Reaction of Arylmethyl Isocyanides/Arylmethyl- amines with Xanthate Esters: A Facile and Unexpected Synthesis of Carbamothioates

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Introduction
Carbamothioates are reported as antimicrobial, [1] antifungal (tolnaflate and tolciclate drugs), [2] antimycobacterial, [3] human leucocyte elastase inhibitors, [4] TRPV1 antogonists, [5] PPARα1γ dual antagonist, [6] intermediates in the synthesis of HIV-1 integrase ligands, [7] insecticides (cartep), [8] and herbicides. [9] Besides, they are also used as key intermediates in the generation of carbonyl sulfide/hydrogen sulfide, [10] synthesis of isothiocyanates, [11] asymmetric thioureas [12] and thiazolidine/thiaoxazine. [13] Consequently therefore, numerous synthetic methods for carbamothioates have been reported. These include reactions of chlorothioformates with amines, [14] thiocarbonyl benzotriazoles with alcohols, [15] copper-catalyzed reactions of α-substituted stannanes with thiocarbamates, [16] reactions of isothiocyanates with alcohols, [6,17] and reactions of xanthate esters with amines. [18] Furthermore, many methods have also been reported for the synthesis of cyclic thiocarbamates and these include reactions of isothiocyanates with aldehydes in the presence of organocatalysts, [19] reactions of vicinal diols with potassium thiocyanate, [20] reactions of 2-napthol, aldehyde with thiourea catalyzed by iron nanoparticles, [21] isothiocyanatooxindoles with ketones, [22] ammonium isothiocyanates with chalcones [23] and α-isothiocyanatoesters with α-keto amides. [24] Among the synthetic methods available for the synthesis of open-chain thiocarbamates, however, any of them suffer from limitations such as the use of less stable and sensitive reactants such as chlorothioformates, [6,14,16,17] toxic stannates [16] and isothiocyanates. In a single patent disclosure thiocarbamtes were reported to have been synthesized from xanthate esters, but the methodology described is limited to only a few examples with aliphatic substituents and besides, suffers from a tedious isolation protocol. [18] As a part of our work on the development of new synthetic methods, [25] we have recently reported the synthesis of thiazoles from xanthate esters. [26] In a continuation of this on-going work, we planned to synthesize 4-aryl-5-alkoxy thiazoles 3 by the reaction of arylmethyl isocyanides 2 with xanthate esters 1 in the presence of sodium hydride in DMF (Scheme 1). Unexpectedly, however, carbamothioates 4 were instead obtained in 76-88% yields (Scheme 1). Herein we report on this intriguing finding with several examples, including a single crystal X-ray structure of one of the products so obtained. A possible plausible mechanism to explain the reaction using a Density Functional Theory (DFT) analysis is also presented in this article.   (Table 2).   A and B). The structure of one of the carbamothioates 4c was confirmed by a single crystal X-ray diffraction study (CCDC reference number 1831389) 28 (Figure 1). The crystal data and structure refinement parameters of 4c are given in Table 3. Bond lengths and bond angles are given Table 4. A DFT modeling study based upon the structure of 4c for example showed that two conformers generically represented as 4A and 4B in Scheme 2, namely 4cA and 4cB respectively, had very similar computed energies for rotamer observations in the NMR spectra. Also, DFT calculations indicated that 4cB is 14.84 kcal/mol more stable than 4cA. Thus, 4cB in Figure 1 seems to be easily obtained as a single crystal than 4cA. Further, we have analyzed the NMR of 4c by heating at 60°C in DMSO-d6 and recorded the spectra, where also rotamers were observed in almost same ratio as under normal condition, probably due to rapid cooling of sample solution in the NMR probe.   Scheme 3: Proposed reaction mechanism for the formation of carbamothioates 4 and thiazoles 3 from xanthate esters and benzyl isocyanides.
All computations were carried out with the Gaussian 09 package. 29 The location of all transition state geometries was carried out using the HF/6-31G(d) level. The geometries of all reactants, transition states, and intermediates were fully optimized at the HF/6-31G(d) and B3LYP/6-31++G(d,p) levels of theory in the gas phase for simplicity. Intrinsic reaction coordinate (IRC) analysis was conducted for each transition state studied in this work to confirm that the transition states connected with the respective minima. The final IRC structures were further optimized (SI Fig.S1).
Vibrational frequencies for all the optimized structures were calculated to ensure the presence of a single imaginary frequency for each transition state and the absence of imaginary frequencies for reactants, intermediates, and products, and also to obtain    Table 5. Activation energies (Ea; kJ mol -1 ) and Gibbs energies of activation (G ‡ ; kJ mol -1 ) at 298.15 K for the proposed reaction mechanism calculated by the B3LYP/ 6-31++g(d,p) level of theory in gas phase.
Step E a G ‡

Conclusion
In conclusion, we have developed a facile general protocol for the unexpected formation of carbamothioates by the reaction of benzyl isocyanides with xanthate esters in the presence of sodium hydride in DMF (Method A). The rapid reaction time and simple work-up procedure are the noteworthy features of this protocol. As well, these carbamothioates were also synthesized by the condensation of xanthate esters with benzylamines in the presence of sodium hydride in DMF (Method B) for comparison. The yields obtained using method A are greater than those obtained using method B. Also, the reaction times of methods A are less than those required in method B. A probable mechanism is proposed which is supported by quantum chemical calculations. Further, work on isocyanide-cyclization reactions are currently under progress in our laboratory.

Supporting Information
Supporting Information File 1: All experimental procedures, analytical data, computational details and copies of 1 H and 13 C NMR spectra of all studied compounds.