GB2025403A - Improvements in and Relating to the Ullmann Reaction - Google Patents

Abstract

The Ullmann reaction, a substitution reaction of aryl halides, may be carried out at lower temperatures and give improved yields when the catalyst used is a complex of a copper salt with an organic phosphorus, antimony or arsenic compound such as (Ph3P)2. CuCl.

Description

SPECIFICATION Improvements in and Relating to the Ullman Reaction The present invention provides improvements in and relating to the Ullmann reaction. The Ullmann reaction is a substitution reaction of aryl halides which is catalysed by copper. The classic Ullmann reaction involves an alkali metal phenoxide Eg:

The term "Ullmann reaction" is also often used to describe certain analogous substitutions involving, for example, aromatic or aliphatic amines, alkali metal aikoxides or mercaptides and the hydrolysis of aryl halides to phenols.As used herein the term "Ullmann reaction" refers to any copper catalysed reaction according to the general formula:

wherein: Ar is an aryl or substituted aryl group; X is chlorine, bromine, iodine or activated fluorine; Y is O, NH or S; Z is alkali metal, when Y is O or S, and H, when Y is NH; and R is an aryl, substituted aryl, alkyl, substituted alkyl or hydrogen. "Activated Fluorine" means a fluorine atom which has been rendered capable of substitution in an Ullmann reaction by the presence of electronegative substituents, such as, for example, nitro groups, on the aryl nucleus.

The Ullmann reaction is widely used in industry, especially for the synthesis of various substituted diphenyl ethers which are useful as herbicides, insecticides and pharmaceuticals, or as intermediates in the production thereof. For this reason it has been extensively studied in an attempt to overcome some of its disadvantages. The ease with which the Ullmann reaction occurs varies very considerably according to the activity of the reagents. In some instances the condensation will proceed even in the absence of catalyst. In most instances, however, relatively high temperatures of the order of 200 to 3000C and long reaction times, frequently 10 to 20 hours are required in addition to the catalyst, and yields are often poor.

In order to overcome these disadvantages, attempts have been made to replace copper metal with cuprous salts and to activate the catalyst with solvents and/or complexants. Pyridine, for example, is a solvent and complexant for copper salts, and provides a small improvement in the effectiveness of cuprous salts as Ullmann catalysts. However, the preferred solvents are expensive and require careful separation and recovery from the reaction products.

It is believed that the Ullmann reaction proceeds via the formation of an intermediate copper salt of the phenol, or equivalent reagent, e.g.

2 ArONa+Cu2CI2o2 ArOCu+2 NaCI Kawaki and Hashimoto (Bull Chem. Soc. Japan 45 1499) prepared such a copper salt, i.e. phenoxy copper, and showed that it reacted with bromobenzene in the expected manner. They also made complexes of phenoxy copper with various ligands. Typical weak complexants such as pyridine accelerated the formation of diphenyl ether slightly. However, typical strong complexants such as triphenyl phosphine greatly retarded the reaction with bromobenzene. For example three molar proportions of pyridine gave a yield of 46% of Ph2O, compared with 38% obtained from the phenoxy copper in the absence of complexant but three molar proportions of triphenylphosphine reduced the yield to only 8.2%.Since this work was published it has been assumed as a generalisation by those sknled in this art that the presence of weak complexants, such as pyridine, will assist the Ullmann reaction, while the presence of strong complexant, such as triphenyl phosphine, will retard it.

We have now discovered, surprisingly, that a very substantial improvement in the yields obtainable from an Ullmann reaction can be obtained at lower temperatures than are normally employed by using as catalyst particular complexes of copper salts with certain strong complexants such as triphenyl phosphine. The improvements are in many instances very much greater than has hitherto been achieved with weaker complexing agents such as pyridine.

Our invention therefore, provides a method of carrying out the Ullmann reaction as herein defined which comprises using as catalyst a complex of a copper salt with at least one ligand of formula R3Q or (R2Q)2R' wherein each R is an organic substituent, R1 is alkylene or arylene, and Q is phosphorus, arsenic or antimony.

