Title of Invention	A CLEAN PROCESS FOR THE PREPARATION OF ALKYL AND ARYL ISOTHIOCYANATES.
Abstract	A cost-effective, eco-friendly and energy efficient process for the preparation of high purity alkyl and aryl isothiocyanates by the direct treatment of alkyl and aryldithiocarbamate salts with thiophilic halogens in the presence of base in organic solvent or a biphasic medium of water and organic solvent demonstrating nearly quantitative yields with good purity of the products. The process involves safe and inexpensive reagents and is energy efficient and is therefore favoured for wide industrial application and use.

Title of Invention

A CLEAN PROCESS FOR THE PREPARATION OF ALKYL AND ARYL ISOTHIOCYANATES.

Abstract

A cost-effective, eco-friendly and energy efficient process for the preparation of high purity alkyl and aryl isothiocyanates by the direct treatment of alkyl and aryldithiocarbamate salts with thiophilic halogens in the presence of base in organic solvent or a biphasic medium of water and organic solvent demonstrating nearly quantitative yields with good purity of the products. The process involves safe and inexpensive reagents and is energy efficient and is therefore favoured for wide industrial application and use.

Full Text	FIELD OF INVENTION The invention relates to the synthesis of alkyl and aryl isothiocyanates and more particularly an eco-friendly and energy efficient process to produce the same involving very simple and cost-effective process steps. More specifically the alkyl and aryl isothiocyanates with high purity and yield are obtained involving direct treatment of the alkyl and aryl dithiocarbamate salts with thiophilic halogen in the presence of base and in organic solvent or in a biphasic medium. The reagents are easily available and safe being non-corrosive, environmentally safe and inexpensive. The process is further directed to a simple and faster production of the alkyl and aryl isothiocyanates with no extraneous heating making it further energy efficient. BACKGROUND ART Isothiocyanates are an important class of molecules in synthetic organic chemistry wherein they act as electrophiles with the carbon atom being the electrophilic center and are thus key intermediates for the preparation of both sulfur and nitrogen containing organic compounds especially for heterocycles including thiohydantoins, thioquinazolones, mercaptoimidazoles, thioamidazolones, pyridinethiones, pyrrolidine, benzothiazine etc. and are also used as synthons for dithiadiazafulvalenes. Isothiocyanates are also used in the synthesis of various agrochemicals that have antifungal and anathematic activities. Isothiocyanate functionality is frequently encountered in many natural products such as in cruciferous plants and vegetables. By virtue of cruciferous plants defense mechanism, the glucosinates that are present in these plants are converted into isothiocyanates by the action of plant myrosinase and gastrointestinal microflora on glucosinates. A number of isothiocyanates and a limited number of glucosinolates were examined and were found to effectively block chemical carcinogenesis in animal models. Several sesquiterpene isothiocyanates have been isolated from marine natural products. Additionally, synthetic isothiocyantes have been proved to have some biological activity, such as anti-proliferative and antitumourous. Amongst the synthetic isothiocyanates, phenethyl isothiocyanate (PEITC) and sulforaphane, have been shown .o inhibit carcinogenesis and tumorigenesis and as such are useful chemo preventive agents against the development and proliferation of cancer wherein they work on a variety of levels. Most notably, they have been shown to inhibit carcinogenesis through inhibition of cytochrome P450 enzymes, which oxidize compounds such as benzopyrene and other polycyclic aromatic hydrocarbons (PAHs) into more polar epoxy-diols which can then cause mutation and induce cancer development. Phenethyl isothiocyanate (PEITC) has been shown to induce apoptosis in certain cancer cell lines, and in some cases, is even able to induce apoptosis in cells that are resistant to some currently used chemotherapeutic crugs. For example, in drug resistant leukemia cells which produce the powerful apoptosis inhibitor protein BCI-2. The biological activity also extends to the use of synthetic isothiocyanates as enzyme inhibitors for the HIV virus. Reduced glutathione (GSH), a major antioxidant defense is depleted in plasma and peripheral and blood mononuclear cells of patients infected with human immunodeficiency virus type 1 (HIV-1). The administration of low molecular weight thiols to raise GSH levels has been advocated as a method to treat HIV-1 infectec patients whereas another not much explored strategy to raise GSH levels is the use of anticarcinogenic enzyme inducing compounds like isothiocyanates, phenolic anti oxidants and the like. Amongst this class of molecules, phenylisothiocyanate (PITC) is used as a reagent in Edman peptide sequencing, wherein the amino terminus of a protein or a polypeptide is first derivatized with phenylisothiocyanate (PITC) under basic conditions. Since PITC is a good electrophile a non-nucleophilic base like tertiary amine such as triethylamine (TEA) or diisopropylethylamine (DIEA) is used to facilitate the coupling step that produces a phenylthiocarbamyl (PTC) peptide or protein. Under acidic conditions, the thiocarbonyl function of the PTC which is a moderately strong nucleophile, attacks the carbonyl carbon of the adjacent peptide bond and this nucleophilic attack or cleavage step results in the production of an anilothiazolinone (ATZ) of the terminal amino acid and leaves the original peptide or protein shortened by exactly one amino acid residue. The ATZ of terminal amino acid has different solubility properties from the peptide or protein, so it can be extracted and subjected to further analysis. The shortened peptide or protein again has a bare amino terminus, so it can be subjected to additional cycles of coupling, cleavage, and extraction. The extracted ATZ of the terminal amino acid, however, is not stable. Under acidic aqueous conditions, ATZ's rearrange rapidly to form more stable phenylthiohydantoins (PTH's), which are more amenable to analysis. The stable PTH's are then analyzed by UV absorption detection reverse phase High Performance Liquid Chromatography (UV/HPLC). Similarly, synthetic isothiocyanates are also used for other biological assays of DI\IA and protein. Several methods exist in literature on the synthesis of alkyl and aryl isothiocyanates. References are drawn to arts, Chem. Ber. 1982, 5, 799; J. Chem. Soc. 1924, 125 1702; J. Am. Chem. Soc. 1932, 54, 777 and Chem. Rev. 1991, 91, 1 wherein isothiocyanates are prepared by reacting amines with thiophosgene under controlled condition using protic solvents like chloroform, toluene etc. The disadvantages of the procedure reside in the high toxicity of thiophosgene and its incompatibility with many functional groups. References are also drawn to Eur. J. Org. Chem. 2008, 6189; Tetrahedron Lett. 2008, 49, 3117; J. Org. Chem. 2007, 72, 3969; Org. Preparation and Procedure Int. 2000, 32, 571; Tetrahedron Lett. 1997, 38, 8743; J. Org. Chem. 1997, 62, 4539; Indian J. chem. 1970, 8, 759; German patent DE2105473 and Chem. Lett. 1977, 573, wherein isothiocyanates are synthesized using diacetoxyiodobenzene (DIB), di-tert-butyl-dicarbonate, tosyl chloride, CIC02Et, Claycop, hydrogen peroxide and 2-chloropyridinium salt mediated decomposition of the in situ generated dithiocarbamic acid salts. The required dithiocarbamic acid salts are generated in situ by treatment of an amine with carbon disulfide and a base (NaOH or triethylamine) in an organic solvent. The disadvantages of these procedures are longer reaction time, low yield of isothiocyanates, use of noisture sensitive lachrymatic and corrosive tosyl chloride and di-tert-butyl carbonate. The use of 2-chloropyridinium salt gives l-methyl-2-pyridinethione as the by product. Other problems associated with the existing methods are requirement of high temperature and hign cost of most of the reagents. The procedure outlined in Synth. Commun. 1998, 28, 1223; Tetrahedron Lett. 2 004, 45, 269 and Synthesis 1982, 596 leads to the desulfurylation of dithiocarbamates that are carried out by various reagents such as uranium and phosphonium including triphenylphosphine dibromide. The drawbacks of the method are the high cost of the said reagent and the associated by products. Chem. Commun. 