Method for preparing aryl sulfones

Abstract

A method of synthesising a compound comprises reacting an aryl sulfonyl halide with a reactive solvent in the presence of a Cu(I) catalyst in a first mixture to obtain a reaction product. The aryl sulfonyl halide has a structure of (102) where R1, R2, R3, R4 and R5 are each independently selected from: H, a halogen, a hydroxy group, an alkyl group, a hydroxyalkyl group, a haloalkyl group, an alkoxy group; an acyl group, an amino group, an alkylamino group; and an acylamido group; and X is a halide. The reactive solvent has a melting point of less than or equal to 115 °C as measured at 1 atm. The reactive solvent has a structure of (104) where: RA is H or a substituent; RB is selected from a nitrile group, a carboxylic acid group, a carboxylic acid ester group, and a carboxylic acid amide group, an aldehyde group, and a ketone group; with the proviso that when RB is a nitrile group or an alkyl ester of a carboxylic acid, RA is not H or a methyl group. The reaction product has a structure of (106).

Description

[0001] Method for preparing aryl sulfones

[0002] Technical Field

[0003] The present invention relates to a method for preparing aryl sulfones.

[0004] Background

[0005] Aryl sulfones, in particular aryl vinyl sulfones, have various industrial uses. For example, 3-(a ryl sulfonyl)-propene nitriles may be used as biocides in industrial processes as disclosed in WO 2019 / 042984 Al and WO 2019 / 042985 Al.

[0006] A number of methods exist for preparing aryl vinyl sulfones. Many of these methods employ solvents that are environmentally harmful, volatile, flammable and / or scarcely available, such as acetonitrile. Furthermore, the existing processes comprise a number of steps which increase the complexity of the processes. There are also only limited possibilities for recycling any of the chemicals used in existing processes.

[0007] An early example of such a process is described by Asscher and Vofsi in J. Chem. Soc. 1964, 4962-4971. This describes the addition of sulfonyl chlorides to vinylic monomers and other olefins. Exemplified are reactions of sulfonyl chlorides with olefins using cupric chloridebased catalyst complexes with triethylammonium chloride. Following an addition reaction with the olefin there is a base catalysed dehydrohalogenation.

[0008] WO 2020 / 094917 Al describes a process for the preparation of aryl sulfonyl propene nitriles. This process also proceeds by an addition reaction in which a sulphonyl halide is reacted with acrylonitrile and a catalyst, followed by a base catalysed elimination so as to form the desired product. According to this disclosure a catalyst complex is prepared immediately before addition to the reaction mixture by the complexation of an inorganic halide with a salt of an organic compound. Exemplified is the preparation of a cuprous iodide-based catalyst complex with triethylamine hydrochloride in acetonitrile. Tosyl chloride is then reacted with acrylonitrile in the presence of this catalyst complex. These processes suffer from some of the above disadvantages. It is therefore an aim of the present invention to provide an improved method for preparing aryl sulfones which minimizes or overcomes at least some of the disadvantages that arise in the existing processes.

[0009] Summary

[0010] The present invention provides a method of synthesising a compound. The method comprises reacting an aryl sulfonyl halide with a reactive solvent in the presence of a Cu(l) catalyst in a first mixture to obtain a reaction product.

[0011] The aryl sulfonyl halide has a structure of: where:

[0012] R1, R2, R3, R4and R5are each independently selected from: H, a halogen, a hydroxy group, an alkyl group, a hydroxyalkyl group, a haloalkyl group, an alkoxy group; an acyl group, an amino group, an alkylamino group; and an acylamido group; and

[0013] X is a halide. The reactive solvent has a melting point of less than or equal to 115 °C as measured at 1 atm.

[0014] The reactive solvent has a structure of: where: RAis H or a substituent;

[0015] RBis selected from a nitrile group, a carboxylic acid group, a carboxylic acid ester group, and a carboxylic acid amide group, an aldehyde group, and a ketone group; with the proviso that when RBis a nitrile group or an alkyl ester of a carboxylic acid, RAis not H or a methyl group.

[0016] The reaction product has a structure of:

[0017] This Summary is provided to introduce a selection of concepts in a simplified form that are further described below in the Detailed Description. This Summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used to limit the scope of the claimed subject matter. Nor is the claimed subject matter limited to implementations that solve any or all of the disadvantages noted herein. Brief Description of the Drawings

[0018] To assist understanding of embodiments of the present disclosure and to show how such embodiments may be put into effect, reference is made, by way of example only, to the accompanying drawings in which:

[0019] Fig. 1 is an example reaction scheme for synthesising an aryl vinyl sulfone; and Fig. 2 is a flow diagram outlining an example method of synthesising an aryl vinyl sulfone.

