Title of Invention	"AN IMPROVED PROCESS FOR THE PREPARATION OF A TERTIARY THIOCYANATE, AN INTERMEDIATE USEFUL FOR THE PREPARATION OF TERTIARY THIOLS"
Abstract	An improved process for the preparation of a tertiary thiocyanate, an intermediate useful for the preparation of tertiary thiols: The process of present invention provides tertiary alkyl thiocyanates in yields superior to those reported in the prior art. The method has high product selectivity as reflected by the higher ratio of thiocyanate .The thiocyanates of the present invention are stable and serve as convenient intermediates for the preparation of the corresponding thiols of formula IV, V,VI, (X=SH) which have potential applications as flavourants.

Title of Invention

"AN IMPROVED PROCESS FOR THE PREPARATION OF A TERTIARY THIOCYANATE, AN INTERMEDIATE USEFUL FOR THE PREPARATION OF TERTIARY THIOLS"

Abstract

An improved process for the preparation of a tertiary thiocyanate, an intermediate useful for the preparation of tertiary thiols: The process of present invention provides tertiary alkyl thiocyanates in yields superior to those reported in the prior art. The method has high product selectivity as reflected by the higher ratio of thiocyanate .The thiocyanates of the present invention are stable and serve as convenient intermediates for the preparation of the corresponding thiols of formula IV, V,VI, (X=SH) which have potential applications as flavourants.