1997, 881 reveals a process involving the treatment of N-(arylimino)- 1,2,3-dithiazole derivative with two equivalents of ethylmagnesium bromide giving corresponding aryl isothiocyanate and provides for a two step conversion of amine into isothiocyanate. Expensive starting materials and the use of sensitive and expensive Grignard reagent are the main set back of the method. Reference is drawn to Nippon Kagaku Kaishi 1998, 5, 822 and Chem. Express 1988, 3, 215 wherein treatment of ammonium dithiocarbamates with PPh3-CCI4 is reported to give isothiocyanate. The reaction rates are known to be accelerated in polar solvents such as MeCN and the yield increases with increase in the concentration of the substrate and also the molar ratio PPh3-CCl4 but decreases with the rise in reaction temperature. Poor yields and isolation problems along with expensive reagents are the associated drawbacks of the methods. Synthesis 1989, 300 relates to a process where Wadsworth- Emmons reaction of (EtO)2P(0)NRNa (R = Ph, Bu, CH2Ph, cyclohexyl, cyclopentyl, CH2CHMe2) with CS2 in benzene containing Bu4NBr gave RNCS. Expensive reagent used is the main disadvantage of the method. Reference is again drawn to J. Chem. Res. 2005, 585 wherein isothiocyanates are prepared from amines via in situ generated dithiocarbamic acid salts using two phosgene equivalents viz. bis-(tricholoromethyl) carbonate (BTC ) and tricholoromethylchloroformates (TFC) in dichloromethane. The drawbacks of this process remain in the use of environmentally unsafe halogenated solvent, longer reaction times and the use of hazardous BTC and TFC. Reference yet again is drawn to J. Org. Chem. 1978, 43, 337; J. Org. Chem 1986, 51, 2613, Tetrahedron Lett. 1985, 26, 1661; Chem. Commun. 1995, 1995 and Justus Liebigs Annalen der Chemie 1962, 657, 104, wherein, the reaction of amines with thiocarbonyl transfer reagents like thiocarbonylditriazole, thiocarbonyldiimidazole and di-1-pyridyl thionocarbonate (DPT) yields the corresponding isothiocyanates. Although these leagents are found to be effective in the specific formation of isothiocyanate and occasionally as desulfurylating agent for thiourea, their scope is somehow limited and lead to extensive formation of the corresponding thiourea as byproduct. The disadvantages of this procedure are the additional preparation of thiocarbonyl transfer reagents and formation of its harmful byproduct along with the use of halo solvent. Bull. Chem. Soc. 1986, 7, 407 illustrates a process wherein isothiocyanate are prepared directly from amines using l,l'-(thiocarbonyldioxy)dibenzotriazole. This eagent is prepared by the reaction of siloxybenzotriazole with thiophosgene. High cost of the reagent is the main disadvantage of this method. Journal of Sulfur Chemistry, 2005, 26, 155 substantiates a process wherein a series of isothiocyanates were readily obtained from the corresponding isocyanates using Lawesson's reagent under microwave irradiation under solvent free condition. The obvious drawback is the high cost of the Lawesson's reagent. Reference is drawn to Zeitschrift fuer Chem. 1990, 30, 89 wherein the reaction of imide acid chlorides with sodium dithiocarbamates gave isothiocyanates and thiocarboxylic acid amides. Moisture sensitive and lachrymatic nature of the reagent are the drawbacks of the method. Synthesis 1982, 969, Bull Chem. Soc. Jpn. 1977, 50, 425; Bull. Chem. Soc. Jpn. ; 975,. 48, 2981 and Organic Synthesis 1956, 36, 56, relates to a process wherein isothiocyanates are obtained by base (NaOH, Grignard Reagent) catalyzed decomposition of thiourea in toluene. Preparation of thiourea and the strong basic condition are the drawbacks of the method. Reference is also made to J. Am. Chem. Soc. 1922, 44, 2896 wherein the isothiozyanates are prepared by acid (H2SO4) mediated decomposition of thiourea. A harsh reaction condition limits its efficacy for the preparation of isothiocyanates. Angew. Chem. Int. Ed. 1966, 5, 963 speaks about a reaction wherein ester bis(trichloromethyl) pentathiodiperoxy carbonate reacts with 3 equivalents of amines, in an aqueous suspension giving isothiocyanates. On reaction with two equivalents of amine the ester produces thiophosgene which subsequently reacts with a further equivalent of amine giving isothiocyanates. The drawback of this process is the use of very expensive and toxic bis(trichloromethyl) pentathiodipeoxy carbonate. Tetrahedron Lett. 1997, 38, 1597 exemplifies isothiocyanates that are synthesized from aldoximes. Aldoxime in DMF when treated with N-chlorosuccinimide or HCI/ Oxone system affords the corresponding hydroximoyl chlorides. To this a THF solution of thiourea (1 equiv.) and triethylamine (1.1 equivalent) is added to obtain isothiocyanate. Longer reaction time, harsh reaction conditions and high expense of handling are the drawbacks of this process. Reference is made to Tetrahedron Lett. 1993, 34, 8283, wherein isothiocyanates are prepared in good yields from nitrile oxide and hydroximidoyl chloride with thiourea. Additional preparation of thiourea, expensive nitrile oxide and hydroximiuoy. chloride makes this method less attractive. Synthesis, 1991, 1001 talks about the amides being transformed into isothiocyanates by reaction of carbon disulfide in acetonitrile in the presence of anhydrous NaOH / K2CO3 mixture. This method is low yielding and requires strongly basic condition. Reference is drawn to Tetrahedron Lett. 1991, 32, 3503 wherein isothiocyanates are synthesized in good yields from the corresponding isocyanides and elemental suliur under mild conditions using catalytic amount of elemental selenium. Metallic selenium is highly toxic, so is isocyanides and hence not a popular method. Chinese patent CN1880302 and Japanese patent no's: JP2002053547, JP11035550, JP10087605, JP03193760, JP06157454 and Chemische Berichte, 1965, 98, 1425, is directed to the synthesis of isothiocyanates from in situ generated dithiocarbamic acid salts by treating with dichlorodimethyl silane, acetic anhydride, dicyandiamide, 2-chloro- 1,3-dimethylimidazolinium chloride and POCl3. The disadvantages of this procedure is that it results is stoichiometric amount of alkali and heavy metal salts as byproduct use of environmentally undesirable halo solvent, longer reaction time and poor yield. Japanese patent JP04297452 and JP04297451 is referred where isothiocyanates are prepared by isomerization of thiocyanates using alkylammonium bromide in the presence of 1,3-dimethyl-2-imidazolidinone at 140°C. This method is a multi step process and carried at a higher temperature giving lesser yield of the product. Reference is drawn to JP63033359, wherein isothiocyanates are prepared by treating amines with 2 equiv. of carbon disulfide, alkyl halide in presence of DBU in benzene at 80 °C. The drawbacks with this process are requirement of high temperature, presence of human carcinogenic solvent benzene and high cost of production. Inspite of the huge number of teachings flowing from the background art, such above said processes for the synthesis of alkyl and aryl isothiocyanates are summarized to suffer from either one or many of the drawbacks which include: a) low yielding and thus less efficient; b) strongly basic and harsh reaction conditions; c) use of hazardous halo solvent ; d) toxic and lachrymatic nature of the reagents; e) moisture sensitive reagent and difficulty in handling; f) formation of harmful by products; g) longer reaction times and high reaction temperatures; e) expensive nature of the reagents and low commercial availability; f) isolation difficulties; In light of the above said there is a continuous need in the art to develop a process for the manufacture of alkyl and arylisothiocyanates in an industrial scale which would circumvent all the aforementioned difficulties associated with the process. More particularly, it would be clearly apparent from the discussion above that there is a strong need in the art to provide for a process for the manufacture oi alkyl and arylisothiocyanates in an industrial scale that would enable an efficient economic, environment friendly and importantly also be high yielding process with highly unity of product obtained by the process. OBJECTS OF THE INVENTION It is thus the basic object of the present invention to provide for a process for the manufacture of alkyl and arylisothiocyanates in an industrial scale that would enable an efficient, economic, environment friendly and importantly also high yielding process with high purity of product. Another object of the invention is to provide for a clean process for a iarge scale manufacture of alkyl and aryl isothiocyanates of general formula RNCS. Yet another object of the invention is to provide for a process for manufacturing alkyl and aryl isothiocyanates of general formula RNCS that would be economically viable, eco- friendly and energy efficient for large scale and faster production of the alky! and aryl isothiocyanates. Yet further object of the present invention is directed to the manufacture of alky; and aryl isothiocyanates involving inexpensive and easily available starting materials and non- corrosive reagents. A further object of the invention is to provide for a process for the manufacture of alkyl and aryl isothiocyanates that would be simple and easy to operate and would not involve harsh reaction conditions. Yet another object of the invention is to provide for a process for the manufacture of alkyl and aryl isothiocyanates which would be energy efficient with no requirement for any external heating. It is a further object of the invention to provide for a process for the manufacture of alkyl and aryl isothiocyanates that would be economical and can be accomplished withe a short time. Still another object: of the invention is to provide for a process for the manufacture of alkyl and aryl isothiocyanates that would results in highly pure product specifications. Yet another object of the invention is to provide for a process for the manufacture of alkyl and aryl isothiocyanates wherein the desired products of alkyl and aryl isoth ocyanates could be obtained in quantitative yields. SUMMARY OF THE INVENTION This according to the basic aspect of the present invention there is provided a process