[0020] Detailed Description

[0021] The verb 'to comprise' is used herein as shorthand for 'to include or to consist of'. In other words, although the verb 'to comprise' is intended to be an open term, the replacement of this term with the closed term 'to consist of' is explicitly contemplated, particularly where used in connection with chemical compositions.

[0022] The term "about" where used in connection with a numeral contemplates a variance of ± 10 %.

[0023] All melting and boiling points are measured at standard atmospheric pressure (1 atm; 101,325 Pa) unless otherwise specified.

[0024] Provided herein is a method of synthesising a compound. The method will be described in detail with reference to Figs. 1 and 2. Fig. 1 is an example reaction scheme, and Fig. 2 is a flow diagram outlining an example implementation of the method.

[0025] The method comprises, at block 201, reacting an aryl sulfonyl halide 102 with a reactive solvent 104 in the presence of a Cu(l) catalyst in a first mixture, to obtain a reaction product The aryl sulfonyl halide has a structure of:

[0026] 102 where:

[0027] R1, R2, R3, R4and R5are each independently selected from: H, a halogen, a hydroxy group, an alkyl group, a hydroxyalkyl group, a haloalkyl group, an alkoxy group; an acyl group, an amino group, an alkylamino group; and an acylamido group; and

[0028] X is a halide.

[0029] In examples where one or more of R1, R2, R3, R4and R5represents a group selected from an alkyl group, a hydroxyalkyl group, a haloalkyl group, an alkoxy group; an acyl group, an amino group, an alkylamino group; and an acylamido group, the number of carbon atoms in the group is not particularly limited provided that the aryl sulfonyl halide is soluble in the reactive solvent. Typically, the number of carbon atoms in the group is less than or equal to 4. Alkylamino and acylamido groups may have up to 10 carbon atoms. Optionally, the number of carbon atoms in each R1, R2, R3, R4and R5group is less than or equal to 1 or 2.

[0030] Optionally, R1, R2, R3, R4and R5may each be independently selected from H, a Cl to C4 alkyl group, or a Cl to C4 alkoxy group. For example, R1, R2, R3, R4and R5may each be independently selected from H, a methyl group, an ethyl group, a propyl group, a butyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a n-butoxy group, or a tertiary butoxy group. Optionally, one or more of R1, R2, R3, R4and R5may represent an acyl group having 1 to 4 carbon atoms. As used herein, the term acyl group encompasses in particular to aldehydes, ketones, esters, and amides.

[0031] Optionally, R1, R2, R3, R4and R5may each be independently selected from: H; a halogen, such as chlorine, fluoride or bromide; a hydroxy group; a Cl to C4 hydroxyalkyl group, optionally a Cl or C2 hydroxyalkyl group; a Cl to C4 haloalkyl (e.g., fluoroalkyl) group, optionally a Cl or C2 haloalkyl group, such as a trifluoromethyl group; an amino group; an alkylamino group having 1 to 10 carbon atoms; or an acylamido group having 1 to 10 carbon atoms.

[0032] Optionally, at least two of R1, R2, R3, R4and R5are H.

[0033] For example, R1, R2, R4, and R5may each be H and R3may be a methyl group.

[0034] More specific examples of useful aryl sulfonyl halides include: benzene sulfonyl halide; an alkyl substituted benzene sulfonyl halide, such as a toluene sulfonyl halide (e.g., toluene sulfonyl chloride or toluene sulfonyl bromide) or a xylene sulfonyl halide; a halo-substituted benzene sulfonyl halide, such as 4-chlorobenzene sulfonyl halide; an alkoxy-substituted benzene sulfonyl halide, such as 4-methoxybenzene sulfonyl halide.

[0035] In particular, the aryl sulfonyl halide may be a 4-toluene sulfonyl halide, optionally 4-toluene sulfonyl chloride or4-toluene sulfonyl bromide, further optionally 4-toluene sulfonyl chloride.

[0036] The reactive solvent has a melting point of less than or equal to 115 °C as measured at 1 atm. The reactive solvent has a structure of:

[0037] 104 where:

[0038] RAis H or a substituent; and

[0039] RBis selected from a nitrile group, a carboxylic acid group, a carboxylic acid ester group, and a carboxylic acid amide group, an aldehyde group, and a ketone group; with the proviso that when RBis a nitrile group or an alkyl ester of a carboxylic acid, RAis not H or a methyl group. In other words, the reactive solvent is not (meth)acrylonitrile or alkyl (meth)acrylate.

[0040] The nature of RAis not particularly limited and may be selected as appropriate, provided that the reactive solvent has a melting point of less than or equal to 115 °C. For example, RAmay be selected from H; an alkyl group, optionally a Cl to C5 alkyl group; and an alkoxycarbonyl group. In particular, RAmay be an alkoxycarbonyl group.

[0041] RBis optionally selected from a nitrile group, a carboxylic acid group, a carboxylic acid ester group, a carboxylic acid amide group.