Full Text	This invention relates to an improved process for the preparation of a tertiary thiocyanate, an intermediate useful for the preparation of tertiary thiols The uses of the present invention are, i) it provides a facile access to the preparation of tertiary alkyl thiocyanates, which are otherwise difficult to prepare and ii) the thiocyanates, thus prepared, can be converted easily into tertiary alkyl thiols, some of which possess guaya, grapefruit and black currant-like aroma. These compounds are of value in the art of application of aroma chemicals to foodstuffs, beverages, perfumery and cosmetics, air fresheners, medicinal^ and oral hygiene products. Many volatile organic sulphur compounds are important constituents of foods, beverages and natural isolates (Maarse H (ed) Volatile Compounds in Foods and Beverages, Marcel Dekker, New York, 1991). Of these, many thiols (mercaptans) are found to be the character-impact constituents of natural flavours e.g., 3-methyl-2-butene-1-thiol (beer), /?-menth-l-ene-8-thiol (grapefruit) and (lS,4S)-/?-menthan-3-one-8-thiol (buchu leaf oil) ( Boelens M H, Perfumer & Flavorist, 18(3),29, 1993 and references cited therein). These volatiles have low threshhold values and are, usually, present in very low concentrations. For example, /?-menth-l-ene-8-thiol has a .4 threshold value of (Demole E, Enggist P & Ohloff G, Helv. Chim. Acta, 65, 1785,1982). Thiols can be prepared from different classes of compounds like olefins, alkyl halides, alcohols and their derivatives, amines, disulphides, sulphonic acids and their derivatives ( Wardell J L , The Chemistry of Functional Groups, Thiols, part 1, Ed. Patai S, John Wiley and Sons, London, 1974). The more useful of them are the direct methods like reaction of hydrogen sulphide with alkenes or indirect methods like transformation of alkyl halides via thiouronium salts or xanthate intermediates. Thiols can also obtained from episulphides which are derivable from the corresponding epoxides. Reference may be made to the preparation of allylic terpene thiols from the corresponding terpenic alcohols or olefins via xanthogenate (Prater G, Sigg-Grutter T & Wild J., Ger. Offen, 2,615,393, 1976) and W-sulphinyl benzenesulphonamide (Gadras A, Dunogues J, Galas R & Deleris G, J Org. Chem, 49, 442, 1984) intermediates respectively. The main drawback of these methods is that they are not applicable to the synthesis of tertiary terpenic thiols. Reference may be made to the direct addition of hydrogen sulphide to olefinic bonds in terpene hydrocarbons in the presence of catalysts like aluminium trihalide (Toltikbv G. A., Kanzafarov F. Y., Dzhemilev U. M., Kantyukova R. G. & Zelenova L. M., Zh. Org. Khim. 19, 2075, 1984 & Janes J. F, Marr I. M, Unwin N, Banthorpe D. V &» Yusuf A., Flav. Fragr. J. 8, 289, 1993). The drawbacks of these methods are that they afford terpenic thiols in low yield and yield a number of by-product. Reference may also be made to a patent ( Masuda H, Kikuiri H & Mihara S, Jpn Kokai Tokkyo, 63,201,162, 1988) wherein /?-menth-l-ene-8-thiol was synthesised from (+)-limonene using this approach. A drawback of this method is that cyclic sulphides are formed as by-products and separation of thiol from the complex mixture is cumbersome and difficult.Reference may be made to two patents, Demole E & Enggist P, EP 54,847,1982, Mookherjee B D, Chant B J, Evers W J, Wilson R A, Zampino M J, and Vock M H, US patent 4,536,583, 1985, describing the synthesis of /?-menth-l-ene-8 thiol in an overall yield of 40% from (+)-limonene via its episulphide by two alternative procedures. The drawbacks of these inventions are that they are multi-stepped and involve selective epoxidation of the sidechain double bond of (+)-limonene using an unconventional reagent. Thiols being not very stable generally during storage, they could readily be prepared from their corresponding thiocyanates, which in turn could be prepared from the corresponding alkyl halides. In the known art, several methods are reported for the synthesis of alkyl thiocyanates ( Guy R.C in Chemistry ofCyanates and their Thio Derivatives, S.Patai ed. part 2, pp. 819-886, John Wiley and Sons, New York, 1977). But the common ones are by the nucleophilic substitution of alkyl halides, sulphonates or azides with metal thiocyanates. Accordingly, primary and secondary halides react with alkali metal (potassium and sodium) thiocyanates to afford the corresponding thiocyanates in good yields.' However, the drawbacks of this method are that it is not readily applicable to tertiary halides as the reaction leads to the formation of both iso- and thiocyanates, the former £eing a major one in most cases, and overall yield of substitution products is poor ( Watanabe N, Okamo M and Vemura S, Bull. Chem. Soc., Japan, 47, 2745, 1974). Transition metal thiocyanates like mercury, silver or copper salts do afford better yields of substitution products with SN! -active halides. The main drawback of these methods is that they yield isothiocyanates, predominantly. Reference may be made to the employment of zinc salts for the preparation of thio- and isothiocyanates from SN! -active halides like tertiary, allylic and benzylic halides ( Gurudutt K N, Sanjay Rao and Srinivas P, Indian J. Chem. 30B, 343-344, 1991) wherein thiocyanates could be obtained in higher proportions than sothiocyanates viz., range of 2 to 4.5 : 1 respectively. The main drawback of this discovery is that super ambient temperatures ( 40 -80°C) have to be employed for accelerating the reaction which also promote the isomerisation of the initially formed thiocyanates into thermodynamically more stable isothiocyanates. The main object of the present invention is to evolve an improved process for the preparation of tertiary thiols, which obviates the drawbacks of the existing processes as described above. Accordingly , the present invention provides an improved process for the preparation of a tertiary thiocyanate, an intermediate useful for the preparation of a tertiary thiol, which comprises preparing a zinc thiocyanate by reacting equimolar quantities of an anhydrous alkali metal thiocyanate salt and anhydrous zinc chloride in an organic solvent such as herein described , under stirring and reflux followed by evaporation of the solvent and drying the resultant under reduced pressure, reacting the obtained zinc thiocyanate of 1.4 mol equivalent with 1 mol