for the preparation of isothiocyanates of general formula RNCS wherein R is an alkyl or an aryl group and NCS is the isothiocyanate group comprising of (a) reacting or decomposing dithiocarbamate salts with thiophilic halogen in the presence of a base in organ c solvent or in a biphasic medium of water and an organic solvent and (b) obtaining there from the said isothiocyanates. In accordance with a preferred aspect of the process of the present invention the said step of obtaining the isothiocyanates by decomposing the dithiocarbamate salts it organic solvent comprises of (i) separating the precipitated sulphur and evaporating the solvent, (ii) redissolving the residue in a water immiscible solvent, washing with HCI unci Na,S,.02 solutions preferably 5% aqueous solution, (iii) drying the water immiscible layer with anhydrous l\la2SO4 followed by (iv) evaporation of the solvent layer to thereby obtain the said alkyl and aryl isothiocyanates of general formula RNCS. In accordance with another preferred aspect of the process of the present invention the said step of obtaining the isothiocyanates from a biphasic medium of water and an organic solvent comprises of (i) separating the organic layer preferably hexane layer f-om the aqueous layer, (ii) washing the hexane layer with HCI and Na2SO3 solutions preferably 5% aqueous solution, (iii) drying the hexane layer over anhydrous INa2SO4, (iv) evaporating the solvent to leave a residue, (v) dissolving the residue in a polar solvent preferably Ethanol to precipitate the Sulfur (vi) filtering Sulfur and evaporating ethanol to thereby obtain the said alkyl and aryl isothiocyanates of general formula RNCS. Advantageously, the process accordance with the invention comprises providing isothiocyanates of the said general formula RIMCS wherein R is an alky! and aryl group preferably selected from the group of aliphatic and aromatic amines consisting of cyclohexyl, n-butyl, benzyl, phenyl, 4-bromophenyl, 4-chloro phenyl, 3-chloro phenyl, 2- chloro phenyl, 4-methoxy phenyl, 4-methyl phenyl, 2,4-dimethyl phenyl. 2 o-dimethyl phenyl, 2-fluoro phenyl, 2,4-fluoro phenyl, 1-napthyl, furfuryl, 3-nitro phenyl, (R)-(+)-0- methylbenzyl. In the above process of the invention the said dithiocarbamate salts of the general formula RNHCS2M + where R = alkyl or aryl and M is preferably NH4+, Et3NH+, Na+, K' and the like. The said thiophilic halogen is selected from I2, Br2 and its equivalents comprising tribromides selected from the tribromides of tetramethylammonium, tetraethylammonium, tetrabutylammonium, cetyltriethylammonium, phenyltrimethylammomum, benzyltrimethylammonium, pyridine hydrobromideperbromide, DABCO, HBU. brrim, MPH, and 1,1'-(ethane-l,2-diyl) dipyridinium bis-tribromide preferably L. The said base is preferably selected from triethylamine, Pyridine, DBU, NH., NaH, NaOH, KOH, Na2CO3, K2CO3 and most preferably Et3N or NaHCO3. The said organic solvent comprise aprotic solvent preferably CH2CI2, CHCI3, tolut ne, THE, hexane and the like and most preferably CH3CN; and polar protic solvent preferab y MeOH, EtOH and the like. The said water immiscible solvent is selected from hexane, pentane CHCI2, CHCl3, EtOAc and the like more preferably hexane. In accordance with another aspect of the invention in the above process the molor ratio of the said dithiocarbamate salt to thiophilic halogen is in the range of 1:1 0.1, 1.1 preferably 1:1 more preferably 1:1.05 and the molar ratio of the said dithiocarbamate salt to base is in the range of 1:1.5 to 1:1.75 preferably 1:1.5. Importantly also, in the above process the said thiophilic halogen is added in a controlled manner over a period of 15-20 minutes to an ice-cooled solution of the said dithiocarbamate salt and said base in said solvent or in said biphasic medium. Preferably also, the said dithiocarbamate salts are freshly prepared comprising treating of alkyl or arlyamines to a mixture of carbon disulfide and triethylamine, filtered, oried under vacuum and then used. In accordance with an aspect in the above process the dithiocarbamate salt is suspended in organic solvent or dissolved in a biphasic medium of water and hexane and coaled in an ice bath. Advantageously, in the above process the product obtained is found to have a yield of 90- 99% and purity of >97%. DETAILED DESCRIPTION OF THE INVENTION As already disclosed herein before the present invention comprises of a simple and cost- effective and environment friendly process for manufacture of alkyl and aryl isothiocyanates of the general formula R-NCS, wherein R is an alkyl and aryl group selected from the group of aliphatic and aromatic amines comprising of cyclohexyl. n- butyl, benzyl, phenyl, 4-bromo phenyl, 4-chloro phenyl, 3-chloro phenyl, 2-chloro phenyl, 4-methoxy phenyl, 4-methyl phenyl, 2,4-dimethyl phenyl, 2,6-dimethyl phenyi. 2-fluoro phenyl, 2,4-fluoro phenyl, 1-napthyl, furfuryl, 3-nitro phenyl, (R)-(+)-α-methylbenzyl and wherein NCS is the thiocyanate group. The above mentioned alkyl and aryl isothiocyanates are obtained in almost quantitative yields from the reaction involving a thiophilic halogen preferably iodine nediated decomposition of dithiocarbamic acid salts in aprotic or polar protic solvent \|. eferably acetonitrile (aprotic). The dithiocarbamic acid salts are easily prepared by the following known prior art' (J. Org. Chem. 1956, 21, 404, J. Org. Chem.1964, 29, 3098, J. Org. Chem. 1997, 62, 4539, J. Org. Chem. 2007, 72, 3969), obtained by treating an amine with carbon disalfide in presence of triethylamine. Also, the dithiocarbamate salts are freshly prepated filtered dried under vacuum prior to use. Once the synthesis of the dithocarbamic acid salt is accomplished, a thiophilic reagent preferably iodine proved to be an effective reagent for the decomposition to the desired isothiocyanate in quantitative yield within 20-30 minutes in the presence of triethylamine or NaHCO3. In comparison to the present method of this invention the previously reported methods for dithiocarbamate decomposition were not as mild and high yielding. The reagent iodine for the decomposition of dithiocarbamate salt is non corrosive, inexpensive and environmentally safe. Thus the method provides an economically viable process for the preparation of isothiocyanates. The reaction is rapid and facile and accomplished under mild conditions. The product obtained is in high yields and high purity thereby needing no further purification. Aryl and alkyl isothiocyanates obtained by this process is very stable and have a long shelf life. The details of the invention, its objects and advantages are explained here under in greater detail in relation to non-limiting exemplary illustrations as per the following examples: Example I: Preparation of dithiocarbamic acid salt Synthesis for the preparation of the dithiocarbamic salt was carried out as depicted below in Scheme 1 (The procedure disclosed in J. Org. Chem. 1956, 21, 404 and J. Org. Chem. 1964, 29, 3098, J. Org. Chem. 1997, 62, 4539, J. Org. Chem. 2007, 72, 3969), was followed for the purpose). Scheme 1 Example II: Manufacture of alkyl and aryl isothiocyanates from dithiocarbamic acid salt in organic solvent The phenyldithiocarbamate salt (540 mg, 2 mmol) obtained as above following Example 1, a base preferably triethylamine (417 μL, 3 mmol) was suspended in a solvent, acetonitrile (15 mL), which is cooled prior to reaction in an ice bath for 5 minutes. The reaction or decomposition of the dithiocarbamate salt was effected by the addition of a thiophilic halogen, iodine (508 mg, 2 mmol) by adding it in a controlled manner pinch wise. The reaction being exothermic addition of iodine in pinches was necessary while cooling for the reaction to proceed and to minimize the side products. Iodine was added in pinches over a period of 15-20 minutes. After iodine addition was over and 10 minutes after a TLC experiment on the reaction mixture was performed to reveal that the reaction was complete and overall time taken for the completion of the reaction was ~30 minutes. The precipitated sulphur was filtered and acetonitrile was evaporated in rotary evaporator under reduced pressure. The residue was redissolved in a water immiscible solvent, hexane (b. p. 60-70 °C). The hexane layer was washed with (2x5 mL) of 1N HCI solution and (2x2 mL) of 5% thiosulphate solution. The hexane layer was dried over anhydrous Na2SO4 and subsequently evaporated on a rotary evaporator to yield the pure alkyl and the aryl isothiocyanates (>97% purity) in almost quantitative yield of 98 %. The above synthetic procedure followed is further briefly outlined below in Scheme 2 hereunder. Example III: Manufacture of alkyl and aryl isothiocyanates from dithiocarbamic acid salt in a biphasic medium of water and an organic solvent The phenyldithiocarbamate salt (540 mg, 2 mmol) obtained as above following Example I, was dissolved in water (10 mL) and layered with hexane (15 mL), a base preferably sodium bicarbonate (253 mg, 3 mmol) was added to it, which is cooled prior to reaction in an ice bath for 5 minutes. The reaction or decomposition of the dithiocarbamate salt was effected by the addition of a thiophilic halogen, iodine (508 mg, 2 mmol) by adding it in a controlled manner pinch wise. The reaction being exothermic addition of iodine in pinches was necessary while cooling for the reaction to proceed and to minimize the