MXPA97006205A - Process for the preparation of olefi - Google Patents

Abstract

The present invention relates to a process, characterized in that it comprises the preparation of an olefinic compound corresponding to the formula C (R3) (R4) = C (R2) A by reaction of an organic compound having the formula AX with a compound vinyl or substituted vinyl having the C (R3) (R4) = C (R2) H in the presence of a catalyst containing (a) palladium or palladium salt and (b) a ligand corresponding to the formula: activated reaction mixture containing a substantial amount of said olefinic compound: in these formulas A is aryl, substituted aryl, heteroaryl, substituted heteroaryl, benzyl, substituted benzyl, vinyl or substituted vinyl, R2, R3 and R4 are independently selected from hydrogen, alkyl, cycloalkyl, substituted alkyl of cycloalkyl, aryl, substituted aryl alkoxy, alkylthio, heteroaryl, substituted heteroaryl, alkanoyl, aroyl, substituted aroyl, heteroarylcarbonyl, substituted heteroarylcarbonyl, trifluoromethyl and halo; X is chlorine, bromine, iodine or diazonium, Ar is phenyl, substituted phenyl, naphthyl or substituted naphthyl, R 'and R "are independently selected from hydrogen, alkyl, aryl or substituted aryl, and n is an integer of

Description

PROCESS FOR THE PREPARATION OF QLEPHINS FIELD OF THE INVENTION The invention relates to a method for the preparation of substituted olefins by means of palladium catalyst coupled to vinyl compounds with organic halides and the subsequent preparation of carboxylic acids or esters.

Ante? Qdenteg Palladium-catalyzed vinylation of organic halides provides a very convenient method for the formation of carbon-carbon bonds in unsubstituted vinyl positions. The reaction, reported by Heck (Palladium Reasents in Organnic Syntheses. Academic Press, Canada 1985) can be used to prepare fine organics, pharmaceuticals, and especially monomers. For example, the reaction allows a one-step synthesis of substituted aryl bromide esters and is an excellent method for the preparation of a wide variety of styrene derivatives.

Heitz et al., Makromol Chem. 1 £ 2, 119 (1968). A new process for preparing aliphatic carboxylic acids substituted with aryl or their alkyl esters is provided in U.S. Pat. No. 5,315,026. A substituted 1-aryl olefin reacts with carbon monoxide in REF: 25366 presence of water or an alcohol at a temperature between 25 ° C and 200 ° C. A mixture of palladium compound and a copper compound with a stable acidic cyclic phosphine having the formula: where R 'is the same or different than R "and is hydrogen, alkyl or aryl, said aryl, substituted or unsubstituted, and Ar is phenyl, naphthyl, substituted phenyl or substituted naphthyl and n is an integer from 3 to 6 used as a catalyst.