[0042] RBmay be a nitrile group. In such implementations, the reactive solvent may be ethacrylonitrile.

[0043] Alternatively, RBmay be a carboxylic acid ester group.

[0044] In accordance with another possibility, RBmay be a carboxylic acid group. Examples of carboxylic acids useful as reactive solvents include acrylic acid, methacrylic acid, ethacrylic acid, and 3-methyl-2-methylenebutanoic acid.

[0045] The reaction of the aryl sulfonyl halide 102 with the reactive solvent 104 produces a reaction product having a structure of: with R1, R2, R3, R4, R5, RA, RBand X being determined by the selection of the aryl sulfonyl halide 102 and reactive solvent 104.

[0046] Typically, the first mixture is free of ligands for the Cu(l) catalyst other than the aryl sulfonyl halide; the reactive solvent; and a counterion for the Cu(l) catalyst, such as a halide counterion.

[0047] The first mixture may be free of sulfonates.

[0048] The first mixture may be free of amines. In implementations where the aryl sulfonyl halide includes an amine group, the first mixture may be free of any other amines.

[0049] The first mixture may be free of solvents other than the reactive solvent. In such implementations, no other solvents than the reactive solvent are added to the first mixture.

[0050] Optionally, the first mixture consists of the aryl sulfonyl halide, the reactive solvent, a Cu(l) salt, products of the method, and optional Cu(ll). Products of the method comprise the products of the reaction between the aryl sulfonyl halide and the reactive solvent, and any side-reactions. It has surprisingly been found that avoiding the presence of any species that might form a complex with the Cu(l) catalyst, with the exception of the reactive solvent and a counterion such as a halide, improves the method. Higher yields may be obtainable. It may be made possible to operate the method at a lower temperature. The reactant compositions are simplified avoiding the need for any pre-treatment steps to produce a catalyst complex, which was hitherto thought to be essential in the method. The simplification of the method may also allow reactant and catalyst materials to be readily recycled.

[0051] In implementations where no ligand is present other than the arylsulfonyl halide, the reactive solvent, and an optional halide counterion, the Cu(l) catalyst may be described herein as "uncomplexed". Without wishing to be bound by theory, it is believed that in the first mixture as described herein the Cu(l) catalyst may be uncomplexed and may comprise a monovalent copper ion, optionally in the presence of a counterion, to which ion is attached no ligands.

[0052] The Cu(l) catalyst may be a Cu(l) halide catalyst, for example with an iodide, bromide or chloride counterion. A preferred catalyst is a Cu(l) chloride catalyst. The Cu(l) halide is typically added to the first mixture as a solid.

[0053] The Cu(l) catalyst is dissolved in the reactive solvent, whereby the first mixture in solution form is obtained. The reactive solvent functions both as a reactant and a solvent in the method.

[0054] The Cu ( I ) catalyst may be present in the first mixture in an amount of 5 to 30 mol%, optionally 10 to 25 mol%, further optionally 15 to 20 mol% based on the amount of the aryl sulfonyl halide present in the first mixture.

[0055] The first mixture may further comprise Cu(ll) ions. For example, Cu(ll) may be present in an amount of 0.5 to 5 mol%, based on the total amount of copper present in the first mixture. Cu(ll) may inhibit undesired polymerization of the reactive solvent. The reactive solvent is optionally added in excess, which may ensure the dissolution of the other components of the first mixture. It has been found that the reactive solvent is able to dissolve the Cu(l) catalyst effectively, even at room temperature. No heating for forming the first mixture is thus required. Providing an excess of reactive solvent may facilitate the desired reaction, and may improve the conversion and / or yield of the process.

[0056] For example, the aryl sulfonyl halide may be present in the first mixture in an amount of 0.3 to 0.7 equivalents, optionally 0.3 to 0.7 equivalents, further optionally 0.4 to 0.6 equivalents or about 0.5 equivalents relative to the amount of reactive solvent.

[0057] The aryl sulphonyl halide may be added to the first mixture as one single dose, or as a plurality of successive doses, such as two, three or more successive doses. A continuous addition may also be possible. Optionally, the aryl sulphonyl halide is added to the first mixture as a single dose.

[0058] The reaction between the aryl sulfonyl halide and the reactive solvent may be performed in an inert gas atmosphere, optionally under nitrogen or argon.

[0059] The first mixture may be prepared at room temperature. The first mixture may be heated during the reaction. The reaction between the aryl sulfonyl halide and the reactive solvent may be performed at a temperature in the range 80 to 95 °C, optionally 85 to 92 °C, further optionally 85 to 87 °C. Performing the reaction at elevated temperature may increase yield and / or restrict the formation of side-products.

[0060] In implementations where the reaction product 106 is the desired final product, the method may terminate after block 201.