side products. Iodine was added in pinches over a period of 15-20 minutes. After iodine addition was over and 10 minutes after a TLC experiment on the reaction mixture was performed to reveal that the reaction was complete and overall time taken for the completion of the reaction was ~30 minutes. The hexane layer was separated and was washed with (2x5 mL) of IN HCI solution and (2x2 mL) of 5% thiosulphate solution. The hexane layer was dried over anhydrous Na2SO4 and subsequently evaporated on a rotary evaporator. The product was dissolved in ethanol (5 mL) and precipitated elemental sulfur was removed by filtration. Ethanol layer was evaporated to yield the pure alkyl and the aryl isothiocyanates (>97% purity) in almost quantitative yield of 96%. The above synthetic procedure followed is further briefly outlined below in Scheme 3 hereunder. The following examples are given by way of illustration of the present invention and therefore should not be construed to limit the scope of the present invention. All percentages are by weight. The above exemplary illustration of the process of the invention clearly reveals the efficient, economic and environment friendly method for the preparation of alkyl and arylisothiocyanates directed to overcome the difficulties associated with what is already known in the art in its preparative process. Importantly, it is found by way of the invention that Iodine being highly thiophilic (electrophilic) in nature can interact with sulphur (nucleophile) thus assisting the desulphurization process. This is facilitated by the abstraction of NH protons by triethylamine / NaHCO3 present as a base in the reaction medium. Formation of elemental sulfur as the sole byproduct of the reaction supports the mechanism as proposed in Scheme 2. Performing the reaction under ice-cold conditions minimizes the side products. Thus the preferred use of iodine as a thiophilic reagent favours decomposition of pre-synthesized dithiocarbamate salts to isothiocyanates. Controlled addition of iodine in pinches over a time span of 15-20 minutes in the reaction flask is a prerequisite to prevent side reactions. The mechanism for the formation of alkyl and aryl isothiocyanates is further illustrated in the following Scheme 4. Thus the examples clearly illustrate an overall simple, fast and efficient process for the manufacture of alkyl and aryl isothiocyanates. The above process is quick in yielding the said isothiocyanates in a short time span of ~30 minutes, more preferably within 15 minutes and in >97% pure form in near quantitative yields of >95% more preferably >99%. It is also noteworthy that the process is very economical for the inexpensive nature and easy commercial availability of the reagents employed. Advantageously the process provided in this invention is environmentally safe for the non corrosive, non toxic nature of the reagents and mild basic conditions needed for the process. Accordingly the process provided in this invention is favourable with respect to easy handling of the reagents which are moisture insensitive and non lachrymators. The advantage associated with the above said process also resides in the easily isolable and harmless byproduct such as sulphur which can be separated by simple filtration. The above process is advantageously also energy efficient since no external heating is required. It is thus possible by way of the present invention to provide for a process for the manufacture of alkyl and aryl isothiocyanates which is efficient in terms of energy needed for activation for the formation of products from reactants, time required and highly pure isolated yields of the product. The process is environment friendly especially in terms of non toxic nature of the reagents needed, mild reaction conditions employed and the harmless by product obtained. It is easy to operate in terms of the moisture insensitive and non lachrymator reagents needed for the purpose. WE CLAIM: 1. A process for the preparation of isothiocyanates of general formula RNCS wherein R is an arkyl or an aryl group and NCS is the isothiocyanate group comprising of (a) reacting or decomposing dithiocarbamate salts with thiophilic halogen in the presence of a base in organic solvent or in a biphasic medium of water and an organic solvent and (b) obtaining therefrom the said isothiocyanates. 2. A process as claimed in claim 1 wherein said step of obtaining the isothiocynates by decomposing the dithiocarbamate salts in organic solvent comprises of (i) separating the precipitated sulphur and evaporating the solvent (ii) redissolving the residue in a water immiscible solvent, washing with HCI and Na2S2O3 solutions preferably 5% aqueous solution, (iii) drying the water immiscible layer with anhydrous Na2SO4 followed by (iv) evaporation of the solvent layer to thereby obtain the said alkyl and aryl isothiocyanates of general formula RNCS. 3. A process as claimed in claim 1 wherein the said step of obtaining the isothiocynates from a biphasic medium of water and an organic solvent comprises of (i) separating the organic layer preferably hexane layer from the aqueous layer, (ii) washing the hexane layer with HCI and Na2S2O3 solutions preferably 5% aqueous solution, (iii) drying the hexane layer over anhydrous Na2SO4, (iv) evaporating the solvent to leave a residue, (v) dissolving the residue in a polar solvent preferably Ethanol to precipitate the Sulfur (vi) filtering Sulfur and evaporating ethanol to thereby obtain the said alkyl and aryl isothiocyanates of general formula RNCS. 4. A process as claimed in anyone of the preceeding claims comprising providing isothiocyanates of the said general formula RNCS wherein R is an alkyl and aryl group preferably selected from the group of aliphatic and aromatic amines comprising of cyclohexyl, n-butyl, benzyl, phenyl, 4-bromophenyl, 4-chloro phenyl, 3-chloro phenyl, 2-chloro phenyl, 4-methoxy phenyl, 4-methyl phenyl, 2,4-dimethyl phenyl, 2,6-dimethyl phenyl, 2-fluoro phenyl, 2,4-fluoro phenyl, 1-napthyl, furfuryl, 3-nitro phenyl, (R)-( + )-a-methylbenzyl. 5. A process as claimed in any one of the preceding claims wherein the said dithiocarbamate salts is of general formula RNHCS2M+ where R = alkyl or aryl and M is preferably NH4+, Et3NH+, Na+, K+ and the like. 6. A process as claimed in any one of the preceding claims wherein the said thiophilic halogen is selected from I2, Br2 and its equivalents comprising tribromides selected from the tribromides of tetramethylammonium, tetraethylammonium, tetrabutylammonium, cetyltriethylammonium, phenyltrimethylammonium, benzyltrimethylammonium, pyridine hydrobromideperbromide, DABCO, HBU, bmim, MPH, and 1,1'-(ethane-l,2-diyl) dipyridinium bis-tribromide preferably I2. 7. A process as claimed in any one of the preceding claims wherein the said base is preferably selected from triethylamine, pyridine, DBU, NH3, NaH, NaOH, KOH, NaHCO3, Na2CO3, K2CO3 and most preferably Et3N or NaHCO3. 8. A process as claimed in any one of the preceeding claims wherein the said organic solvent comprise aprotic solvent preferably CH2CI2, CHCI3, toluene, THF, hexane and the like and most preferably CH3CN; and polar protic solvent preferably MeOH, EtOH and the like. 9. A process as claimed in any one of the preceding claims wherein the said water immiscible solvent is selected from hexane, pentane CHCI3, CHCI2, EtOAc and the like more preferably hexane. 10. A process as claimed in any one of the preceding claims wherein the molar ratio of the said dithiocarbamate salt to thiophilic halogen is in the range of 1: 1 to 1: 1.1 preferably 1 : 1 more preferably 1 : 1.05 and the molar ratio of the said dithiocarbamate salt to base is in the range of 1: 1.5 to 1 : 1.75 preferably 1: 1.5. 11. A process as claimed in any one of the preceding claims wherein the said thiophilic halogen is added in a controlled manner over a period of 15-20 minutes to an ice- cooled solution of the said dithiocarbamate salt and said base in said solvent or in said biphasic medium. 12. A process as claimed in anyone of the preceding claims wherein the said dithiocarbamate salts are freshly prepared comprising treating of alkyl or arlyamines to a mixture of carbon disulfide and triethylamine, filtered, dried under vacuum and then used. 13. A process as claimed in anyone of the preceding claims wherein the dithiocarbamate salt is suspended in organic solvent or in a biphasic medium of water and organic solvent preferably hexane and cooled in an ice bath. 14. A process as claimed in anyone of the preceding claims wherein the product obtained comprise a yield% of 90-99 % and purity of >97 %. 15. A process for the preparation of isothiocyanates of general formula RNCS wherein R is an arkyl or an aryl group and NCS is the isothiocyanate group substantially as herein described and illustrated with reference to the accompanying examples. A cost-effective, eco-friendly and energy efficient process for the preparation of high purity alkyl and aryl isothiocyanates by the direct treatment of alkyl and aryldithiocarbamate salts with thiophilic halogens in the presence of base in organic solvent or a biphasic medium of water and organic solvent demonstrating nearly quantitative yields with good purity of the products. The process involves safe and inexpensive reagents and is energy efficient and is therefore favoured for wide industrial application and use.

