Triton-B catalyzed , efficient and solvent-free approach for the synthesis of dithiocarbamates

Article history: Received November 14, 2016 Received in revised form June 20, 2017 Accepted July 4, 2017 Available online July 5, 2017 A novel one-pot, solvent-free method for the synthesis of dithiocarbamates was developed through the reaction of corresponding alkyl halides, amines and carbon disulfide employing catalytic amount of benzyl trimethyl ammonium hydroxide (Triton-B). The reaction conditions are milder with extremely simple work-up procedures than the reported methods, afforded high yields (82-98%) of the desired products.


Organic
dithiocarbamates have extensively been used as agrochemicals, 1 pharmaceuticals, 2 intermediates in organic synthesis, 3 protection of amino groups in peptide chemistry, 4 linkers in solid phase organic synthesis, 5 radical precursors in free-radical chemistry 6 and synthesis of ionic liquids. 7Furthermore, different transition metal complexes of dithiocarbamates have been synthesized for various studies, primarily because of their applications as organic superconductors. 8In recent years, dithiocarbamates have been emerged as a novel class of potential agrochemicals (e. g. pesticides, 9 herbicides, 10 insecticides, 11 fungicides 12 etc.) such as carbamorph, ziram, benzathiazole derivatives etc.(Fig.1).As-pharmaceuticals, they have been used as drugs and prodrugs for the different type of biological activities such as anti-microbial, 13 anticancer, 14 antiprotozoal, 15 antileprosy, 16 antitubercular, 17 anti-fungal, 18 anti-alzheimer, 19 and contraceptive agents 20 etc. Furthermore, recently it has been realized through various published reports that by incorporating dithiocarbamate linkage into structurally diverse biologically potent synthetic/semisynthetic/natural molecules may lead to manifold increase in biological activities. 21As a useful synthon, organic dithiocarbamates have been extensively used for the synthesis of structurally diverse biological potent scaffolds such as isothiocyanates, 22 thiourea, 23 cynamide, 24 dithiobenzophene, 25 glycosides, 26 amide, 27 dicarboxylates, 28 benzimidazole, 29 carbamate, 30 pyran, 31 flavonoids 32 etc.In view of their tremendous importance and wide applications, their syntheses have gained considerable attention, and therefore have become a focus of synthetic organic chemistry.
Traditional synthesis of organic dithiocarbamates involves use of phosgene 33 and its derivatives. 34owever, these methods are associated with several drawbacks like use of costly and toxic reagents such as thiophosgene and its derivatives, longer reaction time and lesser yield.Therefore, their syntheses has been changed from harmful reagents to abundantly available, cheap and safe reagent like carbon disulfide. 35However, their formation using carbon disulfide employed harsh reaction conditions such a use of strong bases, higher reaction temperatures and longer reaction times. 36Therefore, there is still need for the development of safer and efficient synthetic protocols for the syntheses of dithiocarbamates.Our group has been engaged from past several years for the development of new methodologies for the preparation of carbamates, dithiocarbamates and related compounds using cheap, abundantly available and safe reagents like carbon dioxide and carbon disulphide respectively. 37In recent years, we found that Triton-B has emerged as a best catalyst for the synthesis of carbamates, dithiocarbamates, carbazates, dithiocarbazates, dithiocarbonates employing a variety of reagents and catalytic systems. 38In the present communication, we report here an efficient and novel, one-pot, solvent-free synthesis ofdithiocarbamates starting from their corresponding alkyl halides, amines employing Triton B/CS2 system.