Description of Preferred Modes Definitions In the following specification the meaning of the substituent groups is as follows: "alkyl" means straight or branched alkyl chain having from 1 to 20 carbon atoms and includes, for example, methyl, ethyl, propyl , isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, octyl, 2-ethylhexyl, 1, 1, 3, 3, -tetrametilbutilo, nonyl, decyl, dodecyl, tetradecyl, heptadecyl, octadecyl and eicosyl, (for the purposes of this definition, "alkyl" could be replaced by "aliphatic." This term includes "Cs alkyls" which is 1 to 6 linear carbon atoms. or branched); "cycloalkyl" means cyclic alkyl having 3 to 7 carbon atoms and includes, e.g. ex. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; "aryl" means phenyl, naphthyl or biphenyl; "substituted aryl" means phenyl, naphthyl, or biphenyl substituted by at least one substituent selected from the group consisting of aryl (as defined above), halogen (chloro, bromo, fluoro or iodo), amino, nitro, hydroxy, alkyl, alkoxy (which means straight or branched chain alkoxy having from 1 to 10 carbon atoms, and includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, secondary butoxy, tertiary butoxy, pentyloxy, isopentyloxy, hexyloxy, heptyloxy , octyloxy, nonyloxy, decyloxy), aryloxy including phenoxy and phenoxy substituted with halo, alkyl, or alkoxy, haloalkyl which means straight or branched chain alkyl having from 1 to 8 carbon atoms which are substituted by at least one halogen, and includes, for example, chloromethyl, bromomethyl, fluoromethyl, iodomethyl, 2-chloroethyl, 2-bromomethyl, 2-fluoromethyl, 3-chloropropyl, 3-bromopropyl, 3-fluoropropyl, 4-chlorobutyl, 4-fluorobutyl, dichloroethyl, dibromomethyl, diflu romethyl, diiodomethyl, 2,2-dichloroethyl, 2,2-dibromoethyl, 2,2-difluoroethyl, 3,3-dichloropropyl, 3,3-difluoropropyl, 4,4-dichlorobutyl, 4,4-difluorobutyl, trichlororaethyl, trifluoromethyl, 2, 2, 2-trifluoroethyl, 2,3,3-trifluoropropyl, 1, 1,2, 2-tetrafluoroethyl and 2,2,3,3-tetrafluoropropyl; "substituted cycloalkyl alkyl" means that the cycloalkyl compound is cyclic alkyl having 3 to 7 carbon atoms and the alkyl compound is straight or branched chain alkyl having 1 to 8 carbon atoms and includes, for example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, 2-cyclopropylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, 3-cyclopropylpropyl, 3-cyclohexylpropyl, 4-cyclopropylbutyl, 4-cyclopentylbutyl, 4-cyclohexylbutyl, 6-cyclopropylhexyl and 6-cyclohexylhexyl; "alkylthio" means a sulfur divalent with alkyl occupying one of the valences and includes the groups methylthio, ethylthio, propylthio, butylthio, pentthylthio, hexylthio and octylthio; "heteroaryl" means 5 to 10 mono- or fused-hetero-aromatic rings having at least one heteroatom and includes those selected from the group consisting of nitrogen, oxygen and sulfur, and includes, for example, 2-furyl, 3-furyl, 2-dienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazolyl, imidazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzimidazolyl, quinolyl, oxazolyl, thiazolyl and indolyl; "substituted heteroalyl" means 5 to 10 mono- or fused-hetero-aromatic having at least one heteroaromatic selected from a group consisting of nitrogen, oxygen and sulfur and which is substituted by at least one substituent selected from a group consisting of halogen, amino, nitro, hydroxy, alkyl, alkoxy and haloalkyl in the aforementioned heteroaromatic nucleus; "alkanoyl" means alkanoyl having from 2 to 18 carbon atoms and includes, for example, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl, haxanoyl, octanoyl, lauroyl and stearoyl; "Aroyl" means benzoyl or naphthoyl; "substituted aroyl" means benzoyl or naphthoyl substituted by at least one substituent including those selected from a group consisting of halogen, amino, nitro, hydroxy, alkyl, alkoxy and haloalkyl in the benzene and naphthalene ring; "heteroarylcarbonyl" means that the heteroaryl compound is 5 to 10 mono- or fused-heteroaromatic rings having at least one heteroatom and includes those selected from the group consisting of nitrogen, oxygen and sulfur as mentioned above, and includes, example, furoyl, tinoyl, nicotinoyl, isonicotinoyl, pyrazolylcarbonyl, imidazolylcarbonyl, pyrimidinylcarbonyl and benzimidazolylcarbonyl; "substituted heteroarylcarbonyl" means the aforementioned heteroarylcarbonyl which is substituted by at least one substituent selected from a group consisting of halogen, amino, nitro, hydroxy, alkoxy and haloalkyl in the heteroaryl nucleus; and includes, for example, 2-oxo-l, 3-dioxollan-4-ylmethyl, or 2-oxo-l, 3-dioxan-5-yl; "vinyl" means an unsaturated substituent having at least one unsaturated double bond and having the formula CH, = CH-; "substituted vinyl" means the above vinyl substituent having at least one of the protons at the terminal carbon atom replaced with alkyl, cycloalkyl, substituted alkyl of cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl. In one of the embodiments of the present invention, olefin compounds are produced having the formula: where R2, R3 and R are the same or different and are individually hydrogen, alkyl, cycloalkyl, substituted alkyl cycloalkyl, substituted or unsubstituted aryl, alkoxy, alkylthio, substituted or unsubstituted heteroalyl, alkanoyl, substituted or unsubstituted aroyl, unsubstituted or substituted heteroarylcarbonyl, trifluoromethyl or halo, and A is aryl, substituted aryl, heteroaryl, substituted heteroaryl, benzyl, substituted benzyl, vinyl or substituted vinyl. Preferably, in the compounds of formula II, A is substituted or unsubstituted aryl, R 2, R 3 and R "are hydrogen, from Ci to Cs alkyl, phenyl or substituted or unsubstituted trifluoromethyl. More preferably A is phenyl substituted with alkyl (eg, isobutyl) or naphthyl substituted with alkoxy (eg, methoxy), R 2, R 3 and R * are hydrogen, methyl or trifluoromethyl, especially hydrogen. The compounds of Formula II are produced by reaction of an organic halide of Formula AX where X is chlorine, bromine, iodine, diazonium, triflate, or other leaving groups found in organic texts, and A as defined above, with a vinyl or substituted vinyl compound of the formula RJ l = c / RR_H where R, R3 and R "are as previously defined. The reaction, sometimes called the "vinylation" reaction, is carried out in the presence of a reaction promoter catalyst which is palladium metal or palladium compound (Pd) with Pd of valence 0, 1 or 2 and a cyclic ligand of formula ( where R 'and R "are the same or different and are individually hydrogen, alkyl, aryl or substituted aryl, Ar is phenyl, naphthyl, substituted phenyl or substituted naphthyl and n is an integer from 3 to 6. Preferably R1 and R" are the same or different and are alkyl of a Cß, Ar is phenyl or naphthyl and n is 3 or 4. More preferably R * is methyl or ethyl, R "is a branched alkyl of Cx to Cs, Ar is phenyl and n is 4. Preferred especially neomentildiphenyl-phosphine co or cyclic ligand The vinylation reaction is carried out in the presence or in the absence of a solvent When a solvent is used, it may be a polar solvent such as, for example, acetonitrile, tetrahydrofuran, dioxane or dimethylformamide.