equivalent of an alkyl or alkyl aryl substituted tertiary halide of formula I, where R-i, R2, R3 is alkyl or alkyl aryl or a mixture thereof and C = Cl or Br, in an organic solvent such as herein described, in the presence of an equimolar quantity of an organic base as defined herein, using ultrasonic sound in the range of 40 - 50 kHz frequency and RF power in the range of 70 - 90 Watts , at a temperature in the range of 10 - 25°C for a period ranging from 3.5 to 27 h , followed by isolation of the product by conventional method. R- =alkyl or aryl or a mixture thereof X = CI or Br In an embodiment of the present invention, the zinc thiocyanate salt may be generated by contacting equimolar quantities of anhydrous zinc chloride with an alkali metal thiocyanate like potassium thiocyanate in an organic solvent like benzene under reflux followed by the evaporation of the solvent and drying of the reagent under reduced pressure at 1-2 mm Hg over calcium chloride in a desiccator for 12 hours. In yet another embodiment of the present invention, an organic base used may be selected from the group consisiting of pyridine, trimethylamine and triethylamine. In yet another embodiment of the invention the reaction may be carried out under the influence of an ultrasonic sound in the range of 40-50 kHz frequency and » RF power in the range of 70-90 Watts. In yet another embodiment of the invention, the temperatures employed for the reaction may be in the range of 10-25 C. In yet another embodiment of the invention, the organic solvent employed for the reaction may be selected from the group consisting of dichloromethane, chloroform, benzene, and tetrahydrofuran. In an another embodiment of the present invention, an alkyl or alkyl aryl substituent used may be an alkyl or aryl substituted tertiary thiocyanate prepared may be selected from the group consisting of methyl, ethyl, substituted cyclohexenyl, phenyl, allyl, part of cycloalkyl moiety and a mixture thereof. 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. EXAMPLE-1 Preparation of tertiary butyl thiocyanate (Figure Removed) Zinc thiocyanate was prepared by stirring anhydrous potassium thiocyanate (4.08 gm, 42 mmol) with anhydrous zinc chloride (2.86 gm, 21 mmol) in refluxing benzene (40 ml) under stirring for 8 h. The solvent was decanted off and the salt dried under reduced pressure (10-1 mm Hg) in a flash evaporator and then in a vacuum desiccator (1-2 mm Hg) over fused calcium chloride for 12 h . Zinc thiocyanate (21 mmol) was taken in a dry dichloromethane ( 40 ml) in a 100 ml round bottommed flask. To it pyridine (30 mmol) was added followed by drop-wise addition of a solution of tertiary butyl chloride of formula II (X = Cl, 2.77g, 30 mmol) or tertiary butyl bromide of formula II (X=Br, 4.11g, 30 mmol) dichloromethane ( 5 ml each). The flask containing the mixture was suspended in an ultrasonic bath maintained at 25 C and in the frequency range of 40-50 kHz and RF power of 70-90 Watts. The reactants were sonicated until the completion of the reaction which was monitored by NMR for disappearance of the signal for methyl protons at 1.65 in case of tertiary butyl chloride and 1.82 in case of tertiary butyl bromide. The product was poured into chilled dilute acid (2.8 ml hydrochloric acid in 100 ml water) and the organic layer separated. The aqueous layer was extracted with dichloromethane ( 4x 15 ml). The combined organic layer was washed free of acid with 5 % sodium bicarbonate solution followed by water, dried over anhydrous sodium sulphate and the solvent evaporated. The residue was fractionated to afford pure tertiary butylthiocyanate formula H( X= SCN, b.p.55°C/35 mm Hg). The results are given in Table 1. TABLE 1. RESULTS OF REACTION OF t-BUTYL HALIDES WITH ZINC TfflOCYANATE IN DICHLOROMETHANE SOLVENT AS EFFECTED BY ULTRASOUND (Table Removed) EXAMPLE-2 Preparation of tertiary amyl thiocyanate (Figure Removed) Zinc thiocyanate was prepared by stirring anhydrous potassium thiocyanate (4.08 gm, 42 mmol) with anhydrous zinc chloride (2.86 gm, 21 mmol) in refluxing benzene (40 ml) under stirring for 8 h. The solvent was decanted off and the salt dried under reduced pressure (10-1 mm Hg) in a flash evaporator and then in a vacuum desiccator (1-2 mm Hg) over fused calcium chloride for 12 h . Zinc thiocyanate( 21 mmol) was taken in dry dichloromethane (40 ml) in a 100 ml round bottommed flask. To it pyridine (30 mmol) was added followed by drop-wise addition of a solution of tertiary amyl chloride (formula HI, X=C1, 3.2g, 30 mmol) indichloromethane ( 5 ml). The flask was suspended in an ultrasonic bath maintained at 25°C and in the frequency range of 40-50 kHz and RF power of 70-90 Watts. The reactants were sonicated until the completion of the reaction ( 8 h). The product was poured into ice-cold dilute acid (2.8 ml hydrochloric acid in 100 ml water) and the organic layer separated. The aqueous layer was extracted with dichloromethane ( 4x 15 ml). The combined organic layer was washed free of acid with 5 % sodium bicarbonate solution followed by water, dried over anhydrous sodium sulphate and the solvent evaporated. The residue (4.16 g), was fractionated using a Vigreux column to afford pure tertiary amyl thiocyanate ( formula III, X= SCN, 2.47g , 64 %, b.p.45-47°C 715 mm Hg ). EXAMPLE-3 Preparation of a-terpinyl thiocyanate (Figure Removed) Zinc thiocyanate was prepared by stirring anhydrous potassium thiocyanate (4.08 gm, 42 mmol) with anhydrous zinc chloride (2.86 gm, 21 mmol) in refluxing benzene (40 ml) under stirring for 8 h. The solvent was decanted off and the salt dried under reduced pressure (10-1 mm Hg) in a flash evaporator and then in a vacuum desiccator (1-2 mm Hg) over fused calcium chloride for 12 h . Zinc thiocyanate (21 mmol) was taken in 40 ml of dry organic solvent ( see Table 2) in a 100 ml round bottommed flask. To it, pyridine (30 mmol) was added followed by dropwise addition of a solution of a-terpinyl chloride of formula IV ( X= Cl, 5.17 gm, 30 mmol) in the solvent ( 5ml). The flask was suspended in an ultrasonic bath maintained at 25 C and in the frequency range of 40-50 kHz and RF power of 70-90 Watts. The reactants were sonicated until the completion of the reaction ( reaction times in Table 2). The product was poured into ice-cold dilute acid (2.8 ml hydrochloric acid in 100 ml water) and the organic layer separated. The aqueous layer was extracted with the