Results and Discussion
In connection with our ongoing interest pertaining to the use of Triton-B (Fig. 1.) for the synthesis of carbamates, dithiocarbamates, carbazates, dithiocarbazates and dithiocarbonates (xanthates). 38In the present paper, we wish to report a simple and effective one-pot procedure for the synthesis ofdithiocarbamates,through the nucleophilic attack of S -ion of monoalkylammonium alkyl dithiocarbamate ion 2 (Figure 1.) upon the carbocation, generated from the electrophilic carbon of the corresponding alkyl halide (Scheme 1.).Thus, a mixture of amine and CS2 were taken without any solvent and Triton-B was added into it with constant stirring at room temperature.It has been reported by our group that by reacting two molar ratio of amine with carbon dioxide afforded the corresponding monoalkylammonium alkyl carbamate (MAAAC) ion 1, by adopting similar approach, monoalkylammonium alkyldithiocarbamate (MAAADC) ion 2 should be obtained through reaction of two molar equivalents of amine with CS2 (Fig. 1.).
CS2 is more reactive than CO2, therefore thereaction was tried at room temperature.It has been observed that the nucleophilicity of 2 could be increased by using basic phase transfer catalyst (PTC) like Triton-B.The nucleophilic attack of 2 to the electrophilic carbon of the corresponding alkyl halide may led to the corresponding dithiocarbamate (Scheme 1).The confirmation of product was made based on the spectroscopic and analytical data with our previously synthesized authentic dithiocarbamate.It is important to note here that amine used for this reaction should have at least one available hydrogen atom to help in the formation of 2. Therefore, this reaction could not be successful for the dithiocarbamates synthesized from tertiary amines which do not have at least one hydrogen atom.In order to study the effects of various phase transfer catalysts (PTC) on the yield of the reaction, a reaction of phenyl ethyl chloride with n-butyl amine employing various phase transfer catalysts (PTC) such as tetra-n-butyl ammonium iodide (TBAI), tetra-n-butyl ammonium bromide (TBAB), tetra-nbutyl ammonium chloride (TBAC), tetra-n-butyl ammonium hydrogen sulfate (TBAHS), tetra-n-butyl ammonium hydrogen carbonate (TBAHC), and benzyl trimethyl ammonium hydroxide (Triton-B) etc. was tried.We found that Triton-B is the best in achieving high yields of the desired dithiocarbamates (Table 1).In order to study the effect of halide group (I, Cl, Br) of corresponding alkyl halide on the yield of the dithiocarbamates, we tried a reaction of each of 2-chloro/bromo/iodo ethyl benzene with n-butyl amine employing Triton-B/CS2 system at room temperature, wherein we found that alkyl halide bearing iodide group gives best yields as compared to corresponding chloride and bromide compounds (Table 2).

Table 2. Effect of different alkyl halides in the formation of dithiocarbamates
After optimizing the reaction conditions, this reaction was employed to a variety of primary, secondary, and tert.alkyl halides with various kinds of primary, secondary aliphatic, alicyclic, heterocyclic, aromatic amines employing Triton-B/CS2 system at room temperature (Table 3).This reaction works well with primary alkyl halides in comparison to secondary and tertiary alkyl halides.Steric hindrance could be the reason for lesser yield of secondary or tertiary alkyl halides.It has also been observed that aromatic amines with electron releasing group (EWG) like p-anisidine and ptoluedine afforded high yields and lesser reaction time as compared to aromatic amine without EWG like aniline.Also, dithiocarbamates of cyclic amines such as cyclohexyl amine was obtained in lesser yields as compared to aliphatic long chain amines.The spectral characterization of all the dithiocarbamates obtained from various amines and alkyl halides were confirmed through the data of authentic dithiocarbamates prepared in our Laboratory from various starting materials .

Conclusions
We have developed a convenient and efficient protocol for one-pot, solvent-free coupling of various primary and secondarysubstituted aliphatic, aromatic, alicyclic, heterocyclic amineswith a variety of primary, secondary and tertiary alkyl halides employing Triton-B/CS2 system.This method generates the corresponding dithiocarbamates in good to excellent yields.Furthermore, this method exhibits substrate versatility, mild reaction conditions and experimental convenience.This synthetic protocol developed in our laboratory is believed to offer a more general method for the formation of carbonoxygen bonds essential to numerous organic syntheses.

Experimental
Chemicals were procured from Merck, Aldrich, and Fluka chemical companies.Reactions were carried out under an atmosphere of Argon.Infra-Red (IR) spectra 4000-200 cm -1 were recorded on Bomem MB-104-FTIR spectrophotometer using neat technique, whereas NMRs were scanned on AC-300F, NMR (300 MHz), instrument using CDCl3 and some other deutrated solvents and TMS as internal standard.Elemental analysis were conducted by means of a Carlo-Erba EA 1110-CNNO-S analyser and agreed favourably with calculated values.

Typical experimental procedure for the synthesis of dithiocarbamates
An equimolar amount (6mmol) ofTriton-B and CS 2 was and was allowed to stir20 min at room temperature.Amine (5 mmol) was added and the reaction was continued at rt for 1 h.Now corresponding alkyl halide (2 m mol) compound were added.The reaction was further continued until completion (Table 1).The reaction mixture was poured into 50 cm 3 distilled H2O and extracted with ethyl acetate thrice.The organic layer was separated, dried (Na2SO4), and concentrated to get the desired compound.

1 .
Scheme 1. Proposed mechanism of formation of dithiocarbamates of general formula I

Table 1 .
Effect of various phase transfer catalysts on the yield of dithiocarbamates

Table 3 .
Conversion of alkyl halides into dithiocarbamates of general formula I