The conditions for the vinylation reaction usually require an equimolar ratio of organic halide to vinyl or substituted vinyl compound, although an excess of vinyl compound is preferred. The catalyst / ligand ratio is typically used in a ratio of 1 mol of organic halide to 0.0005 mol of palladium or palladium compound. The cyclic ligand is present in the same or greater molar ratio as the metal or metal compound. It should be noted that levels of palladium metal or palladium compound and ligand can be substantially higher (up to 10 times). When relatively inactive vinyl or halide species are found, for example, highly substituted olefins and / or Strongly stable organic halides substituents that donate electrons may require these high amounts of catalyst / ligand. The reaction temperatures are very moderate, varying between 25 ° C to 200 ° C (preferably 60 ° C to 150 ° C) with pressures (for gaseous vinyl compounds) being from atmospheric to 3000 psi (preferably 400 to 1000 psi) . With the improved catalyst combination of the present invention, the reaction times are unusually short, typically giving the complete reaction between 1 to 24 hours, typically 2 to 4 hours. Higher temperatures and pressures tend to cause decomposition of reagents and olefin products and this should be avoided. The olefin formed in the reaction mixture is easily separated by conventional methods, e.g. ex. , distillation or extraction with a non-polar solvent, p. ex. , liquid hydrocarbons such as hexane having from 5 to 12 carbon atoms both linear or branched. A further embodiment of the present invention is one in which the olefin compound of Formula II can be used with or without isolation (preferably without isolation) of the reaction mixture in the catalytic carboxylation step to produce compounds of Formula III where RL, R2, R3, R «and A are as previously defined.

The catalytic carboxylation of the compound of Formula II is carried out, at a temperature between 25 ° C and 200 ° C, preferably of 25"- 120 ° C, and more preferably 25 ° - 100 ° C. High temperatures can also be used. has found that a small performance advantage is obtained by gradually increasing the temperature in the preferred range during the course of the reaction.The partial pressure of the carbon monoxide in the reaction vessel is at least one atmosphere (0 psig). ) at room temperature (or the temperature at which the container is fed) Some higher carbon monoxide pressures may be used up to the pressure limits of the reaction apparatus A pressure up to about 3000 psig is desirable in the process. is a pressure of 0 to 3000 psig at the reaction temperature and more preferred is a reaction of 0 to 1000 psig It should be noted that the presence of oxygen is undesirable in the reaction n hydrocarboxylation of this invention. Because of this, a 100% atmosphere of carbon monoxide is preferred for carry out this process. Several inert gases (eg, nitrogen and argon) can, however, be incorporated into the reaction mass, the only criterion being that the process should not be delayed at the point requiring exceptionally long periods to complete the reaction. Carboxylation is carried out in the presence of at least one mole of water or aliphatic alcohol per mole of the compound of Formula II; however, an excess is preferred to aid in driving the entire reaction. Although there is no actual upper limit for the amount of water or alcohol except that imposed by practice (eg the size of the reaction vessel), an amount of up to about 100 moles per mole of the compounds of Formula II is useful in the process. Furthermore, controlling the amount of water or alcohol used in the process of this invention is advantageous in terms of producing higher yields. Accordingly, an amount of 1 to 50 moles of water or alcohol per mole of the compounds of Formula II is preferred, and an amount of 2 to 24 moles of water or alcohol per mole of such olefinic compound is more preferred. The product of the reaction is a carboxylic acid (where Rt is hydrogen) or carboxylic acid ester (where Ri is alkyl) of Formula III. The present invention encompasses any individual racemate and optical isomers of the compounds of Formula III that have a chiral carbon atom. For example, when the compounds of Formula III wherein the acid is 2- (6-methoxy-2-naphthyl) propionic acid, they are subjected to resolution as set forth in U.S. Pat. 4,246,164, the analgesic compound naproxen is produced. Any alcohol that produces an ester of the carboxylic acid could be used in the practice of this invention. In a preferred embodiment, aliphatic alcohols Cj are used. to C «. 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, pentyl alcohols, (isoamine alcohol, especially form the naproxen ester), and the hexyl alcohols. Methyl alcohol is highly preferred, and methyl alcohol is much preferred. Other alcohols, glycols, or aromatic hydroxy compounds could also be used. In the broadest sense, these alcohols provide a source of alkoxide ions for this reaction. However, any other "alkoxide ion source" could also be used. The source of such ions is a compound selected from the group consisting of HCOROR, (R) 2C (ORx) a, HC (0) ORlf BÍOR ,, Ti (0Rx) 4, Al (0Rt) 3 where R is hydrogen or individually the same or different than Rt and Ri is as previously defined. In a preferred embodiment of this invention, the carboxylation reaction is initiated under neutral conditions, e.g. ex. , without adding acid. It can also develop in the presence of an acid addition. When the acids are added, such acids include sulfuric acid, phosphoric acid or sulfonic acid. A hydrogen halide acid such as hydrochloric or hydrobromic acid is preferred. The hydrogen halide could be added in the gas phase or in the liquid phase. Any concentration could be used. Hydrochloric acid is particularly preferred, in a concentration of up to 10%; more preferred is a concentration of 10% to 30%. The amount of acid added is such that it provides up to 40 moles of hydrogen ion per mole of the compound of Formula II; more preferred is an amount to provide up to 10 moles of hydrogen ion per mole of the compound; the most preferred amount provides up to 4 moles of hydrogen ion per mole of the compounds of Formula II. The catalytic carboxylation process of this invention is carried out in the presence of an amount that promotes the reaction of (i) palladium metal or palladium compounds in which the palladium has a valence of zero, 1 or 2, or (ii) a mixture of palladium or palladium compound and a copper compound, with (iii) the cyclic ligand of Formula I. The palladium and copper compounds are sometimes referred to as palladium and copper salts.

In one embodiment, the palladium and copper compounds are inorganic salts and are added as a preformed complex of, for example, palladium (II) chloride or bromide, copper (II) chloride or bromide and carbon monoxide or any other complex Similary. In a preferred embodiment, the active catalyst species are formed in situ by the addition to the reaction mixture of the individual components, e.g. ex. , a ligand, a copper compound and a palladium compound such as the inorganic salts of palladium (II) and copper (II). These inorganic salts include chlorides, bromides, nitrates, sulfates or acetates. In the most preferred embodiment, neomentildiphenylphosphine, copper (II) chloride and palladium (II) chloride are used and are added individually or together, simultaneously or sequentially. The metallic palladium or the palladium compound of the mixture of palladium and copper compounds can be supported on carbon, silica, alumina, zeolite, clay, other polymeric materials and used as heterogeneous catalysts. The amount of the mixture of copper and palladium or palladium metal compounds or their compounds preferably employed is such as to provide from 4 to 8000 moles of the compound of Formula II per mole of the metal or metal salt mixture. More preferable, 1 to 40 moles of ligand per mole of the mixture, and more preferably 1 to 20 moles of the ligand are used per mole of the mixture. The presence of a solvent in the process of this invention is not required, although it may be desirable in some circumstances. Solvents that can be used include one or more of the following: ketones, for example, acetone, methyl ethyl ketone, diethyl ketone, methyl n-propyl ketone and acetophenone; linear, poly and cyclic esters, for example, diethyl ether, di-n-propyl ether, di-n-butyl ether, ethyl n-propyl ether, glime (ethylene glycol dimethyl ether), diglyme (diethylene glycol dimethyl ether) , tetrahydrofuran, dioxane and 1,3-dioxolane; and aromatic hydrocarbons, for example, toluene, ethylbenzene and xylenes. Alcohols are also suitable as solvents, for example, methanol, ethanol, 1-propanol, 2-propanol, isomers of butanol and isomers of pentanol. Acids and esters, such as formic or acetic acid or ethyl acetate, could also be used. When an ester or alcohol is used as a solvent, the product is the corresponding ester of the carboxylic acid. More highly preferred are the ethers, especially tetrahydrofuran. When solvents are used, the amount can be up to 100 mL per gram of the compounds of Formula II, but the process is more advantageously carried out in the presence of 1 to 30 mL per gram of the compound of Formula II.

In the preferred embodiments of this invention in which an ester is produced, e.g. ex. alkyl ibuprofen ester, the ester could conveniently be converted to the acid (the same ibuprofen) by conventional methods of hydrolysis. The hydrolysis base can also be employed if it is desired to produce pharmaceutically acceptable salts wherein the cation is sodium, potassium, calcium, acid carbonate or a quaternary ammonium compound. Examples of compounds produced by the use of this invention include ibuprofen; 2- (6-methoxy-2-naphthiDpropionic acid; 2- (3-fluoro-4-biphenylyl) -propionic acid (also known as flurbiprofen) and 2- (3-bezoylphenyl) propionic acid (also known as ketoprofen).

As described herein the bromine precursor of each of the above compounds reacts with ethylene in the presence of a base (e.g., triethylamine) and a palladium catalyst (as described herein, including a ligand such as neomentildiphenylphosphine). The base should be selected to avoid beta hydride removal under reaction conditions and should not react with the olefin or bromine precursor to any appreciable degree. The bromine precursor substituted by ethylene provides the substituted olefin which is then carboxylated (using carbon monoxide and palladium catalyst as described herein) to produce the corresponding acid product (if the water is part or is all the system solvent) or the corresponding ester (if an alcohol such as methyl, ethyl or isoamyl alcohol) is used as all or part of the solvent. The above reactions can be exemplified as follows: 1BUPROPENO FLURBIPROBßHO CETOPROPHENE © nrj, ...., -c? Qfc H = C H. CO C H COOH NAPROXEN ROXENO PHENOPROPHENE In the above reactions the ethylene pressure should be 50 to 3000 psi (preferably 400 to 1000 psi), the temperature is 30QC to 200ßC (preferably 60 °C to 150ßC). The temperatures and pressures are selected to minimize the decomposition of olefin. Palladium '* "is used in the form of its salts (eg, acetate or chloride) together with a ligand as described with the preferred phosphine ligands.

Bromine precursors are often commercially available and / or can be easily prepared by art practices. For example, Aldrich Chemical Company sells m-bromophenol and m-bromoanisole while Albermale PCC (Paris, France) sells 6-methoxy-2-bromonaphthalene. Ibuprofen bromide precursors can be prepared by methylbenzoate bromination (or a similar minor hydrocarbon ester) using aluminum chloride followed by hydrolysis of NaOH, conversion to acid chloride (e.g., with SOC1,) and reaction with benzene (again, using a Friedel-Crafts catalyst such as A1C13). In addition to the prophene compounds described above, other prophene compounds that can be prepared by the use of this invention to convert to the corresponding bromine precursors by means of the reaction with ethylene include protic acid, thiaprofenic acid, indoprofen, benoxaprofen, carprofen, pirprofen, pranoprofen, alminoprofen, suprofen and loxoprofen. The following examples are given to illustrate the process of this invention and it is not intended to do so as a limitation thereof.

EXAMPLES NMDP = Neomentildiphenylphosphine IBS = 4-Isobutylstyrene BIBB = 4-Bromoisobutylbenzene DIBE a i,? -Bis (4-isobutylphenyl) ethylene DIBS = 4,4'-Diisobutylstilbene Example i Pd (OAc) 2 (11.0 mg, 0.0490 mmol) and NMDP (0.100 g, 0.308 mmol) were loaded in an autoclave (Hastelloy C, 100 mL) in a dry box. The reactor was assembled in the dry box and mounted on the cover. CH3CN (12.5 mL), Et3 N (12.5 mL) and BIBB (10.6 g, 49.7 mmol) were added via syringe. The reactor was purged with ethylene (2x150 psig) and then filled with ethylene (280 psig). The mixture was stirred at 120-125CC for 2 h. The GC analysis of an aliquot showed IBS (95.5% of the area), DIBE (0.6%), and DIBS (4.0%).

Example 2. Pd (OAc) 2 (11.0 mg, 0.0490 mmol) and NMDP (0.100 g, 0.308 mmol) were charged in an autoclave (Hastelloy B, 100 mL) in a dry box. The reactor was assembled in the dry box and mounted on the cover. CH3CN (12.5 mL), Et3 N (12.5 mL) and BIBB (10.6 g, 49.7 mmol) were added via syringe. The reactor was purged with ethylene (2x150 psig) and then filled with ethylene (320 pßig). The mixture was stirred at 100-105 ° C for 2 h. The GC analysis of an aliquot showed IBS (97.6% of the area), DIBE (0.1%), and DIBS (2.4%).

Bj? I? Pln 1 Pd (OAc) 2 (11.0 mg, 0.0490 mmol) and NMDP (0.100 g, 0.308 mmol) were loaded in an autoclave (Hastelloy C, 100 mL) in a dry box. The reactor was assembled in the dry box and mounted on the cover. CH3CN (12.5 mL), Et3 N (12.5 mL) and BIBB (10.6 g, 49.7 mmol) were added via syringe. The reactor was purged with ethylene (2x150 psig) and then filled with ethylene (330 psig). The mixture was stirred at 80-85 ° C for 4 h. The GC analysis of an aliquot showed IBS (97.9% of the area) and DIBS (2.0%).

Example 4 (Comparative) Pd (0Ac) 2 (11.0 mg, 0.0490 mmol) and (o-Tol) 3P (94.0 mg, 0.309 mmol) were loaded in an autoclave (Hastelloy B, 100 mL) in a dry box. The reactor was assembled in the dry box and mounted on the deck. CH3CN (12.5 mL), Et3 N (12.5 mL) and BIBB (10.6 g, 49.7 mmol) were added via syringe. The reactor was purged with ethylene (2x150 psig) and then filled with ethylene (330 psig). The mixture was stirred at 80-85 ° C for 8 h. The GC analysis of an aliquot showed IBS (24.0% of the area), BIBB (76.0%), and DIBS (trace).

Example 5 (ComparatiYQ-Pd (OAc) 2 (11.0 mg, 0.0490 mmol) and (Cyclohexyl) 3P (87.0 mg, 0.310 mmol) were loaded in an autoclave (Hastelloy B, 100 mL) in a dry box. in the dry box and mounted on the cover CH3CN (12.5 mL), Et3 N (12.5 mL) and BIBB (10.6 g, 49.7 mmol) were added via syringe The reactor was purged with ethylene (2x150 psig) and then filled with ethylene (300 psig) .The mixture was stirred at 80-85eC for 8 h.The GC analysis of an aliquot showed no reaction.

Example 6 (CgnparatiyjpJ.Pd (OAc) 2 (11.0 mg, 0.0490 mmol) and Ph3P (81.0 mg, 0.309 mmol) were loaded in an autoclave (Hastelloy B, 100 raL) in a dry box The reactor was assembled in the box dried and mounted on the cover CH3CN (12.5 mL), Et3 N (12.5 mL) and BIBB (10.6 g, 49.7 mmol) were added via syringe The reactor was purged with ethylene (2x150 psig) and then filled with ethylene (320 psig) The mixture was stirred at 80-85 ° C and monitored by GC, Bl GC analysis of an aliquot in 8 h showed IBS (14.4% GC area), BIBB (84.6%), and DIBS (trace) . yjffipifi 7 Pd (OAc) 2 (5.0 mg, 0.022 mmol) and NMDP (45 mg, 0.14 mmol) were loaded in an autoclave (Hastelloy B, 100 mL) in a dry box. The reactor was assembled in the dry box and mounted on the cover. CH3CN (14 mL), Et3 N (14 mL) and BIBB (11.8 g, 55 mmol) were added via syringe. The reactor was purged with ethylene (2x150 psig) and then filled with ethylene (280 psig). The mixture was stirred at 100-105CC for 4 h. The GC analysis of an aliquot showed IBS (97.8% of the area) and dimers (2.2%).

Example 8 PdCl2 (9.0 mg, 0.0510 mmol) and NMDP (0.100 g, 0.308 mmol) were charged in an autoclave (Hastelloy C, 100 mL) in a dry box. The reactor was assembled in the dry box and mounted on the cover. CH3CN (12.5 mL), Et, N (12.5 mL) and BIBB (10.7 g, 50.2 mmol) were added via syringe. The reactor was purged with ethylene (2x150 psig) and then filled with ethylene (300 psig). The mixture was stirred at 80-85 ° C for 4 h. The GC analysis of an aliquot showed IBS (98.2% of the area), DIBE (0.1%), and DIBS (1.6%).

Using 9 PdCl2 (9.0 mg, 0.0510 mmol) and NMDP (0.100 g, 0.308 mmol), CaO (1.5 g, 26.7 mmol) were loaded in an autoclave (Hastelloy C, 100 mL) in a dry box. The reactor was assembled in the dry box and mounted on the cover. DMF (30 mL) and BIBB (10.6 g, 49.7 mmol) were added via syringe. The reactor was purged with ethylene (2x150 psig) and then filled with ethylene (360 psig). The mixture was stirred at 80-85 ° C for 6 h. The GC analysis of an aliquot showed IBS (95.9% of the area), BIBB (2.0%), DIBE (0.1%), and DIBS (2.1%).

Example 1Q PdCl2 (9.0 mg, 0.0510 mmol) and NMDP (0.100 g, 0.308 mmol) were charged in an autoclave (Hastelloy C, 100 mL) in a dry box. The reactor was assembled in the dry box and mounted on the cover. DMF (20 mL), Et3 N (7.5 mL) and BIBB (10.7 g, 50.2 mmol) were added via syringe. The reactor was purged with ethylene (2x150 psig) and then filled with ethylene (300 psig). The mixture was heated to 80-85 ° C and the reactor was pressurized with ethylene at 520 psig. The mixture was stirred at this temperature for 2.5 h. The GC analysis of an aliquot showed IBS (97.5% of the area), DIBE (0.1%), and DIBS (2.5%).

Example n PdCl2 (7.0 mg, 0.0395 mmol) and NMDP (0.130 g, 0.401 mmol) were charged in an autoclave (Hastelloy C, 100 mL) in a dry box. The reactor was assembled in the dry box and mounted on the cover. DMF (15 mL), Bt3 N (10.2 g) and BIBB (21.0 g, 98.5 mmol) were added via syringe. The reactor was purged with ethylene (2x150 psig) and then filled with ethylene (300 psig). The mixture was stirred at 120 ° C for 1 h. The GC analysis of an aliquot showed IBS (92.0% of the area), BIBB (0.4%), DIBE (0.7%) and DIBS (6.9%).

B-Example 12 Pd (OAc) 2 (11.0 mg, 0.0490 mmol), NMDP (0.100 g, 0.308 mmol), and 2-bromo-6-methoxynaphthalene (11.8 g, 49.8 mmol) were loaded in an autoclave (Hastelloy B, 100 mL) in a dry box. The reactor was assembled in the dry box and mounted on the cover. CH3CN (20 mL) and Et3 N (8 mL) were added via syringe. The reactor was purged with ethylene (2x150 psig) and then filled with ethylene (320 pßig). The mixture was stirred at 80-85 ° C for 5 h. The GC analysis showed only 2-methoxy-6-vinylnaphthalene. The reaction mixture was cooled to room temperature and the ethylene pressure was released. The mixture was filtered and the precipitate was washed with CHjClj (150 mL). The combined filtrate was washed with HC1 (1N, 2x50 mL), H20 (50 mL), and brine (50 mL). The organic film was dried (Na2SO4) and concentrated under reduced pressure to give a white solid (8.76 g, 96%): mp »92-9 ° C.

Claims (9)

1. Claims l. A process, characterized in that it comprises the preparation of an olefinic compound corresponding to the formula C (R3) (R4) = C (R2) A by reaction of an organic compound having the formula AX with a vinyl or substituted vinyl compound having C (R3) (R = C (R2) H in the presence of a catalyst containing (a) palladium or palladium salt and (b) a ligand corresponding to the formula: to form an activated reaction mixture containing a substantial amount of said olefinic compound; in these formulas A is aryl, substituted aryl, heteroaryl, substituted heteroaryl, benzyl, substituted benzyl, vinyl, or substituted vinyl; R2, R, and R, are independently selected from hydrogen, alkyl, cycloalkyl, substituted alkyl of cycloalkyl, aryl, substituted aryl, alkoxy, alkylthio, heteroaryl, substituted heteroaryl, alkanoyl, aroyl, substituted aroyl, heteroarylcarbonyl, substituted heteroarylcarbonyl, triforomethyl and halo; X is chlorine, bromine, iodine or diazonium; Ar is phenyl, phenyl substituted, naphthyl or substituted naphthyl; R 'and R "are independently selected from hydrogen, alkyl, aryl or substituted aryl, and n is an integer of 3-6 2. The process of claim 1, characterized in that the palladium component of the catalyst is a salt of Pd ** and the ligand is neomentildiphenylphosphine. 3. The process of claim 1, characterized in that A is substituted or unsubstituted aryl and R2, R3 and R4 are independently selected from hydrogen, alkyl containing 1-6 carbons, trifluoromethyl, and substituted or unsubstituted phenyl. The process of claim 3, characterized in that A is isobutylphenyl, methoxynaphthyl, 3-fluorobiphenyl, 3-phenoxyphenyl or 3-benzoylphenyl; and each of R2, R3 and R4 is hydrogen. 5. The process of claim 4, characterized in that A is isobutylphenyl. 6. The process of claim 4, characterized in that A is methoxynaphthyl. The process of any of the preceding claims including the further step of reacting said olefinic compound with carbon monoxide to convert it into a carboxylic compound corresponding to the formula CH (R3) (R4) -C (R2) (A) -C (O) -ORt, characterized in that Rx is hydrogen or alkyl. 8. The process of claim 7, characterized in that the reaction with carbon monoxide is carried out by the addition of carbon dioxide and an aliphatic alcohol to the reaction mixture containing said olefinic compound as well as to form an ester corresponding to the Formula CH (R3) (R «) -C (R2) (A) -C (0) -0R1 # characterized in that Rx is alkyl. The process of claim 7, characterized in that the reaction with carbon monoxide is carried out by the addition of carbon dioxide and a water to the reaction mixture containing said olefinic compound as well as to form an ester corresponding to the formula CH (R3) (R4) -C (R2) (A) -C (O) -ORlf characterized in that Rt is hydrogen. PROCESS FOR THE PREPARATION OF OLEFINS SUMMARY OF THE INVENTION 4-Isobutylstyrene and other olefinic compounds corresponding to the formula C (R3) (R4) = C (R2) A were prepared by reacting an organic compound having the formula AX with a vinyl or substituted vinyl compound having C (R3) (R = C (R2) H in the presence of a catalyst containing (a) palladium or palladium salt and (b) a ligand corresponding to formula (I) in this formula A is aryl , substituted aryl, heteroaryl, substituted heteroaryl, benzyl, substituted benzyl, vinyl, or substituted vinyl; R3, R3 and R4 are independently selected from hydrogen, alkyl, cycloalkyl, substituted alkyl of cycloalkyl, aryl, substituted aryl, alkoxy, alkylthio, heteroaryl , substituted heteroaryl, alkanoyl, aroyl, substituted aroyl, heteroarylcarbonyl, substituted heteroarylcarbonyl, trifluoromethyl and halo; X is chloro, bromo, iodo or diazonium; Ar is phenyl, substituted phenyl, naphthyl or substituted naphthyl; R 'and R "are independently selected preferably hydrogen, alkyl, aryl or substituted aryl; and n is an integer of 3-6. The olefinic compounds by the reaction could be carbonylated to the corresponding carboxylic compounds. R 'A ~ C H-P (A r), fc? V CH-R