Typically our invention is applicable to substitution of aryl halides ArX wherein the aryl group Ar may be phenyl or substituted phenyl, e.g. where the substituent is one or more alkyl groups as in o-, por m- tolyl, cresyl, isopropyiphenyl, hexylphenyl, nonylphenyl or the like, or one or more of a nitrohydroxy-, carboxy-, alkoxy, aryloxy, amino-, alkylamino-, arylamino-, aldehyde, keto-, cyano-, sulphonate, phosphonate, carboxy, carboxylic ester or amido group. Alternatively the aryl group may comprise a naphthyl, anthracyl or phenanthryl nucleus, optionally substituted by, for example, any of the aforesaid substituents, or an aromatic heterocyclic nucleus such as pyridyl. The halogen X is preferably bromine, but may also be iodine, chlorine, or activated fluorine.Fluoro compounds react much less readily than chloro- or bromo- compounds unless the fluorine atom is activated by the presence of an electronegative substituent group, such as a nitro group on the aromatic nucleus.

The substituting group is preferably an alkali metal phenate of the formula MOAr' wherein M is alkali metal, such as lithium, or preferably sodium or potassium and Ar' is an aryl or substituted aryl group, including any of the aryl substituted groups specified hereinbefore with reference to said group Ar. It is possible for the compound MOAR' and ArX to be the same where the reagent has both a hydroxy and a halogen substitient. Such self condensations may be used to prepare polyphenylene ethers where the substitients are in a para- or meta-relationship, or dimers of the dioxin type when the substituents are in an ortho-relationship.In view of the notoriously hazardous nature of certain products of the latter type it is recommended that great care should be exercised whenever a halogenated phenol is employed as a reagent in accordance with our invention, particularly if there is any possibility of trichlorophenol being present. Apart from self condensations, halogenated phenols may also be reacted according to our invention with other aryl halides, especially where the halogen of the latter is more active than that of the former, e.g. chlorophenol with aryl bromides or with certain nitro-substituted aryl halides.

The substituting group may also be: an alkali metal alkoxide MOR where R is alkyl, cycloalkyl, alkenyl, or any of the foregoing substituted with any of the substituents hereinbefore specified in relation to the group Ar; or an alkyl or aryl mercaptide MSR or MSAr' where M, R and Ar' have the same significance as before; or an aromatic or aliphatic amine RNH2 or Ar'NH2 where R and Ar' have the same significance as before. The substituting group may also be an alkali hydroxide in order to prepare from the aryl halide.

The catalyst for use in our invention may be any of the copper complexes: [CuXL]m, where m=1, 2, 3, or 4 Cu2X2L(biL), [CuX(biL)]n where n=1 or 2, Cu X L(biL), or Cu X (biL)2; wherein: X is a preferably monovalent anion, e.g. a halogen such as fluoride, iodide, bromide or preferably chloride, or else for example a cyanide, nitrate, phenoxide, chlorate, borohydride, azide or thiocyanate;L is a ligand of the formula:

wherein Q is arsenic or antimony or preferably phosphorus and each of the Rs, (which may be the same or, less preferably different) is alkyl, alkoxy, aryl, aryloxy, alkylthio, arylthio, alkylamino or aryl amino group any of which may optionally be substituted with any of the substituent groups referred to hereinbefore in relation to Ar; and (biL) is either two ligands L as defined above or a bidentate ligand having two Q atoms and of formula (R2Q)2Ra wherein R1 is alkylene or arylene e.g. methylene, ethylene, or phenylene, such as R2QCH2CH2QR2 or

where Q and R have the same significance as before.

It is strongly preferred that the catalyst be soluble in the reaction medium. The catalysts described above are generally sufficiently soluble. The copper in the catalyst is preferably present as cuprous copper.