[0061] In implementations where an excess of reactive solvent 104 is used, the method may proceed to block 202, in which unreacted reactive solvent is separated from the first mixture to obtain a second mixture. The second mixture comprises the reaction product and the Cu(l) catalyst. The unreacted reactive solvent may be removed using any suitable separation method, such as distillation.

[0062] Following the separation, the unreactive reactive solvent may be recycled, e.g. used in a further instance of the operations of block 201. In this manner it is possible to reuse the unreacted reactive solvent in the preparation of the first mixture and effectively reduce the amount of chemical waste which is produced. Advantageously, little or no purification of the separated reactive solvent is necessary.

[0063] The method may then subsequently proceed to block 203, in which an orthogonal solvent is added to the second mixture, thereby precipitating the Cu(l) catalyst and dissolving the reaction product to obtain a third mixture.

[0064] The operations of block 203 may be performed while the second mixture is still at elevated temperature following the reaction in the first mixture. Once the orthogonal solvent has been added, the resulting third mixture may be allowed to cool.

[0065] As used herein, an "orthogonal solvent" refers to any solvent which is capable of dissolving the reaction product but not the Cu(l) catalyst. Typically, the orthogonal solvent comprises a low polarity solvent having a relative polarity of less than or equal to 0.4, optionally less than or equal to 0.3, further optionally less than or equal to 0.25.

[0066] For purposes of the present context, the relative polarity values given, for example, in Reichardt, C. (ed.) and Welton, T. (ed.), "Solvents and Solvent Effects in Organic Chemistry", 4th Ed., 2011, Wiley-VCH Verlag GmbH & Co., Weinheim, Appendix A, or in other similar handbooks, may be used. The low polarity of the low polarity solvent reduces its ability to mix with water, which may simplify the separation of the reaction product in implementations where the third mixture includes an aqueous phase. The low polarity solvent may be considered hydrophobic. The low polarity solvent may be free of carboxyl or hydroxyl groups.

[0067] Examples of useful low polarity solvents include ethyl acetate, butyl acetate, tetrahydrofuran, dioxane, and toluene. In particular, the low polarity solvent may be ethyl acetate. The precipitated Cu(l) catalyst may be separated from the third mixture, for example by filtration. The catalyst may then be recycled. Typically, purification of the catalyst is not necessary.

[0068] Removal of the catalyst at this stage, before performing any further reactions, may avoid contamination and / or oxidation of the catalyst.

[0069] The method may terminate after block 203. Alternatively, the method may proceed to block 204, in which an elimination of the halide group Xfrom the reaction product 106 is performed to obtain an aryl vinyl sulfone having a structure of:

[0070] The elimination may be performed in the third mixture. The elimination may be a basecatalysed elimination.

[0071] A base may be added to the third mixture for elimination of the halogen atom from the intermediate product to form the aryl vinyl sulfone 108. The reaction product 106 undergoes an elimination reaction in the presence of the base, where the halogen atom is removed from the reaction product 106, i.e. a base-catalysed elimination of the halogen atom, and the aryl vinyl sulfone 108 is obtained. The base used may be an inorganic base, an organic base, or a combination of an inorganic and organic base. Optionally, the base comprises an organic base. The elimination reaction is exothermic, and therefore the base is preferably added, and the elimination reaction is allowed to proceed under cooling. The third mixture may be maintained at a temperature of 15 to 40 °C, optionally 20 to 35 °C, further optionally 20 to 25 °C during the elimination of the halogen atom from the reaction product 106.

[0072] The base may be added to the third mixture in an amount (in mol) of at least 1 equivalent, preferably at least 1.3 equivalent, relative to the amount of the dissolved reaction product 106 in the second mixture.

[0073] The base added to the third mixture may comprise an inorganic base, optionally selected from bicarbonates and carbonates of alkali metals and carbonates of alkaline earth metals or any mixtures thereof. For example, the inorganic base may be selected from sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, lithium bicarbonate, lithium carbonate, caesium carbonate, calcium carbonate, magnesium carbonate, or any mixture thereof. Optionally sodium bicarbonate or sodium carbonate is used as inorganic base.

[0074] Optionally, the base added to the third mixture comprises an organic base. The organic base may be selected from trialkylamines, such as triethylamine, trimethylamine; N-methylmorpholine; N-methylpyrrolidine; N,N-diisopropylethylamine (Hunig's base);

[0075] 1.4-diazabicyclo[2.2.2]octane (DABCO); l,8-diazabicyclo[5.4.0]undec-7-ene (DBU); or

[0076] 1.5-diazabicyclo[4.3.0]non-5-ene (DBN), or any mixtures thereof, for example, the organic base may comprise triethylamine.

[0077] The base may comprise a combination of an inorganic base and an organic base.

