A very large number of papers and patents in the last 15-20 years have dealt with the reaction of substances containing the thiol (SH) groups such as thiols, hydrogen sulphide and thio-acids with various unsaturated compounds.

The thiylation reaction is one of the most versatile pathways for the formation of carbon-sulphur bonds and involves the addition of compounds containing a labile S-H bond with unsaturated systems such as alkenes, alkynes and carbonyls as shown below: R = H, alkyl, aryl, R'CO (R'= aryl or alkyl) The thiylation of unsaturated compounds is also of interest, since these reactions can be regarded as models for certain processes of physiological importance, taking place in living microorganisms, particularly the synthesis of natural mercapto-amino-acids and its derivatives. These reactions provide a convenient method for synthesising various thiols and sulphides with properties of practical interest: regulators for polymerisation processes, vulcanisation accelerators, insecticides, drugs, etc. Some of these syntheses have acquired industrial importance.

The thiylation reaction can progress via a radical and/or an ionic mechanism. It appears in the literature that the difference in the thiylation reaction mechanism depends upon the nature of the unsaturated substrates. In fact, when the unsaturated substrate is an unsaturated system having an

nucleophilic character, the mechanism is preferentially radical. In this case, photoactivation or chemical activation (peroxides, AIBN) is the most efficient method.

A problem associated with such methods is that the reaction time is long and experimental conditions are extreme, typically carried out at a temperature in excess of 65°C. Furthermore, the regioselectivity of the addition is weak and purification by fraction distillation is more often necessary. Indeed, when the unsaturated compounds contains an electron-withdrawing substituant, the main mechanism is ionic. Trialkylamines or alcoholates are generally used. In the presence of free radical initiators or under photochemical irradiation in homogeneous medium, the thiol reagents add to double bond by a free radical mechanism and the orientation is anti-Markovnikov. In basic medium, the addition occurs by nucleophilic attack of thiolates to olefins by a Michael type mechanism and the orientation is also anti-Markovnikov.

It is known to produce sulphur-containing organic compounds through the reaction of a sulphur-containing compound such as thiols, hydrogen sulphide or thio-acids and an unsaturated hydrocarbon as is evidenced by US Patents No.

2515120,2411961 and 2828321 and DE 831841. The reactions used in these patent applications are carried out at a temperature of up to 60°C and require an initiator. Unwanted by-products are produced which have to be separated at the end of the synthesis route, thereby adding an additional step to the process.

We have found that sulphur-containing organic compounds can be prepared by a simple synthesis route which does not produce undesired by- products and can be carried out under less severe reaction conditions.

Accordingly, the present invention provides a process for the production of organic sulphur-containing product having the general formula (I)

wherein: R1 is H, alkyl, aryl, arylthio-acid or alkylthio-acid; R2, R3 and Rare each independently hydrogen, alkyl or aryl, and R'is (CHOH ; (CH2)nNH2 ; (CH2) nCN ; R10NXY, CH (CH2) OR 12 OR"or where Ris H or alkyl ; R'is H, alkyl, aryl or ester; R8 is CN, (CH2)nOH or COOR9 where R9 is H, alkyl or aryl and n is from 1 to 6; R'° is CHCO2R"where R"is hydrogen, alkyl or aryl, and X and Y are independently selected from hydrogen, alkyl, aryl, ester (CH3CO or PhCO) ; Rl2 and R'3 are the same or different and may be hydrogen, alkyl or aryl or the two groups may be linked by (CH2) n to form a cyclic ring, where n is from 1 to 6; which process comprises reacting a sulphur-containing compound of general formula (II) R'-SH (II) wherein R'is as defined above with an unsaturated hydrocarbon of general formula (III)

wherein the various symbols are as defined above, in the presence of a boron compound and at a temperature of less than or equal to 50°C.

The process of the present invention provides the advantage over the known prior art in that the reaction conditions are less severe and there is substantially no unwanted by-products.

The process of the present invention involves reacting a sulphur-containing compound of general formula (II) with a unsaturated hydrocarbon. R'of compound (II) may be selected from hydrogen, alkyl, aryl or an ester R'2CO where Rl2 is alkyl or aryl. Where R'is alkyl, this functional group may be C, to C6 alkyl, preferably C, to C3 alkyl, especially methyl and ethyl. Where R'is aryl, this functional group may be phenyl or substituted phenyl, for example halo phenyl, alkoxy phenyl or alkyl phenyl. A particularly preferred compound for use in the present process is where R'is methyl or phenyl.

As regards the unsaturated hydrocarbon compound, this compound may be an alkene, an allylic acid, an allylic alcohol, an allylic-alpha-acetoxy nitrile or an alpha amino acid vinyl such as D or L-vinylglycine. In particular, R, R3 and R4 of general formula (III) may be the same or may be different and may be hydrogen, alkyl or aryl. Where any one of these groups is alkyl, suitable alkyls are C, to C6 alkyl, preferably C, to C3 alkyl, especially methyl. Where any one of these groups is aryl, this functional group may be phenyl or substituted phenyl, for example halo phenyl, alkoxy phenyl or alkyl phenyl.

R5 is of the formula as given above where R6 is H or alkyl ; alkyl being as defined above. Preferably R6 is hydrogen. R'is H, alkyl, aryl or ester. Where R' is alkyl or aryl, these groups are as defined above. Where W is ester, this group may be for example CH3CO, or ether, for example CH3 (CH2) nOCH (CH2) nCH3 or CH3OCH2. R8 is CN, (CH2)nOH or COOR9, n is from 0 to 6 and R9 is H, alkyl or aryl, these groups being as defined above. Preferably, R9 is hydrogen. Examples of preferred unsaturated compounds are

where R12, R13 and R14 are hydrogen or methyl and R15 and R16 are hydrogen, alkyl, aryl, CH3CO, CH3CH2OCHCH3 or CH30CH2 The process of the present invention is particularly suitable for the preparation of multifunctional sulphides, methionine derivatives and hydroxyanalogue methionine derivatives.

The sulphur-containing compound and the unsaturated hydrocarbon may be reacted in any suitable amount to allow complete reaction. The amount of sulphur-containing compound to unsaturated hydrocarbon may be in a ratio 2 to 1 or 1 to 1; preferably the sulphur-containing compound is present in excess, typically up to 5% excess.

The process of the present invention is carried out in the presence of a boron compound. Suitable boron compounds are alkyl boranes such as methyl, ethyl and propyl. The preferred compound is triethyl borane. The boron compound may be present in an amount of from 0.1 to 30% molar concentration, preferably from 2 to 20%.

The process of the present invention may also be carried out in the presence of ultra violet (uv) irradiation. Although not necessary, it is preferred to use uv irradiation when the unsaturated hydrocarbon contains the CN functional group. The amount of uv light used in such as to enable complete reaction.

The process is carried out at a temperature of less than or equal to 50°C, preferably ambient temperature or less, especially between ambient temperature and minus 20°C.

The process of the present invention will now be illustrated with reference to the following examples: Comparative Example A: Synthesis of 4-methylthio-butyric acid using benzoyl peroxide as: CH3S (CH2) 3COOH 1.1 ml (0.02 mol) of CH3SH and 0.024 g (0.1 mmol) of benzoyl peroxide were placed in a closed stirred tank reactor. The reactor contents were stirred and cooled to minus 10°C. 1.72 g (0.02 mol) of vinylacetic acid was introduced into the reactor and the temperature then increased to ambient temperature. The solution was then heated to 80°C. The product obtained gave a 65% yield and was identified by'H NMR and mass spectroscopy as 4-methylthio-butyric acid.

Comparative Example B Synthesis of 4-methylthio-butyric acid: CH3S (CH2) 3COOH using AIBN The procedure of Comparative Example A was repeated using AIBN instead of benzoyl peroxide. The product obtained gave a 70% yield and was identified by'H NMR and mass spectroscopy as 4-methylthio-butyric acid.

Example 1: Synthesis of 4-methylthio-butvric acid: CH3S (CH2) 3COOH 1.72 g (0.02 mol) of vinylacetic acid and 1.1 ml (0.02 mol) of CH3SH were placed in a closed stirred tank reactor. The mixture was cooled to minus 10°C and stirred for 5 minutes. The vessel was then warmed to ambient temperature. 0.5 mL (0.5 mmol) of molar triethylborane was slowly added. The resulting mixture was stirred for 30 minutes. The gas formed was eliminated and the resulting mixture was washed with 20 ml of water and then extracted with ether (3 x 40 mL). The ether phased dried with sodium sulphate, followed by filtration and evaporation. The product obtained gave a 99% yield and was identified by'H NMR and mass spectroscopy as 4-methylthio-butyric acid.

Example 2: Synthesis of 4-ethYlthio-buteric acid: CH3CHzS (CH2) 3COOH The procedure of Example 1 was repeated using 1.72 g (0.02 mol) of vinylacetic acid, 1.25 g (0.02 mol) of CH3CH2SH and carried out at ambient temperature. 0.5 ml (0.5 mmol) of molar triethylborane was slowly added to the mix. The yield of product obtained was 99% and was identified by'H NMR and mass spectroscopy as 4-ethylthio-butyric acid.

Example 3: Synthesis of 4-hexvlthio-butvric acid: n-C6H13S(CH2)3COOH The procedure of Example 2 was repeated using 1.72 g (0.02 mol) of vinylacetic acid, 2.36 g (0.02 mol) of CH3 (CH2) 5SH. 0.5 mL (0.5 mmol) of molar triethylborane was slowly added to the mix. The yield of product obtained was 89% and was identified by'H NMR and mass spectroscopy as 4-hexylthio-butyric acid.

Example 4: Synthesis of 1-methylthio-3-hydroxy-butane : CH3S(CH2), CH (OH ! CH3 The procedure of Example 1 was repeated using 1.45 g (0.02 mol) of but- 3-en-2-ol and 1.1 ml (0.02 mol) of CH3SH. 0.5 ml (0.5 mmol) of molar triethylborane was slowly added to the mix. The yield of product obtained was 97% and was identified by'H NMR and mass spectroscopy as 1-methylthio-3- hydroxy-butane.

Example 5 : Synthesis of 1-ethylthio-3-hydroxy-butane: CH3CH2S(CH2)2CH(OH)CH3 The procedure of Example 2 was repeated using 1.45 g (0.02 mol) of but- 3-en-2-ol and 1.25 g (0.02 mol) of CH3CH2SH. 0.5 ml (0.5 mmol) of molar triethylborane was slowly added to the mix. The yield of product obtained was 95% and was identified by'H NMR and mass spectroscopy as l-ethylthio-3- hydroxy-butane.

Example 6: Synthesis of 1-methylthio-3-hydroxv-3-methvl-butane : CH3S(CH2)2C(CH3)2OH The procedure of Example 1 was repeated using 1.72 g (0.02 mol) of 2- methylbut-3-en-2-ol and 1.1 mL (0.02 mol) of CH3SH. 0.5 ml (0.5 mmol) of molar triethylborane was slowly added to the mix. The yield of product obtained was 98% and was identified by'H NMR and mass spectroscopy as 1-methylthio- 3-hydroxy-3-methyl-butane.

Example7 : Synthesis of 1-ethylthio-3-hvdroxv-3-methyl-butane CH3CH2S(CH2)2C(CH3)2OH The procedure of Example 2 was repeated using 1.72 g (0.02 mol) of 2- methylbut-3-en-2-ol and 1.25 g (0.02 mol) of CH3CH2SH. 0.5 ml (0.5 mmol) of molar triethylborane was slowly added to the mix. The yield of product obtained was 97% and was identified by'H NMR and mass spectroscopy as 1-ethylthio-3- hydroxy-3-methyl-butane.

Example 8: Synthesis of 1-methvlthio-2-methylpropan-3-ol : CH3SCH(CH1) CH20H The procedure of Example 1 was repeated using 1.45 g (0.02 mol) of 2- methylprop-2-en-1-ol and 1.1 ml (0.02 mol) of CH3SH. 0.5 ml (0.5 mmol) of molar triethylborane was slowly added to the mix. The yield of product obtained was 99% and was identified by'H NMR and mass spectroscopy as 1-methylthio- 2-methylpropan-3-ol.

Example 9: Synthesis of 1-ethylthio-2-methylpropan-3-ol : CH3CHoSCH ? CH (CH3a20H The procedure as for Example 2 was repeated using 1.45 g (0.02 mol) of 2- methylprop-2-en-1-ol and 1.25 g (0.02 mol) of CH3CH2SH. 0. 5mL (0.5 mmol) of molar triethylborane was slowly added to the mix. The yield of product obtained was 98% and was identified by'H NMR and mass spectroscopy as 1-ethylthio-2- methylpropan-3-ol.

Example 10: Synthesis of 2-hdroxv-4-methvlthiobutyronitrile : CH3S (CH,, CH (OH) CN 3.6 g (0.043 mol) of acrolein cyanhydrin and 4.0 ml (0.072 mol) of CH3SH were placed in a closed stirred tank reactor. The mixture was cooled to minus 10°C and stirred for 5 minutes. The vessel was then warmed to ambient temperature. 5 ml (5 mmol) of molar triethylborane was slowly added. The resulting mixture was stirred and subjected to UV light until all of the acrolein cyanhydrin was converted. On termination of the reaction, the gas formed was eliminated and the resulting mixture was washed with 30 ml of water and then extracted with ether (3 x 50 ml). The ether phased dried with sodium sulphate, followed by filtration and evaporation. The product obtained gave a 96% yield and was identified by'H NMR and mass spectroscopy as 2-hydroxy-4- methylthiobutyronitrile.

Example 11: Synthesis of 2-h,oxv-4-ethylthiobutyronitrile : CH3CH9S (CH2) 9CH (OH ! CN The procedure of Example 10 was repeated using 3.06 g (0.037 mol) of acrolein cyanhydrin and 5. 0 ml (0.069 mol) of CH3CH2SH and carried out at ambient temperature. 5mL (5 mmol) of molar triethylborane was slowly added to the mix. The yield of product obtained was 95% and was identified by'H NMR and mass spectroscopy as 2-hydroxy-4-ethylthiobutyronitrile.

Example 12: Synthesis of 2-acetoxy-4-methylthiobutyronitrile : CH35fCH2), CH (CN) OC (O) CH3 The procedure of Example 10 was repeated using 2.0 ml (0.02 mol) of 2- acetoxy-but-3-ene nitrile and 1.6 g (0.028 mol) of CH3SH and carried out at ambient temperature. 4.0 ml (4 mmol) of molar triethylborane was slowly added to the mix. The yield of product obtained was 97% and was identified by'H NMR and mass spectroscopy as 2-acetoxy-4-methylthiobutyronitrile.

Example 13: Synthesis of 2-acetoxy-4-ethylthiobutyronitirle : CH3CH7S (CH217CH (CN) OC (O ! CH3 The procedure of Example 11 was repeated using 2.0 ml (0.02 mol) of 2- acetoxy-but-3-ene nitrile and 2.0 ml (0.028 mol) of CH3CH2SH and carried out at ambient temperature. 4.0 ml (4 mmol) of molar triethylborane was slowly added to the mix. The yield of product obtained was 94% and was identified by'H NMR and mass spectroscopy as 2-acetoxy-4-ethylthiobutyronitrile.

Example 14: Synthesis of 2- (1-ethoxvethoxy)-4-meththiobutyronitrile : CH3S(CH2)2CH(CN)OCH(CH3)OCH2CH3 The procedure of Example 10 was repeated using 3.2 g (0.02 mol) of 2- (1- ethoxyethoxy)-but-3-ene nitrile and 2.0 ml (0.036 mol) of CH3SH and carried out at ambient temperature. 2.0 ml (2 mmol) of molar triethylborane was slowly added to the mix. The yield of product obtained was 72% and was identified by 'H NMR and mass spectroscopy as 2-(1-ethoxyethoxy)-4-methylothiobutyronitrile.

Example 15: Synthesis of 2-methoxvmethoxy-4-methylthiobutvronitrile : CH3S (CH2) 2CH (CN) OCH70CH3 The procedure of Example 10 was repeated using 0.2 g (1.6 mmol) of 2- (methoxyethoxy)-but-3-ene nitrile and 0.2 ml (3.6 mmol) of CH3SH and carried out at ambient temperature. 0.25 ml (0.25 mmol) of molar triethylborane was slowly added to the mix. The yield of product obtained was 95% and was identified by'H NMR and mass spectroscopy as 2-methoxymethoxy-4- methylthiobutyronitrile.

Example 16: Synthesis of 4-methylthiobutane-1. 2-diol : CH3S (CH2), CH (OH) CH., OH 2.0 g (0.024 mol) of but-3-ene-1, 2-diol and 1.5 ml (0.024 mol) of CH3SH were placed in a closed stirred tank reactor. The mixture was cooled to minus 10°C and stirred for 5 minutes. The vessel was then warmed to ambient temperature. 0.5 ml (0.5 mmol) of molar triethylborane was slowly added. The gas formed was eliminated and the resulting mixture was washed with 20 ml of water and then extracted with ether (3 x 40 ml). The ether phased dried with

sodium sulphate, followed by filtration and evaporation. The product obtained gave a 96% yield and was identified by'H NMR and mass spectroscopy as 4- methylthiobutane-1,2-diol.

Example 17: Synthesis of acid 2-hvdroxv-4-methylthiobutanoic acid: CH3S (CH2), CH (OH) CO H The procedure of Example 10 was repeated using 6.5 g (0.065 mol) of acid 2-hydroxy-but-3-enol and 4 ml (0.072 mol) of CH3SH and carried out at ambient temperature. 5 ml (5 mmol) of molar triethylborane was slowly added to the mix.

The yield of product obtained was 85% and was identified by'H NMR and mass spectroscopy as acid 2-hydroxy-4-methylthiobutanoic acid.