WO1998037052A1

WO1998037052A1 - Preparation of aryl bromoaryl ketones and carboxylic derivatives thereof

Info

Publication number: WO1998037052A1
Application number: PCT/US1998/003219
Authority: WO
Inventors: Venkataraman Ramachandran; Tse-Chong Wu; C. Bernard Berry
Original assignee: Albemarle Corporation
Priority date: 1997-02-19
Filing date: 1998-02-18
Publication date: 1998-08-27

Abstract

An aroyl halide is brominated in the liquid phase with bromine and with a Lewis acid catalyst. If the reaction mixture comprises excess bromine along with m-bromoaroyl halide, substantially all of the excess bromine is removed from the mixture. The m-bromoaroyl halide mixing and reacting with a substituted or unsubstituted aromatic compound to produce a reaction mixture comprising a substituted diaryl ketone in which the substitution comprises a bromine atom in the meta position of one of its rings directly bonded to the carbonyl group. Preferably, the substituted diaryl ketone is reacted with a vinylic olefin in a palladium-catalyzed arylation of the olefin to form a substituted diaryl ketone in which the substitution comprises an olefinic substituent in the meta position of one of its rings formerly occupied by a bromine atom. This product can then be reacted with carbon monoxide in a palladium-catalyzed hydrocarboxylation or hydrocarbalkoxylation reaction. The process enables the efficient large scale production of carboxylic acids, or derivatives thereof, such as 2-(3-benzoylphenyl)propionic acid (also known as ketoprofen), a well known commercially successful anti-inflammatory and analgesic agent.

Description

PREPARATION OF ARYL BROMOARYL KETONES AND CARBOXYLIC DERIVATIVES THEREOF

TECHNICAL FIELD

This invention relates to the synthesis of certain substituted diaryl ketones, and also to subsequent conversion of such compounds to carboxylic acids, or derivatives thereof, such as salts or esters.

SUMMARY OF THE INVENTION

This invention provides in one of its embodiments a novel, highly efficient process for the production of aryl bromoaryl ketones. Such compounds are useful, for example, as intermediates for the synthesis of a variety of end products, such as carboxylic acids, and derivatives thereof such as carboxylate salts and esters. Among the acids and salts that can now be produced in accordance with another embodiment of this invention are various (3-beι_zoylphenyl)alkanoic acids and salts described in U.S. Pat. No. 3,641,127. Those compounds are reported to be anti-inflammatory agents, and included in that class of compounds is 2-(3-benzoylphenyl)propionic acid (also known as ketoprofen), a well known commercially successful anti-inflammatory and analgesic agent. Thus in accordance with one embodiment of this invention there is provided a process which comprises a) forming a reaction mixture from at least the following ingredients: (i) bromine, (ii) a catalytically effective amount of at least one bromination catalyst, and (iii) at least one aroyl halide, in a mole ratio of at least one mole of (i) per mole of (iii); b) maintaining at least a portion of the reaction mixture formed in a) at an elevated temperature to produce a reaction mixture comprising (i) m-bromoaroyl halide and/or a catalyst complex thereof (e.g., a complex with a Lewis acid), and (ii) optionally, excess bromine; c) if excess bromine is present in the mixture from b), removing from such mixture substantially all excess bromine; and d) mixing and reacting at least one substituted or unsubstituted aromatic compound with at least a portion of the mixture from b) if no excess bromine is present therein, and otherwise from c) to produce a reaction mixture comprising at least one substituted diaryl ketone in which the substitution at least comprises a bromine atom in the meta position of one of its rings directly bonded to the carbonyl group (i.e., an aryl m-bromoaryl ketone which may contain additional substitution on either or both of the aryl groups).

Pursuant to another embodiment of this invention, the aryl m-bromoaryl ketone formed as above is utilized in conducting a palladium-catalyzed arylation of an olefinic compound to produce a reaction mixture comprising at least one substituted diaryl ketone in which the substitution at least comprises an olefmic substituent (e.g. , a vinyl substituent) in the meta position of one of its rings (e.g, an aryl m-alkenylaryl ketone), and subjecting at least a portion of such reaction mixture to palladium-catalyzed hydrocarboxylation or hydrocarbalkoxylation with carbon monoxide in the presence of water or alcohol to produce a reaction mixture comprising at least one substituted diaryl ketone in which the substitution at least comprises an alkylcarboxylic acid moiety or an alkylcarboxylic acid alkyl ester moiety, depending on whether the reaction is conducted in the presence of water or an alcohol.

The above and other embodiments will be apparent from the ensuing description and appended claims. FURTHER DETAILED DESCRIPTION

Bromination Reaction

The aroyl halides used in the practice of this invention include, for example, benzoyl chloride, 2-methylbenzoyl chloride, 2,4-dimethylbenzoyl chloride, 2,4,6- trimethylbenzoyl chloride, 2-chlorobenzoyl chloride, 2,4-dichlorobenzoyl chloride, 2,4,6- trichlorolbenzoyl chloride, 3-nitrobenzoyl chloride, 2-hydroxybenzoyl chloride, 2- methoxybenzoyl chloride, 4-methoxy benzoyl chloride, 4-ethoxybenzoyl chloride, 4- propoxybenzoyl chloride, 4-isopropoxybenzoylbromide, 4-butoxybenzoyl chloride, 4- isobutoxybenzoyl chloride, 4-sec-butoxybenzoyl chloride, 4-tert-butoxybenzoyl chloride, 2,4-dimethoxybenzoyl chloride, 4-methylthiobenzoyl chloride, 4-ethylthio-benzoyl chloride, 4-propylthiobenzoyl chloride, 4-butylthiobenzoyl chloride, 4-amino-benzoyl chloride, 4-dimethylaminobenzoyl chloride, 4-c__loro-2-methylber_zoyl chloride, 1-naphthoyl chloride, 2-naphthoyl chloride; 4-methyl-l-naphthoyl chloride, 4-ethyl-l- naphthoyl chloride, 4-butyl-l-naphthoyl chloride, 4-methoxy-l-naphthoyl chloride, 4- diethylamino-1-naphthoyl chloride, 4-chloro-l-naphthoyl chloride, 4-methylthio-l- naphthoyl chloride, 2,4-dimethyl-l-naphthoyl chloride, 2,6-dimethyl-l-naphthoyl chloride, 2,7-dimethyl-l-naphthoyl chloride, l-methyl-2-naphthoyl chloride, 1,3- dimethyl-2-naphthoyl chloride, l,5-dimethyl-2-naphthoyl chloride, l,8-dimethyl-2- naphthoyl chloride, l-chloro-2-naphthoyl chloride, l,3-dichloro-2-naphthoyl chloride, 1- amino-2-naphthoyl chloride, l-methylamino-2-naphthoyl chloride, l-methylthio-2- naphthoyl chloride, and analogous aroyl halides such as the aroyl bromides and iodides which have at least one unsubstituted meta position relative to the acyl group and which, when further substituted have one or more groups that tend to direct the bromination to an unsubstituted meta position. In this connection, the term "unsubstituted" is used herein as chemists use the term, i.e., a position on the aromatic ring where a carbon atom is substituted only by a hydrogen atom rather than by some other type of substituent. Typically the aroyl halides have up to about 24 carbon atoms in the molecule. Preferred are the aroyl chlorides. Most preferred is benzoyl chloride.

A wide variety of bromination catalysts, typically Lewis acid catalysts or strong protic acid catalysts, can be used for this reaction. Since such materials are so well known, a only a few preferred examples will be mentioned. Thus preferred catalysts for conducting the bromination of the aroyl halide pursuant to this invention include, for example, Lewis acid catalysts such as aluminum chloride, aluminum bromide, zinc chloride, ferric chloride, ferric bromide, boron trifluoride, stannic chloride, titanium tetrachloride, sulfur trioxide, and other like compounds. Most preferred as the catalyst for the bromination reaction are aluminum bromide, and especially, aluminum chloride. The strong protic acids that can be used include, for example, sulfuric acid, fuming sulfuric acid, trifluoromethane sulfonic acid, trifluoroacetic acid, and similar protic acid bromination catalysts of comparable acid strength. For further details concerning bromination catalysts suitable for use in the practice of this invention, one may refer, if necessary, to such literature references as de la Mare, "Electrophylic Halogenation" , Cambridge University Press, London, 1972; Buehler and Pearson, "Survey of Organic

Synthesis", pp. 392-404, Interscience, New York, 1970; Norman and Taylor, "Electrophylic Substitution in Benzenoid Compounds" , pp. 119-155, American Elsevier, New York, 1965; and Braendlin and McBee, in Olah, "Friedel-Crafts and Related Reactions" , Vol. 3, pp. 1517-1593, Interscience, New York, 1964. The catalyst is used in a catalytically effective amount, and thus when a Lewis acid catalyst is used, it is used in an amount at least chemically equivalent to the amount of aroyl halide being used. In other words, when using a Lewis acid catalyst such as A1CI, or AlBr₃ to form the initial bromination mixture, the mole ratio of catalyst to aroyl halide is at least about 1: 1, and preferably the amount is such as to provide a mole ratio of at least about 1.3 moles of catalyst per mole of aroyl halide. Without desiring to be bound by theoretical considerations, it is believed that Lewis acids such as A1C1₃ and AlBr₃ form a complex with the m-bromoaroyl halide formed in the reaction.