[0078] The third mixture may additionally include water.

[0079] Water may be introduced into the third mixture before addition of base. The elimination reaction proceeds when the base is added to the third mixture. Alternatively, water may be added to the third mixture together with or after the addition of base. In such implementations, the base is optionally a combination of an inorganic base and an organic base, as defined above. The base may comprise 0.8 to 0.95 equivalent, optionally 0.9 to 0.95 equivalent of an inorganic base; and 0.05 to 0.2 equivalent, optionally 0.05 to 0.1 equivalent of an organic base, given as molar equivalents. The inorganic and organic base may be added to the third mixture separately and simultaneously, or separately and successively. Optionally, the inorganic base is added first, followed by addition of the organic base.

[0080] The amount of water in the third mixture may be 15 to 200 weight-%, preferably 40 to 150 weight-%, more preferably 55 to 100 weight-%, calculated from the amount of the base in the third mixture. Efficient stirring of the third mixture during the elimination reaction prevents the phase separation between the water and the low polarity solvent. When both an organic base and an inorganic base are used, the water content of the third mixture enables a phase transfer process involving the organic base and inorganic base that improves the efficiency of the base-catalysed elimination reaction.

[0081] After the elimination reaction is complete, the aryl vinyl sulfone 108 may be separated from the third mixture. The third mixture may contains immiscible aqueous and organic phases which allow the unwanted aqueous phase to be readily separated. The organic phase contains a precipitate of the aryl vinyl sulfone 108 which may be easily separated from the organic solvent phase, e.g. by filtration. The filtrate may be washed using an acid such as dilute HCI. The product may be recrystallized from an alcohol such as a Cl to C3 alcohol, preferably isopropyl alcohol. This is followed by filtration and evaporation of solvent. Recrystallisation typically recovers the E-isomer at a purity of at least 99.5 %.

[0082] Reference Example 1

[0083] The present invention may be more fully understood in light of the following Reference Example.

[0084] All chemicals and reagents used in this example were reagent grade purity unless indicated otherwise. Preparation of intermediate product

[0085] At room temperature 2.74 g, Cu(l) chloride, 34 g p-toluene sulfonyl chloride and 20 g acrylonitrile were mixed together in a reactor. The mixture was heated to a temperature in the range 85 to 87° C. This temperature was maintained for 16 hours while stirring the mixture. Excess acrylonitrile was removed by vacuum distillation at a temperature in the range 72 to 92° C. 50 g ethyl acetate was added to the remaining mixture, which was then stirred and allowed to cool. Greenish-grey-white catalyst particles were thereby precipitated. The remaining mixture contained the intermediate product.

[0086] Catalyst removal

[0087] The catalyst precipitate was removed once the mixture reached approximately 45° C. This may be recycled after two washes in 5 g ethyl acetate followed by drying and storage under nitrogen.

[0088] Elimination reaction

[0089] After catalyst removal the reaction mixture was cooled to room temperature. 25 g water was added, followed by 18.2 g triethylamine. The temperature was maintained below 25° C. Two solvent layers formed. The aqueous layer was removed. The organic layer contained a yellowish white precipitate of p-toluene sulfonyl propenenitrile product. This was separated by filtration and washed twice with dilute HCI.

[0090] Recrystallisation

[0091] The product following the washing steps contained residual solvent which was allowed to evaporate. 30 g isopropyl alcohol was added to the solid product, which was stirred well to ensure full dissolution. The solution was left at refrigeration temperature of 6° C overnight to allow the formation of crystals. The crystals were filtered and washed with chilled isopropyl alcohol followed by drying at 45° C under nitrogen. A yield of 73 % was obtained.

[0092] Analysis of the product showed E-3-[(4-methylphenyl)sulfonyl]-2-propenenitrile.

[0093] Example 2

[0094] Illustrative examples of reactive solvents useful in the methods provided herein are listed in the table below: n.t.: not tested.

[0095] Clauses

[0096] The present disclosure provides the following Clauses:

[0097] Clause 1. A method of synthesising a compound, which method comprises reacting an aryl sulfonyl halide with a reactive solvent in the presence of a Cu(l) catalyst in a first mixture to obtain a reaction product, wherein the aryl sulfonyl halide has a structure of: wherein:

[0098] R1, R2, R3, R4and R5are each independently selected from: H, a halogen, a hydroxy group, an alkyl group, a hydroxyalkyl group, a haloalkyl group, an alkoxy group; an acyl group, an amino group, an alkylamino group; and an acylamido group; and X is a halide; wherein the reactive solvent has a melting point of less than or equal to 115 °C as measured at 1 atm; wherein the reactive solvent has a structure of: wherein:

[0099] RAis H or a substituent;

[0100] RBis selected from a nitrile group, a carboxylic acid group, a carboxylic acid ester group, and a carboxylic acid amide group, an aldehyde group, and a ketone group; with the proviso that: when RBis a nitrile group or an alkyl ester of a carboxylic acid, RAis not H or a methyl group; and wherein the reaction product has a structure of:

[0101] Clause 2. The method according to Clause 1, wherein the first mixture is free of ligands for the Cu ( I ) catalyst other than the aryl sulfonyl halide, the reactive solvent, a counterion, and products of the method.

[0102] Clause 3. The method according to Clause 1 or Clause 2, wherein the first mixture is free of sulfonates.

[0103] Clause 4. The method according to any preceding Clause, wherein the first mixture is free of amines other than the aryl sulfonyl halide.

[0104] Clause 5. The method according to any preceding Clause, wherein the first mixture is free of solvents other than the reactive solvent.

[0105] Clause 6. The method according to Clause 1, wherein the first mixture consists of the aryl sulfonyl halide, the reactive solvent, a Cu( I ) salt, products of the method, and optionally Cu(ll).

[0106] Clause 7. The method according to any preceding Clause, wherein R1, R2, R3, R4and R5are each independently selected from: H; a halogen; a hydroxy group; a Cl to C4 alkyl group, optionally a Cl or C2 alkyl group; a Cl to C4 hydroxyalkyl group, optionally a Cl or C2 hydroxyalkyl group; a Cl to C4 haloalkyl group, optionally a Cl or C2 haloalkyl group; a Cl to C4 alkoxy group, optionally a Cl or C2 alkoxy group; a Cl to C4 acyl group, optionally a Cl or C2 acyl group; an amino group; a Cl to CIO alkylamino group, optionally a Cl to C4 alkylamino group or a Cl or C2 alkylamino group; and a Cl to CIO acylamido group, optionally a Cl to C4 acylamido group further optionally a Cl or C2 acylamido group.

[0107] Clause 8. The method according to Clause 7, wherein R1, R2, R3, R4and R5are each independently selected from: H, a methyl group, an ethyl group, a propyl group, a butyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a n-butoxy group, a tertiary butoxy group, and a trifluoromethyl group.

[0108] Clause 9. The method according to any preceding Clause, wherein at least two of R1, R2, R3, R4and R5are H.

[0109] Clause 10. The method according to Clause 8, wherein R1, R2, R4, and R5are each H.

[0110] Clause 11. The method according to any preceding Clause, wherein R3is a methyl group.

[0111] Clause 12. The method according to any preceding Clause, wherein the aryl sulfonyl halide is selected from: benzene sulfonyl halide; an alkyl substituted benzene sulfonyl halide, such as a toluene sulfonyl halide or a xylene sulfonyl halide; a halo-substituted benzene sulfonyl halide, such as 4-chlorobenzene sulfonyl halide; an alkoxy-substituted benzene sulfonyl halide, such as 4-methoxybenzene sulfonyl halide. Clause 13. The method according to Clause 12, wherein the aryl sulfonyl halide is a 4-toluene sulfonyl halide, optionally 4-toluene sulfonyl chloride or4-toluene sulfonyl bromide, further optionally 4-toluene sulfonyl chloride.

[0112] Clause 14. The method according to any preceding Clause, wherein RAis selected from H; an alkyl group, optionally a Cl to C5 alkyl group, further optionally a C2 to C5 alkyl group; and an alkoxycarbonyl group, optionally a C2 to C5 alkoxycarbonyl group; optionally wherein RAis an alkoxycarbonyl group.

[0113] Clause 15. The method according to any preceding Clause, wherein RBis selected from a nitrile group, a carboxylic acid group, a carboxylic acid ester group, a carboxylic acid amide group.

[0114] Clause 16. The method according to Clause 15, wherein RBis a nitrile group.

[0115] Clause 17. The method according to Clause 16, wherein the reactive solvent is ethacrylonitrile.

[0116] Clause 18. The method according to Clause 15, wherein RBi a carboxylic acid ester group.

[0117] Clause 19. The method according to Clause 15, wherein RBi a carboxylic acid group.

[0118] Clause 20. The method according to Clause 19, wherein the reactive solvent is selected from: acrylic acid, methacrylic acid, ethacrylic acid, and 3-methyl-2- methylenebutanoic acid.

[0119] Clause 21. The method according to any preceding Clause, wherein the aryl sulfonyl halide is present in the first mixture in an amount of 0.3 to 0.7 equivalents, optionally 0.3 to 0.7 equivalents, further optionally 0.4 to 0.6 equivalents or about 0.5 equivalents relative to the amount of reactive solvent. Clause 22. The method according to any preceding Clause, wherein the reaction between the aryl sulfonyl halide and the reactive solvent is performed in an inert gas atmosphere, optionally under nitrogen or argon.

[0120] Clause 23. The method according to any preceding Clause, wherein the reaction between the aryl sulfonyl halide and the reactive solvent is performed at a temperature in the range 80 to 95 °C, optionally 85 to 92 °C, further optionally 85 to 87 °C.

[0121] Clause 24. The method according to any preceding Clause, wherein the Cu(l) catalyst is present in the first mixture in an amount of 5 to 30 mol%, optionally 10 to 25 mol%, further optionally 15 to 20 mol% based on the amount of the aryl sulfonyl halide present in the first mixture.

[0122] Clause 25. The method according to any preceding Clause, wherein the Cu(l) catalyst is copper (I) chloride.

[0123] Clause 26. The method according to any preceding Clause, wherein the first mixture further comprises Cu(ll) ions.

[0124] Clause 27. The method according to any preceding Clause, wherein the first mixture includes an excess of the reactive solvent, and wherein the method further comprises: separating unreacted reactive solvent from the first mixture to obtain a second mixture; and subsequently adding an orthogonal solvent to the second mixture, thereby precipitating the Cu(l) catalyst and dissolving the reaction product to obtain a third mixture. Clause 28. The method according to Clause 27, further comprising recycling the unreacted reactive solvent, optionally further comprising distilling the unreacted reactive solvent.

[0125] Clause 29. The method according to Clause 27 or Clause 28, further comprising separating the precipitated Cu(l) catalyst from the third mixture.

[0126] Clause 30. The method according to Clause 29, further comprising recycling the precipitated Cu(l) catalyst, optionally without purification.

[0127] Clause 31. The method according to any of Clauses 27 to 30, wherein the orthogonal solvent is a low polarity solvent having a relative polarity of less than or equal to 0.4, optionally less than or equal to 0.3, further optionally less than or equal to 0.25.

[0128] Clause 32. The method according to Clause 31, wherein the orthogonal solvent is selected from ethyl acetate, butyl acetate, tetrahydrofuran, dioxane, and toluene.

[0129] Clause 33. The method according to any of Clauses 27 to 32, wherein the third mixture further comprises water.

[0130] Clause 34. The method according to Clause 33, wherein the third mixture further comprises a base, and wherein the water is present in the third mixture in an amount of 15 to 200 wt%, optionally 40 to 150 wt%, further optionally 55 to 100 wt% based on the weight of the base. Clause 35. The method according to any preceding claim, further comprising eliminating halide group X from the reaction product to obtain an arylvinylsulfone of formula:

[0131] Clause 36. The method according to Clause 35, further comprising isolating the arylvinylsulfone.

[0132] Clause 37. The method according to Clause 36 further comprising, after isolating the arylvinylsulfone, recrystallizing the arylvinylsulfone from an alcoholic solvent.

[0133] Clause 38. The method according to any of Clauses 35 to 37, wherein the halide group X is eliminated by base-catalysed elimination.

[0134] Clause 39. The method according to Clause 38, wherein the base catalysed elimination comprises adding at least 1 mole equivalent, optionally at least 1.3 mole equivalents, of base relative to the amount of the intermediate product in the third mixture.

[0135] Clause 40. The method according to Clause 38 or Clause 39, wherein the base comprises an inorganic base. Clause 41. The method according to Clause 40, wherein the inorganic base comprises one or more of: a carbonate of an alkali metal; a bicarbonate of an alkali metal; and a carbonate of an alkaline earth metal.

[0136] Clause 42. The method according to any of Clauses 38 to 41, wherein the base comprises an organic base.

[0137] Clause 43. The method according to Clause 42, wherein the organic base comprises one or more of: a trialkylamine, such as trimethylamine, triethylamine, or N,N-diisopropylethylamine; N-methylmorpholine; N-methylpyrrolidone;

[0138] 1.4-diazobicyclo[2.2.2]octane; l,8-diazabicyclo[5.4.0]undec-7-ene; and

[0139] 1.5-diazabicyclo[4.3.0]non-5-ene.

[0140] Clause 44. The method according to any of Clauses 38 to 43, wherein the base comprises a mixture of an organic base and an inorganic base.

[0141] Clause 45. The method according to Clause 44, wherein the base comprises 80 to 95 mol%, optionally 90 to 95 mol%, of the inorganic base, with the balance being the organic base.

[0142] Clause 46. The method according to any of Clauses 38 to 45, wherein the basecatalysed elimination is performed at a temperature in the range 15 to 40 °C, optionally 20 to 35 °C, further optionally 20 to 25 °C.

[0143] It will be appreciated that the above embodiments have been described by way of example only.

[0144] Other variants or use cases of the disclosed techniques may become apparent to the person skilled in the art once given the disclosure herein. The scope of the disclosure is not limited by the described embodiments but only by the accompanying claims.