The preferred catalysts are LCuCl and L2CuCl, especially where L is triphenyl phosphine or triphenyl phosphite. The invention has been found to be of particular value where the reaction is not sterically hindered e.g. where Ar and Ar' do not carry bulky substituent groups, and in particular where they are not substituted in the ortho position relative to the reactive site, or only substituted in those positions by single atoms or other compact groups. The advantage of the invention declines as the amount of steric hindering at the reactive site increases. Thus we prefer nonortho-substituted reagents, followed by reactions in which only one of the reagents has only one ortho site substituted, followed by reactions in which both reagents have one ortho site each substituted, or in which only two ortho substituents in total are present on the two reagents. Where ortho substituents are present we prefer single atom substituents such as halo-, and prefer that the substituent is not an organic substituent having more than one carbon atom.

The reaction temperature depends on the activity of the reagents. With the more active reagents, the reaction will proceed at room temperature, but generally it is preferred to employ elevated temperatures, usually above 100 C, preferably above 1500 C, e.g. up to 25O0C, most preferably between 1 600C and 2000C.

The reaction according to our invention will generally proceed satisfactorily in the presence of very low concentrations of copper compared with the amounts conventionally used. Typically we find that concentrations of from 0.1 to 1% of copper are adequate, although it is possible to use very much larger concentrations, e.g. up to or in excess of saturation. Smaller concentrations e.g. down to 0.01% are also operative but many give reduced yields compared with the optimum.

Typically the alkali phenate is prepared in situ by heating the appropriate phenol with an alkali metal hydroxide and distilling off water. The catalyst is then added followed by the aryl halide, which may be added at a controlled rate to maintain the reaction.

The invention is illustrated by the following examples: Example I Meta-phenoxytoluene tPh3P)2. CuCI catalyst Meta-cresol (324 g., 3 moles), sodium hydroxide (40 g., 1 mole), potassium hydroxide (56 g. of purity 86%=0.86 mole) and bromobenzene (52 g.) were stirred together in a one litre flask fitted with a thermometer and a Dean and Stark distillation head for water removal. The mixture was heated over 2 hours to 1850C removing water azeotropically and returning bromobenzene to the flask. The total water removed was 41 ml.

The viscous mixture was allowed to cool to 1 400C and the catalyst, bis(triphenylphosphine)cuprous chloride complex (2 g.) added. The temperature of the mixture rose 40 on adding catalyst and the catalyst appeared to react and dissolve. Bromobenzene (bringing the total added to 314 9.) was added dropwise over a period of 1 hour 40 minutes to the stirred mixture at 160--1800C. After heating for a further 1 5 minutes at 1 8000, G.L.C. analysis indicated reaction to be complete.

The mixture was cooled and water (400 ml.) added to dissolve the inorganic salts. The pH of the mixture was pH 10. This was adjusted to pH 6-7 with hydrochloric acid to minimise loss of cresol.

Fractional distillation of the top organic phase gave three fractions I, recovered bromobenzene; II, recovered meta-cresol and Ill, meta-phenoxy-toluene B.P. 1600C/20 mm. 324 9.=94.5% yield on moles of Na and K cresate used. The product is a colorless liquid.

Example II Meta-phenoxytoluene (Ph3P)2 . CuCI catalyst A slurry of potassium metacresate (from 119 g.=1 .1 moles metacresol, and 1.0 mole of 85% solid potassium hydroxide) in bromobenzene (202 g.=1 .3 moles) was made by stirring the reactants to a pot temperature of 1 6000 whilst removing water azeotropically with the bromobenzene and returning bromobenzene to the reactor.On adding the catalyst (1 g. bis (triphenylphosphine) cuprous chloride) at 1 600C there was an exothermic reaction which raised the temperature of the reactants to 21000 over a period of 20 minutes with no external heating. G.L.C. analysis showed the reaction to be essentially complete and work-up as in Example 1 gave a yield of 1 52 g. metaphenoxytoluene=82.5% on the potassium cresate used.

Catalyst preparation. The catalyst was prepared from triphenylphosphine and cupric chloride in acetone water solvent following the procedure given by Collier, Fox, Hinton and Mann, J. 1964, page 1 823 for the preparation of bis(2-phenyl isophosphindoline) cuprous chloride.

Example ill Meta-phenoxytoluene Ph3P . CuCI catalyst A mixture of meta-cresol (324 g.), sodium hydroxide (40 g.), potassium hydroxide (62 g. of 86% pure) and chlorobenzene (55 g.) was stirred and heated to a pot temperature of 1 8000 as in Example I to form a slurry of Na/K meta-cresates. Triphenylphosphine-cuprous chloride catalyst (5 g.) was added and the mixture stirred and heated at reflux with a pot temperature of 1 800C. Over the course of 3.5 hours as the chlorobenzene underwent reaction the temperature in the pot rose to 19900 and a further 20 g. chlorobenzene was added bringing the temperature back to 1850C. Continuing in this manner a further 2 additions each of 20 g. chlorobenzene was made over 4 hours.After this time reaction appeared to cease and the catalyst had decomposed to a red powdery solid. Working up gave metaphenoxytoluene 84 9.=23% yield.

Example IV Meta-phenoxytoluene (m-CH3CeH4O)3P . CuCI catalyst Catalyst preparation. Cuprous chloride (35 9.=0.2 mole) was added in in small portions to a solution of tris(metacresyl) phosphite (70.4 g.) in bromobenzene (200 g.) at 500 C. The solution became dark blue but with continued stirring the color faded to almost colourless. Unreacted cuprous chloride (17.5 g) was removed by filtration giving an almost colourless filtrate containing the catalyst which remains in solution at ambient temperature.

A mixture of meta-cresol (324 g.), bromobenzene (75 g.) sodium hydroxide (40 g.=1 mole) and potassium hydroxide (62 9.=0.95 mole) was treated as in Example 1 to give a slurry of Na/K metacresate.

The catalyst solution prepared above (7 9.=2 g. (m . CH3C6H4O)3P . CuCI) was added at 1 530C.

There was an exothermic reaction which raised the temperature of the reactants to 1 750C in 6 minutes. Bromobenzene (to a total of 314 g.) was added in small portions over 1.5 hours to 17500.

During the early part of reaction the heat of reaction was sufficient to maintain the reaction temperature. G.L.C. analysis after a further 40 minutes at 17500 showed reaction to be complete.

Working up as described in Example 1 gave meta-phenoxytoluene 327 9.=91 % yield on Na/K cresate having B.P. 900C/1 mm (88-940C range).

Example V Meta-phenoxytoluene (Bu3P . Cu 1)4 catalyst Catalyst Preparation. Prepared as per F. C. Mann J. (1936)1506.

Tributylphosphine and cuprous iodide complex (2 g.) was added to a siurry of sodium and potassium meta-cresate and bromobenzene prepared as in Example IV at 1 600 C. The heat of reaction was sufficient to maintain the temperature at 1 6000 for a further 10 minutes. On adding a further 75 g. bromobenzene the temperature fell to 1500C but then rose over 12 minutes to 1 870C. The temperature of the mixture was allowed to fall back to 17600 over a further 13 minutes and the remainder of the bromobenzene (to total 31 4 g.) added slowly over 1.5 hours at 1 70--1600C. The mixture was finally heated at 1 700C for 2 hours. Working up gave meta-phenoxytoluene 238 g.=66% B.P.1300C/14mm.

Example VI i-naphthylphenylether (PhO)3P . CuCI catalyst A mixture of phenol (320 9.=3.4 moles), sodium hydroxide (40 g.=1 mole) and potassium hydroxide (62 g. of 85%=0.96 mole) was stirred and heated to 1 900 (pot) taking off water phenol azeotrope and returning phenol to the pot.

The slush of Na/K phenate was cooled to 1 7000 and 1-bromo-naphthalene (60 g.) added bringing the temperature down to 1 6000.

Triphenyl phosphite-cuprous chloride catalyst (2 g.) was added and resulted in a rise in temperature from 160--1700C over 5 minutes. 1 -Bromonaphthalene (total 374 g.) was added over a period of 2.5 hours keeping the temperature between 1 60 and 1 700 C. G.L.C. analysis after a further 1 hour at 1 7000 showed reaction complete i.e. all the bromonaphthalene reacted.

The mixture was cooled and water (400 ml.) added to dissolve the inorganic salts. The organic phase was diluted with toluene (200 ml.) and washed with a solution of NaOH (50 g.) in water (600 ml.) to remove phenol.

Distillation gave 1 -naphthylphenylether B.P. 1 4000./0.3 mm. which distilled as a very page yellow liquid which solidified in the receiver. Yield 340 g.=88%, F.P. 1 220F=5000.

Catalyst Preparation. To a well stirred solution of triphenyl phosphite (62 g.) dissolved in benzene (200 ml.) at ambient temperature was slowly added cuprous chloride (20 g.). The mixture was stirred 2 hours at ambient temperature and then heated to 600C. Filtration gave 6 g. of insoluble cuprous chloride. The colourless benzene solution was allowed to partially evaporate and then methylated spirit added to precipitate the product as a white solid m.p. 6000. (Note: Chemical Abstracts 56 11430 records m.p. 88--890C).

Example VII 4-Acetyldiphenylether (Ph3P)2. CuCI catalyst Catalyst Preparation. c.f. Jardine, Rue and Volva J. (1970) A 238 Cotton and Goodgame J.

(1960) 5267.

A solution of cupric chloride (4.4 g.=1 equ.) dissolved in 100 ml. methylated spirits containing 1 ml. water was added slowly over 5 minutes to a solution of triphenyl phosphine (40 9.=4.5 equ.) in 350 ml. methylated spirit at 700C. An initial red colouration which formed rapidly faded and when about 75% of the copper solution had been added the product separated as a white solid. The solution was stirred for 1 hour at just below reflux and the product filtered off from the hot solution. Yield 27 g.

white solid m.p. 1 60-1 650C.

A suspension of Na/K phenate in excess phenol was prepared from phenol (188 9.=2 moles), NaOH (20 g.) and KOH (31 g. of 85%=0.5 mole) as previously described. p-Chloroacetophenone (138 g.=1 mole) and catalyst (2 g.) were added to the stirred mixture at 1700C and the mixture stirred and heated at 170--1900C for 8 hours. Working up as indicated in previous examples gave pchloroacetophenone (13 g. B.P. 800C/0.5 mm) and 4-acetyl diphenyl-ether B.P. 1420C/0.5 mm (69 9.=40.5% on p-chloroacetophenone used) and residue of high boiling unidentified material. The product solidified on being cooled, mp 470C (ex. methanol)-mp recorded 490C (JACS 68 1107).

Example VIII Meta-phenoxytoluene (Ph3As. Cu 1)4 catalyst Catalyst Preparation. As Jardine and Young J. (1971) A 2444.

A slurry of potassium metacresate in excess m-cresol and bromo-benzene was prepared as previously described from m-cresol (313 ml.=3 moles) bromobenzene (122 g.), and potassium hydroxide (124 g. of 86%=1 .90 moles). Air was removed from the flask with a steady stream of nitrogen. The temperature of the stirred slurry was allowed to fall to 1 630C and catalyst (2 g.) added.

The temperature rose within 4 minutes to 2240C. The mixture was allowed to cool back to 1 600C and the remainder of the bromobenzene (to total 31 4 g.) added portionwise over 2.5 hours keeping the temperature between 1 60 and 1 750C. G.L.C. analysis after a further 30 minutes showed the bromobenzene had reacted almostto completion.

Working up gave meta-phenoxytoluene 320 g., B.P. 88-920C/1 mm.=91.5% yield on potassium metacresate used.

Example IX N-Phenyl-anthranilic acid Ph3P . CuCI catalyst A mixture of aniline (1 55 g., 1.66 moles), o-chloro-benzoic acid (41 g., 0.26 moles), anhydrous potassium carbonate (41 g., 0.3 moles) and triphenyl-phosphine cuprous chloride complex (1.0 g.) was stirred and heated at 11 50C for 2 hours. The excess of aniline was removed by steam distillation, and 20 g. of decolourising carbon was added to the residue. The mixture was boiled for 1 5 minutes and filtered. The N-phenylanthranilic acid was obtained from the filtrate by acidification with hydrochloric acid, filtration and drying. The yield of almost colourless product, m.p. 1 750C, was 46.6 9.=84%.

Comparative Example A reaction was carried out as described in Organic Syntheses Coll. Vol. 2 page 13, using copper oxide 1 g. in place of the triphenyl-phosphine-cuprous chloride. The reactants were heated at reflux (1 55 OC) for two hours. After work-up as above a yield of 35 g. (63%) of brown coloured N-phenylanthranilic acid m.p. 1 750C was obtained.

Other products prepared according to the invention include reaction products of: alkali metal 2:4 dichlorophenate with o-chioroacetophenone; alkali metal phenate with m-bromotoluene to form metaphenoxytoluene.

Claims (20)

Claims

1. A method of carrying out the Ullmann reaction as herein defined which comprises using as catalyst a complex of a copper salt with at least one ligand of formula R3Q or (R2Q)2R1 wherein each R is an organic substituent, R' is alkylene or arylene and Q is phosphorus, arsenic or antimony.

2. A method according to claim 1, wherein the Ullmann reaction comprises a substitution reaction of an aryl halide with an alkali metal phenoxide.

3. A method according to claim 1, wherein the Ullmann reaction comprises a substitution reaction of an aryl halide with an aromatic or aliphatic amine.

4. A method according to claim 1, wherein the Ullmann reaction comprises a substitution reaction of an aryl halide with an alkali metal mercaptide.

5. A method according to any of claims 2, 3 or 4, wherein the substituting reagent is an aromatic compound which is not substituted in the ortho position relative to the reactive site.

6. A method according to claim 1, wherein the Ullmann reaction comprises a substitution reaction of an aryl halide with an alkali metal alkoxide.

7. A method according to claim 1, wherein the Ullmann reaction comprises the hydrolysis of an aryl halide to a phenol.

8. A method according to any of claims 2 to 7, wherein the aryl halide is an optionally substituted naphthyl, anthracyl or phenanthryl halide.

9. A method according to any of claims 2 to 7, wherein the aryl halide is a phenyl halide or substituted phenyl halide.

10. A method according to any of claims 2 to 9, wherein the aryl halide is not substituted in the ortho position relative to the reactive site.

11. A method according to claim 1, wherein metaphenoxytoluene is formed as a product of the Ullmann reaction.

12. A method according to any preceding claim, wherein the catalyst is soluble in the reaction medium.

13. A method according to any preceding claim, wherein the copper in the catalyst is present as cuprous copper.

14. A method according to any preceding claim, wherein the copper salt is a chloride.

1 5. A method according to any preceding claim, wherein Q is phosphorus.

1 6. A method according to any preceding claim, wherein the catalyst is of formula R3QCuCI or (R3Q)2 CuCI.

1 7. A method according to claim 1 6, wherein RsQ is triphenyl phosphine or triphenyl phosphite.

1 8. A method according to any preceding claim which is carried out at a temperature above 1 500C and up to 250at.

19. A method according to claim 1 substantially as described in any one of the examples herein.

20. Phenols, polyphenylene ethers and aryl ethers, thioethers and amines whenever prepared by the method of any of the preceding claims.