The bromine is preferably used in its liquid state, and thus the bromination reaction is typically conducted under temperature and pressure conditions that maintain the bromine in a non-vaporous condition. The bromination reaction tends to be an exothermic reaction, and therefore it is desirable to conduct the reaction in a reactor equipped with adequate heat exchanger (cooling) means, such as a reactor equipped with internal cooling coils, a jacketed reactor with coolant circulated through the jacket, or the like. The reaction can be conducted under superatmospheric pressure, but usually it is more convenient to conduct the reaction at ambient atmospheric pressures. Heat can be applied whenever deemed appropriate or desirable. Typically the reaction is performed at one or more temperatures within the range of 20 to 60 °C. For effective operation, the bromine should be charged to the reactor in an amount such that the mole ratio is at least one mole of bromine (Br₂) per mole of aroyl halide. If less than a 1 : 1 mole ratio of bromine: aroyl halide is used, the bromine becomes the limiting reactant and thus only a portion of the aroyl halide is brominated. Preferably an excess of bromine, e.g., at least about 1.3 moles of bromine per mole of aroyl halide, is charged to the reactor. Generally speaking, there is no upper limit to the amount of bromine charged relative to the aroyl halide, as the excess serves as a reaction medium and can be recycled. Thus matters of practicality and expense will usually come into play as regards the maximum amount of bromine used. The reaction mixture should be stirred or otherwise agitated to ensure intimate contact among the components in the mixture. If desired, an ancillary solvent suitable for use in bromination reactions can be used, such as one or more liquid saturated aliphatic or cycloaliphatic chlorohydrocarbons or bromohydrocarbons, or one or more liquid fluorocarbons, or carbon disulfϊde, or the like, in order to make the reaction mixture more fluid. However unless the reaction mixture tends to form a sticky, viscous or solid mass which is difficult or impossible to stir or otherwise mix, it is not necessary to use an ancillary solvent. Use of excess bromine serves this function admirably. Upon completion of the reaction, which typically involves from 2 to 6 hours depending upon scale and reaction temperature, excess bromine, if any, is purged from the system, for example by blowing a stream of dry nitrogen or other inert gas through the reaction mixture.

The desired product formed in the bromination reaction can be depicted by the formulas

Br - AT' - COX and/or Br - Ar' - COX/L (I) where Ar' is a meta-arylene group, X is a halogen atom (most preferably a chlorine atom), and L is a Lewis acid moiety such as AlCl, or AlBr₃ in the form of a Lewis acid complex with the bromoaroyl halide, and where Ar' has at least the depicted bromine atom as a substituent in a meta position relative to the ring carbon atom bonded to the acyl (-COX) functionality. Aromatic Condensation Reaction In this reaction m-bromoaroyl halide and/or Lewis acid complex thereof (Formula

(I) above) is condensed with an aromatic compound to form a diaryl ketone in which at least one (and preferably only one) of the aryl groups has a bromine substituent in a meta position relative to the ketone functionality. This desired product of this reaction (sometimes referred to herein for convenience as aryl m-bromoaryl ketone) can be depicted by the formula

Ar - CO - Ar' - Br (II) where Ar is an aryl or substituted aryl group, and Ar' is a meta-arylene group having at least the depicted bromine atom as a substituent in a meta position relative to the ring carbon atom bonded to the carbonyl (ketone) functionality. In conducting this reaction, all, or at least a portion, of the reaction product from the bromination reaction, when substantially freed of elemental bromine, is mixed and reacted with at least one substituted or unsubstituted aromatic compound to produce a reaction mixture comprising at least one substituted diaryl ketone in which the substitution at least comprises a bromine atom in the meta position of one of its rings (i.e., an aryl m-bromoaryl ketone; Formula (II) above). This reaction is conducted in the presence of residual Lewis acid catalyst in whatever form it exists upon completion of the bromination reaction. Again without desiring to be bound by theoretical considerations, it is believed that Lewis acids such as A1C1₃ and AlBς may be complexed with the m-bromoaroyl halide formed in the reaction. In any event, the reaction that takes place when mixing the substituted or unsubstituted aromatic compound and the reaction mixture from the bromination reaction results in the formation of a substituted or unsubstituted aryl m- bromoaryl ketone.

While it is definitely preferable to simply remove excess bromine, if any, from the reaction product of the bromination reaction and conduct this condensation reaction as a "one pot" reaction by addition thereto of the aromatic reactant, it is possible to recover, and if desired, purify the m-bromoaroyl halide or the Lewis acid complex thereof, and use all or a portion of this recovered, and optionally purified, product as feed for the aromatic condensation reaction.

Examples of suitable substituted and unsubstituted aromatic compounds which can be used as reactants in this ketone-forming reaction include benzene, toluene, xylene, mesitylene, ethylbenzene, propylbenzene, butylbenzene, chlorobenzene, bromobenzene, trifluoromethylbenzene, methoxybenzene, ethoxy benzene, 2,4-dimethoxybenzene, o-di- chlorobenzene, methylthiobenzene (methyl phenyl thioether), biphenyl, methylbiphenyl, o-methoxybiphenyl, m-methoxybiphenyl, p-methoxybiphenyl, p-dimethylaminobiphenyl, diphenylether, diphenylthioether, methylenebisbenzene, naphthalene, tetrahydro- naphthalene, 1-methylnaphthalene, 2-methylnaphthalene, 1-chloronaphthalene, 2-chloro- naphthalene, 1,4-diethylnaphthalene, 1,8-dimethoxynaphthalene, 1 ,5-di(methylthio)- naphthalene, 2-trifluoromethylnaphthalene, pyridine, and similar aromatic compounds having at least one position of an aromatic ring sufficiently unhindered to be capable of entering into the condensation reaction to form the keto linkage between the aromatic moieties of the two reactants. Generally speaking, this aromatic reactant has in the range of up to about 24 carbon atoms in the molecule. Benzene is a preferred reactant. This condensation reaction tends to be another exothermic reaction. One way of controlling the temperature of this exothermic reaction is to slowly add the reaction mixture from the bromination reaction into a suitable excess quantity of the liquid aromatic hydrocarbon reactant, preferably benzene. Another way of controlling temperature is to conduct the reaction in a suitable essentially inert ancillary solvent such as, for example, nitrobenzene, 4-chloro-3-nitrotoluene, l-chloro-2-nitrobenzene, 2- chloro-6-nitrotoluene, 4-chloro-2-nitrotoluene, 3-nitro-o-xylene, liquid fluoronitroben- zenes, carbon disulfide, liquefied carbon dioxide, and liquefied sulfur dioxide. When using an ancillary solvent it is desirable, especially when conducting the process on a large scale, to add the solvent to the bromination reaction product mixture before removing excess bromine, as this tends to keep the reaction mixture in at least a wet condition, and preferably in a liquid phase.

In a preferred embodiment both the bromination reaction and the aromatic condensation reaction are conducted in the same reactor, as this reduces capital requirements for the process, and enables use of a reactor suitably equipped with cooling coils or other refrigeration apparatus to assist in controlling both exothermic reactions. The reaction is usually conducted at one or more temperatures in the range of 0 to 60°C, and preferably in the range of 30 to 55 °C.

The m-bromoaroyl halide (including Lewis acid complex thereof) and the substituted or unsubstituted aromatic compound used as reactant are charged to the reaction vessel in amounts such that the mole ratio of such aromatic reactant to the m- bromoaroyl halide (including Lewis acid complex thereof) to is at least about 1 :1, respectively. Preferably 2 to 20 moles of the aromatic reactant per mole of the m- bromoaroyl halide and/or Lewis acid complex thereof (in whatever form or forms this reactant exists) are charged to the reactor. Reaction periods are typically in the range of

0.1 to 24 hours, depending upon reaction scale and reaction temperature. Olefin Arylation Reaction

Palladium-catalyzed arylations of olefins with aryl halides are well known and reported in the literature. See for example, C.B. Ziegler, Jr., and R.F. Heck, /. Org. Chem. , 1978, 43, 2941 and references cited therein, and U.S. Pat. No. 5,536,870 to T-C

Wu. In the practice of this invention, the arylation reaction is used for preparing an olefinic compound of the formula

Ar - CO - Ar' - R (III) where Ar is an aryl or substituted aryl group, and Ar' is a meta-arylene group having at least an olefinic substituent in a meta position relative to the ring carbon atom bonded to the carbonyl (ketone) functionality. This is accomplished by reacting the at least one aryl m-bromoaryl ketone (Formula (II) above) with at least one vinylic compound, i.e. , a compound having a terminal -CH=CH₂ group. Compounds of Formula (III) above are often referred to hereinafter for convenience as "arylated olefin product".

It will be noted that the olefmic substituent, R, of Figure (III) is in the meta position formerly occupied by the bromine atom depicted in Figure (II).

A wide variety of products can be produced in this reaction by suitable selection of the vinylic compound. For example, the vinylic compound used can be a cyclic compound having a vinylic group such as, for example, styrene, o-methylstyrene, m- methylstyrene, p-methylstyrene, p-tert-butylstyrene, p-methoxy styrene, p-dimethylamino- styrene, vinyl-cyclohexane, 4-vinylanisole, 9-vinylanthracene, vinyl benzoate, 1-vinyl- imidazole, 2- vinyl-naphthalene, 4-vinylbiphenyl, vinylferrocene, 5-vinyl-2-norbornene, 4-vinylphenylboronic acid, 2-vinyl-l,3-dioxolane, N-vinylphthalimide, 2-vinylpyridine, 4-vinylpyridine, l-vinyl-2-pyrrolidinone, 4-vinylaniline, allylbenzene, allylanisole, N- allylaniline, allyl benzyl ether, ally ley clohexylamine, allylcyclopentane, N-allyl- cyclopentylamine, 4-allyl-l,2-dimethoxyber_zene, 4-allyl-2,6-dimethoxyphenol, 1-allyl- imidazole, allylpentfluorobenzene, 2-allylphenol, allyl phenyl ether, allyl phenyl sulfone, 3-allylrhodanine, 2-(allylthio)benz-imidazole, 4-phenyl-l-butene, 6-phenyl-l-hexene, and similar compounds. Acyclic vinyl compounds containing additional functionality in the molecule can also be used, examples of which include, vinylacetate, vinylacetic acid, alkylacrylate, vinyl chloride, vinyl bromide, alkylcrotonate, vinyl decanoate, alkyl- methacrylate, vinylphosphonic acid, vinyl stearate, vinyl sulfone, vinyl trifluoroacetate, vinyltrimethoxy silane, vinyltrimethylsilane, allyl alcohol, allylamine, allyl bromide, allyl butyl ether, allyl butyrate, allyl cyanide, allyl diethylphosphonoacetate, allyl 1,1,2,3,3,3- hexafluoropropyl ether, 4-allyl-3-thiosemicarbazide, allyltributyltin, ally ltriethoxy silane, allyl trifluoroacetate, allyl urea, 4,4,4-trifluoro-l-butene, and analogous compounds.

Preferred olefinic compounds used in this reaction are branched olefins and more preferably linear olefins, such as ethylene, propylene, 1-butene, 1-pentene, 3 -methyl- 1- butene, 1-hexene, 4-methyl-l-pentene, 1-heptene, 1-octene, 1-nonene, 1-decene, 1- undecene, 1-dodecene, 1-tridecene, 1-tetradecene, and their homologs. Generally speaking, the olefinic reactant will typically contain up to about 30 or more carbon atoms in the molecule. The most preferred olefinic reactant is ethylene.

The reaction is typically conducted in a liquid medium formed from (i) one or more liquid polar organic solvent/diluents, and (ii) one or more organic or inorganic bases to function as hydrogen halide acceptor(s). When it is desired to utilize the product from this reaction as an intermediate for the synthesis of a carboxylic derivative by a hydrocarboxylation reaction or a hydrocarbalkoxylation reaction (described more fully hereinafter), it is desirable to select one or more secondary amines and/or tertiary amines that boil(s) below the boiling temperature of the solvent/diluent if only one solvent/diluent is used in forming the medium or that boil(s) below the boiling temperature of at least one, but not necessarily all, of the polar solvent/diluents used in forming the medium if more than one solvent/diluent is used in forming the medium. The solvent/diluent should have at least a measurable polarity at a temperature in the range of 20 to 25 °C, and yet be free of functionality that would prevent or materially impair, inhibit or otherwise materially interfere with the olefin arylation reaction. Examples of suitable solvent/diluents include tetrahydrofuran, 1,4-dioxane, diglyme, triglyme, acetonitrile, propionitrile, benzonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl- sulf oxide, nitrobenzene, sulfolane, acetone, butanone and cyclohexanone. Preferred solvent/diluents are one or more aprotic solvents each having a dielectric constant of at least 10 (especially 10 to 30) at a temperature in the range of 20 to 25 °C. From the cost- effectiveness standpoint, hydrocarbyl ketones with 4 or more carbon atoms in the molecule (e.g. , 4 to 8) are especially preferable. Examples include diethyl ketone, methyl isobutyl ketone, 2-pentanone, 2-hexanone, 2-heptanone, 3-heptanone, 4-hepta- none, and like liquid ketones, as well as mixtures of two or more such ketones. Most preferred is diethyl ketone (3-pentanone). The olefin arylation reaction inherently tends to be an exothermic reaction, and the use of diluents having a dielectric constant in the range of 10 to 30 (as measured at 20 to 25 °C), such as a ketone meeting this qualification provides a readily controllable reaction. Typical organic bases used as hydrogen halide acceptors are secondary amines, and preferably tertiary amines. Suitable inorganic hydrogen halide acceptors are typically inorganic bases such as K₂CO₃, LiOH, Ca(OH)₂ and like materials. The hydrogen halide acceptors preferably are used in at least a stoichiometric amount relative to the amount of hydrogen halide to be released in the reaction. Thus if the aryl m-bromoaryl ketone being used in this reaction has only one reactive halogen atom (i.e. , the meta bromine atom), it is desirable to provide at least one mole of a secondary or tertiary monoamine per mole of the aryl m-bromoaryl ketone, or at least one-half mole of a secondary or tertiary diamine per mole of the aryl m-bromoaryl ketone. However it is possible, though less desirable, to use less than a stoichiometric amount of amine, by allowing the reaction with less than a stoichiometric amount of amine to proceed only part way, and by recycling the reaction mixture for further reaction in the presence of additional amine added thereto.

Use can be made of any liquid secondary or tertiary amine that is free of functionality that would prevent or materially impair, inhibit or otherwise materially interfere with the olefin arylation reaction, and preferably that boils below the boiling temperature of the polar solvent/diluent used when only one is used in forming the liquid medium for the reaction, or that boils below at least one of a plurality of polar solvent/diluents used in at least a substantial amount (e.g., at least 20 or 30% of the total volume of the solvent/diluents), when more than one is used in forming the liquid medium for the reaction. In addition the amine must have sufficient basicity to serve as a hydrogen halide acceptor for the HBr and other hydrogen halide, if any, to be released in the reaction. Preferred are liquid tertiary amines. The amines may be polyamines such as for example, N,N,N' ,N'-tetramethylethylenediamine (b.p. ca. 120-122°C), but in most cases monoamines are preferable. Among useful liquid amines having suitably low boiling points are diethylamine (bp 55°C), N,N-dimethylethylamine (bp 36-38°C), N,N-diethylmethyl-amine (bp 63-65°C), diisopropylamine (bp 84°C), triethylamine (bp ca. 89°C), dipropyl-amine (bp ca. 105-110°C), and di-sec-butylamine (bp ca. 135°C). Triethylamine is a particularly preferred amine. Liquid media formed from diethyl ketone and acetonitrile (e.g. in a weight ratio in the range of 1:9 to 4: 1, and more preferably in the range of 1:3 to 3: 1) plus triethylamine, or from diethyl ketone and N,N-dimethylformamide (e.g., in a weight ratio in the range of 1:9 to 9:1) plus triethylamine are typical desirable liquid media for use in this invention.

Liquid media formed from diethyl ketone and triethylamine or from methyl isobutyl ketone and triethylamine are particularly preferred.

In the practice of this invention, the olefin arylation reaction is typically conducted in the presence of a catalytically effective amount of a catalyst system formed from (a) palladium and/or at least one compound of palladium in which the palladium has a valence of zero, 1 or 2, and (b) a tertiary phosphine. The organic groups on the tertiary phosphine can be the same or different and can be alkyl, cycloalkyl, aralkyl, aryl, alkenyl, and/or cycloalkenyl groups, and if functionally substituted (e.g., by a functional group containing or composed of at least one atom of halogen, oxygen, nitrogen, sulfur, silicon or phosphorus), the organic group is free of functionality that would prevent or materially impair, inhibit or otherwise materially interfere with the olefin arylation reaction. Preferably at least one of organic groups of the tertiary phosphine is an aryl group, as, for example, in such compounds as monoaryl dialkyl phosphines, diaryl monoalkyl phosphines, monoaryl dicycloalkyl phosphines, diaryl monocycloalkyl phosphines, monoaryl monoalkyl monocycloalkyl phosphines, monoaryl diaralkyl phosphines, diaryl monoaralkyl phosphines, monoaryl monoalkyl monoaralkyl phosphines, monoaryl monocycloalkyl monoaralkyl phosphines, and triaryl phosphines.

Tertiary phosphines in which the three organic groups are hydrocarbyl groups of which at least one is an aryl group are more preferred as they are more readily available at lower cost and thus are more cost-effective.

The use of salts of palladium in forming the catalysts is preferable because catalyst compositions formed from palladium salts appear to have greater activity than those made from palladium metal itself. Of the salts, palladium(II) salts such as the Pd(II) halides (chloride, bromide, iodide) and Pd(II) carboxylates (e.g., acetate, and propionate) are most preferred.

A highly preferred type of tertiary phosphine (sometimes referred to herein as "ligand") used is one or more tertiary phosphine ligands of the formula

where R' and R" are the same or different and are individually hydrogen or hydrocarbyl (preferably alkyl or aryl), Ar is aryl (preferably an aryl hydrocarbon group such as phenyl, tolyl, xylyl, ethylphenyl, and naphthyl) and n is an integer from 3 to 6. Preferably, R' and R" are the same or different and are to C₆ alkyl, Ar is phenyl or naphthyl and n is 3 or 4. Most preferably, R' is methyl or ethyl, R" is to C₆ branched alkyl, Ar is phenyl and n is 4. Especially preferred as the phosphine ligand is neomenthy ldipheny lphosphine .

Active catalytic species are preferably formed in situ by the addition to the reaction mixture of the foregoing individual components. However the catalyst can be preformed externally to the reaction mixture and charged to the reactor as a preformed catalyst composition.

Desirably, a small reaction-accelerating amount of water is included or present in the reaction mixture, as described in commonly-owned U.S. application Serial No. 08/780,310, filed January 8, 1997. This amount is typically in the range of 0.5 to 5 wt% of the total weight of the entire reaction mixture. Within the range of 0.5 to 5 weight percent water there is often an optimum amount of water which gives the highest or peak reaction rate which falls off if more or less water is used. This optimum amount of water may vary depending upon the identity and proportions of the ingredients used in forming the reaction mixture. Thus in any given situation it may be desirable to perform a few preliminary experiments with the particular reaction to be conducted, wherein the amount of water is varied within the range of 0.5 to 5 wt% to locate the optimum rate-enhancing amount of water in the mixture. Preferably, the amount of water used will be insufficient to form a second liquid phase (i.e., a separate water layer) in a mixture consisting of (i) the amount of the liquid organic solvent/diluent(s) selected for use, (ii) the selected amount of the liquid secondary and/or tertiary amine(s) selected for use, and (iii) the selected amount of water, when such mixture is agitated for 10 minutes at 25 °C and allowed to stand for 15 minutes at the same temperature. Thus when conducting the process on a large scale with recycle of solvent(s) and amine, the amount of water carried over from product workup should be monitored and/or controlled such that the water content of the reaction mixture remains at or below 5 wt% of the total weight thereof. Conversely if the amount of recycled water is insufficient to maintain the desired water content in the reaction mixture, additional water should be added to bring the water content up to the desired amount within the foregoing range. Preferably the arylation reaction mixtures have a water content in the range of 1 to 3.5 weight percent.

In conducting an operation wherein a mixture of (i) liquid organic solvent/diluents), (ii) secondary and/or tertiary amine(s), and (iii) water that does not separate into a two-phase system is used, the liquid mixture of these components may nonetheless be hazy or cloudy, but a distinct coalesced second liquid phase does not and should not exist as a separate layer in such liquid mixture.

The olefin arylation reaction is performed under conditions such that olefinic compound of Formula (III) above is formed. Such conditions usually require an equimolar ratio of olefinic compound to aryl m-bromoaryl ketone, although an excess of olefinic compound is preferred. The palladium catalyst and the phosphine ligand are typically used at about a ratio of 1 mole of organic halide to 0.0005 mole of palladium or palladium compound. The ligand is present in the same or higher molar proportion as the palladium or palladium compound. It should be noted that levels of (a) palladium or palladium compound, and (b) ligand can be substantially higher (up to 10 times).

When relatively inactive species of olefinic compound or a less reactive species of aryl m-bromoaryl ketone is employed, for example, highly substituted olefins and/or substituted aryl m-bromoaryl ketones bearing strongly electron donating substituents, these higher amounts of catalyst and ligand may be required. Thus the mole ratio of aryl m-bromoaryl ketone :Pd: ligand used will generally be a suitable ratio within the range of

200-20,000:1 : 1-20, respectively.

Temperatures of reaction are quite modest, varying from 25°C to 200°C (preferably 60 °C to 150°C) with pressures (for the gaseous vinyl compounds) being from atmospheric up to 3000 psi (preferably 200 to 1000 psi). With the preferred catalyst systems and liquid media referred to above, reaction times are unusually short, typically giving complete reaction in the range of 1 to 24 hours, typically in the range of 2 to 6 hours. Higher temperatures and lower pressures tend to cause increased by-product formation.

The preferred and the optimum conditions will depend to some extent upon the identity of the particular ingredients being used. However based on research results available to date, when conducting a reaction using an aryl m-bromoaryl ketone in which the meta bromine atom is the only reactive halogen atom in the compound (ABAK) using (a) ethylene as the olefinic reactant, (b) a palladium (II) salt such as PdC^ and neomenthyldiphenylphosphine (NMDP) as catalyst or catalyst precursors, (c) a C₄-C₈ ketone especially diethyl ketone and a C₄-C₉ trialkyl amine especially triethylamine as the liquid medium, and (d) a reaction accelerating amount of water, the ABAK:Pd:NMDP mole ratio is preferably in the range of 1000-5000: 1:2-10, respectively, (e.g., an ABAK:Pd:NMP mole ratio of 2000:1:6), the mole ratio of amine: ABAK preferably is in the range of 1-2:1 respectively, the mole ratio of ketone: amine is preferably in the range of 1.0-4.0: 1 respectively, the weight of water based on the total weight of ABAK + ketone + amine + Pd catalyst ingredient + tertiary phosphine ligand + water is preferably in the range 1 to 3.5 wt%, the reaction temperature is typically in the range of 60 to 150°C and preferably in the range of 80 to 110°C (e.g. , 95 °C), and the pressure of the ethylene used is preferably in the range of 200 to 1000 psig (e.g., 420 psig). Under these conditions, reaction should be complete within 1 to 24 hours, and oftentimes within 2 to 6 hours. It is to be clearly understood that the foregoing conditions given in this paragraph are, as stated, preferred conditions for carrying out the specified reaction. On the basis of the information presented in this disclosure, one skilled in the art could readily operate outside of the ranges given in this paragraph, and still achieve good performance in accordance with this invention. Thus this invention is not limited to use of the conditions given in this paragraph, and it is within the scope of this invention when performing the specified reaction to depart from any one or more of such ranges, whenever deemed necessary or desirable in any given situation.

For best results, the overall olefin arylation reaction mixture is essentially solids- free when at reaction temperatures, except for some precipitation of palladium and formation of some solid co-products such as amine-hydrohalide salt and products formed by interaction of the ABAK with the arylated olefin product and/or by dimerization of such arylated olefin product that may occur as the reaction proceeds. Since the reaction tends to be exothermic, it is desirable to utilize reactors equipped with internal cooling coils, cooling jackets or other highly effective cooling means to ensure suitable temperature control. Workup of Olefin Arylation Product

The arylation reaction produces a reaction mixture comprising olefinically- substituted aromatic ketone (i.e., olefin arylation product; Formula (III) above), amine- hydrobromide and one or more of the polar organic solvents. Any suitable procedure for recovering the arylated olefin product from the reaction mixture can be used. Where it is desired to convert the arylated olefin product into a carboxylic acid or derivative thereof, the procedure given in the Example hereinafter is one preferred way of effecting this separation.

Other workup procedures developed in these laboratories which may be used for effecting the workup of arylated olefin product produced in accordance with this invention are procedures set forth in commonly-owned copending U.S. application Serial No.

08/780,308, filed January 8, 1997. Such procedures are as follows:

A concentrated aqueous solution of inorganic base such as K₂CO₃, or NaHCO₃, having a base strength greater than that of the amine(s) of the amine hydrohalide, and more preferably a concentrated aqueous alkali metal hydroxide solution, is mixed with at least a portion (preferably, all) of the reaction mixture to convert the amine-hydrohalide therein to free amine and inorganic halide salt such as alkali metal halide, and to form (i) an aqueous phase containing dissolved halide salt, and (ii) an organic phase comprising olefinically-substituted aromatic ketone, amine, and one or more of the polar organic solvents. Although well known to those skilled in the art, it is deemed necessary, or at least prudent, to point out that because the conversion of the amine-hydrohalide to free amine and, say, "alkali metal halide" is conducted in the presence of water, the "alkali metal halide", or at least a substantial proportion thereof, exists in ionic form while dissolved in the water. Thus according to known chemical principles, the water contains alkali metal cations and halide anions. However chemists would commonly refer to this as forming alkali metal halide because upon removal of water, alkali metal halide would indeed exist as such. Thus when referring in the specification and claims hereof to converting the amine-hydrohalide to free amine and halide salt such as alkali metal halide, it is to be understood that this means that the resulting mixture contains the liberated amine and the halide salt in whatever chemical forms they exist in the environment and under the conditions used. The concentrated alkali metal hydroxide solution may be formed by dissolving alkali metal oxide or hydroxide, or both, in water. The preferred alkali metal oxides and/or hydroxides are those of sodium or potassium, or mixtures thereof. These are plentiful and less expensive than the lithium, rubidium and cesium oxides and hydroxides, which could, however, be used. If desired, the sodium hydroxide or potassium hydroxide solution may be formed from small or even trace amounts of one or more of these other more expensive alkali metal oxides and/or hydroxides together with large amounts of the sodium and/or potassium oxides and/or hydroxides. Again it is to be noted that in the aqueous solution, the alkali metal hydroxide is ionized so that the solution contains, according to well established chemical principles, alkali metal cations and hydroxyl anions. Therefore, reference in the specification and claims hereof to alkali metal hydroxide solution means that the alkali metal hydroxide is in whatever chemical form it exists while in a concentrated aqueous solution.

Whether conducted in stages or all at once, ultimately at least a stoichiometric amount of the inorganic base should be, and in most cases is, employed relative to the amount of amine-hydrohalide present in the reaction mixture.

As to the concentration of these inorganic base solutions, it is desirable to use solutions that contain the equivalent of at least 10 weight percent of the base, such as alkali metal hydroxide, being used. Saturated aqueous alkali metal hydroxide solutions can be used, but typically the concentration will be at least slightly less than this. Preferred aqueous solutions contain the equivalent of 20 to 50 wt% of sodium hydroxide or of potassium hydroxide, or of both. Particularly preferred aqueous solutions contain the equivalent of 23 to 27 wt% of sodium hydroxide and/or potassium hydroxide. Most preferred is 25 wt% sodium hydroxide aqueous solution.

Preferably the aqueous solution of inorganic base such as alkali metal hydroxide is used in an amount that produces an alkali metal halide solution containing the equivalent of at least 30 wt% of sodium bromide, and more preferably the equivalent of at least 40 to 50 wt% of sodium bromide, as this makes the ensuing phase separation easier if the aqueous phase has the higher densities of such concentrated solutions. In addition, less of the organic solvent/diluent(s) and amine(s) are soluble in the aqueous phases having such higher metal halide concentrations, and thus solvent losses are thereby reduced.

The conditions for the mixing of the inorganic base solution such as alkali metal hydroxide solution with the olefin arylation reaction mixture are not critical. All that is required is to ensure that these materials are sufficiently well mixed so that intimate contact is established between these materials. Temperatures will typically be in the range of 40 to 70°C, but other temperatures may be used. Agitation periods in the range of 5 to 15 minutes will normally suffice, but longer periods of up to 30 minutes or more (e.g. , one hour or more) can be used, if desired.

After mixing, the resulting mixture is allowed or caused to separate into the organic and aqueous phases, usually by allowing the mixture to stand in a quiescent state. Standing periods of one hour or less are usually sufficient. In fact, when treating an olefin arylation reaction mixture with sufficiently concentrated sodium hydroxide solution to produce an aqueous phase containing 40-45 wt% of sodium bromide, the phases separate quickly, e.g., in as little as 15 minutes. Moreover the phase interface is distinct and easy to detect since oligomeric coproducts tend to float on top of such a concentrated aqueous phase. Then the phases are separated from each other, for example by decantation or, more usually, by draining off the lower aqueous layer.

Next, substantially all of the amine is distilled from the remainder of the organic phase under low temperature and pressure conditions that suppress thermal oligomer- ization of the olefinically-substituted aromatic ketone contained in the residual liquid phase. This distillation can be performed at any suitable reduced pressure such as, for example, in the range of 50 to 600 mm Hg, and preferably at pressures in the range of 200 to 350 mm Hg. Residual amine if present in excessive amounts in the remainder of the organic phase after distillation can have adverse effects upon the ensuing carboxylation reaction. For example, excessive amounts of such residual amine can cause the carboxylation reaction to stop prematurely with consequent loss of conversions and yields. The amount of such residual amine that can be tolerated in the remainder of the organic phase after distillation may vary depending upon such factors as the makeup of the organic phase, the identity of olefinically-substituted aromatic compound contained therein, and the conditions to be used in the carboxylation reaction. Thus in any given situation it may be desirable to perform a few preliminary experiments to determine the amount of amine that can be tolerated without significant adverse effects. Thus sufficient amine is removed such that residual amine, if any, remaining in the remainder of the organic phase does not cause (a) more than about a 5% reduction in conversion of olefinically-substituted aromatic ketone contained in the remainder of such organic phase, and (b) more than about a 5% loss of yield of carboxylated product in the ensuing carboxylation as compared to an identical carboxylation of another portion of the same original organic phase from which the amine has been rigorously removed to the extent possible without significantly reducing the olefinically-substituted aromatic compound content of the organic phase. Preferably the amount of residual amine, if any, remaining in the remainder of the organic phase is sufficiently small so that (a) no more than about a 1 % reduction in conversion of olefinically-substituted aromatic ketone contained in the remainder of such organic phase, and (b) no more than about a 1 % loss of yield of carboxylated product in the ensuing carboxylation will occur as compared to an identical carboxylation of another portion of the same original organic phase from which the amine has been rigorously removed to the extent possible without significantly reducing the olefinically-substituted aromatic ketone content of the organic phase. To ensure no material adverse effects of amine on the carboxylation reaction, residual amounts of amine are preferably maintained below about one (1) percent by weight of the distilland remaining after the distillation of amine therefrom.

Preferably, liquid organic makeup solvent is mixed with the liquid mixture during or after the distillation of the amine whereby the liquid mixture for carboxylation further comprises at least a portion (preferably, all) of the distilland and the makeup solvent. While various solvents may be used, the makeup solvent preferably comprises at least one ether, preferably a liquid cyclic monoether such as tetrahydrofuran, methyltetra- hydrofuran, or tetrahydropyran, or a cyclic diether such as 1,3-dioxolane, or 1,4-dioxane, or a mixture of such materials with or without one or more acyclic ethers such as diethyl ether, or methyl tert-butyl ether. The most preferred makeup solvent is tetrahydrofuran as this material appears to exert a rate enhancing effect upon the carboxylation reaction. It is expected that at least some alkyl-substituted tetrahydrofurans may also behave in this manner.

When a mixture of acetonitrile and a liquid ketone having a boiling point above the amine, such as diethyl ketone and/or methyhsobutyl ketone, is used as the solvent or diluent in the olefin arylation reaction, minor variants in the above workup procedure are preferably employed. In one such procedure, (1) the acetonitrile is distilled from the olefin arylation reaction mixture, (2) the concentrated aqueous solution of inorganic base is mixed with the residual reaction product to form the aqueous and organic phases (as above), (3) the phases are separated, and (4) the amine is distilled from the organic phase.

Then makeup solvent (e.g. , tetrahydrofuran) is added to the organic phase, and the resultant organic phase is then utilized in the ensuing carboxylation reaction. Another such procedure involves (1) mixing the concentrated aqueous solution of inorganic base with the olefin arylation reaction mixture, (2) separating the phases, and (3) distilling the acetonitrile and the amine from the separated organic phase. Then the makeup solvent is added to the organic phase, and the resultant organic phase is then utilized in the carboxylation reaction.

Another process for effecting workup of the olefin arylation reaction product involves using a dilute aqueous acid washing procedure. This procedure comprises mixing with at least a portion of the olefin arylation reaction product composition, a dilute aqueous acid to thereby form (i) an organic phase containing the arylated olefin product, and (ii) an acidic aqueous phase containing dissolved amine hydrohalide, and separating at least a portion of these phases from each other. The dilute aqueous acid is preferably dilute aqueous hydrochloric acid, e.g., in the range of 1 to 20 wt% aqueous HC1. The amount used should be sufficient to form an acidic aqueous phase containing substantially all of the amine-hydrohalide, which can readily be separated from the organic phase comprising the polar solvent(s) and the arylated olefin product. At least a portion of the separated organic phase is then suitable as feed to a palladium-catalyzed carboxylation to form arylcarboxylic acid or ester or substituted arylcarboxylic acid or ester in accordance with conditions and procedures described hereinafter. Before conducting the carboxylation reaction, an ethereal solvent such as a cyclic ether solvent (tetrahydrofuran, methyltetrahydrofuran, and 1,4-dioxane), can be added to the separated organic phase to enhance the ensuing carboxylation reaction. To accommodate the added ethereal solvent, the separated organic phase may be subjected to a stripping or distillation step to remove some of the polar solvent(s) from the separated organic phase, before adding the ethereal solvent. The stripped polar solvent may be used as recycle solvent in the olefin arylation process.

It is also desirable to recover the secondary and/or tertiary amine from the separated aqueous phase. This is accomplished by mixing together at least a portion of the separated aqueous phase and a strong inorganic base to form free amine and an aqueous solution of inorganic halide. Suitable strong bases include NaOH, KOH,

NH₄OH, Na₂O, K₂O, Ca(OH)₂, Na₂CO₃, K₂CO₃, CaO, and other inorganic bases of comparable base strength. This results in the formation of an aqueous phase and an organic phase consisting essentially of the free amine(s). Separation of these phases provides the amine for use as recycle. The amine can be purified by distillation, if necessary.

Carboxylation

In this operation at least a portion of the arylated olefin product (Formula (III) above) is converted into a carboxylic acid or carboxylic acid derivative such as a salt or ester thereof. This involves converting the vinylic functional substituent of the arylated olefin product into an alkylcarboxylic functional group by means of a carboxylation reaction. The resultant product can be depicted by the formula

Ar - CO - Ar' - Z (IV) where Ar is an aryl or substituted aryl group, and Ar' is a meta-arylene group having at least an alkylcarboxylic functional group, Z, in a meta position relative to the ring carbon atom bonded to the carbonyl (ketone) functionality. The alkylcarboxylic functional group, Z, is typically one of three types:

1) An alkylcarboxylic acid moiety, -CHR-COOH; where R is an organic group;

2) An alkylcarboxylic acid ester moiety, -CHR-COOR' ; where R and R' are the same or different organic groups; 3) An alkylcarboxylate salt functionality, -CHR-COO M ; where R is an organic group and M is a cation, typically an alkali metal cation, such as a sodium or potassium cation. The alkylcarboxylic functional group, Z, is located on the aromatic ring in the meta position formerly occupied by the olefinic substituent, R, in Formula (III). The procedures and conditions for effecting the carboxylation leading to the formation of compounds of Formula (IV) are described below. By suitable modifications of or additions to such procedures, compounds of Formula (IV) can be produced in which the cation, M, can be any of a wide variety of other groups, non-limiting exemplifications of which include ammonium, quaternary ammonium, one-half equivalent of a divalent metal atom, one-third equivalent of a trivalent metal cation, and so on.

The catalytic carboxylation of the compound of Formula (III) is effected with carbon monoxide and water and/or alcohol, and is conducted, at a temperature between 25°C and 200°C, preferably 25°-120°C, and most preferably 25°-100°C. Higher temperatures can also be used. The best yields are obtained when the temperature is maintained at a relatively low level throughout the reaction.

The partial pressure of carbon monoxide in the reaction vessel is at least 1 atmosphere (0 psig) at ambient temperature (or the temperature at which the vessel is charged). Any higher pressures of carbon monoxide can be used up to the pressure limits of the reaction apparatus. A pressure up to about 3000 psig is convenient in the process. More preferred is a pressure from 0 to 3000 psig at the reaction temperature and most preferred is a pressure from 200 to 2000 psig. It should be noted that the presence of oxygen is undesirable in the hydrocarboxylation reaction of this invention. Hence, an atmosphere of 100% carbon monoxide is most preferred to carry out this process. Various inert gases can, however, be incorporated in the reaction mass (nitrogen, or argon), the only criterion being that the process should not be slowed to the point of requiring exceptionally long periods to complete the reaction.

As noted above, the carboxylation is conducted in the presence of an appropriate amount of water or aliphatic alcohol. Strictly speaking, when the reaction is conducted in the presence of water it is a hydrocarboxylation reaction, and when conducted in the presence of an alcohol it can be termed a hydrocarbalkoxylation reaction. Consequently, unless otherwise qualified or specified, the term "carboxylation" is used herein in a generic sense to denote both hydrocarboxylation (using water) and hydrocarbalkoxylation (using an alcohol).

In conducting the hydrocarboxylation, at least one (1) mole of water per mole of the arylated olefin product should be used, and 3 to 20 moles, and preferably 3 to 6 moles, of water per mole of the arylated olefin product is typically employed. When using alcohols, it is desirable to employ a co-solvent such as one or more ethers and/or ketones, and in such cases, amounts of alcohols in the range of up to 30 moles per mole of arylated olefin product in the reaction mixture can be used. The product of the reaction is a carboxylic acid when water is present or a carboxylic acid ester when an alcohol is used.

If desired, any alcohol which produces an ester of the carboxylic acid may be used in conducting hydrocarbalkoxylation. In a preferred embodiment, the C, to C₆ aliphatic alcohols are used. Examples of the alcohols to be used in this embodiment include methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-, iso-, sec-, and tert-butyl alcohols, the pentyl alcohols, and the hexyl alcohols. Methyl alcohol is highly preferred, and ethyl alcohol is most highly preferred. Other alcohols, glycols, or aromatic hydroxy compounds may also be used. In the broadest sense, these alcohols provide a source of alkoxide ions for this reaction. However, any other "source of alkoxide ions" may also be used. The source of such alkoxide ions is from a compound selected from the group consisting of HC(OR_j)₃,

(R)₂C(OR,)₂, HC(O)OR,, B(OR,)₃, Ti(OR,)₄ and Al(OR,)₃ where R is hydrogen or individually the same as or different from R and R_j is alkyl or substituted alkyl.

In some cases, the carboxylation reaction is initiated under neutral conditions, i.e. , with no added acid. However, the inclusion of aqueous HC1 in the reaction mixture is deemed important, if not almost essential for most efficient operation. Thus in a preferred embodiment of this invention, the hydrocarboxylation reaction is initiated in the presence of halide ions which are best provided by use of a halogen acid, especially hydrochloric acid, which preferably is an aqueous acid which may for example have a concentration up to 25 wt%, but preferably has a concentration in the range of 5 to 15 wt% , and more preferably in the range of 7 to 15 wt% . It is especially preferred to use approximately 10 wt% aqueous HC1. Dilute aqueous HC1 also provides water for effecting the hydrocarboxylation. Gaseous HC1 can be used to generate hydrochloric acid in situ when water is present when conducting this reaction. HBr and hydrobromic acid may be used, but these appear less effective based on studies conducted to date. Other acids may be considered for use but to date the most effective material is the aqueous hydrochloric acid. Any suitable proportion of hydrochloric acid may be used, typically a reaction accelerating quantity in the range that provides up to 1 mole of hydrogen ion per mole of compound of arylated olefin product, and preferably a quantity that provides in the range of 1 to 20 moles of hydrogen ion per mole of the arylated olefin product. The catalytic carboxylation process of this invention is conducted in the presence of a reaction-promoting quantity of (i) palladium and/or at least one palladium compound in which the palladium has a valence of zero, 1 or 2, (most preferably 2) or (ii) a mixture of (a) palladium and/or at least one palladium compound, and (b) at least one copper compound, with (iii) at least one tertiary phosphine of the type described above. When a copper compound is not employed, the palladium and/or one or more compounds of palladium used in forming the catalyst is/are sometimes collectively referred to herein for convenience as "the Pd ingredient", and the combination of palladium and/or one or more compounds of palladium and one or more compounds of copper used in forming the catalyst (when a copper compound is employed) is sometimes collectively referred to herein for convenience as "the Pd-Cu ingredient". Thus in general the Pd ingredient and the tertiary phosphine ligand are the same type of materials as described above in connection with the olefin arylation reaction. Indeed the same preferred types of materials preferred for use in the olefin arylation reaction are preferred for use in the carboxylation reaction. Fresh catalyst is employed for each such reaction, however. The same species of Pd ingredient and the same species of tertiary phosphine ligand need not be used in these two reactions. Either such component or both of them might differ. Thus, for example, palladium(II) chloride and tri-o-tolylphosphine might be used in the olefin arylation and palladium(II) acetate and triphenylphosphine might be used in the carboxylation, or vice versa, but in the most preferred case the same species (PdCl₂ and neomenthyldiphenylphosphine) are in fact used in both such reactions.

As in the case of the olefin arylation reaction, active catalytic species are preferably formed in situ by the addition to the reaction mixture of the individual components. However the catalyst can be preformed externally to the reaction mixture and charged to the reactor as a preformed catalyst composition.

When it is desired to use a copper compound in forming the carboxylation catalyst system, copper complexes such as copper acetylacetonates, copper alkylacetoacetates, or other chelated forms of copper may be used. The preferred copper compounds for this use, however, are salts especially divalent copper salts such as the halides (chloride, bromide, iodide) of copper(II) and the carboxylates of copper(II) such as copper(II) acetate, and copper(II) propionate. In one embodiment, the Pd ingredient and copper compounds are inorganic salts and are added as a preformed complex of, for example, a complex formed from palladium(II) chloride or bromide, copper(II) chloride or bromide and carbon monoxide, or any other similar complex. In a preferred embodiment, active catalytic species are formed in situ by the addition to the reaction mixture of the individual components, i.e., either (i) at least one tertiary phosphine and at least one palladium compound such as the inorganic or carboxylate salts of palladium(II), or (ii) at least one tertiary phosphine, at least one copper compound, and at least one palladium compound such as the inorganic or carboxylic salts of palladium(II) and copper(II). These inorganic salts include the chlorides, bromides, nitrates, and sulfates. Organic palladium and/or copper compounds that may be used include complexes and salts such as the carboxylates, e.g. , the acetates or propionates. In one preferred embodiment, neomenthyldiphenylphosphine, copper(II) chloride, and palladium(II) chloride are used and are added individually or together, either simultaneously or sequentially. In another preferred embodiment, neomenthyldiphenylphosphine and palladium(II) chloride are used and are added individually or together, either simultaneously or sequentially.

The Pd ingredient or the Pd-Cu ingredient may be supported on carbon, silica, alumina, zeolite, clay and other polymeric materials, but use of a homogeneous catalyst system is definitely preferable.

The amount of the Pd ingredient or of the Pd-Cu ingredient employed is preferably such as to provide from 4 to 8000 moles of the arylated olefin product per mole of the Pd ingredient or per total moles of the Pd-Cu ingredient. More preferred is an amount to provide from 40 to 6000 moles (most preferably 100 to 3000 moles) of the arylated olefin product per mole of the Pd ingredient or per total moles of the Pd-Cu ingredient. The reaction is conducted in the presence of at least one mole of the tertiary phosphine per mole of the Pd ingredient or per total moles of the Pd-Cu ingredient. More preferably, 1 to 40 moles of tertiary phosphine are used per mole of the Pd ingredient or per total moles of the Pd-Cu ingredient, and most preferably 1 to 20 moles of tertiary phosphine are used per mole of the Pd ingredient or per total moles of the Pd-Cu ingredient.

The presence of a solvent is not always required in the carboxylation reaction, although it is desirable in some circumstances. Those solvents which can be used include one or more of the following: ketones, for example, acetone, methyl ethyl ketone, diethyl ketone, methyl n-propyl ketone, acetophenone, and cyclohexanone; linear, poly and cyclic ethers, for example, diethyl ether, di-n-propyl ether, di-n-butyl ether, ethyl n- propyl ether, glyme (the dimethyl ether of ethylene glycol), diglyme (the dimethyl ether of diethylene glycol), tetrahydrofuran, dioxane, 1,3-dioxolane, and similar compounds; and aromatic hydrocarbons, for example, toluene, ethyl benzene, xylenes, and similar compounds. Alcohols are also suitable as solvents, for example, methanol, ethanol, 1- propanol, 2-propanol, isomers of butanol, and isomers of pentanol. Esters may also be used, such as ethyl acetate. When an ester or an alcohol is used as solvent, the product is usually the corresponding ester of the carboxylic acid. Most highly preferred are ethers, especially tetrahydrofuran, or mixtures of one or more ethers and one or more ketones, especially mixtures of tetrahydrofuran and diethylketone. When solvents are used, the amount can be up to 100 mL per gram of the arylated olefin product, but the process is most advantageously conducted in the presence of 1 to 30 mL per gram of the arylated olefin product.

In those specific embodiments of this invention in which an ester is produced, the ester may be conveniently converted to the acid by conventional methods of hydrolysis. Base hydrolysis can also be employed if desired to produce pharmaceutically acceptable salts wherein the cation is sodium, potassium, calcium, hydrogen carbonate or a quaternary ammonium compound. Workup and Recovery of Carboxylation Product

As noted above, the carboxylation reaction forms a reaction product composition comprising a carboxylic acid or a carboxylic acid derivative (formula IV above), such as, for example, 2-(3-benzoylphenyl)propionic acid or an ester thereof (depending on whether water or an alcohol is used in the carboxylation process), and a liquid medium comprising polar organic solvent (preferably one or more ketones), water and/or alcohol, HCl, and preferably at least one ether (e.g., THF) with a boiling temperature below that of at least one such polar solvent. Also present are catalyst residues and typically some coproducts formed during the reaction. One preferred workup procedure for recovering the desired carboxylic acid product is illustrated in the Example presented hereinafter.

Other workup procedures developed in these laboratories which may be used for effecting the workup of carboxylic acid product produced in accordance with this invention are procedures set forth in commonly-owned copending U.S. application Serial No. 08/780,308, filed January 8, 1997. Such procedures are as follows:

The carboxylic acid is converted in situ into an inorganic salt of such acid by reaction with an aqueous solution of inorganic base (neutralization step). In addition, when the reaction product composition contains (i) at least one low boiling ether (e.g. , THF) and/or (ii) at least one low boiling polar solvent, where either or both such low boiling materials boil(s) below the boiling temperature of at least one polar solvent contained in the reaction product mixture, some or all of such low boiling materials are distilled from the reaction product composition (distillation step). If the reactor overheads are susceptible to attack by aqueous HCl, the neutralization step should precede or at least be conducted concurrently with the distillation step. On the other hand, if the reactor overheads are formed from acid-resistant materials of construction, the distillation step can precede and/or follow and/or be conducted concurrently with the neutralization step; the HCl in the mixture will not cause excessive corrosion of the reactor overheads even if the distillation precedes the neutralization. In whatever sequence the neutralization step and the distillation step are conducted, a mixture of residual organic phase and an aqueous phase containing dissolved inorganic salt of the carboxylic acid remain in the reactor as a distillation residue (distilland or pot residue). These phases are separated from each other. The aqueous phase is then subjected to a distillation, preferably at or near atmospheric pressure, to remove residual organic impurities such as, for example, THF and DEK. At this point it is desirable to ensure that the residual aqueous phase has a concentration in the range of 10 and 35 wt% of dissolved inorganic salt of the arylcarboxylic acid or substituted arylcarboxylic acid and where necessary, adjusting the concentration of the aqueous phase to 10 and 35 wt% solution by removal or addition of water. The aqueous solution is then washed (extracted) with substantially non-polar liquid organic solvent (preferably a paraffinic solvent, or an aromatic hydrocarbon solvent, such as toluene or xylene), preferably at least twice. The free arylcarboxylic acid or substituted arylcarboxylic acid is then produced by mixing non-oxidizing mineral acid (e.g., sulfuric acid) with the aqueous phase in the presence of substantially non-polar liquid solvent to form (i) an organic phase composed of a solution of arylcarboxylic acid or substituted arylcarboxylic acid in substantially non-polar liquid solvent and (ii) an aqueous phase. After separating these phases from each other, arylcarboxylic acid or substituted arylcarboxylic acid is crystallized from the substantially non-polar liquid solvent.

The aqueous solution of inorganic base used in the above neutralization step is preferably a 10 to 50 wt% solution of NaOH or KOH. However other inorganic bases that can be used include Na^, K₂O, Ca(OH)₂, CaO, Na^O_;,, K₂CO₃, and other inorganic bases of similar basicity. Such solutions are used in an amount at least sufficient to neutralize the arylcarboxylic acid or substituted arylcarboxylic acid and the HCl present in the reaction product composition.

When the carboxylation reaction is conducted using an alcohol so that an ester of the arylcarboxylic acid or substituted arylcarboxylic acid is present in the reaction product composition, it is preferred to saponify the ester in situ by mixing a concentrated aqueous solution of a strong inorganic base such as NaOH or KOH with the reaction product composition and applying sufficient heat (e.g., heating to a temperature in the range of up to about 80 °C) to form the inorganic salt of the arylcarboxylic acid or substituted arylcarboxylic acid. Then the workup procedure for the carboxylation product as described above is carried out.

The low boiling materials recovered in the initial distillation step are preferably recycled for use in the hydrocarboxylation reaction.

Some examples of compounds that can be produced by use of the invention include

2-(3-benzoylphenyl)propionic acid (also known as ketoprofen),

2-(3-benzoylphenyl)butanoic acid, 2-(3-benzoylphenyl)pentanoic acid,

2-(3-benzoylphenyl)hexanoic acid,

2-(3-benzoylphenyl)heptanoic acid,

2-(3-benzoylphenyl)octanoic acid,

2-(3-benzoylphenyl)decanoic acid, 2-(3-benzoylphenyl)-5-methylhexanoic acid,

2-(3-benzoyl-5-nitrophenyl)propionic acid,

2-(3-benzoyl-6-nitrophenyl)propionic acid,

2-[3-(4-methoxybenzoyl)phenyl]propionic acid,

2-[3-(4-ethoxybenzoyl)phenyl]propionic acid, 2-[3-(4-propoxybenzoyl)phenyl]propionic acid,

2-[3-(4-butoxybenzoyl)phenyl]propionic acid,

2-[3-(4-methylthiobenzoyl)phenyl]propionic acid,

2- [3 -(4-ethy lthiobenzoy l)pheny 1] propionic acid ,

2-[3-(4-(propylthiobenzoyl)phenyl]propionic acid, 2-[3-(4-(butylthiobenzoyl)phenyl]propionic acid,

2-[3-(2-methylbenzoyl)phenyl]propionic acid,

2- [3 -(4-methy lbenzoy l)pheny ljpropionic acid ,

2-[3-(4-methoxybenzoyl)-5-nitrophenyl]butanoic acid, and analogous acids, as well as alkyl esters, and alkali metal, ammonium, alkaline earth metal, quaternary ammonium, and quaternary phosphonium salts thereof.

The practice of this invention is illustrated by the following non-limiting example in which the following designations are used: BBP is m-bromobenzophenone, NMDP is neomenthyldiphenylphosphine, DEK is diethyl ketone, TEA is triethylamine, and VBP is m-vinylbenzophenone. Unless otherwise specified, all parts and percentages in the examples are by weight. EXAMPLE

Preparation of m-Bromobenzophenone

Charge A1C1₃ (10 g, 1.3 eq) and Br₂ (12.5 g, 1.3 eq) to a reactor at room temperature and slowly add PhCOCl (8.0 g, 1.0 eq). (Note: exothermic reaction!) Heat the mixture at 47-54 °C and monitor the reaction by GC. A 95% conversion was achieved in 2-3 hours. Add PhΝO₂ (5.0 g, 0.7 eq) and remove excess Br₂ by bubbling nitrogen through the reaction mixture at 55-60 °C. Add benzene (9.0 g, 2.0 eq) at 55 °C and stir the mixture for 0.5 hr. (Note: exothermic reaction! Thus the reaction mixture may be added to benzene to control heat formation.) Pour the reaction mixture onto crushed ice (30 g) and stir the mixture for 1 hr. Add toluene (20 mL) with stirring and phase cut. (Note: toluene may be eliminated.) Remove toluene/H_jO under reduced pressure and distill PhNO- off (55 °C at 1 mm Hg, pot temperature = 100°C). GC analysis showed 3.7 area% PhNO₂. Remove the heat and add hexanes through a condenser very slowly (21 g, 1.5 eq of theoretical BBP weight). Cool to room temperature with stirring and filter to give an off-white solid (about 80% yield), mp = 72-74°C. Preparation of m-Vinylbenzophenone

Charge PdCl₂ (6.0 mg, 0.0005 eq), NMDP (66 mg, 0.003 eq) and BBP (17.5 g, 1.0 eq) to a 100-mL autoclave in a drybox. Add Et,N (7.85 g, 1.15 eq) and DEK (32 mL) via syringe. Purge the reactor with ethylene and then pressurize with ethylene to 200 psig. Heat the mixture at 95 °C and keep ethylene at 400-450 psig. Cool to room temperature after complete conversion (8 hr), and then release pressure. Filter TEA/HBr salt off and wash the solid with DEK (35 mL). (Note: about 97% salt recovery.) Wash the filtrate with HCl (IN, 20 mL) and 20% aqueous ΝaCl (20 mL). Concentrate under reduced pressure to form a yellow oil (about 99% crude yield). (Note: The dimer is almost insoluble in hexanes and VBP is soluble in hexanes.) Purification with hexanes gave a yellow oil (about 93 % yield) and a light brown powder (0.57 g, about 4%). Preparation of 2-.3-Benzoylphenyl)propionic Acid Charge PdCl₂ (6.0 mg, 0.0005 eq), CuCl₂ (12 mg, 0.00013 eq), and ΝMDP

(66 mg, 0.003 eq) to a 100-mL autoclave in a drybox. Add a solution of VBP (14.0 g, 1.0 eq) in THF (30 mL) and then add HCl (10%, 5.4 g, 4.0 eq) and THF (10 mL) via syringe. Purge the reaction with CO and pressurize with CO to 250 psig. Heat the reaction mixture at 75 °C and keep CO pressure at 300-350 psig. Cool to room temperature after complete conversion (4.5 hr) and release the pressure. Add aq. NaOH (ca. 25% , 11.9 g NaOH with 35 g H₂O) and remove THF by rotary evaporation. Heat the resulting red solution at 75-80°C for 1 hr. Dilute with H,O (50 g) and remove the insoluble brown solid (0.3 g, dry weight) by filtration. Wash the filtrate with CH₂C1₂ (3 x 40 mL) and acidify the aqueous phase with cone. H_jSO,,, (8.2 g) to pH < 1. Extract with CH₂C1₂ (3 x 50 mL) and wash the combined organic layers with H₂O (2 x 30 mL). Concentrate under reduced pressure to give a yellow syrup

(about 94% yield). It solidified in hexanes at 0°C. Dry under vacuum to give 2-(3- benzoylphenyl)propionic acid (ketoprofen) as a slightly yellow solid (about 90% yield), mp = 93-95 °C.

It is to be understood that the reactants and components referred to by chemical name or formula anywhere in the specification or claims hereof, whether referred to in the singular or plural, are identified as they exist prior to coming into contact with another substance referred to by chemical name or chemical type (e.g. , another reactant, or a solvent). It matters not what preliminary chemical changes, transformations and/ or reactions, if any, take place in the resulting mixture or solution or reaction medium as such changes, transformations and/or reactions are the natural result of bringing the specified reactants and/or components together under the conditions called for pursuant to this disclosure. Thus the reactants and components are identified as ingredients to be brought together in connection with performing a desired chemical reaction or in forming a mixture to be used in conducting a desired reaction. Accordingly, even though the claims hereinafter may refer to substances, components and/or ingredients in the present tense ("comprises", and/or "is"), the reference is to the substance, component or ingredient as it existed at the time just before it was first contacted, blended or mixed with one or more other substances, components and/or ingredients in accordance with the present disclosure. Without limiting the generality of the foregoing, as an illustrative example, where a claim specifies that a catalyst is a palladium compound in combination with a tertiary phosphine ligand, this phraseology refers to the makeup of the individual substances before they are combined and/or mixed separately or concurrently with one or more other materials, and in addition, at the time the catalyst is actually performing its catalytic function it need not have its original makeup — instead whatever transformations, if any, that occur in situ as the catalytic reaction is conducted is what the claim is intended to cover. Thus the fact that a substance, component or ingredient may have lost its original identity through a chemical reaction or transformation during the course of contacting, blending or mixing operations, if conducted in accordance with this disclosure and with the application of common sense and the ordinary skill of a chemist, is thus wholly immaterial for an accurate understanding and appreciation of the true meaning and substance of this disclosure and the claims thereof.

The term "substantially" is used in this specification and in the claims to avoid the possibility of an erroneous assertion that what is being described or claimed refers to an absolute. As those of ordinary skill in chemistry readily understand, absolutes in respect to chemical reactions are the exception rather than the rule; usually small amounts of undesired materials (e.g., impurities) can be tolerated without materially affecting the desired reaction in an adverse manner. For example reference in the claims to removing substantially all excess bromine from the bromination reaction mixture before proceeding further does not mean that every last trace of bromine must be removed. It simply means that to whatever extent the bromine can be readily removed with the apparatus at hand, it is prudent to do so. Likewise, reference to a solvent being substantially inert means that if it exhibits a small amount of reactivity in the given reaction, this is permissible as long as the desired reaction is not prevented or seriously interfered with. Chemists know these things, but unfortunately, sometimes persons with hypertechnical semantic proclivities are tempted to make an issue out of such matters. Thus the use of the term

"substantially" is used herein as a chemist of ordinary skill would understand it, with the application of common sense.

Claims

1. A process which comprises a) forming a mixture from at least the following ingredients: (i) bromine, (ii) a catalytically effective amount of at least one bromination catalyst, and (iii) at least one aroyl halide, in a mole ratio of at least one mole of (i) per mole of (iii); b) maintaining at least a portion of the mixture formed in a) at one or more temperatures that produce a reaction mixture comprising (i) m-bromoaroyl halide and/or a catalyst complex thereof, and (ii) optionally, excess bromine; c) if excess bromine is present in the reaction mixture from b), removing from such mixture substantially all excess bromine; and d) either (i) mixing and reacting at least one substituted or unsubstituted aromatic compound with at least a portion of the reaction mixture from b) if no excess bromine is present in the reaction mixture from b), to produce a reaction mixture comprising at least one substituted diaryl ketone in which the substitution at least comprises a bromine atom in the meta position of one of its rings directly bonded to the carbonyl group; or (ii) if excess bromine was present in the reaction mixture from b), mixing and reacting at least one substituted or unsubstituted aromatic compound with at least a portion of the reaction mixture from c) to produce a reaction mixture comprising at least one substituted diaryl ketone in which the substitution at least comprises a bromine atom in the meta position of one of its rings directly bonded to the carbonyl group.

2. A process according to Claim 1 wherein excess bromine is employed in a), and wherein in c) substantially all excess bromine is removed from the reaction mixture from b).

3. A process according to Claim 1 wherein the catalyst used in forming the mixture of a) is a Lewis acid catalyst employed in a mole ratio of at least one mole per mole of (iii).

4. A process according to Claim 1 wherein the catalyst used in forming the mixture of a) is A1C1₃ or AlBr₃, and wherein the aroyl halide is an aroyl chloride.

5. A process according to Claim 4 wherein excess bromine is employed in a), wherein the catalyst used in forming the mixture of a) is AlCl_j, wherein the aroyl chloride is benzoyl chloride, and wherein in c) substantially all excess bromine is removed from the reaction mixture from b).

6. A process according to Claim 1 wherein b) and d) are both conducted in the presence of an ancillary substantially inert solvent, and wherein these solvents can be the same or different from each other.

7. A process according to Claim 3 wherein said mole ratio in a) is at least about 1.3 moles of (i) and at least about 1.3 moles of (ii) per mole of (iii).

8. A process according to Claim 1 wherein in d), reaction mixture from b) or from c) as the case may be, is slowly added to at least a stoichiometric amount of said substituted or unsubstituted aromatic compound so as to control the temperature of the resultant exothermic reaction.

9. A process according to Claim 1 wherein a), b), c), and d) are conducted in the same reaction vessel.

10. A process which comprises a) forming a mixture from at least the following ingredients: (i) bromine, (ii) aluminum chloride, and (iii) benzoyl chloride, in a mole ratio of at least about 1.3 moles of (i) and at least about 1.3 moles of (ii) per mole of (iii); b) maintaining at least a portion of the mixture formed in a) at one or more reaction temperatures that produce a reaction mixture comprising (i) m-bromobenzoyl chloride and/or m-bromobenzoyl bromide and/or an aluminum chloride complex of either or both of them, and (ii) excess bromine; c) removing from the reaction mixture from b) substantially all excess bromine; and d) mixing and reacting at least one substituted or unsubstituted aromatic compound with at least a portion of the reaction mixture from which excess bromine was removed in c), to produce a reaction mixture comprising at least one substituted diaryl ketone in which the substitution at least comprises a bromine atom in the meta position of one of its rings directly bonded to the carbonyl group.

11. A process according to Claim 10 wherein the substituted or unsubstituted aromatic compound used in d) is benzene.

12. A process according to Claim 10 wherein in d), said at least a portion of the reaction mixture from which excess bromine was removed is slowly added to the substituted or unsubstituted aromatic compound to control the temperature of the resultant exothermic reaction.

13. A process which comprises a) forming a mixture from at least the following ingredients: (i) bromine, (ii) a catalytically effective amount of at least one bromination catalyst, and (iii) at least one aroyl halide, in a mole ratio of at least one mole of (i) per mole of (iii); b) maintaining at least a portion of the mixture formed in a) at one or more temperatures that produce a reaction mixture comprising (i) m-bromoaroyl halide and/or a catalyst complex thereof, and (ii) optionally, excess bromine; c) if excess bromine is present in the reaction mixture from b), removing from such mixture substantially all excess bromine; d) either (i) mixing and reacting at least one substituted or unsubstituted aromatic compound with at least a portion of the reaction mixture from b) if no excess bromine is present in the reaction mixture from b), to produce a reaction mixture comprising at least one substituted diaryl ketone in which the substitution at least comprises a bromine atom in the meta position of one of its rings directly bonded to the carbonyl group; or (ii) if excess bromine was present in the reaction mixture from b), mixing and reacting at least one substituted or unsubstituted aromatic compound with at least a portion of the reaction mixture from c) to produce a reaction mixture comprising at least one substituted diaryl ketone in which the substitution at least comprises a bromine atom in the meta position of one of its rings directly bonded to the carbonyl group; e) reacting at least a portion of said substituted diaryl ketone formed in d) with a vinylic olefin compound in a palladium-catalyzed arylation of the olefin compound to produce a reaction mixture comprising at least one substituted diaryl ketone in which the substitution at least comprises an olefinic substituent in the meta position of one of its rings formerly occupied by a bromine atom; and f) reacting at least a portion of said substituted diaryl ketone formed in e) with carbon monoxide in a palladium-catalyzed hydrocarboxylation or hydrocarb- alkoxylation in the presence of water or alcohol to produce a reaction mixture comprising at least one substituted diaryl ketone in which the substitution at least comprises (i) if water is used, an alkylcarboxylic acid moiety in the meta position formerly occupied by the olefinic substituent, or (ii) if an alcohol is used, an alkylcarboxylic acid alkyl ester moiety in the meta position formerly occupied by the olefinic substituent.

14. A process according to Claim 13 wherein f) is conducted in the presence of water and hydrochloric acid to produce a substituted diaryl ketone in which the substitution at least comprises an alkylcarboxylic acid moiety in the meta position formerly occupied by the olefinic substituent.

15. A process according to Claim 14 wherein in e) and in f) the respective palladium catalysts are formed from (i) palladium and/or at least one palladium compound in which the palladium has a valence of zero, 1 or 2, and (ii) at least one tertiary phosphine.

16. A process according to Claim 14 wherein in e) the palladium catalyst is formed from (i) palladium and/or at least one palladium compound in which the palladium has a valence of zero, 1 or 2, and (ii) at least one tertiary phosphine; and wherein in f) the palladium catalyst is formed from (i) palladium and/or at least one palladium compound in which the palladium has a valence of zero, 1 or 2, (ii) at least one copper compound, and (iii) at least one tertiary phosphine.

17. A process according to Claim 14 wherein in e) and in f) the respective palladium catalysts are formed from (i) a palladium(II) halide or carboxylate salt, and (ii) at least one tertiary phosphine having two aryl groups and one cycloalkyl group.

18. A process according to Claim 17 wherein the respective palladium catalysts are formed from palladium(II) chloride and neomenthyldiphenylphosphine.

19. A process according to Claim 14 wherein in e) the palladium catalyst is formed from (i) a palladium (II) halide or carboxylate salt, and (ii) at least one tertiary phosphine having two aryl groups and one cycloalkyl group; and wherein in f) the palladium catalyst is formed from (i) a palladium (II) halide or carboxylate salt, (ii) a copper halide salt, and (iii) at least one tertiary phosphine having two aryl groups and one cycloalkyl group.

20. A process according to Claim 19 wherein in e) the palladium catalyst is formed from palladium(II) chloride and neomenthyldiphenylphosphine, and wherein in f) the palladium catalyst is formed from palladium(II) chloride, copper(II) chloride and neomenthyldiphenylphosphine .

21. A process according to Claim 13 wherein excess bromine is employed in a), and wherein in c) substantially all excess bromine is removed from the reaction mixture from b).

22. A process according to Claim 13 wherein the bromination catalyst used in forming the mixture of a) is a Lewis acid catalyst employed in a mole ratio of at least one mole per mole of (iii).

23. A process according to Claim 22 wherein the Lewis acid catalyst used in forming the mixture of a) is A1C1₃ or AlBr₃ , and wherein the aroyl halide is an aroyl chloride.

24. A process according to Claim 22 wherein b) is conducted in the presence of an ancillary substantially inert solvent.

25. A process according to Claim 13 wherein a), b), c) and d) are all conducted in the same reactor.

26. A process according to Claim 13 wherein the vinylic olefin compound used in e) is linear or branched olefinic hydrocarbon.

27. A process according to Claim 13 wherein the vinylic olefin compound used in e) is ethylene.

28. A process which comprises a) forming a mixture from at least the following ingredients: (i) bromine, (ii) aluminum chloride, and (iii) benzoyl chloride, in a mole ratio of at least about 1.3 moles of (i) and at least about 1.3 moles of (ii) per mole of (iii); b) maintaining at least a portion of the mixture formed in a) at one or more reaction temperatures that produce a reaction mixture comprising (i) m-bromobenzoyl chloride and/or m-bromobenzoyl bromide and/ or an aluminum chloride complex of either or both of them, and (ii) excess bromine; c) removing from the reaction mixture from b) substantially all excess bromine; d) mixing and reacting at least one substituted or unsubstituted aromatic compound with at least a portion of the reaction mixture from which excess bromine was removed in c), to produce a reaction mixture comprising at least one substituted diaryl ketone in which the substitution at least comprises a bromine atom in the meta position of one of its rings directly bonded to the carbonyl group; e) reacting at least a portion of said substituted diaryl ketone formed in d) with a vinylic olefin compound in a palladium-catalyzed arylation of the olefin compound to produce a reaction mixture comprising at least one substituted diaryl ketone in which the substitution at least comprises an olefinic substituent in the meta position of one of its rings formerly occupied by a bromine atom; and f) reacting at least a portion of said substituted diaryl ketone formed in e) with carbon monoxide in a palladium-catalyzed hydrocarboxylation or hydrocarbalkoxylation in the presence of water or alcohol to produce a reaction mixture comprising at least one substituted diaryl ketone in which the substitution at least comprises (i) if water is used, an alkylcarboxylic acid moiety in the meta position formerly occupied by the olefinic substituent, or (ii) if an alcohol is used, an alkylcarboxylic acid alkyl ester moiety in the meta position formerly occupied by the olefinic substituent.

29. A process according to Claim 28 wherein f) is conducted in the presence of water and hydrochloric acid to produce a substituted diaryl ketone in which the substitution at least comprises an alkylcarboxylic acid moiety in the meta position formerly occupied by the olefinic substituent.

30. A process according to Claim 29 wherein the substituted or unsubstituted aromatic compound used in d) is benzene.

31. A process according to Claim 29 wherein the vinylic olefin compound used in e) is linear or branched olefinic hydrocarbon.

32. A process according to Claim 31 wherein the vinylic olefin compound used in e) is ethylene.

33. A process according to Claim 29 wherein a), b), c) and d) are all conducted in the same reactor.

34. A process according to Claim 29 wherein the substituted or unsubstituted aromatic compound used in d) is benzene, wherein the vinylic olefin compound used in e) is ethylene, wherein in e) the palladium catalyst is formed from palladium(II) chloride and neomenthyldiphenylphosphine, and wherein in f) the palladium catalyst is formed from palladium(II) chloride, copper (II) chloride and neomenthyldiphenylphosphine.

35. A process according to Claim 34 wherein a), b), c) and d) are all conducted in the same reactor.

36. A process according to Claim 29 wherein in e) and in f) the respective palladium catalysts are formed from palladium(II) chloride and neomenthyldiphenylphosphine.

37. A process according to Claim 36 wherein a), b), c) and d) are all conducted in the same reactor.