Process for the removal and return of a catalyst to a liquid phase medium

Abstract

A process for the selective removal of a component from a liquid phase and subsequently returning the component to a liquid phase is disclosed. A novel compound of formula (I) [SUP]-[[L]-[G]]a (I) in which L is a linking group, G is an aryl group having a leaving group LG selected from Cl, Br, I, sulfonate such as triflate, a diazo group, a nitrile, an ester and an alkoxy group and substituent Q is selected from H, NR2, OR, CO2R, F, Cl, NO2 CN and SUP is a support having a plurality of groups -[L]-[G] bound to the support is contacted with the liquid phase to bind the component to the compound I thereby forming a captured component which is separated from and may be returned to the liquid phase. The compound I is especially useful in binding homogeneous catalysts to remove it from a reaction medium and selectively returning the catalyst to the reaction medium at a later stage. The compound is particularly useful for cross-coupling reactions, for example in Suzuki reactions.

Claims

1. A process for the selective removal of a soluble catalyst component from a reaction medium and subsequently returning the soluble catalyst component to a reaction medium comprising contacting a compound of formula I below with a first reaction medium to bind the soluble catalyst component to the Compound I thereby forming a bound component, separating the bound component and the first reaction medium, subsequently returning the bound catalyst component to a second reaction medium in which the bound component undergoes a reaction whereby the soluble catalyst component is released from Compound I wherein the Compound I is of formula:
[SUP]-[[L]-[G]].sub.n(I) wherein: L is a group linking G to SUP- of formula: (CH.sub.2).sub.h[S(O).sub.d].sub.m(CHD).sub.nZ.sub.m((CH.sub.2).sub.nY(CH.sub.2).sub.n).sub.m where D is selected from H, CN, OH, C(O)OR, C(O)NR.sub.2, C(O)OG, CONRG and Y is selected from O, NR, S(O).sub.d, CO, CO.sub.2, NRCOZ.sub.m, Z.sub.mCONR, CN, a heterocyclic ring where Z is independently O, S, NR; and wherein d is independently 0 to 2, h is from 0 to 15, m is independently 0 or 1 and n is independently 0 to 4 and R is independently selected from H or a C.sub.1-12 alkyl group and a phenyl group; or L is not present and G is linked directly to SUP; G is selected from an alkyl group, an aryl group, a heterocyclic group and a heteroaryl group wherein the group G has a. a leaving group LG selected from Cl, Br, I and a pseudohalide; and b. substituent Q selected from H, NR.sub.2, N.sup.+R.sub.3, N(R)CO.sub.2H, NCR.sub.2, OR, O.sup.+(R)SiR.sub.3, CO.sub.2R, CO.sub.2.sup., CONR.sub.2, NRC(O)R, F, Cl, NO.sub.2, CN and a ring formed between group Q and a part of group L; SUP is a support having a plurality n of groups -[L]-[G] bound to the support.

2. A process according to claim 1 wherein the support SUP is selected from a polymer, silica and alumina.

3. A process according to claim 1 wherein the Compound I is an organopolysiloxane wherein the support SUP comprises silica and group G is an optionally substituted haloaryl, haloheteroaryl or haloalkyl group.

4. The process according to claim 1, wherein h is from 0 to 4 and G is selected from an alkyl group, an aryl group and a heteroaryl group.

5. A process for the selective removal of a catalyst component from a reaction medium and subsequently returning the catalyst component to a reaction medium comprising contacting a compound of formula IA below with the reaction medium to bind the catalyst component to the Compound IA thereby forming a bound component, separating the bound component and the reaction medium, subsequently returning the bound component to a reaction medium and treating the bound component so as to release the catalyst component from Compound IA wherein the Compound IA is of formula:
[SUP]-[G].sub.n(IA) wherein G is linked directly to SUP; G is selected from an alkyl group, an aryl group, a heterocyclic group and a heteroaryl group wherein the group G has i) a leaving group LG selected from Cl, Br, I and a pseudohalide; and ii) substituent Q selected from H, NR.sub.2, N.sup.+R.sub.3, N(R)CO.sub.2H, NCR.sub.2, OR, O.sup.+(R)SiR.sub.3, CO.sub.2R, CO.sub.2.sup., CONR.sub.2 NRC(O)R, F, Cl, NO.sub.2 and CN; SUP is a support having a plurality n of groups -[G] bound to the support.

Description

EXAMPLE 1

Production of 4-Bromophenyl amidoethyl sulfide ethyl silica

(1) ##STR00006##

(2) Cysteamine hydrochloride (193.10 g, 1.7 mol) was stirred and heated to 120 C. When the material had become molten, vinyl trimethoxysilane (229.95 g, 1.55 mol) and tert-butyl peroxide (2.0 mL, 10.89 mmol) was added over 30 min. The heterogeneous mixture was heated at 120-130 C. for a further hour, before a second addition of tert-butyl peroxide (2.0 mL, 10.9 mmol). The reaction mixture was stirred for 2 hours at this temperature whereupon the solution had become homogeneous. The solution was then cooled to room temperature to provide a crude product.

(3) A mixture of this crude product above, silica (1.00 kg, 70-230 mesh) and toluene (2.5 L) was heated at reflux for 4 h. After cooling, the reaction mixture was filtered and washed with toluene, methanol and water before being dried on the sinter funnel until mobile. A mixture of the semi-dried material and water (2 L) was stirred and a pH probe was carefully immersed in the solution. Sodium hydroxide solution (853 mL, 1.5 M) was added over 10 minutes. The solution pH was monitored during the addition and requires an end-point of pH 8.8-9.2. The mixture is stirred for a further 20 minutes then filtered, washed with water and methanol and dried in a vacuum oven. The structure was verified by NMR techniques.

(4) A mixture of 4-bromobenzoic acid (1.2 g, 6 mmol, 1.05 eq. based on functional group (FG) loading and DMF (15 mL) was stirred for 5 min at room temperature to afford a colourless solution. Diisopropylamine (1.05 eq. based on FG loading) followed by O-(Benzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (1.6 g, 6 mmol, 1.05 eq. based on FG loading) are added at 5 min intervals with continual stirring. After a further 5 min, the product from above (5.0 g) is added and stirring continued for 1 h, whereupon the reaction mixture is filtered and washed with methanol, 1 M aqueous Na.sub.2CO.sub.3, water and methanol and dried. The structure was verified by NMR techniques.

EXAMPLE 2A

Production of 4-Bromophenyl amidopropyl silica

(5) ##STR00007##

(6) Silica (50 g, 70-200 micron, 60 ), 3-aminopropyl trimethoxysilane (11.2 g, 62.5 mmol) and toluene (140 mL) were heated at reflux for 4 h. The reaction was then allowed to cool and was filtered. The solid was washed with methanol and dried in a vacuum oven.

(7) 4-Bromobenzoic acid (1.21 g, 6 mmol) and DMF (15 mL) were stirred for 5 minutes at room temperature to afford a colourless solution. Diisopropylamine (1.58 g, 6 mmol) followed by O-(Benzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (2.28 g, 6 mmol) were added at 5 min intervals with continual stirring. After a further 5 min 3-aminopropyl functionalised silica (from above) (5.00 g, 1.25 mmol/g functional group loading) is added and stirring continued for 1 h whereupon the reaction mixture is filtered and the silica washed with methanol, water, 1 M aqueous Na.sub.2CO.sub.3, water and methanol and dried in a vacuum oven. The structure was verified by NMR techniques.

EXAMPLE 2B

Production of 4-Bromophenyl amidopropyl silica

(8) ##STR00008##

(9) A solution of benzoic acid (2.11 g, 10.5 mmol) and DMF (25 mL) was stirred at room temperature for 5 min. Triethylamine (2.00 g, 20.0 mmol) was added and the stirring continued at room temperature, after 5 min HBTU (3.98 g, 10.5 mmol) was added, followed 5 min later by aminopropyl trimethoxysilane (1.79 g, 10.0 mmol). The reaction mixture was shaken at room temperature for a further 1 h.

(10) A mixture of the crude product above, silica (10.00 g, 70-230 mesh) and toluene (50 mL) was heated at reflux for 4 h. After cooling, the reaction mixture was filtered and washed with toluene and methanol before being dried. The structure was verified by NMR techniques.

EXAMPLE 3

Production of Bromophenyl silica

(11) ##STR00009##

(12) A mixture of bromophenyltrimethoxysilane (1.00 g, 3.6 mmol), silica (5.00 g, 70-230) and toluene (20 mL) was heated at reflux for 4 h. After cooling, the reaction mixture was filtered and washed with toluene and before being dried. The structure was verified by NMR techniques.

EXAMPLE 4

Production of 4-Bromophenyl sulfide ethyl Silica

(13) ##STR00010##

(14) A mixture of trimethoxyvinylsilane (1.48 g, 10.0 mmol), 4-bromothiophenol (2.27 g, 12.0 mmol), AlBN (0.08 g) and toluene (10 mL) was heated to 50 C. The temperature was maintained for 6 h, with AlBN (0.08 g) being added hourly and further 4-bromothiophenol (1.14 g, 6.0 mmol) being added after 3 h.

(15) A mixture of the crude product above, silica (10.00 g, 70-230 mesh) and toluene (50 mL) was heated at reflux for 4 h. After cooling, the reaction mixture was filtered and washed with toluene and methanol before being dried. The structure was verified by NMR techniques.

EXAMPLE 5

Production of 3-Bromobenzyl succinimido sulfide ethyl silica

(16) ##STR00011##

(17) Mercaptosuccinic acid (99.87 g, 0.67 mol) was heated until an internal pot temperature of 80 C. is reached, then a solution of vinyl trimethoxysilane (81.34 g, 0.59 mol) and di tert butyl peroxide (1.74 mL, 9.5 mmol) was added dropwise. The mixture was heated for a further 2 hours, reaching a temperature of 105 C. A further addition of di tert butyl peroxide (1.74 mL, 9.5 mmol) was made and the mixture refluxed for a further hour. Once satisfied (by proton NMR sample analysis) that the reaction was complete, methanol (120 mL) was added and the material cooled to room temperature.

(18) Silica (0.38 kg, 70-200 m, 60 ) toluene (1.0 L) and material from Step 1 (0.59 mol) were heated at reflux for 4 h. The reaction was then allowed to cool and the solid material was washed with methanol, sodium hydroxide, water and methanol and then dried on the sinter funnel until mobile.

(19) 3-Bromobenzylamine hydrochloride (8.90 g, 40 mmol), aqueous sodium carbonate solution (50 mL, 1 M) and toluene (50 mL) were stirred and heated to approx. 100 C. for 1 h (or until all solid has dissolved) whereupon the mixture was allowed to cool and the phases separated. The organic phase was then added to a mixture of succinic acid ethyl sulphide silica (29 g, 1.4 mmol/g loading), methane sulfonic acid (0.19 g, 2 mmol) and toluene (50 mL). The resultant mixture was heated at reflux under Dean-Stark conditions for 4 h before being allowed to cool. The solid was filtered and washed with toluene and methanol and dried in a vacuum oven. The structure was verified by NMR techniques.

EXAMPLE 6

Production of 2-Bromophenyl sulfide ethyl Silica

(20) ##STR00012##

(21) A mixture of trimethoxyvinylsilane (1.48 g, 10.0 mmol), 2-bromothiophenol (2.27 g, 12.0 mmol), AlBN (0.08 g) and toluene (10 mL) was heated to 50 C. The temperature was maintained for 6 h, with AlBN (0.08 g) being added hourly and further 2-bromothiophenol (1.14 g, 6.0 mmol) being added after 3 h.

(22) A mixture of the resulting crude product above, silica (10.00 g, 70-230 mesh) and toluene (50 mL) was heated at reflux for 4 h. After cooling, the reaction mixture was filtered and washed with toluene and methanol before being dried. The structure was verified by NMR techniques.

EXAMPLE 7

Production of 3-Bromophenyl sulfide ethyl Silica

(23) ##STR00013##

(24) A mixture of trimethoxyvinylsilane (1.48 g, 10.0 mmol), 3-bromothiophenol (2.27 g, 12.0 mmol), AlBN (0.08 g) and toluene (10 mL) was heated to 50 C. The temperature was maintained for 6 h, with AlBN (0.08 g) being added hourly and further 3-bromothiophenol (1.14 g, 6.0 mmol) being added after 3 h.

(25) A mixture of the resulting crude product above, silica (10.00 g, 70-230 mesh) and toluene (50 mL) was heated at reflux for 4 h. After cooling, the reaction mixture was filtered and washed with toluene and methanol before being dried. The structure was verified by NMR techniques.

EXAMPLE 8

Production of 4-Chlorophenyl sulfide ethyl Silica

(26) ##STR00014##

(27) A mixture of trimethoxyvinylsilane (1.48 g, 10.0 mmol), 4-chlorothiophenol (2.17 g, 15.0 mmol), AlBN (0.08 g) and toluene (10 mL) was heated to 50 C. The temperature was maintained for 6 h, with AlBN (0.08 g) being added hourly and further 4-chlorothiophenol (1.00 g, 7.0 mmol) being added after 3 h.

(28) A mixture of the resulting crude product above, silica (10.00 g, 70-230 mesh) and toluene (50 mL) was heated at reflux for 4 h. After cooling, the reaction mixture was filtered and washed with toluene and methanol before being dried. The structure was verified by NMR techniques.

EXAMPLE 9

Production of 4-Bromophenyl sulfoxide ethyl Silica

(29) ##STR00015##

(30) A mixture of the product from Example 4 (1.00 g) and DCM (14 mL) was cooled in an ice-bath and mCPBA (1.0 eq. based on FG loading) was added with stirring. The mixture was allowed to warm to room temperature over 2 h before being filtered and washed with toluene and methanol and then dried. The structure was verified by NMR techniques.

EXAMPLE 10

Production of 4-Bromophenyl sulfone ethyl Silica

(31) ##STR00016##

(32) A mixture of the product from Example 4 (5.00 g) and DCM (14 mL) was cooled in an ice-bath and mCPBA (4.0 eq. based on FG loading) was added with stirring. The mixture was allowed to warm to room temperature over 2 h before being filtered and washed with toluene and methanol and then dried. The structure was verified by NMR techniques.

EXAMPLE 11

Production of N-(4-Bromophenyl)-N-methyl aminopropyl Silica

(33) ##STR00017##

(34) A mixture of chloropropyl trimethoxysilane (1.99 g, 10.0 mmol), 4-bromo-N-methyl aniline (4.65 g, 25.0 mmol), sodium bromide (1.13 g, 11.0 mmol) and DMF (10 mL) was heated to 100 C. and stirred at that temperature for 17.5 h.

(35) A mixture of the resulting crude product above, silica (10.00 g, 70-230 mesh) and toluene (50 mL) was heated at reflux for 4 h. After cooling, the reaction mixture was filtered and washed with toluene and methanol before being dried. The structure was verified by NMR techniques.

EXAMPLE 12

Production of 4-Bromobenzoate propyl Silica

(36) ##STR00018##

(37) A mixture of 4-bromobenzoic acid (4.02 g, 20.0 mmol), cesium carbonate (3.26 g, 10.0 mmol) and DMF (10 mL) was heated to 50 C. for and stirred for 30 min. Sodium bromide (1.23 g, 12.0 mmol), chloropropyltrimethoxysilane (1.99 g, 10.0 mmol) and DMF (10 mL) were then added and the resultant mixture heated at 80 C. for 16 h.

(38) A mixture of the resulting crude product above, silica (10.00 g, 70-230 mesh) and toluene (50 mL) was heated at reflux for 4 h. After cooling, the reaction mixture was filtered and washed with water and methanol before being dried. The structure was verified by NMR techniques.

EXAMPLE 13

Production of 4-Bromophenyl ethyl Silica

(39) ##STR00019##

(40) A mixture of trimethoxy(2-phenylethyl)silane (0.50 g, 2.2 mmol) and DCM (5 mL) was cooled in an ice bath and bromine (1.40 g, 8.8 mmol) was added dropwise. The resultant mixture was stirred and allowed to warm to room temperature over 1 h before being diluted with DCM (5 mL) and partitioned with aqueous Na.sub.2S.sub.2O.sub.7 solution (10 mL, 1 M). The organic phase was separated and washed with water (10 mL) and brine (20 mL), toluene (10 mL) was then added and the DCM removed in vacuo.

(41) A mixture of the resulting crude product above, silica (10.00 g, 70-230 mesh) and toluene (50 mL) was heated at reflux for 4 h. After cooling, the reaction mixture was filtered and washed with toluene and methanol before being dried. The structure was verified by NMR techniques.

EXAMPLE 14

Production of 4-Bromophenoxy propyl functionalised Silica

(42) ##STR00020##

(43) A mixture of chloropropyl trimethoxysilane (1.99 g, 10.0 mmol), sodium iodide (1.80 g, 12.0 mmol) and DMF (10 mL) was heated to 50 C. for 1.5 h. 4-Bromophenol (5.19 g, 30.0 mmol), potassium carbonate (2.07 g, 15.0 mmol) and DMF (10 mL) were then added and the resultant mixture heated at 80 C. for 22.5 h.

(44) A mixture of the resulting crude product above, silica (10.00 g, 70-230 mesh) and toluene (50 mL) was heated at reflux for 4 h. After cooling, the reaction mixture was filtered and washed with water and methanol before being dried. The structure was verified by NMR techniques.

EXAMPLE 15

Production of 4-Bromophenyl sulfide ethyl; propyl functionalised Silica

(45) ##STR00021##

(46) A mixture of the product from Example 4, trimethoxypropyl silane (1.0 mmol/g silica input) and toluene (3.5 mL/g silica, or minimum 50 mL) was heated at reflux for 4 h. After cooling, the reaction mixture was filtered and washed with toluene and methanol before being dried. The structure was verified by NMR techniques.

EXAMPLE 16

Production of Bromophthalimido propyl functionalised Silica

(47) ##STR00022##

(48) A mixture of chloropropyl trimethoxysilane (1.99 g, 10.0 mmol), phthalimide (3.68 g, 25.0 mmol), caesium carbonate (3.58 g, 11.0 mmol), sodium bromide (1.13 g, 11.0 mmol) and DMF (10 mL) was stirred and heated to 55 C. for 16 h.

(49) A mixture of the resulting crude product from above, silica (10.00 g, 70-230 mesh) and toluene (50 mL) was heated at reflux for 4 h. After cooling, the reaction mixture was filtered and washed with water and methanol before being dried. The structure was verified by NMR techniques.

(50) A mixture of the product from above (6.00 g) and DCM (30 mL) was cooled to 0 C. and bromine (1.0 eq. based on FG loading) added dropwise. The reaction mixture was allowed to warm to room temperature over 4 h before being filtered and washed with DCM, water and methanol before being dried. The structure was verified by NMR techniques.

EXAMPLE 17

Phenyl 4-trifluoromethanesulfonate sulfide propyl functionalised Silica

(51) ##STR00023##

(52) A mixture of chloropropyl trimethoxysilane (3.62 g, 18.0 mmol), thiophenol (5.75 g, 46.0 mmol), sodium bromide (2.06 g, 20.0 mmol), potassium carbonate (3.78 g, 27.0 mmol) and DMF (18 mL) was stirred and heated to 100 C. for 18 h.

(53) A mixture of the resulting crude product from above, silica (22.00 g, 70-230 mesh) and toluene (80 mL) was heated at reflux for 4 h. After cooling, the reaction mixture was filtered and washed with water and methanol before being dried. The structure was verified by NMR techniques.

(54) A mixture of the product from above (8.00 g), 4-nitrophenyl trifluoromethanesulfonate (1.0 eq. based on FG loading), potassium carbonate (1.0 eq. based on FG loading) and DMF (25 mL) was stirred at room temperature for 4 h before being filtered and washed with water and methanol before being dried. The structure was verified by NMR techniques.

EXAMPLE 18

Preparation of Supported Palladium Catalyst

(55) A sample of Palladium (bis(di-tert-butylphosphin)ferrocene)dichloride (1 mmol) was dispensed to a reaction tube. Phenyl boronic acid (3 mmol) and potassium carbonate (3 mmol) were added. The supported Aryl Br produced in Example 3 was added (5 mmol). Acetonitrile (20 rel volumes) and water (5 rel volumes) were added to the reaction mixture. The reaction was stirred and heated to 60 C. The reaction was analysed by GCMS after 1 h showing complete consumption of phenylboronic acid. The supported Aryl Br contained the colour and the solvent was a very light yellow colour. The catalyst is coloured and the colour comes out of solution onto the supported aryl bromide. Upon washing the support, catalyst is released and the support is usable in a new reaction.

EXAMPLE 19

Removal of Palladium from a Suzuki Reaction

(56) A sample of Palladium (bis(di-tert-butylphosphin)ferrocene)dichloride (0.05 mmol) was dispensed to a reaction tube. 4-Bromobenzonitrile (1 mmol), phenyl boronic acid (1.1 mmol) and potassium carbonate (1.1 mmol) were added. Acetonitrile (5 rel volumes) and water (5 rel volumes) were added to the reaction mixture. The reaction was stirred and heated to 60 C. The reaction was analysed by GCMS after 18 h showing complete consumption of 4-bromobenzonitrile. The supported Aryl Br produced in Example 3 was added (0.5 mmol) and the mixture stirred at 60 C. overnight. The supported Aryl Br contained the colour and the solvent was a very light yellow colour.

EXAMPLE 20

Use of Supported Palladium Catalyst for Suzuki Reaction

(57) 4-Bromobenzonitrile (1 mmol), phenyl boronic acid (1.1 mmol) and potassium carbonate (1.1 mmol) were added to a reaction tube. Acetonitrile (5 rel volumes) and water (5 rel volumes) were added to the reaction mixture. The supported aryl bromide produced in Example 18 with attached Pd ligand organometallic species was added to the reaction. The reaction was stirred and heated to 60 C. The reaction was analysed by GCMS after 18 h showing complete consumption of 4-bromobenzonitrile. The supported Aryl Br was added (0.5 mmol) and the mixture stirred at 60 C. overnight. The supported Aryl Br contained the colour and the solvent was a very light yellow colour, the catalyst being coloured. The support may be washed to release the catalyst and then reused as desired.