Full Text

FIELD OF INVENTION
The invention relates to the synthesis of alkyl and aryl isothiocyanates and more
particularly an eco-friendly and energy efficient process to produce the same involving
very simple and cost-effective process steps. More specifically the alkyl and aryl
isothiocyanates with high purity and yield are obtained involving direct treatment of the
alkyl and aryl dithiocarbamate salts with thiophilic halogen in the presence of base and in
organic solvent or in a biphasic medium. The reagents are easily available and safe being
non-corrosive, environmentally safe and inexpensive. The process is further directed to a
simple and faster production of the alkyl and aryl isothiocyanates with no extraneous
heating making it further energy efficient.
BACKGROUND ART
Isothiocyanates are an important class of molecules in synthetic organic chemistry wherein
they act as electrophiles with the carbon atom being the electrophilic center and are thus
key intermediates for the preparation of both sulfur and nitrogen containing organic
compounds especially for heterocycles including thiohydantoins, thioquinazolones,
mercaptoimidazoles, thioamidazolones, pyridinethiones, pyrrolidine, benzothiazine etc. and
are also used as synthons for dithiadiazafulvalenes.
Isothiocyanates are also used in the synthesis of various agrochemicals that have
antifungal and anathematic activities.
Isothiocyanate functionality is frequently encountered in many natural products such as in
cruciferous plants and vegetables. By virtue of cruciferous plants defense mechanism, the
glucosinates that are present in these plants are converted into isothiocyanates by the
action of plant myrosinase and gastrointestinal microflora on glucosinates. A number of
isothiocyanates and a limited number of glucosinolates were examined and were found to
effectively block chemical carcinogenesis in animal models.
Several sesquiterpene isothiocyanates have been isolated from marine natural products.
Additionally, synthetic isothiocyantes have been proved to have some biological activity,
such as anti-proliferative and antitumourous. Amongst the synthetic isothiocyanates,
phenethyl isothiocyanate (PEITC) and sulforaphane, have been shown .o inhibit
carcinogenesis and tumorigenesis and as such are useful chemo preventive agents against
the development and proliferation of cancer wherein they work on a variety of levels. Most
notably, they have been shown to inhibit carcinogenesis through inhibition of cytochrome
P450 enzymes, which oxidize compounds such as benzopyrene and other polycyclic
aromatic hydrocarbons (PAHs) into more polar epoxy-diols which can then cause mutation
and induce cancer development. Phenethyl isothiocyanate (PEITC) has been shown to
induce apoptosis in certain cancer cell lines, and in some cases, is even able to induce
apoptosis in cells that are resistant to some currently used chemotherapeutic crugs. For
example, in drug resistant leukemia cells which produce the powerful apoptosis inhibitor
protein BCI-2.
The biological activity also extends to the use of synthetic isothiocyanates as enzyme
inhibitors for the HIV virus. Reduced glutathione (GSH), a major antioxidant defense is
depleted in plasma and peripheral and blood mononuclear cells of patients infected with
human immunodeficiency virus type 1 (HIV-1). The administration of low molecular weight
thiols to raise GSH levels has been advocated as a method to treat HIV-1 infectec patients
whereas another not much explored strategy to raise GSH levels is the use of
anticarcinogenic enzyme inducing compounds like isothiocyanates, phenolic anti oxidants
and the like.
Amongst this class of molecules, phenylisothiocyanate (PITC) is used as a reagent in
Edman peptide sequencing, wherein the amino terminus of a protein or a polypeptide is
first derivatized with phenylisothiocyanate (PITC) under basic conditions. Since PITC is a
good electrophile a non-nucleophilic base like tertiary amine such as triethylamine (TEA)
or diisopropylethylamine (DIEA) is used to facilitate the coupling step that produces a
phenylthiocarbamyl (PTC) peptide or protein. Under acidic conditions, the thiocarbonyl
function of the PTC which is a moderately strong nucleophile, attacks the carbonyl carbon
of the adjacent peptide bond and this nucleophilic attack or cleavage step results in the
production of an anilothiazolinone (ATZ) of the terminal amino acid and leaves the original
peptide or protein shortened by exactly one amino acid residue. The ATZ of terminal amino
acid has different solubility properties from the peptide or protein, so it can be extracted
and subjected to further analysis. The shortened peptide or protein again has a bare

amino terminus, so it can be subjected to additional cycles of coupling, cleavage, and
extraction. The extracted ATZ of the terminal amino acid, however, is not stable. Under
acidic aqueous conditions, ATZ's rearrange rapidly to form more stable
phenylthiohydantoins (PTH's), which are more amenable to analysis. The stable PTH's are
then analyzed by UV absorption detection reverse phase High Performance Liquid
Chromatography (UV/HPLC).
Similarly, synthetic isothiocyanates are also used for other biological assays of DI\IA and
protein.
Several methods exist in literature on the synthesis of alkyl and aryl isothiocyanates.
References are drawn to arts, Chem. Ber. 1982, 5, 799; J. Chem. Soc. 1924, 125 1702; J.
Am. Chem. Soc. 1932, 54, 777 and Chem. Rev. 1991, 91, 1 wherein isothiocyanates are
prepared by reacting amines with thiophosgene under controlled condition using protic
solvents like chloroform, toluene etc. The disadvantages of the procedure reside in the
high toxicity of thiophosgene and its incompatibility with many functional groups.
References are also drawn to Eur. J. Org. Chem. 2008, 6189; Tetrahedron Lett. 2008, 49,
3117; J. Org. Chem. 2007, 72, 3969; Org. Preparation and Procedure Int. 2000, 32, 571;
Tetrahedron Lett. 1997, 38, 8743; J. Org. Chem. 1997, 62, 4539; Indian J. chem. 1970,
8, 759; German patent DE2105473 and Chem. Lett. 1977, 573, wherein isothiocyanates
are synthesized using diacetoxyiodobenzene (DIB), di-tert-butyl-dicarbonate, tosyl
chloride, CIC02Et, Claycop, hydrogen peroxide and 2-chloropyridinium salt mediated
decomposition of the in situ generated dithiocarbamic acid salts. The required
dithiocarbamic acid salts are generated in situ by treatment of an amine with carbon
disulfide and a base (NaOH or triethylamine) in an organic solvent. The disadvantages of
these procedures are longer reaction time, low yield of isothiocyanates, use of noisture
sensitive lachrymatic and corrosive tosyl chloride and di-tert-butyl carbonate. The use of
2-chloropyridinium salt gives l-methyl-2-pyridinethione as the by product. Other problems
associated with the existing methods are requirement of high temperature and hign cost of
most of the reagents.
The procedure outlined in Synth. Commun. 1998, 28, 1223; Tetrahedron Lett. 2 004, 45,
269 and Synthesis 1982, 596 leads to the desulfurylation of dithiocarbamates that are

carried out by various reagents such as uranium and phosphonium including
triphenylphosphine dibromide. The drawbacks of the method are the high cost of the said
reagent and the associated by products.
Chem. Commun. 1997, 881 reveals a process involving the treatment of N-(arylimino)-
1,2,3-dithiazole derivative with two equivalents of ethylmagnesium bromide giving
corresponding aryl isothiocyanate and provides for a two step conversion of amine into
isothiocyanate. Expensive starting materials and the use of sensitive and expensive
Grignard reagent are the main set back of the method.
Reference is drawn to Nippon Kagaku Kaishi 1998, 5, 822 and Chem. Express 1988, 3,
215 wherein treatment of ammonium dithiocarbamates with PPh3-CCI4 is reported to give
isothiocyanate. The reaction rates are known to be accelerated in polar solvents such as
MeCN and the yield increases with increase in the concentration of the substrate and also
the molar ratio PPh3-CCl4 but decreases with the rise in reaction temperature. Poor yields
and isolation problems along with expensive reagents are the associated drawbacks of the
methods.
Synthesis 1989, 300 relates to a process where Wadsworth- Emmons reaction of
(EtO)2P(0)NRNa (R = Ph, Bu, CH2Ph, cyclohexyl, cyclopentyl, CH2CHMe2) with CS2 in
benzene containing Bu4NBr gave RNCS. Expensive reagent used is the main disadvantage
of the method.
Reference is again drawn to J. Chem. Res. 2005, 585 wherein isothiocyanates are
prepared from amines via in situ generated dithiocarbamic acid salts using two phosgene
equivalents viz. bis-(tricholoromethyl) carbonate (BTC ) and
tricholoromethylchloroformates (TFC) in dichloromethane. The drawbacks of this process
remain in the use of environmentally unsafe halogenated solvent, longer reaction times
and the use of hazardous BTC and TFC.
Reference yet again is drawn to J. Org. Chem. 1978, 43, 337; J. Org. Chem 1986, 51,
2613, Tetrahedron Lett. 1985, 26, 1661; Chem. Commun. 1995, 1995 and Justus Liebigs
Annalen der Chemie 1962, 657, 104, wherein, the reaction of amines with thiocarbonyl
transfer reagents like thiocarbonylditriazole, thiocarbonyldiimidazole and di-1-pyridyl
thionocarbonate (DPT) yields the corresponding isothiocyanates. Although these leagents

