Title of Invention

"A METHOD OF MANUFACTURING BIDENTATE PHOSPHINE LIGAND BY METALLATION"

Abstract

A mehod of manufacturing a compound of gecinral fmmula ~ in which mit Ii is id~pendcndy a pendwt. optionally aubuitiated. uu~gank gtoup through which the group is linliod to tinniajy e~rbon atom C; Lt, L2 am independently a group selected from auoptiartally substiroted lower ulkylena chain connecting the reapectivin phouphonis atoni to the group X and X is a ~vidging group camposing an oplionaily subsiibatcd sty) moiety to which the phospltonis atmus am Unkcd cut aveilable adjacent caiboti atone., compnsea~ I) reacting tognihor a compound of formula with an organanietnUin coiupo~nd to form an in nerodiare compotrod of fonnula M.-LLX-L 44, where M is an ulkaM mewi atom; ii) reacting said intannediato camp~nd with a enmpatmd of formula whem A is a halogen acorn, to farm said compound of genera] taunula is preferably lithium, pomuslum or sodium and the intermediate conipowid may be isointed or not. flie rencriort (i) ni,Y ndvazua~aoualy tut eanslad our in the presence of a complexing agent atich as ietoethysthylencdiamtne.

Full Text

PROCESS FOR THE PREPARATION OF BISPHOSPHINES The present invention relates to a phosphine compound which is useful as a component of a catalyst system which may be used In the carbonylation of olefins, and in particular to a method of manufacturing such phosphine compounds. WO 96/19434 discloses a process for the carbonylation of ethylene and a catalyst system for use therein. The catalyst system described in that document comprises a bidentate phosphine of general formula (R3-C)2P-L1-X-L2-P-(C-R3)2, in which each R is independently a pendant, optionally substituted, organic group through which the group is tinted to tertiary carbon atom C; L1,L2 are independently a linking group selected from an optionally substituted lower alkylene chain connecting the respective phosphorus atom to the group X and X is a bridging group comprising an optionally substituted aryi moiety to which the phosphorus atoms are linked on available adjacent carbon atoms. One example of such a bidentate phosphine is bis (di-'butyi phosphino)-o-xylene (also known as 1.2,bis(di-t-butylphosphinomethy!)benzenB). Such catalysts may be made by mixing the phosphine ligand with a suitable source of palladium such as palladium acetate. WO 98/19434 describes the preparation of one form of the ligand via the phoaphonium salt produced from the reaction of the appropriate secondary phosphine with the corresponding aromatic dihalide. In the preferred form of the phosphine ligand in WO 96/19434, R is a lower alky) group, in particular methyl. A problem with manufacturing this ligand by the route described is that the secondary phosphine which is used (e.g. dl-'butyl phosphine) is toxic, highly reactive, smally and flammable. We have also found that the reaction is low yielding and converts some of the di-t>utyl phosphine to a non-redaimable waste product which must be disposed of. Al-Salem et at in Journal of the Chemical Society (Dalian) 1979 page 1950 describes making 1,5 bis(di-t-butylphosphino)pentane by reacting lithium metal with 1,5-dibromopentane and then phosphorylating the resulting lithiated intermediate with t-butylchloraphosphine. This method, for forming a phosphine of an alkyl compound, starts from the haiogenated alkyl compound. Alkyl halidea typically require considerable care during storage and use and may be very unpleasant to use. Therefore using this method of making the phosphine using the non-haloganated alkyl compound 83 a starting material would require an extra step of converting first to the alkyf haiide. particularly lower alky!, e.g. C1 to C4, substituted, lower alkylene, e.g. C, to C4 chain. Especially preferred is when both L1 and L3 are methytene. The bridging group X is an aryl moiety, e.g. a phenyl group, which may be optionally substituted, provided that the two phosphorus atoms are linked to adjacent carbon atoms, e.g. at the 1 and 2 positions on the phenyl group. Optional substitution of the aryl moiety may be by other organic groups, e.g. alky), particularly C1-6 aryl, alkoxy, carbalkoxy, halo, nrtro, trihalomethyl and cyano. Furthermore, the aryl moiety may be a fused polycyclic group, e.g. naphthalene, blphenyfene or indene. Examples of compounds which may advantageously ba made by the method according to the invention are bis (di-tert-butyl phosphino) - o - xylene (also known as 1,2 bis (di-tert-butylphosphinomethyl) benzene), bis (di-t-neopentyl phosphino} - o - xylane and bis 1,2 (di-tert-butyl phosphino) naphthalene. The reaction of a compound of formula H-L1-X-L2-H with a basic organometallic compound of formula RmM to form an intermddlate compound of formula M-L1-X-L2-M, where M is an alkali metal atom, may be carried out by various means which are known in the art of organometallic chemistry. For example such retaliation methods are described by Wilkinson et al in 'Comprehensive Organometallic Chemistry" at page 54; and by Lambert at at in "Preparative Polar Organornetallic Chemistry". The organometallic compound may comprise a compound of formula Rm-M, where Rm is an organic group which tends to withdraw electrons from the metal atom M. Suitable organic groups include aromatic or aliphatic groups, especially alkyl groups, which may be substituted. Lower alkyl groups have been found to be particularly suitable, for example preferred Rm compounds include n-butyl, t-butyi, seobutyl, methyl or pentyl. M may be any suitable alkali metal which forms a polar organometallic group with Rffl. Suitable metals include those of Group IA, e.g. sodium, potassium or lithium. When M comprises K or Na the R"-M metallating agent is preferably generated In situ by an exchange mechanism, e.g. by the reaction between Rm-Li and potassium or sodium t-butoxide as described by Lochman et al in Tetrahedron Letters No. 2 pages 257 - 262 (1966). Preferred retaliating compounds are butyl lithium, butyl sodium and butyl potassium, the tatter compounds preferably being formed in situ by the reaction of butyl lithium with potassium or sodium t-butoxide. Alternative organometalllc compounds are also known in the art and may comprise Me3SiCH,K, alkali amides MNIH2 preferably used in liquid ammonia, lithium dialkylamides a.g,. lithium diisoprapylamide (IDA), lithium, sodium or potassium metals, metal hydrides e.g. KH in the presence of co-ordinating compounds. The reaction between FTM and H-L1-X-L2-H may be carried out in the presence of a solvent. Any solvent used must not contain any component which reacts with the intermediate compound, and suitable such solvents will be well known to the skilled chemist. Favoured solvents include dry aUcyl ethers e.g. diethyl ether, methyl t-butyl ether, dl(n-propyl) ether, tetrahydrafuran (THF). and hydrocarbons such as hexane and heptane. The reaction between FTM and H-L1-X-L2-H may be beneficially carried out in the presence of a basic compound which is capable of forming a complex with the metal. A preferred complexing agent is tstramethylethylenediamine (TMEDA). The presence of TMEDA Is greatly preferred when the metallating agent is alkyl lithium or alkyi sodium. When alkyl potassium (or alkyl lithium/ potassium t-butoxitie mixture) is used, we have found that the reaction proceeds satisfactorily in the absence of TMEDA. The mole ratios of metallating agent :H-L1-X-L2-H are preferably in the range 1:1 to 10:1, more preferably at least 1.5:1. The preferred ratio depends upon the nature of the metallating agent used, for example when aikyl fithium is used a ratio of R-Li: H-L1-X-L2-H of 3:1 may be preferred. Higher ratios may be preferred to encourage the formation of di-substituted product rather than mono-substituted compounds. A preferred ratio of FTM : complexing agent is in the range 1:1 - 4:1, especially preferred is a ratio of about 1:1 to about 2:1. It is preferred to conduct the metallation reaction between RmM and H-L1-X-L2-H at a temperature in the range -20 to 150 °C, more preferably at room temperature or above. The optimum temperature and reaction time depends upon the identity of the reactants, in particular upon the alkali metal which is used. For example we have found, using o-xylene as the compound to be matallated that when alkyl lithium is used, the reaction proceeds well at room temperature (i.e. about 20-22 °C) whereas reactions using alkyl sodium and potassium are preferably conducted at about 60, (e.g. 50 - 70 °C) and about 80 oC (e.g. 70 - 90 9C) respectively. The intermediate compound. M-L1-X-L2-M may be isolated from the reaction mixture prior to conducting the reaction between M-L1-X-L2-M and the compound of formula (R,-C),P-A. However isolation of the intermediate may not be necessary and the reaction has been found to proceed very satisfactorily when the intermediate is not isolated. When the intermediate product M-L1-X-L2-M can be separated relatively easily, for example if it is in a different physical form from the starting materials, then it may be advantageous to isolate the intermediate form the reaction mixture to encourage the formation of more intermediate. We have found that the reaction mixture may contain partially reacted compounds of formula M-L1-X-L2-H which may be reacted to completion by the addition of further quantities of RmM and complexing agent If used. The phosphorylatlon reaction between the intermediate product M-L1-X-L2-M and the halophosphine (R3-C)2P-A is also carried out in the presence of a solvent and similar solvents to those used for the installation are suitable, e.g. ethers, C5+ alkanes and petroleum ethers. We have found that, when the metal used is potassium, the reaction is favoured when dlethyi ether is used as a solvent for the phosphorylation reaction, although an alkane e.g. heptane, may be preferred for the Retaliation reaction. Also, even when sodium or lithium is used as the metal species, it may be beneficial to use a different solvent for the phosphorylation from that used for the metallation, e.g. to enable higher temperatures to be used in one reaction yet allow an easy separation of the solvent from the product of the second reaction. The phosphorylation reaction may be conducted at elevated temperatures, e.g. at temperatures of 60°C or greater, but it is preferred to conduct the reaction at room temperature or below, e.g. at -20 to 25 "C. The compound of general formula (R3-C)2P-L1-X-L2-P-(C-R3)2 may be isolated from the reaction mixture by distilling off the excess solvent, preferably under vacuum and then extracting the product compound into a solvent, e.g. methanol, from which it may be precipitated. The invention will be further described, by way of example only, below, in all reactions, the reactants and apparatus used were prepared to allow the reaction to proceed in anhydrous and anaerobic reaction conditions. N,N,N,'rN'-Tetramethylethylenediam!ne (0.79cm1, 5.25 mmol) was added to a stirred solution of n-butyllithium (2. locm3, 2.5Min hexane, 5.25 mmol) in heptane (15cm3) under an atmosphere of nitrogen. After five minutes, ortho-xylene (0.26cm3, 2-10mmol) was added slowly. A orange-brawn precipitate formed after leaving the solution stirring at room temperature for 96 hours. Di-tert-butytahlorophosphine (1.40cma, 7.37 mmol) was added, then at room temperature the solution was left to stir until the colour disappeared. A sample of the reaction mixture was analysed by 31P{1H} NMR and the conversion to bis (di-tert-butyl phosphino)-o-xylene and to the mono-substituted analogue, was determined. The results are shown in Table 1 . Example 2-8 The experimental procedure of Example 1 was repeated but varying the reactsnt ratios and reaction conditions as shown in Table 1. The experimental procedure described above was repeated using a ratio of butyllithiunvTMEDA: o-xylene of 4 : 4 : 1 , a temperature of 25°C and a reaction time of 48 hrs, but the product of the reaction between the butyl lithium and o-xylene / TMEDA was filtered to separate the brown solid from the red liquid. Each was then reacted separately with di'butylchlorophosphina and the conversion to bis (di-te/f-butyl phosphtno) - o - xylene and to the mono-substituted analogue, was determined. The results are shown in Table 2. n-Butyliithium (1 1 mmol) was added dropwtee to a well-stirred solution of o-xylene (0,8 ml. 5 mmol) and potassium fe/t-butoxide (1.2g 11 mmol) in heptane (25 mi). The reactions were stirred (and sometimes heated) for a predetermined length of time (see Table 3). The system was cooled by placing it in an ica bath and di-tert-butylchlorophosphine (1.87 ml, 11 mmol) was then slowly added to the flask. The system was allowed to stir until all of the colour had disappeared. Oiethyt ether (50 cm3) was added to the flask to ensure that all of the phosphines produced were dissolved. A sample of the resulting solution was collected in a sealed NMR tube and analysed by "P {'H} NMR. Table 1 (Table Removed) Table 3 (Table Removed) Table 3 (Table Removed) O-xylene (3.3 cm3, 270 x 10-2mol) was added by syringe to a suspension of potassium t-butoxide (6.6 g, 5,88 x 10-2mol) in 40/60 petroleum ether (150 cm3). 42 cm3 of a 1.4 M solution of butyl lithium in hexane was added to the ether mixture, with cooling. The 8 mixture was stirred overnight to complete the reaction which resulted in an orange-red solid which was the dipotassio-o-xylane. The mixture was filtered and the solid washed with further petroleum ether. The dipotassio derivative was then suspended in diethyl ether (150 cm3) at -78 °C and di-t-butylchlorophospnine (10 g, 5.54 x 10-2mol) was added by syringe. The mixture was stirred for an hour, brought slowly to room temperature and then filtered. The filtrate was hydrotysed by addition of 1 cm J of degassed water and dried. The yield (based on o-xytene) was 94%. Analysis by 31P (1H) NMR showed that the yield of a,a'bis(dit-butyfphosphino)o-xylene was 80%, whilst that of the monophosphina was 10%. Potassium-tert-butoxide (3.99 g, 35.6 mmol), heptane {150 cm3) and o-xylene (1.47 cm3. 12 mmol) were added to a 500 ml round bottomed flask. To this stirred solution iMJutyllithium (14.45 cm3. 36.1 mmol, 2.5M in hexane) was added slowly and the flask heated to 80 "C for 1 hour. An orange/red precipitate formed which was separated by filtration and washed with pentane (3 x 100cm2) before being resuspended in diethyl ether (100 cm3) which had been pre-cooled to -20°C. To this solution maintained at -20°C was added di-t-butylchlorophosphine (4.56 cm3, 24.1 mmol) and the reaction allowed to warm to room temperature before being stirred overnight The in-eitu reaction yield of α,α 'bis(dit-butylphosphino)o-xylene as determined by 31P NMR was 64%. Example 16 The reaction described in Example 15 was repeated except that the orange-red precipitate of dipotassio-o-xytene was resuspended in 100 cm3 of diethyl ether which had been pre-cooled to 0 °c and the solution was maintained at 0°C while di-t-butylchlorophosphine (4.58 cm3, 24.1 mmol) was added. The reaction was allowed to warm to room temperature before being stirred overnight. The in-situ reaction yield of o,o'bis(di-t-butylphosphino)o-xylene as determined by 3'P NMR was 74.8%. Example 17 The reaction described In Example 15 was repeated except that the orange-red precipitate of dipotassio-o-xyiene was resuspended in 100 cm3 of diethyl ether at room temperature and the solution was maintained at room temperature while di-t-butylchlorophosphine (4.58 cm3, 24.1 mmol) was added. The reaction was stirred overnight. The in-situ reaction yield of a,a'bis(dit-butylphosphlno)o-xylene as determined by 31P NMR was 75.5%. Example18 Sodium-tert-butoxida (17.29 g, 180 mmol), N,N,N',N'-Tetramethylethylenediamine (27.1 cm9, 180 mmol}, heptane (100 cm3) and o-xylene (7.32 cm3, 60 mmol) were added to a 1 litre round bottomed flask. To this stirred solution n-butyllithium (72.0 cm3, 180 mmol, 2.5M in hexane) was added slowly and the flask heated to 60 *C for 2 hours. An orange precipitate formed which was separated by filtration and washed with pentane (100cm3) before being resuspended in pentane (100 cm5). To this was added di-t-butylchlornphosphlne (22.75 cm3, 120 mmol) and the reaction stirred at room temperature overnight. The reaction was quenched by the addition of degassed / delonised water (50 cm') when two dear layers formed and the pentane layer (upper layer) was isolated. The solvent was removed in-vacuo and the product purified by washing with cold methanol (-10C). Yield (20.0g, 84.6%). Claims 1. A method of manufacturing a compound of general formula (R3-C)2P-L1-X-L2-P-(C-R3)2 in which each R is Independently a pendant optionally substituted, organic group through which the group is linked to tertiary carbon atom C; L1. L2 are independently a linking group selected from an optionally substituted lower alkyiene chain connecting the respective phosphorus atom to the group X and X is a bridging group comprising an optionally substituted aryt moiety to which the phosphorus atoms are linked on available adjacent carbon atoms comprising; i) reacting together a compound of formula H-L1-X-L2-H with an organometallic compound to form an intermediate compound of formula M-L1-X-L2-M, where M is an alkali metal atom, ii) reacting said intermediate compound with a compound of formula (R3-C)2P-A, where A is a halogen atom, to form said compound of general formula (R3-C)2P-L1-X-L2-P-(C-R3)2 2. A method as claimed in claim 1, wherein M is a Group IA metal selected from sodium, potassium or lithium. 3. A method as claimed in daim 1 or 2, wherein R™-M is generated in situ by an exchange reaction between Rm-Li and potassium or sodium alkyl oxide. 4. A method as claimed in any of claims 1-3, wherein the reaction between R*M and H-L'-X-L2-H is carried out in the presence of a basic compound which is capable of forming a complex with the metal. 5. A method as claimed in claim 4. Wherein said basic compound comprises tetramethylethylenadiamine. 6. A method as claimed in any preceding daim, wherein said compound of general formula (R3-C)2P-L1-X-L2-P-(C-R3)2 is selected from the group consisting of a,a'bis{di-t-butylphosphino)o-xylene (also known as 1,2 bis (di-t-butylphosphinomethyl) benzene), bis (dl-t-neopentyl phosphino) - o - xylene or bis 1 , 2 (di-t-butyl phosphino) naphthalene. 7. A catalyst suitable for catalysing the carbonylation of ethytene comprising compound of general formula (R3-C)2P-L1-XL2-P-(C-R3)2 prepared by a method as claimed in claim 1, and palladium or a compound thereof. 8. A method of manufacturing a compound substantially as herein described with reference to the foregoing examples. 9. A catalyst suitable for catalysing the carbonylation of ethylene substantially as herein described with reference to the foregoing examples.

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in-pct-2000-151-del-pct-311.pdf

in-pct-2000-151-del-pct-409.pdf

in-pct-2000-151-del-petition-137.pdf

in-pct-2000-151-del-petition-138.pdf