Claims

25Claims1. A method of synthesising a compound, which method comprises reacting an aryl sulfonyl halide with a reactive solvent in the presence of a Cu(l) catalyst in a first mixture to obtain a reaction product, wherein the aryl sulfonyl halide has a structure of:wherein:R1, R2, R3, R4and R5are each independently selected from: H, a halogen, a hydroxy group, an alkyl group, a hydroxyalkyl group, a haloalkyl group, an alkoxy group; an acyl group, an amino group, an alkylamino group; and an acylamido group; andX is a halide; wherein the reactive solvent has a melting point of less than or equal to 115 °C as measured at 1 atm; wherein the reactive solvent has a structure of:wherein:RAis H or a substituent;RBis selected from a nitrile group, a carboxylic acid group, a carboxylic acid ester group, and a carboxylic acid amide group, an aldehyde group, and a ketone group;with the proviso that: when RBis a nitrile group or an alkyl ester of a carboxylic acid, RAis not H or a methyl group; and wherein the reaction product has a structure of:

2. The method according to claim 1, wherein the first mixture is free of ligands for the Cu(l) catalyst other than the aryl sulfonyl halide, the reactive solvent, a counterion, and products of the method.

3. The method according to claim 1 or claim 2, wherein the first mixture is free of solvents other than the reactive solvent.

4. The method according to claim 1, wherein the first mixture consists of the aryl sulfonyl halide, the reactive solvent, a Cu(l) salt, products of the method, and optionally Cu(ll).

5. The method according to any preceding claim, wherein R1, R2, R3, R4and R5are each independently selected from: H; a halogen; a hydroxy group; a Cl to C4 alkyl group, optionally a Cl or C2 alkyl group; a Cl to C4 hydroxyalkyl group, optionally a Cl or C2 hydroxyalkyl group; a Cl to C4 haloalkyl group, optionally a Cl or C2 haloalkyl group; a Cl to C4 alkoxy group, optionally a Cl or C2 alkoxy group; a Cl to C4 acyl group, optionally a Cl or C2 acyl group; an amino group; a Cl to CIO alkylamino group, optionally a Cl to C4 alkylamino group or a Cl orC2 alkylamino group; and a Cl to CIO acylamido group, optionally a Cl to C4 acylamido group further optionally a Cl or C2 acylamido group; optionally wherein R1, R2, R3, R4and R5are each independently selected from: H, a methyl group, an ethyl group, a propyl group, a butyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a n-butoxy group, a tertiary butoxy group, and a trifluoromethyl group.

6. The method according to any preceding claim, wherein at least two of R1, R2, R3, R4and R5are H; optionally wherein R1, R2, R4, and R5are each H.

7. The method according to any preceding claim, wherein the aryl sulfonyl halide is selected from: benzene sulfonyl halide; an alkyl substituted benzene sulfonyl halide, such as a toluene sulfonyl halide or a xylene sulfonyl halide; a halo-substituted benzene sulfonyl halide, such as 4-chlorobenzene sulfonyl halide; an alkoxy-substituted benzene sulfonyl halide, such as 4-methoxybenzene sulfonyl halide.

8. The method according to any preceding claim, wherein RAis selected from H; an alkyl group, optionally a Cl to C5 alkyl group, further optionally a C2 to C5 alkyl group; and an alkoxycarbonyl group, optionally a C2 to C5 alkoxycarbonyl group; optionally wherein RAis an alkoxycarbonyl group.

9. The method according to any preceding claim, wherein RBis selected from a nitrile group, a carboxylic acid group, a carboxylic acid ester group, a carboxylic acid amide group.

10. The method according to claim 9, wherein the reactive solvent is selected from: ethacrylonitrile, acrylic acid, methacrylic acid, ethacrylic acid, and 3-methyl-2- methylenebutanoic acid.

11. The method according to any preceding claim, wherein the reaction between the aryl sulfonyl halide and the reactive solvent is performed at a temperature in the range 80 to 95 °C, optionally 85 to 92 °C, further optionally 85 to 87 °C.

12. The method according to any preceding claim, wherein the first mixture further comprises Cu(ll) ions.

13. The method according to any preceding claim, wherein the first mixture includes an excess of the reactive solvent, and wherein the method further comprises: separating unreacted reactive solvent from the first mixture to obtain a second mixture; and subsequently adding an orthogonal solvent to the second mixture, thereby precipitating the Cu(l) catalyst and dissolving the reaction product to obtain a third mixture.

14. The method according to claim 13, wherein the orthogonal solvent is a low polarity solvent having a relative polarity of less than or equal to 0.4, optionally wherein the orthogonal solvent is selected from ethyl acetate, butyl acetate, tetrahydrofuran, dioxane, and toluene.

15. The method according to any preceding claim, further comprising eliminating halide group X from the reaction product to obtain an arylvinylsulfone of formula:

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