are found to be effective in the specific formation of isothiocyanate and occasionally as
desulfurylating agent for thiourea, their scope is somehow limited and lead to extensive
formation of the corresponding thiourea as byproduct. The disadvantages of this procedure
are the additional preparation of thiocarbonyl transfer reagents and formation of its
harmful byproduct along with the use of halo solvent.
Bull. Chem. Soc. 1986, 7, 407 illustrates a process wherein isothiocyanate are prepared
directly from amines using l,l'-(thiocarbonyldioxy)dibenzotriazole. This eagent is
prepared by the reaction of siloxybenzotriazole with thiophosgene. High cost of the
reagent is the main disadvantage of this method.
Journal of Sulfur Chemistry, 2005, 26, 155 substantiates a process wherein a series of
isothiocyanates were readily obtained from the corresponding isocyanates using
Lawesson's reagent under microwave irradiation under solvent free condition. The obvious
drawback is the high cost of the Lawesson's reagent.
Reference is drawn to Zeitschrift fuer Chem. 1990, 30, 89 wherein the reaction of imide
acid chlorides with sodium dithiocarbamates gave isothiocyanates and thiocarboxylic acid
amides. Moisture sensitive and lachrymatic nature of the reagent are the drawbacks of the
method.
Synthesis 1982, 969, Bull Chem. Soc. Jpn. 1977, 50, 425; Bull. Chem. Soc. Jpn. ; 975,. 48,
2981 and Organic Synthesis 1956, 36, 56, relates to a process wherein isothiocyanates are
obtained by base (NaOH, Grignard Reagent) catalyzed decomposition of thiourea in
toluene. Preparation of thiourea and the strong basic condition are the drawbacks of the
method.
Reference is also made to J. Am. Chem. Soc. 1922, 44, 2896 wherein the isothiozyanates
are prepared by acid (H2SO4) mediated decomposition of thiourea. A harsh reaction
condition limits its efficacy for the preparation of isothiocyanates.
Angew. Chem. Int. Ed. 1966, 5, 963 speaks about a reaction wherein ester
bis(trichloromethyl) pentathiodiperoxy carbonate reacts with 3 equivalents of amines, in
an aqueous suspension giving isothiocyanates. On reaction with two equivalents of amine
the ester produces thiophosgene which subsequently reacts with a further equivalent of

amine giving isothiocyanates. The drawback of this process is the use of very expensive
and toxic bis(trichloromethyl) pentathiodipeoxy carbonate.
Tetrahedron Lett. 1997, 38, 1597 exemplifies isothiocyanates that are synthesized from
aldoximes. Aldoxime in DMF when treated with N-chlorosuccinimide or HCI/ Oxone system
affords the corresponding hydroximoyl chlorides. To this a THF solution of thiourea (1
equiv.) and triethylamine (1.1 equivalent) is added to obtain isothiocyanate. Longer
reaction time, harsh reaction conditions and high expense of handling are the drawbacks
of this process.
Reference is made to Tetrahedron Lett. 1993, 34, 8283, wherein isothiocyanates are
prepared in good yields from nitrile oxide and hydroximidoyl chloride with thiourea.
Additional preparation of thiourea, expensive nitrile oxide and hydroximiuoy. chloride
makes this method less attractive.
Synthesis, 1991, 1001 talks about the amides being transformed into isothiocyanates by
reaction of carbon disulfide in acetonitrile in the presence of anhydrous NaOH / K2CO3
mixture. This method is low yielding and requires strongly basic condition.
Reference is drawn to Tetrahedron Lett. 1991, 32, 3503 wherein isothiocyanates are
synthesized in good yields from the corresponding isocyanides and elemental suliur under
mild conditions using catalytic amount of elemental selenium. Metallic selenium is highly
toxic, so is isocyanides and hence not a popular method.
Chinese patent CN1880302 and Japanese patent no's: JP2002053547, JP11035550,
JP10087605, JP03193760, JP06157454 and Chemische Berichte, 1965, 98, 1425, is
directed to the synthesis of isothiocyanates from in situ generated dithiocarbamic acid
salts by treating with dichlorodimethyl silane, acetic anhydride, dicyandiamide, 2-chloro-
1,3-dimethylimidazolinium chloride and POCl3. The disadvantages of this procedure is that
it results is stoichiometric amount of alkali and heavy metal salts as byproduct use of
environmentally undesirable halo solvent, longer reaction time and poor yield.
Japanese patent JP04297452 and JP04297451 is referred where isothiocyanates are
prepared by isomerization of thiocyanates using alkylammonium bromide in the presence

of 1,3-dimethyl-2-imidazolidinone at 140°C. This method is a multi step process and
carried at a higher temperature giving lesser yield of the product.
Reference is drawn to JP63033359, wherein isothiocyanates are prepared by treating
amines with 2 equiv. of carbon disulfide, alkyl halide in presence of DBU in benzene at 80
°C. The drawbacks with this process are requirement of high temperature, presence of
human carcinogenic solvent benzene and high cost of production.
Inspite of the huge number of teachings flowing from the background art, such above said
processes for the synthesis of alkyl and aryl isothiocyanates are summarized to suffer from
either one or many of the drawbacks which include:
a) low yielding and thus less efficient;
b) strongly basic and harsh reaction conditions;
c) use of hazardous halo solvent ;
d) toxic and lachrymatic nature of the reagents;
e) moisture sensitive reagent and difficulty in handling;
f) formation of harmful by products;
g) longer reaction times and high reaction temperatures;
e) expensive nature of the reagents and low commercial availability;
f) isolation difficulties;
In light of the above said there is a continuous need in the art to develop a process for the
manufacture of alkyl and arylisothiocyanates in an industrial scale which would circumvent
all the aforementioned difficulties associated with the process.
More particularly, it would be clearly apparent from the discussion above that there is a
strong need in the art to provide for a process for the manufacture oi alkyl and
arylisothiocyanates in an industrial scale that would enable an efficient economic,
environment friendly and importantly also be high yielding process with highly unity of
product obtained by the process.

OBJECTS OF THE INVENTION
It is thus the basic object of the present invention to provide for a process for the
manufacture of alkyl and arylisothiocyanates in an industrial scale that would enable an
efficient, economic, environment friendly and importantly also high yielding process with
high purity of product.
Another object of the invention is to provide for a clean process for a iarge scale
manufacture of alkyl and aryl isothiocyanates of general formula RNCS.
Yet another object of the invention is to provide for a process for manufacturing alkyl and
aryl isothiocyanates of general formula RNCS that would be economically viable, eco-
friendly and energy efficient for large scale and faster production of the alky! and aryl
isothiocyanates.
Yet further object of the present invention is directed to the manufacture of alky; and aryl
isothiocyanates involving inexpensive and easily available starting materials and non-
corrosive reagents.
A further object of the invention is to provide for a process for the manufacture of alkyl
and aryl isothiocyanates that would be simple and easy to operate and would not involve
harsh reaction conditions.
Yet another object of the invention is to provide for a process for the manufacture of alkyl
and aryl isothiocyanates which would be energy efficient with no requirement for any
external heating.
It is a further object of the invention to provide for a process for the manufacture of alkyl
and aryl isothiocyanates that would be economical and can be accomplished withe a short
time.

Still another object: of the invention is to provide for a process for the manufacture of alkyl
and aryl isothiocyanates that would results in highly pure product specifications.
Yet another object of the invention is to provide for a process for the manufacture of alkyl
and aryl isothiocyanates wherein the desired products of alkyl and aryl isoth ocyanates
could be obtained in quantitative yields.
SUMMARY OF THE INVENTION
This according to the basic aspect of the present invention there is provided a process for
the preparation of isothiocyanates of general formula RNCS wherein R is an alkyl or an aryl
group and NCS is the isothiocyanate group comprising of (a) reacting or decomposing
dithiocarbamate salts with thiophilic halogen in the presence of a base in organ c solvent
or in a biphasic medium of water and an organic solvent and (b) obtaining there from the
said isothiocyanates.
In accordance with a preferred aspect of the process of the present invention the said step
of obtaining the isothiocyanates by decomposing the dithiocarbamate salts it organic
solvent comprises of (i) separating the precipitated sulphur and evaporating the solvent,
(ii) redissolving the residue in a water immiscible solvent, washing with HCI unci Na,S,.02
solutions preferably 5% aqueous solution, (iii) drying the water immiscible layer with
anhydrous l\la2SO4 followed by (iv) evaporation of the solvent layer to thereby obtain the
said alkyl and aryl isothiocyanates of general formula RNCS.
In accordance with another preferred aspect of the process of the present invention the
said step of obtaining the isothiocyanates from a biphasic medium of water and an organic
solvent comprises of (i) separating the organic layer preferably hexane layer f-om the
aqueous layer, (ii) washing the hexane layer with HCI and Na2SO3 solutions preferably 5%
aqueous solution, (iii) drying the hexane layer over anhydrous INa2SO4, (iv) evaporating
the solvent to leave a residue, (v) dissolving the residue in a polar solvent preferably
Ethanol to precipitate the Sulfur (vi) filtering Sulfur and evaporating ethanol to thereby
obtain the said alkyl and aryl isothiocyanates of general formula RNCS.

Advantageously, the process accordance with the invention comprises providing
isothiocyanates of the said general formula RIMCS wherein R is an alky! and aryl group
preferably selected from the group of aliphatic and aromatic amines consisting of
cyclohexyl, n-butyl, benzyl, phenyl, 4-bromophenyl, 4-chloro phenyl, 3-chloro phenyl, 2-
chloro phenyl, 4-methoxy phenyl, 4-methyl phenyl, 2,4-dimethyl phenyl. 2 o-dimethyl
phenyl, 2-fluoro phenyl, 2,4-fluoro phenyl, 1-napthyl, furfuryl, 3-nitro phenyl, (R)-(+)-0-
methylbenzyl.
In the above process of the invention the said dithiocarbamate salts of the general formula
RNHCS2M + where R = alkyl or aryl and M is preferably NH4+, Et3NH+, Na+, K' and the like.
The said thiophilic halogen is selected from I2, Br2 and its equivalents comprising
tribromides selected from the tribromides of tetramethylammonium, tetraethylammonium,
tetrabutylammonium, cetyltriethylammonium, phenyltrimethylammomum,
benzyltrimethylammonium, pyridine hydrobromideperbromide, DABCO, HBU. brrim, MPH,
and 1,1'-(ethane-l,2-diyl) dipyridinium bis-tribromide preferably L.
The said base is preferably selected from triethylamine, Pyridine, DBU, NH., NaH, NaOH,
KOH, Na2CO3, K2CO3 and most preferably Et3N or NaHCO3.
The said organic solvent comprise aprotic solvent preferably CH2CI2, CHCI3, tolut ne, THE,
hexane and the like and most preferably CH3CN; and polar protic solvent preferab y MeOH,
EtOH and the like.
The said water immiscible solvent is selected from hexane, pentane CHCI2, CHCl3, EtOAc
and the like more preferably hexane.
In accordance with another aspect of the invention in the above process the molor ratio of
the said dithiocarbamate salt to thiophilic halogen is in the range of 1:1 0.1, 1.1
preferably 1:1 more preferably 1:1.05 and the molar ratio of the said dithiocarbamate salt
to base is in the range of 1:1.5 to 1:1.75 preferably 1:1.5.
Importantly also, in the above process the said thiophilic halogen is added in a controlled
manner over a period of 15-20 minutes to an ice-cooled solution of the said
dithiocarbamate salt and said base in said solvent or in said biphasic medium.

Preferably also, the said dithiocarbamate salts are freshly prepared comprising treating of
alkyl or arlyamines to a mixture of carbon disulfide and triethylamine, filtered, oried under
vacuum and then used.
In accordance with an aspect in the above process the dithiocarbamate salt is suspended
in organic solvent or dissolved in a biphasic medium of water and hexane and coaled in an
ice bath.
Advantageously, in the above process the product obtained is found to have a yield of 90-
99% and purity of >97%.
DETAILED DESCRIPTION OF THE INVENTION
As already disclosed herein before the present invention comprises of a simple and cost-
effective and environment friendly process for manufacture of alkyl and aryl
isothiocyanates of the general formula R-NCS, wherein R is an alkyl and aryl group
selected from the group of aliphatic and aromatic amines comprising of cyclohexyl. n-
butyl, benzyl, phenyl, 4-bromo phenyl, 4-chloro phenyl, 3-chloro phenyl, 2-chloro phenyl,
4-methoxy phenyl, 4-methyl phenyl, 2,4-dimethyl phenyl, 2,6-dimethyl phenyi. 2-fluoro
phenyl, 2,4-fluoro phenyl, 1-napthyl, furfuryl, 3-nitro phenyl, (R)-(+)-α-methylbenzyl and
wherein NCS is the thiocyanate group.
The above mentioned alkyl and aryl isothiocyanates are obtained in almost quantitative
yields from the reaction involving a thiophilic halogen preferably iodine nediated
decomposition of dithiocarbamic acid salts in aprotic or polar protic solvent |. eferably
acetonitrile (aprotic).
The dithiocarbamic acid salts are easily prepared by the following known prior art' (J. Org.
Chem. 1956, 21, 404, J. Org. Chem.1964, 29, 3098, J. Org. Chem. 1997, 62, 4539, J.
Org. Chem. 2007, 72, 3969), obtained by treating an amine with carbon disalfide in
presence of triethylamine. Also, the dithiocarbamate salts are freshly prepated filtered
dried under vacuum prior to use.

Once the synthesis of the dithocarbamic acid salt is accomplished, a thiophilic reagent
preferably iodine proved to be an effective reagent for the decomposition to the desired
isothiocyanate in quantitative yield within 20-30 minutes in the presence of triethylamine or
NaHCO3.
In comparison to the present method of this invention the previously reported methods for
dithiocarbamate decomposition were not as mild and high yielding.
The reagent iodine for the decomposition of dithiocarbamate salt is non corrosive,
inexpensive and environmentally safe. Thus the method provides an economically viable
process for the preparation of isothiocyanates. The reaction is rapid and facile and
accomplished under mild conditions. The product obtained is in high yields and high purity
thereby needing no further purification. Aryl and alkyl isothiocyanates obtained by this
process is very stable and have a long shelf life.
The details of the invention, its objects and advantages are explained here under in greater
detail in relation to non-limiting exemplary illustrations as per the following examples:
Example I: Preparation of dithiocarbamic acid salt
Synthesis for the preparation of the dithiocarbamic salt was carried out as depicted below in
Scheme 1 (The procedure disclosed in J. Org. Chem. 1956, 21, 404 and J. Org. Chem.
1964, 29, 3098, J. Org. Chem. 1997, 62, 4539, J. Org. Chem. 2007, 72, 3969), was
followed for the purpose).

Scheme 1

Example II: Manufacture of alkyl and aryl isothiocyanates from dithiocarbamic
acid salt in organic solvent
The phenyldithiocarbamate salt (540 mg, 2 mmol) obtained as above following Example 1,
a base preferably triethylamine (417 μL, 3 mmol) was suspended in a solvent, acetonitrile
(15 mL), which is cooled prior to reaction in an ice bath for 5 minutes. The reaction or
decomposition of the dithiocarbamate salt was effected by the addition of a thiophilic
halogen, iodine (508 mg, 2 mmol) by adding it in a controlled manner pinch wise. The
reaction being exothermic addition of iodine in pinches was necessary while cooling for the
reaction to proceed and to minimize the side products. Iodine was added in pinches over a
period of 15-20 minutes. After iodine addition was over and 10 minutes after a TLC
experiment on the reaction mixture was performed to reveal that the reaction was
complete and overall time taken for the completion of the reaction was ~30 minutes. The
precipitated sulphur was filtered and acetonitrile was evaporated in rotary evaporator
under reduced pressure. The residue was redissolved in a water immiscible solvent,
hexane (b. p. 60-70 °C). The hexane layer was washed with (2x5 mL) of 1N HCI solution
and (2x2 mL) of 5% thiosulphate solution. The hexane layer was dried over anhydrous
Na2SO4 and subsequently evaporated on a rotary evaporator to yield the pure alkyl and
the aryl isothiocyanates (>97% purity) in almost quantitative yield of 98 %. The above
synthetic procedure followed is further briefly outlined below in Scheme 2 hereunder.

Example III: Manufacture of alkyl and aryl isothiocyanates from dithiocarbamic
acid salt in a biphasic medium of water and an organic solvent
The phenyldithiocarbamate salt (540 mg, 2 mmol) obtained as above following Example I,
was dissolved in water (10 mL) and layered with hexane (15 mL), a base preferably
sodium bicarbonate (253 mg, 3 mmol) was added to it, which is cooled prior to reaction in
an ice bath for 5 minutes. The reaction or decomposition of the dithiocarbamate salt was
effected by the addition of a thiophilic halogen, iodine (508 mg, 2 mmol) by adding it in a
controlled manner pinch wise. The reaction being exothermic addition of iodine in pinches
was necessary while cooling for the reaction to proceed and to minimize the side products.
Iodine was added in pinches over a period of 15-20 minutes. After iodine addition was
over and 10 minutes after a TLC experiment on the reaction mixture was performed to
reveal that the reaction was complete and overall time taken for the completion of the
reaction was ~30 minutes. The hexane layer was separated and was washed with (2x5
mL) of IN HCI solution and (2x2 mL) of 5% thiosulphate solution. The hexane layer was
dried over anhydrous Na2SO4 and subsequently evaporated on a rotary evaporator. The
product was dissolved in ethanol (5 mL) and precipitated elemental sulfur was removed by
filtration. Ethanol layer was evaporated to yield the pure alkyl and the aryl isothiocyanates
(>97% purity) in almost quantitative yield of 96%. The above synthetic procedure
followed is further briefly outlined below in Scheme 3 hereunder.

The following examples are given by way of illustration of the present invention and
therefore should not be construed to limit the scope of the present invention. All
percentages are by weight.

The above exemplary illustration of the process of the invention clearly reveals the efficient,
economic and environment friendly method for the preparation of alkyl and
arylisothiocyanates directed to overcome the difficulties associated with what is already
known in the art in its preparative process. Importantly, it is found by way of the invention
that Iodine being highly thiophilic (electrophilic) in nature can interact with sulphur
(nucleophile) thus assisting the desulphurization process. This is facilitated by the
abstraction of NH protons by triethylamine / NaHCO3 present as a base in the reaction
medium. Formation of elemental sulfur as the sole byproduct of the reaction supports the
mechanism as proposed in Scheme 2. Performing the reaction under ice-cold conditions
minimizes the side products. Thus the preferred use of iodine as a thiophilic reagent favours
decomposition of pre-synthesized dithiocarbamate salts to isothiocyanates. Controlled
addition of iodine in pinches over a time span of 15-20 minutes in the reaction flask is a
prerequisite to prevent side reactions. The mechanism for the formation of alkyl and aryl
isothiocyanates is further illustrated in the following Scheme 4.

Thus the examples clearly illustrate an overall simple, fast and efficient process for the
manufacture of alkyl and aryl isothiocyanates.
The above process is quick in yielding the said isothiocyanates in a short time span of ~30
minutes, more preferably within 15 minutes and in >97% pure form in near quantitative
yields of >95% more preferably >99%. It is also noteworthy that the process is very
economical for the inexpensive nature and easy commercial availability of the reagents
employed.

Advantageously the process provided in this invention is environmentally safe for the non
corrosive, non toxic nature of the reagents and mild basic conditions needed for the
process. Accordingly the process provided in this invention is favourable with respect to
easy handling of the reagents which are moisture insensitive and non lachrymators.
The advantage associated with the above said process also resides in the easily isolable
and harmless byproduct such as sulphur which can be separated by simple filtration. The
above process is advantageously also energy efficient since no external heating is
required.
It is thus possible by way of the present invention to provide for a process for the
manufacture of alkyl and aryl isothiocyanates which is efficient in terms of energy needed
for activation for the formation of products from reactants, time required and highly pure
isolated yields of the product. The process is environment friendly especially in terms of
non toxic nature of the reagents needed, mild reaction conditions employed and the
harmless by product obtained. It is easy to operate in terms of the moisture insensitive
and non lachrymator reagents needed for the purpose.

WE CLAIM:
1. A process for the preparation of isothiocyanates of general formula RNCS wherein R
is an arkyl or an aryl group and NCS is the isothiocyanate group comprising of (a)
reacting or decomposing dithiocarbamate salts with thiophilic halogen in the
presence of a base in organic solvent or in a biphasic medium of water and an
organic solvent and (b) obtaining therefrom the said isothiocyanates.
2. A process as claimed in claim 1 wherein said step of obtaining the isothiocynates by
decomposing the dithiocarbamate salts in organic solvent comprises of (i)
separating the precipitated sulphur and evaporating the solvent (ii) redissolving the
residue in a water immiscible solvent, washing with HCI and Na2S2O3 solutions
preferably 5% aqueous solution, (iii) drying the water immiscible layer with
anhydrous Na2SO4 followed by (iv) evaporation of the solvent layer to thereby
obtain the said alkyl and aryl isothiocyanates of general formula RNCS.
3. A process as claimed in claim 1 wherein the said step of obtaining the
isothiocynates from a biphasic medium of water and an organic solvent comprises
of (i) separating the organic layer preferably hexane layer from the aqueous layer,
(ii) washing the hexane layer with HCI and Na2S2O3 solutions preferably 5%
aqueous solution, (iii) drying the hexane layer over anhydrous Na2SO4, (iv)
evaporating the solvent to leave a residue, (v) dissolving the residue in a polar
solvent preferably Ethanol to precipitate the Sulfur (vi) filtering Sulfur and
evaporating ethanol to thereby obtain the said alkyl and aryl isothiocyanates of
general formula RNCS.
4. A process as claimed in anyone of the preceeding claims comprising providing
isothiocyanates of the said general formula RNCS wherein R is an alkyl and aryl
group preferably selected from the group of aliphatic and aromatic amines
comprising of cyclohexyl, n-butyl, benzyl, phenyl, 4-bromophenyl, 4-chloro phenyl,
3-chloro phenyl, 2-chloro phenyl, 4-methoxy phenyl, 4-methyl phenyl, 2,4-dimethyl

phenyl, 2,6-dimethyl phenyl, 2-fluoro phenyl, 2,4-fluoro phenyl, 1-napthyl, furfuryl,
3-nitro phenyl, (R)-( + )-a-methylbenzyl.
5. A process as claimed in any one of the preceding claims wherein the said
dithiocarbamate salts is of general formula RNHCS2M+ where R = alkyl or aryl and M
is preferably NH4+, Et3NH+, Na+, K+ and the like.
6. A process as claimed in any one of the preceding claims wherein the said thiophilic
halogen is selected from I2, Br2 and its equivalents comprising tribromides selected
from the tribromides of tetramethylammonium, tetraethylammonium,
tetrabutylammonium, cetyltriethylammonium, phenyltrimethylammonium,
benzyltrimethylammonium, pyridine hydrobromideperbromide, DABCO, HBU, bmim,
MPH, and 1,1'-(ethane-l,2-diyl) dipyridinium bis-tribromide preferably I2.
7. A process as claimed in any one of the preceding claims wherein the said base is
preferably selected from triethylamine, pyridine, DBU, NH3, NaH, NaOH, KOH,
NaHCO3, Na2CO3, K2CO3 and most preferably Et3N or NaHCO3.
8. A process as claimed in any one of the preceeding claims wherein the said organic
solvent comprise aprotic solvent preferably CH2CI2, CHCI3, toluene, THF, hexane and
the like and most preferably CH3CN; and polar protic solvent preferably MeOH,
EtOH and the like.
9. A process as claimed in any one of the preceding claims wherein the said water
immiscible solvent is selected from hexane, pentane CHCI3, CHCI2, EtOAc and the
like more preferably hexane.
10. A process as claimed in any one of the preceding claims wherein the molar ratio of
the said dithiocarbamate salt to thiophilic halogen is in the range of 1: 1 to 1: 1.1
preferably 1 : 1 more preferably 1 : 1.05 and the molar ratio of the said
dithiocarbamate salt to base is in the range of 1: 1.5 to 1 : 1.75 preferably 1: 1.5.
11. A process as claimed in any one of the preceding claims wherein the said thiophilic
halogen is added in a controlled manner over a period of 15-20 minutes to an ice-

cooled solution of the said dithiocarbamate salt and said base in said solvent or in
said biphasic medium.
12. A process as claimed in anyone of the preceding claims wherein the said
dithiocarbamate salts are freshly prepared comprising treating of alkyl or
arlyamines to a mixture of carbon disulfide and triethylamine, filtered, dried under
vacuum and then used.
13. A process as claimed in anyone of the preceding claims wherein the
dithiocarbamate salt is suspended in organic solvent or in a biphasic medium of
water and organic solvent preferably hexane and cooled in an ice bath.
14. A process as claimed in anyone of the preceding claims wherein the product
obtained comprise a yield% of 90-99 % and purity of >97 %.
15. A process for the preparation of isothiocyanates of general formula RNCS wherein R
is an arkyl or an aryl group and NCS is the isothiocyanate group substantially as
herein described and illustrated with reference to the accompanying examples.

A cost-effective, eco-friendly and energy efficient process for the preparation of high purity alkyl and aryl isothiocyanates by the direct treatment of alkyl and aryldithiocarbamate
salts with thiophilic halogens in the presence of base in organic solvent or a biphasic
medium of water and organic solvent demonstrating nearly quantitative yields with good purity of the products. The process involves safe and inexpensive reagents and is energy efficient and is therefore favoured for wide industrial application and use.

Documents:

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Patent Number

278099

Indian Patent Application Number

2138/KOL/2008

PG Journal Number

52/2016

Publication Date

16-Dec-2016

Grant Date

14-Dec-2016

Date of Filing

11-Dec-2008

Name of Patentee

INDIAN INSTITUTE OF TECHNOLOGY

Applicant Address

INDIAN INSTITUTE OF TECHNOLOGY GUWAHATI, GUWAHATI

Inventors:

#	Inventor's Name	Inventor's Address
1	PATEL,, BHISMA KUMAR	INDIAN INSTITUTE OF TECHNOLOGY GUWAHATI, DEPARTMENT OF CHEMISTRY GUWAHATI-781039
2	NATH, JAYASHREE	INDIAN INSTITUTE OF TECHNOLOGY GUWAHATI, CENTRE FOR THE ENVIRONMENT, GUWAHATI-781039

PCT International Classification Number

C07C 157/05

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA