O hydrogen bond between the H atom of the thioamide and the carbonyl O atom of the related molecule in the crystal structure extending along the [100] direction.Figure 5 shows the crystal packing diagram.The non-bonding NH . (O1) distance is 2.881(4) Å, similar to the reported values found for other related derivatives. 23The existence of the intramolecular and intermolecular hydrogen bonds, may determine the Z,Z'-conformation (O1-C7-N-C8-S1).
It is noteworthy that C7-N and C8-N [1.380(4) Å and 1.354(5) Å, respectively] are shorter than a normal C-N bond length (1.468 Å), which indicates that these bonds have a pronounced double bond character.Therefore, it is possible to assume an electronic delocalization in that part of the molecule.In addition, C8-O2 bond distance [1.321( 4) Å] indicates a partial double bond and a -type conjugation in the whole system.Table 2. Conformational features of butyl N-benzoylthiocarbamate and its anion (the numbering scheme is shows in Figure 4).Bond distances are given in Å and bond angles and torsion angles in degrees (standard deviations in parenthesis)   The geometrical features predicted by B3LYP/6-311G(d.p)calculations and determined by X-ray diffraction listed in Table 2 showed a satisfactory correspondence of the theoretical values with the experimental values and in spite of some differences found in the torsion angles, the results confirmed that the ab initio method report a reliable geometry for the proposed system.These data indicate that the most stable conformation for the calculated molecule is the Z,Z´.This means that the geometry in gas phase is quite similar to those in solid state.Considering that B3LYP/6-311G(d.p)method reproduces the geometry of these systems, we have determined the preferential conformation of the butyl N-benzoylthiocarbamate anion by the B3LYP/6-311+G(d.p)method.
Figure 6 shows the preferential conformation of the butyl N-benzoylthiocarbamate anion.It becomes evident that the predicted lower energy conformation is in agreement with that observed by X-ray diffraction, being either for the neutral acylthiocarbamate or for its anion the conformation with Z,Z´ geometry.
It should be noted that this geometry provides a greater access to the region of the sulphur atom compared to the O and N1 atoms, and this brings about a qualitative explanation for the higher percentage of the S-alkylated product in comparison to N-and O-alkylation.

The yields of the S-alkylated product obtained form the isopropyl N-(2-furoyl)thiocarbamate
showing a E,Z' conformation (see Figure 1) and those obtained from the methylation of butyl Nbenzoylthiocarbamate being a Z,Z' conformation (see Figure 4), are quite similar ~ 80 % (see Table 1).This means that both geometries provide a greater access to the region of the sulphur atom compared to the O and N atoms in the polydentate system and this brings about a qualitative explanation for the higher percentage of the S-alkylated product in comparison to Nand O-alkylation.
We have also calculated the net charges and the contribution of the three nucleophilic centers present in the anion to the HOMO of the molecule.The values are summarized in Table 4.These parameters are very useful that allow, in first approach the reactivity of the three different reaction sites.The atomic charges predicts by the theoretical method, indicate that the sulphur atom to be the less negative in comparison with the O and N atoms.The orbital coefficient calculations of the different centres show that the contribution to the formation of the HOMO is nearly exclusively from the sulphur atom.The highest occupied molecular orbital is mainly localised on this centre, while the other two atoms (O and N) have a negligible contribution to the HOMO (see Figure 7).These findings reveals the preferential alkylation on the sulphur atom and indicate the high influence that the orbital component has on those reactions in which the anion exhibits a remarkable nucleophilic character.
Both data series, steric factors and the nucleophilic character of S atom in this polydentate system, reveals the preferented alkylation on the sulfur atom.

Conclusions
In summary, the methylation reactions of the polydentate system N-acylthiocarbamate 1 have been studied.Although the synthesis of a mixture of three isomers, derived from the N-, O-and S-alkylation, is possible, only the S-alkylated product was isolated.The X-ray study of N-furoyland N-benzoylthiocarbamate indicates that both E,Z' and Z,Z' conformations where the sulphur atom is readily available for the electrophilic attack in comparison with the more sterically hindered nitrogen and oxygen atoms, account for the highly selective S-alkylation.Theoretical calculations also explain the behaviour of the methylation of alkyl N-acyltiocarbamates.The novel carbonimidothioates 3a-g synthesized were fully characterized by spectroscopic methods.

X -ray structure analysis
Crystal data collection and processing.Crystals of butyl N-benzoylthiocarbate were ground after slow evaporation from acetone solution.Single crystals suitable for X ray diffraction were obtained in a Nonius four circle diffractometer.The structures were solved by direct methods and the missing atoms were found on a difference-Fourier synthesis.The coordinates of the H atoms attached to nitrogen were refined isotropically.The programs SHELXL-97 25 and Ortep III 26 were used for the crystal structure refinement and the graphics processing, respectively.Scattering factors were taken from International Tables for X-ray Crystallography. 27All the calculations were done with the WINGX PC program package. 28The crystallographic and experimental data for these compounds are summarised in Table 5. Detailed crystallographic data have been deposited at the Cambridge Crystallographic Data Centre (CCDC 736719) and are available on request.

Figure 2 .
Figure 2. Analytical HPLC of the reaction mixture to obtain 3e.

Figure 5 .
Figure 5. Packing diagram of butyl N-benzoylthiocarbamate in the unit cell, showing the hydrogen bond scheme.X-ray crystal structures for the studied compound along the (100) axe.

Table 1 .
Synthesis of compounds 3

Table 3 .
Intra-and intermolecular hydrogen bonds for butyl N-benzoylthiocarbamate.Bond distances are given in Å and bond angles in degrees (standard deviations in parenthesis)

Table 4 .
Calculated net charges on S, O and N and orbital coefficient contribution of the S, N and O atoms to the HOMO in the anion of butyl-N benzoylthiocarbamate.