solvent ( 4x 15 ml). The combined organic layer was washed free of acid with 5 % sodium bicarbonate solution followed by water, dried over anhydrous sodium sulphate and the solvent evaporated. The residue (5.41 g), was chromatographed on silica gel ( 65 g) using hexane as eluant to obtain hydrocarbon, and isothiocyanate fractions. Further elution with hexane-ethyl acetate mixture( 98:2) afforded a-terpinyl thiocyanate of formula IV (X=SCN) which was rectified by distillation under reduced pressure ( b.p. 116°C/ 2 mm Hg). The results of the various experiments are given in Table 2. TABLE 2. RESULTS OF REACTION OF a-TERPINYL CHLORIDE WITH ZINC THIOCYANATE AS EFFECTED BY ULTRASOUND (Table Removed) EXAMPLE-4 Preparation of 1-menthanyl thiocyanate (Figure Removed) Zinc thiocyanate was prepared by stirring anhydrous potassium thiocyanate (4.08 gm, 42 mmol) with anhydrous zinc chloride (2.86 gm, 21 mmol) in refluxing benzene (40 ml) under stirring for 8 h. The solvent was decanted off and the salt dried under reduced pressure (10-1 mm Hg) in a flash evaporatorand then in a vacuum desiccator (1-2 mm Hg) over fused calcium chloride for 12 h. Zinc thiocyanate (21 mmol) was taken in dry dichloromethane (40 ml) in a 100 ml round bottommed flask. To it, pyridine (30 mmol) was added followed by drop wise addition of a solution of 1-menthanyl chloride of formula V(X =C1, 5.2gm, 30 mmol) in the dichloromethane ( 5ml). The flask containing mixture was suspended in an ultrasonic bath maintained at 25°C and in the frequency range of 40-50 kHz and RF power of 70-90 Watts. The reactants were sonicated for 27 h. The product was poured into ice-cold dilute acid (2.8 ml hydrochloric acid in 100 ml water) and the organic layer separated. The aqueous layer was extracted with dichloromethane ( 4x 15 ml). The combined organic layer was washed free of acid with 5 % sodium bicarbonate solution followed by water, dried over anhydrous sodium sulphate and the solvent evaporated. The residue (5.0 gm) was chromatographed on silica gel ( 65 g) using hexane as eluant to obtain hydrocarbon, and isothiocyanate fractions. Further elution 5vith hexane-ethyl acetate mixture (98:2) afforded 1-menthanyl thiocyanate of formula V(X=SCN) which was rectified by distillation under reduced pressure. ( 2.1 g, 45 %, b.p. 110°C/ 2 mm Hg). EXAMPLE-5 Preparation of dimethyl(phenyl)carbinyl thiocyanate (Figure Removed) Zinc thiocyanate was prepared by stirring anhydrous potassium thiocyanate (4.08 gm, 42 mmol) with anhydrous zinc chloride (2.86 gm, 21 mmol) in refluxing benzene (40 ml) under stirring for 8 h. The solvent was decanted off and the salt dried under reduced pressure (10-1 mm Hg) in a flash evaporator and then in a vacuum desiccator (1-2 mm Hg) over fused calcium chloride for 12 h. ' Zinc thiocyanate (21 mmol) was taken in dry dichloromethane (40 ml) in a 100 ml round bottommed flask. To it, pyridine (30 mmol) was added followed by solution of dimethyl(phenyl)carbinyl chloride of formula VI (X=C1, 4.7g, 30 mmol) in dichloromethane dropwise ( 5 ml) at 10°C. The reaction flask was suspended in an ultrasonic bath, maintained at 10 C and in the frequency range of 40-50 kHz and RF power of 70-90 Watts. The reactants were sonicated for 3.5 h. The product was poured into ice-cold dilute acid (2.8 ml hydrochloric acid in 100 ml water) and the organic layer separated. The aqueous layer was extracted with dichloromethane ( 4x 15 ml). The combined organic layer was washed free of acid with 5 % sodium bicarbonate solution followed by water, dried over anhydrous sodium sulphate and the solvent evaporated. The residue (4.8g ) was chromatographed on silica gel ( 65 g) using hexane as eluant to obtain hydrocarbon, and isothiocyanate fractions. Further elution with hexane-ethyl acetate mixture ( 98:2) afforded dimethyl(phenyl)carbinyl thiocyanate of formula VI ( X=SCN) which was rectified by distillation ( 1.15g , b.p. 56-58°C/1.5mm, 25%). The advantages of the present invention are as follows : i) The process now developed is simple and affords the tertiary alkyl thiocyanates in yields superior to those reported by known methods, ii) The method has high product selectivity as reflected by the higher ratio of thiocyanate of formula II, III, IV, V,(X= SCN) to isothiocyanate of formula II, III, IV, V, (X= NCS) [4 to 7 : 1] iii) Thiocyanates are easily separable from isothiocyanates, iv) Thiocyanates are stable and serve as convenient intermediates for the preparation of the corresponding thiols of formula IV, V,VT, (X= SH) which have potential applications as flavourants. We Claim: 1. An improved process for the preparation of a tertiary thiocyanate, an intermediate useful for the preparation of a tertiary thiol, which comprises preparing a metal thiocyanate salt and anhydrous zinc chloride in an organic solvent such as herein described , under stirring and reflux followed by evaporation of the solvent and drying the resultant under reduced pressure, reacting the obtained zinc thiocyanate of 1.4 mol equivalent with 1 mol equivalent of an alkyl or alkyl aryl substituted tertiary halide of formula I, where RI, R2, Ra is alkyl or alkyl aryl or a mixture thereof and C = Cl or Br, in an organic solvent such as herein described, in the presence of an equimolar quantity of an organic base as defined herein, using ultrasonic sound in the range of 40 - 50 kHz frequency and RF power in the range of 70 - 90 Watts , at a temperature in the range of 10 - 25°C for a period ranging from 3.5 to 27 h , followed by isolation of the product by conventional method. 2. An improved process as claimed in claim 1 wherein the organic base used is selected from the group consisting of pyridine, trimethylamine and triethylamine. 3. An improved process as claimed in claims 1 to 2 wherein the organic solvent used for the reaction is selected from the group consisting of dichloromethane, chloroform, benzene and tetrahydrofuran. 4. An improved process as claimed in claims 1 to 3, wherein the alkyl aryl substitutent used in alkyl or aryl substituted tertiary thiocyanate is selected from the group consisting of methyl, ethyl, substituted cyclohexenyl, phenyl, allyl, part of cycloalkyl moiety and a mixture thereof. 5. An improved process for the preparation of a tertiary thiocyanate, an intermediate for the preparation of tertiary thiols, substantially as herein described with reference to the examples and figures in the

Full Text

This invention relates to an improved process for the preparation of a tertiary thiocyanate, an intermediate useful for the preparation of tertiary thiols
The uses of the present invention are, i) it provides a facile access to the preparation of tertiary alkyl thiocyanates, which are otherwise difficult to prepare and ii) the thiocyanates, thus prepared, can be converted easily into tertiary alkyl thiols,

some of which possess guaya, grapefruit and black currant-like aroma. These compounds are of value in the art of application of aroma chemicals to foodstuffs, beverages, perfumery and cosmetics, air fresheners, medicinal^ and oral hygiene products.
Many volatile organic sulphur compounds are important constituents of foods, beverages and natural isolates (Maarse H (ed) Volatile Compounds in Foods and Beverages, Marcel Dekker, New York, 1991). Of these, many thiols (mercaptans) are found to be the character-impact constituents of natural flavours e.g., 3-methyl-2-butene-1-thiol (beer), /?-menth-l-ene-8-thiol (grapefruit) and (lS,4S)-/?-menthan-3-one-8-thiol (buchu leaf oil) ( Boelens M H, Perfumer & Flavorist, 18(3),29, 1993 and references cited therein). These volatiles have low threshhold values and are,
usually, present in very low concentrations. For example, /?-menth-l-ene-8-thiol has a
.4 threshold value of (Demole E, Enggist P & Ohloff G, Helv. Chim. Acta, 65, 1785,1982).
Thiols can be prepared from different classes of compounds like olefins, alkyl halides, alcohols and their derivatives, amines, disulphides, sulphonic acids and their derivatives ( Wardell J L , The Chemistry of Functional Groups, Thiols, part 1,

Ed. Patai S, John Wiley and Sons, London, 1974). The more useful of them are the direct methods like reaction of hydrogen sulphide with alkenes or indirect methods like transformation of alkyl halides via thiouronium salts or xanthate intermediates. Thiols can also obtained from episulphides which are derivable from the corresponding epoxides.
Reference may be made to the preparation of allylic terpene thiols from the corresponding terpenic alcohols or olefins via xanthogenate (Prater G, Sigg-Grutter T & Wild J., Ger. Offen, 2,615,393, 1976) and W-sulphinyl benzenesulphonamide (Gadras A, Dunogues J, Galas R & Deleris G, J Org. Chem, 49, 442, 1984) intermediates respectively. The main drawback of these methods is that they are not applicable to the synthesis of tertiary terpenic thiols.
Reference may be made to the direct addition of hydrogen sulphide to olefinic bonds in terpene hydrocarbons in the presence of catalysts like aluminium trihalide (Toltikbv G. A., Kanzafarov F. Y., Dzhemilev U. M., Kantyukova R. G. & Zelenova L. M., Zh. Org. Khim. 19, 2075, 1984 & Janes J. F, Marr I. M, Unwin N, Banthorpe D. V &» Yusuf A., Flav. Fragr. J. 8, 289, 1993). The drawbacks of these methods are that they afford terpenic thiols in low yield and yield a number of by-product.
Reference may also be made to a patent ( Masuda H, Kikuiri H & Mihara S, Jpn Kokai Tokkyo, 63,201,162, 1988) wherein /?-menth-l-ene-8-thiol was synthesised from (+)-limonene using this approach. A drawback of this method is that cyclic sulphides are formed as by-products and separation of thiol from the complex mixture is cumbersome and difficult.Reference may be made to two patents, Demole E & Enggist P, EP 54,847,1982, Mookherjee B D, Chant B J, Evers W J, Wilson R A, Zampino M J, and Vock M H, US patent 4,536,583, 1985, describing the synthesis of

/?-menth-l-ene-8 thiol in an overall yield of 40% from (+)-limonene via its episulphide by two alternative procedures. The drawbacks of these inventions are that they are multi-stepped and involve selective epoxidation of the sidechain double bond of (+)-limonene using an unconventional reagent.
Thiols being not very stable generally during storage, they could readily be prepared from their corresponding thiocyanates, which in turn could be prepared from the corresponding alkyl halides.
In the known art, several methods are reported for the synthesis of alkyl thiocyanates ( Guy R.C in Chemistry ofCyanates and their Thio Derivatives, S.Patai ed. part 2, pp. 819-886, John Wiley and Sons, New York, 1977). But the common ones are by the nucleophilic substitution of alkyl halides, sulphonates or azides with metal thiocyanates. Accordingly, primary and secondary halides react with alkali metal (potassium and sodium) thiocyanates to afford the corresponding thiocyanates in good yields.' However, the drawbacks of this method are that it is not readily applicable to tertiary halides as the reaction leads to the formation of both iso- and thiocyanates, the former £eing a major one in most cases, and overall yield of substitution products is poor ( Watanabe N, Okamo M and Vemura S, Bull. Chem. Soc., Japan, 47, 2745, 1974). Transition metal thiocyanates like mercury, silver or copper salts do afford better yields of substitution products with SN! -active halides. The main drawback of
these methods is that they yield isothiocyanates, predominantly.
Reference may be made to the employment of zinc salts for the preparation of thio- and isothiocyanates from SN! -active halides like tertiary, allylic and benzylic halides ( Gurudutt K N, Sanjay Rao and Srinivas P, Indian J. Chem. 30B, 343-344, 1991) wherein thiocyanates could be obtained in higher proportions than

sothiocyanates viz., range of 2 to 4.5 : 1 respectively. The main drawback of this discovery is that super ambient temperatures ( 40 -80°C) have to be employed for accelerating the reaction which also promote the isomerisation of the initially formed thiocyanates into thermodynamically more stable isothiocyanates.
The main object of the present invention is to evolve an improved process for the preparation of tertiary thiols, which obviates the drawbacks of the existing processes as described above.
Accordingly , the present invention provides an improved process for the preparation of a tertiary thiocyanate, an intermediate useful for the preparation of a tertiary thiol, which comprises preparing a zinc thiocyanate by reacting equimolar quantities of an anhydrous alkali metal thiocyanate salt and anhydrous zinc chloride in an organic solvent such as herein described , under stirring and reflux followed by evaporation of the solvent and drying the resultant under reduced pressure, reacting the obtained zinc thiocyanate of 1.4 mol equivalent with 1 mol equivalent of an alkyl or alkyl aryl substituted tertiary halide of formula I, where R-i, R2, R3 is alkyl or alkyl aryl or a mixture thereof and C = Cl or Br, in an organic solvent such as herein described, in the presence of an equimolar quantity of an organic base as defined herein, using ultrasonic sound in the range of 40 - 50 kHz frequency and RF power in the range of 70 - 90 Watts , at a temperature in the range of 10 - 25°C for a period ranging from 3.5 to 27 h , followed by isolation of the product by conventional method.

R- =alkyl or aryl or a mixture thereof X = CI or Br
In an embodiment of the present invention, the zinc thiocyanate salt may be generated by contacting equimolar quantities of anhydrous zinc chloride with an alkali metal thiocyanate like potassium thiocyanate in an organic solvent like benzene under reflux followed by the evaporation of the solvent and drying of the reagent under reduced pressure at 1-2 mm Hg over calcium chloride in a desiccator for 12 hours.
In yet another embodiment of the present invention, an organic base used may be selected from the group consisiting of pyridine, trimethylamine and triethylamine.
In yet another embodiment of the invention the reaction may be carried out
under the influence of an ultrasonic sound in the range of 40-50 kHz frequency and
» RF power in the range of 70-90 Watts.
In yet another embodiment of the invention, the temperatures employed for the reaction may be in the range of 10-25 C.
In yet another embodiment of the invention, the organic solvent employed for the reaction may be selected from the group consisting of dichloromethane, chloroform, benzene, and tetrahydrofuran.
In an another embodiment of the present invention, an alkyl or alkyl aryl substituent used may be an alkyl or aryl substituted tertiary thiocyanate prepared may be selected from the group consisting of methyl, ethyl, substituted cyclohexenyl, phenyl, allyl, part of cycloalkyl moiety and a mixture thereof.
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.
EXAMPLE-1 Preparation of tertiary butyl thiocyanate
(Figure Removed)
Zinc thiocyanate was prepared by stirring anhydrous potassium thiocyanate (4.08 gm, 42 mmol) with anhydrous zinc chloride (2.86 gm, 21 mmol) in refluxing benzene (40 ml) under stirring for 8 h. The solvent was decanted off and the salt dried under reduced pressure (10-1 mm Hg) in a flash evaporator and then in a vacuum desiccator (1-2 mm Hg) over fused calcium chloride for 12 h .
Zinc thiocyanate (21 mmol) was taken in a dry dichloromethane ( 40 ml) in a 100 ml round bottommed flask. To it pyridine (30 mmol) was added followed by drop-wise addition of a solution of tertiary butyl chloride of formula II (X = Cl, 2.77g, 30 mmol) or tertiary butyl bromide of formula II (X=Br, 4.11g, 30 mmol) dichloromethane ( 5 ml each). The flask containing the mixture was suspended in an
ultrasonic bath maintained at 25 C and in the frequency range of 40-50 kHz and RF
power of 70-90 Watts. The reactants were sonicated until the completion of the reaction which was monitored by NMR for disappearance of the signal for methyl protons at 1.65 in case of tertiary butyl chloride and 1.82 in case of tertiary butyl bromide. The product was poured into chilled dilute acid (2.8 ml hydrochloric acid in 100 ml water) and the organic layer separated. The aqueous layer was extracted with dichloromethane ( 4x 15 ml). The combined organic layer was washed free of acid with 5 % sodium bicarbonate solution followed by water, dried over anhydrous sodium sulphate and the solvent evaporated. The residue was fractionated to afford pure tertiary butylthiocyanate formula H( X= SCN, b.p.55°C/35 mm Hg). The results are given in Table 1.
TABLE 1. RESULTS OF REACTION OF t-BUTYL HALIDES WITH ZINC TfflOCYANATE IN DICHLOROMETHANE SOLVENT AS EFFECTED BY ULTRASOUND
(Table Removed)
EXAMPLE-2 Preparation of tertiary amyl thiocyanate
(Figure Removed)
Zinc thiocyanate was prepared by stirring anhydrous potassium thiocyanate (4.08 gm, 42 mmol) with anhydrous zinc chloride (2.86 gm, 21 mmol) in refluxing benzene (40 ml) under stirring for 8 h. The solvent was decanted off and the salt dried under reduced pressure (10-1 mm Hg) in a flash evaporator and then in a vacuum desiccator (1-2 mm Hg) over fused calcium chloride for 12 h .
Zinc thiocyanate( 21 mmol) was taken in dry dichloromethane (40 ml) in a 100 ml round bottommed flask. To it pyridine (30 mmol) was added followed by drop-wise addition of a solution of tertiary amyl chloride (formula HI, X=C1, 3.2g, 30 mmol) indichloromethane ( 5 ml). The flask was suspended in an ultrasonic bath maintained at 25°C and in the frequency range of 40-50 kHz and RF power of 70-90
Watts. The reactants were sonicated until the completion of the reaction ( 8 h). The product was poured into ice-cold dilute acid (2.8 ml hydrochloric acid in 100 ml water) and the organic layer separated. The aqueous layer was extracted with dichloromethane ( 4x 15 ml). The combined organic layer was washed free of acid with 5 % sodium bicarbonate solution followed by water, dried over anhydrous sodium sulphate and the solvent evaporated. The residue (4.16 g), was fractionated using a
Vigreux column to afford pure tertiary amyl thiocyanate ( formula III, X= SCN, 2.47g , 64 %, b.p.45-47°C 715 mm Hg ).
EXAMPLE-3 Preparation of a-terpinyl thiocyanate
(Figure Removed)
Zinc thiocyanate was prepared by stirring anhydrous potassium thiocyanate (4.08 gm, 42 mmol) with anhydrous zinc chloride (2.86 gm, 21 mmol) in refluxing benzene (40 ml) under stirring for 8 h. The solvent was decanted off and the salt dried under reduced pressure (10-1 mm Hg) in a flash evaporator and then in a vacuum desiccator (1-2 mm Hg) over fused calcium chloride for 12 h .
Zinc thiocyanate (21 mmol) was taken in 40 ml of dry organic solvent ( see Table 2) in a 100 ml round bottommed flask. To it, pyridine (30 mmol) was added followed by dropwise addition of a solution of a-terpinyl chloride of formula IV ( X= Cl, 5.17 gm, 30 mmol) in the solvent ( 5ml). The flask was suspended in an ultrasonic bath maintained at 25 C and in the frequency range of 40-50 kHz and RF power of
70-90 Watts. The reactants were sonicated until the completion of the reaction ( reaction times in Table 2). The product was poured into ice-cold dilute acid (2.8 ml hydrochloric acid in 100 ml water) and the organic layer separated. The aqueous layer
was extracted with the solvent ( 4x 15 ml). The combined organic layer was washed free of acid with 5 % sodium bicarbonate solution followed by water, dried over anhydrous sodium sulphate and the solvent evaporated. The residue (5.41 g), was chromatographed on silica gel ( 65 g) using hexane as eluant to obtain hydrocarbon, and isothiocyanate fractions. Further elution with hexane-ethyl acetate mixture( 98:2) afforded a-terpinyl thiocyanate of formula IV (X=SCN) which was rectified by distillation under reduced pressure ( b.p. 116°C/ 2 mm Hg). The results of the various experiments are given in Table 2.
TABLE 2. RESULTS OF REACTION OF a-TERPINYL CHLORIDE WITH ZINC THIOCYANATE AS EFFECTED BY ULTRASOUND
(Table Removed)
EXAMPLE-4
Preparation of 1-menthanyl thiocyanate
(Figure Removed)
Zinc thiocyanate was prepared by stirring anhydrous potassium thiocyanate (4.08 gm, 42 mmol) with anhydrous zinc chloride (2.86 gm, 21 mmol) in refluxing benzene (40
ml) under stirring for 8 h. The solvent was decanted off and the salt dried under reduced pressure (10-1 mm Hg) in a flash evaporatorand then in a vacuum desiccator (1-2 mm Hg) over fused calcium chloride for 12 h.
Zinc thiocyanate (21 mmol) was taken in dry dichloromethane (40 ml) in a 100 ml round bottommed flask. To it, pyridine (30 mmol) was added followed by drop wise addition of a solution of 1-menthanyl chloride of formula V(X =C1, 5.2gm, 30 mmol) in the dichloromethane ( 5ml). The flask containing mixture was suspended in an ultrasonic bath maintained at 25°C and in the frequency range of 40-50 kHz and RF power of 70-90 Watts. The reactants were sonicated for 27 h. The product was poured into ice-cold dilute acid (2.8 ml hydrochloric acid in 100 ml water) and the organic layer separated. The aqueous layer was extracted with dichloromethane ( 4x 15 ml). The combined organic layer was washed free of acid with 5 % sodium bicarbonate solution followed by water, dried over anhydrous sodium sulphate and the solvent evaporated. The residue (5.0 gm) was chromatographed on silica gel ( 65 g) using hexane as eluant to obtain hydrocarbon, and isothiocyanate fractions. Further elution 5vith hexane-ethyl acetate mixture (98:2) afforded 1-menthanyl thiocyanate of formula V(X=SCN) which was rectified by distillation under reduced pressure. ( 2.1 g, 45 %, b.p. 110°C/ 2 mm Hg).
EXAMPLE-5 Preparation of dimethyl(phenyl)carbinyl thiocyanate

(Figure Removed)
Zinc thiocyanate was prepared by stirring anhydrous potassium thiocyanate (4.08 gm, 42 mmol) with anhydrous zinc chloride (2.86 gm, 21 mmol) in refluxing benzene (40 ml) under stirring for 8 h. The solvent was decanted off and the salt dried under reduced pressure (10-1 mm Hg) in a flash evaporator and then in a vacuum desiccator (1-2 mm Hg) over fused calcium chloride for 12 h.
' Zinc thiocyanate (21 mmol) was taken in dry dichloromethane (40 ml) in a 100 ml round bottommed flask. To it, pyridine (30 mmol) was added followed by solution of dimethyl(phenyl)carbinyl chloride of formula VI (X=C1, 4.7g, 30 mmol) in dichloromethane dropwise ( 5 ml) at 10°C. The reaction flask was suspended in an ultrasonic bath, maintained at 10 C and in the frequency range of 40-50 kHz and RF
power of 70-90 Watts. The reactants were sonicated for 3.5 h. The product was poured into ice-cold dilute acid (2.8 ml hydrochloric acid in 100 ml water) and the organic layer separated. The aqueous layer was extracted with dichloromethane ( 4x 15 ml). The combined organic layer was washed free of acid with 5 % sodium bicarbonate solution followed by water, dried over anhydrous sodium sulphate and the solvent evaporated. The residue (4.8g ) was chromatographed on silica gel ( 65 g)
using hexane as eluant to obtain hydrocarbon, and isothiocyanate fractions. Further elution with hexane-ethyl acetate mixture ( 98:2) afforded dimethyl(phenyl)carbinyl thiocyanate of formula VI ( X=SCN) which was rectified by distillation ( 1.15g , b.p. 56-58°C/1.5mm, 25%).
The advantages of the present invention are as follows : i) The process now developed is simple and affords the tertiary alkyl thiocyanates in yields superior to those reported by known methods, ii) The method has high product selectivity as reflected by the higher ratio of thiocyanate of formula II, III, IV, V,(X= SCN) to isothiocyanate of formula II, III, IV, V, (X= NCS) [4 to 7 : 1] iii) Thiocyanates are easily separable from isothiocyanates, iv) Thiocyanates are stable and serve as convenient intermediates for the preparation of the corresponding thiols of formula IV, V,VT, (X= SH) which have potential applications as flavourants.

We Claim:
1. An improved process for the preparation of a tertiary thiocyanate,
an intermediate useful for the preparation of a tertiary thiol, which
comprises preparing a metal thiocyanate salt and anhydrous zinc
chloride in an organic solvent such as herein described , under
stirring and reflux followed by evaporation of the solvent and drying
the resultant under reduced pressure, reacting the obtained zinc
thiocyanate of 1.4 mol equivalent with 1 mol equivalent of an alkyl
or alkyl aryl substituted tertiary halide of formula I, where RI, R2, Ra
is alkyl or alkyl aryl or a mixture thereof and C = Cl or Br, in an
organic solvent such as herein described, in the presence of an
equimolar quantity of an organic base as defined herein, using
ultrasonic sound in the range of 40 - 50 kHz frequency and RF
power in the range of 70 - 90 Watts , at a temperature in the range
of 10 - 25°C for a period ranging from 3.5 to 27 h , followed by
isolation of the product by conventional method.
2. An improved process as claimed in claim 1 wherein the organic
base used is selected from the group consisting of pyridine,
trimethylamine and triethylamine.
3. An improved process as claimed in claims 1 to 2 wherein the
organic solvent used for the reaction is selected from the group
consisting of dichloromethane, chloroform, benzene and
tetrahydrofuran.

4. An improved process as claimed in claims 1 to 3, wherein the alkyl
aryl substitutent used in alkyl or aryl substituted tertiary thiocyanate
is selected from the group consisting of methyl, ethyl, substituted
cyclohexenyl, phenyl, allyl, part of cycloalkyl moiety and a mixture
thereof.
5. An improved process for the preparation of a tertiary thiocyanate,
an intermediate for the preparation of tertiary thiols, substantially as
herein described with reference to the examples and figures in the

Documents:

1074-del-2000-abstract.pdf

1074-del-2000-claims.pdf

1074-del-2000-complete specification (granted).pdf

1074-del-2000-correspondence-others.pdf

1074-del-2000-correspondence-po.pdf

1074-del-2000-description (complete).pdf

1074-del-2000-form-1.pdf

1074-del-2000-form-19.pdf

1074-del-2000-form-2.pdf

1074-del-2000-form-3.pdf

« Previous Patent

Next Patent »

Patent Number

217685

Indian Patent Application Number

1074/DEL/2000

PG Journal Number

29/2008

Publication Date

26-Sep-2008

Grant Date

28-Mar-2008

Date of Filing

29-Nov-2000

Name of Patentee

COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH

Applicant Address

RAFI MARG, NEW DELHI-110 001,INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	KAMBADUR NAGARAJA RAO GURUDUTT	CENTRAL FOOD TECHNOLOGICAL RESEARCH INSTTIUTE, MYSORE-570013 INDIA
2	PULLABHATLA SRINIVAS	CENTRAL FOOD TECHNOLOGICAL RESEARCH INSTTIUTE, MYSORE-570013 INDIA.
3	BHEEMANAKERE KEMPAIAH BETTADAIAH	CENTRAL FOOD TECHNOLOGICAL RESEARCH INSTTIUTE, MYSORE-570013 INDIA

PCT International Classification Number

C07D 257/04

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA