The object of the present invention is the transition metal-catalysed hydroxycarbonylation of aryl and vinyl bromides.

The transition metal-catalysed carbonylation of different organic substrates is of major significance in industrial organic synthesis [(a) Conquhoun, H. M. et al., Carbonylation, Direct Synthesis of Carbonyl Compounds, Plenum Press, New York, (1991). (b) Tsuji, J., Palladium Reagents and Catalysts, Wiley : Cbichester, (1995). (c) Beller, M., Applied Homogeneous Catalysis with Organometallic Compounds 1; Cordis, B.; Hemnann, W. A., Eds., VCH: Weinheim, (1996). (d) Grushin, V. V.; Alper, H., Chem. Rev., 94, 1047, (1994)]. The hydroxycarbonylation of aryl and vinyl halogenides or triflates has drawn considerable attention [(a) Cacchi, S et al.., G., Tetrahedron Lett., 26, 1109, (1985). (b) Pri-Bar, L; Buchman, O., J. Org. Chem., 53, 624, (1988). (c) Cacchi, S.; Lupi, A., Tetrahedron Lett., 33, 3939 (1992). (d) Grushin, V. V.; Alper, H., J. Am. Chem. Soα, 117, 4305 (1995). (e) Ziolkowski, J. J.; Trzeciak, A. M., J. MoI. Cat. A: Chem., 154, 93 (2000). (g) CaIo, V. et al., J. Organomet. Chem., 645, 152 (2002)].. Usually, carbon monoxide is used as a substrate for such reactions. This inexpensive technical gas, readily available in industrial quantities, is highly toxic and must be stored in stainless steel containers [(3) The Merck Index: An Encyclopedia of Chemicals, Drugs and Biologicals; Whitehouse Station, NJ, (2001). The use of carbon monoxide in chemical plants requires special equipping and expensive safety measures. It is accordingly highly desirable to develop a new and secure technology, by which carbon monoxide does not have to be introduced directly to reaction mixtures, rather is produced in situ. In addition one particularly high interest in such technology is the use in the pharmaceutical industry. The wide use of automated combinatorial chemistry for the discovery of new drugs requires the replacement of gaseous substrates by liquid and solid materials, which are easier to handle. Also, the production of a plurality of substances on the kilogram scale for pre-clinical studies is often limited, since the medium-scale pharmaceutical industry is not in a position to work safely with carbon monoxide.

In recent years a few sources has been reported for carbon monoxide. Carbonylation was achieved using reagents, which contained a carbonyl group such as for example methyl formate [(a) Lee, J. S. et al., Appl. Catal., 57, 1 (1990). (b) Carpentier, J.-F. et al., Tetrahedron Lett, , 32, 4705 (1991)]. Alper and Grushin, Organometallics, YL, 3846 (1993) have described the catalytic hydroxycarbonylation of aryl iodide, vinyl and benzyl halides by carbon monoxide produced in situ from

chloroform and aqueous alkalis and, more recently, Cacchi et al., Org. Lett., f>, 4269 (2003) have reported on the use of acetic acid anhydride and lithium formate as starting materials for carbon monoxide. A mixed anhydride of acetic acid and formic acid was postulated as carbon monoxide source under these conditions. Aryl iodides were hydroxycarbonylated in this way under mild conditions. Aryl bromides, the more interesting substrates for industrial applications, reacted however only sluggishly under the abovementioned conditions. In some cases PdCl ₂ (dppp) proved to be an efficacious pre-catalyst, though reaction ran extremely slowly (64 hours) and resulted in only moderate yields of the desired products. The study of Pd-catalysed hydroxycarbonylation of aryl bromides using the carbon monoxide source described by Cacchi et al.

through the hydroxycarbonylation of />-bromobiphenyl was disappointing. As put forward by Cacchi et al., 2 equivalents of lithium formate, 3 equivalents of acetic acid anhydride and 2 equivalents of /-Pr ₂ EtN (diisopropyl ethyl amine) in DMF (dimethylformamide) were mixed with one another at room temperature for 1 hour, after which ^-bromobiphenyl, lithium chloride and the Pd catalyst were added, and reaction was carried out at 80°C. Even the simple substitution of the specified PdCl ₂ /dppp (l,3-bis[diphenylphosphino]propane)dichloropalladium for a better available catalytic system such as Pd(OAc) ₂ /dppp and PdCl ₂ /dppp produced the desired acid only in a low yield (Table 1, No. 1, 2).

All methods described to date for hydroxycarbonylation of aryl and vinyl bromides are therefore to be considered as not particularly satisfactory.

The object of the present invention was therefore to overcome the drawbacks of the prior art.

According to the invention, the problem was solved by a novel and efficient catalytic system for the hydroxycarbonylation reaction of aryl and vinyl bromides.

It has now been evidenced that the preparation of aryl or vinyl carboxylic acids via Pd-catalysed hydroxycarbonylation of aryl and vinyl bromides, reacting the aryl or vinyl bromides with a carbon monoxide source comprising lithium formate and a carboxylic acid anhydride (for example acetic acid anhydride), in the presence of the

combination of palladium complexes with the chelating ligand dppf (l,l- bis[diphenylphosphino]ferrocene) produced the desired product in a good yield.

According to the invention the Pd catalyst can be chosen from the combinations of palladium complexes (pre-catalyst) : PdCl ₂ (dichloropalladium), Pd ₂ (dba) ₃ (dba — dibenzylideneacetone) or Pd(OAc) ₂ diacetoxypalladium with the chelating ligand dppf.

According to the invention the reaction is advantageously carried out in the presence of a tertiary amine such as triethylamine, diisopropyl ethyl amine, tetramethylethylenediamine, tributylamine, pyridine, N-methylmorpholine, tetra- methylurea, methylpyrrolidinone, 4-dimethylarninopyridine, proton sponge or dimethylaniline, in a polar solvent such as an amide (dimethylformamide, N-methyl- 2-pyrrolidone for example) at a temperature from 60 to 200 ⁰ C, preferably at a temperature from 80 to 15O ⁰ C and more preferably at a temperature from 80 to 120 ⁰ C, the temperature of 120 ⁰ C being the more preferred. Optionally, the reaction can be carried out in the presence of lithium chloride.

According to the invention, the molar amount of the chelating ligand is from 1 to 20%, preferably 1 to 10%, and the molar amount of the pre-catalyst Pd complex is comprised from 1 to 5%. The ratio pre-catalyst / ligand is advantageously comprised from 0.25 to 1, preferably from 0.3 to 1 and more preferably about 1, The ratio pre- catalyst / ligand of 1 being the more preferred one.

Among aryl and vinyl bromides, the reaction applies to a variety of substrates including a substantial range, and based on neutral aryl bromides, electron-poor and electron-rich aryl bromides which produces the desired acids with good yields. The variety of substrates includes also dibromo-substituted substrates. This shows that the inventive hydroxycarbonylation can surprisingly also be used for the synthesis of dicarboxylic acids. The inventive hydroxycarbonylation can further be used surprisingly for the conversion of vinyl bromides in the corresponding acids with high yields : as a non-limitative example, 2-bromoindene produced the corresponding acid. According to the invention, the aryl bromides can be chosen from the bromides where the aryl is a substituted or unubstituted 5 to 7 members single aromatic or hetero aromatic radical comprising 0 to 4 heteroatoms chosen from oxygen, sulphur or nitrogen or a bi or tricyclic substituted or unsubstituted aromatic or heteroaromatic radical comprising 6 to 14 members and 0 to 4 heteroatoms chosen from oxygen, sulphur or nitrogen and which can be saturated or partially saturated on the cycles that are not bromo-substituted. The substituants can be advantageously chosen from

halogen atoms, or radicals such as alkyl, halogenoalkyl or polyhalogenoalkyl (trifluoromethyl for example), alkoxy, acyl, alkoxycarbonyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonylaminoalkyl or phenyl, the alkyl portions or radicals and the alkyl portion in the acyl radical being linear or branched and having 1 to 10 carbon atoms.

More preferred are the aryl radicals chosen from phenyl or naphtyl, that can be substituted with halogen atoms chosen from chloro, fluoro, bromo or iodo, or substituted with radicals chosen from linear or branched alkyl or alkoxy having 1 to 4 carbon atoms, trifluoromethyl, acyl or alkoxycarbonyl where the alkyl portions are linear or branched and contain 1 to 4 carbon atoms, dialkylaminoalkyl, methoxycarbonylaminoalkyl, ethoxycarbonylaminoalkyl or t.butoxycarbonyl- aminoalkyl or phenyl.

According to the invention, the vinyl bromides can be chosen from the substituted or unsubstituted bromides where the vinyl radical is a vinyl derivative where the bromo is substituted on an unsaturated carbon and where the radical can be an aliphatic linear or branched radical having from 2 to 10 carbon atoms and that can comprise heteroatoms chosen from oxygen, sulphur or nitrogen or a mono, bi or tri cyclic radical comprising from 5 to 14 members, that can be carbocyclic or heterocyclic comprising 0 to 4 heteroatoms chosen from oxygen, sulphur or nitrogen, and which can be partially saturated and where the bromo is substituted on an unsaturated carbon. The substituants can be chosen from the substituants mentioned above for the aryl bromide.

More preferred are the vinyl radical chosen from vinyl or indene-2-yl that can be substituted with substituants chosen from the substituants mentioned above for the aryl bromide.

According to the invention, the concentration of the vinyl or aryl bromide is advantageously from 0.01 to 1 M, preferably from 0.1 to 0.8 M and more preferably from 0.1 to 0.4 M. The reaction is preferably carried out on diluted solutions of the starting vinyl or aryl bromide. According to the invention the more preferred examples are the processes where :

• N-tert-butoxycarbonyl-N-methyl-4-bromobenzylamine is reacted with a carbon monoxide source comprising lithium formate and acetic acid anhydride, in the presence of diisopropyl ethyl amine and in the presence of the combination of palladium complexe Pd ₂ (dba) ₃ with the chelating ligand dppf (l,l-bis[diphenylphosphino]ferrocene) in the ratio palladium pre-

catalyst/ligand of 5/20, at a temperature of 12O ⁰ C, in dimethylformamide, in the presence of lithium chloride ;

• N-tert-butoxycarbonyl-Λ/-methyl-4-bromobenzylamine is reacted with a carbon monoxide source comprising lithium formate and acetic acid anhydride, in the presence of diisopropyl ethyl amine and in the presence of the combination of palladium complexe Pd(OAc) ₂ with the chelating ligand dppf (l,l-bis[diphenylphosphino]ferrocene) in the ratio palladium pre- catalyst/ligand of 5/5, at a temperature of 120°C, in N-methyl-pyrrolidone ;

• jV-tert-butoxycarbonyl-jV-methyl-4-bromobenzylamine is reacted with a carbon monoxide source comprising lithium formate and acetic acid anhydride, in the presence of diisopropyl ethyl amine and in the presence of the combination of palladium complexe Pd(OAc) ₂ with the chelating ligand dppf (1,1 -bis[diphenylphosphino]ferrocene) in the ratio palladium pre- catalyst/ligand of 2.5/2.5, at a temperature of 120 ⁰ C, in dimethylformamide ; • bromotoluene is reacted with a carbon monoxide source comprising lithium formate and acetic acid anhydride, in the presence of diisopropyl ethyl amine and in the presence of the combination of palladium complexe Pd(OAc) ₂ with the chelating ligand dppf (l,l-bis[diphenylphosphino]ferrocene) in the ratio palladium pre-catalyst/ligand of 1/1 at a temperature of 120°C in dimethylformamide ;

• 4-bromofluorobenzol is reacted with a carbon monoxide source comprising lithium formate and acetic acid anhydride, in the presence of diisopropyl ethyl amine and in the presence of the combination of palladium complexe Pd(OAc) ₂ with the chelating ligand dppf (1,1 -bisfdiphenyl- phosphino]ferrocene) in the ratio palladium pre-catalyst/ligand of 1/1 at a temperature of 120 ⁰ C in dimethylformamide ;

• 4-anisole bromide is reacted with a carbon monoxide source comprising lithium formate and acetic acid anhydride, in the presence of diisopropyl ethyl amine and in the presence of the combination of palladium complexe Pd(OAc) ₂ with the chelating ligand dppf (1,1 -bis[diphenyl- phosphinojferrocene) in the ratio palladium pre-catalyst/ligand of 1/1 at a temperature of 120 ⁰ C in dimethylformamide ;

• 2-bromoindene is reacted with a carbon monoxide source comprising lithium formate and acetic acid anhydride, in the presence of diisopropyl ethyl amine and in the presence of the combination of palladium complexe Pd(OAc) ₂ with the chelating ligand dppf (l,l-bis[diphenylphosphino]ferrocene) in the ratio

palladium pre-catalyst/ligand of 1/1 at a temperature of 120°C in dimethylformamide ;

• 1,4-dibromobenzol is reacted with a carbon monoxide source comprising lithium formate and acetic acid anhydride, in the presence of diisopropyl ethyl amine and in the presence of the combination of palladium complexe Pd(OAc) ₂ with the chelating ligand dppf (1,1 -bis[diphenyl- phosphinojferrocene) in the ratio palladium pre-catalyst/ligand of 1/1 at a temperature of 120°C in dimethylformamide ;

The following examples illustrate the invention, EXAMPLES

Example 1 Evaluation of ligands for aryl bromides hydroxycarbonylation

With ligand screening of a series of phosphine ligands using p-bromobiphenyl as model substrate (Table 1) only dppf (assay No. 9) give the desired compound in a high yield, while P(f-Bu) ₃ , P(o-tol) ₃ , PPh ₃ and BINAP [2,2'-bis(diphenylphosphino> ljl'-binaphtyl] were less efficient or ineffective. Reaction conditions : 2 mmol 4- bromobiphenyl, 2 equiv. acetic acid anhydride, 3 equiv. lithium formate, 2 equiv. i- Pr ₂ EtN, 3 equiv. LiCl in 9 ml DMF were caused to react with one another for 24 hours at 80 ^° C. After cooling the reaction mixture was diluted with ethyl acetate, washed with 2 N HCl, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was analysed with ¹ H and ¹³ C NMR. l,l'-bis(di-wo- propylphosphine)ferrocene (-)-(R)-l-[(S)-2-(diphenylphosphine)ferrocenyl]ethyl- methylether (R)-(-)-l-[(S)-2-(dicyclohexylphosphine)ferrocenyl]ethyl- dicyclohexylphosphine

Table 1

* dppp : l,3-bis(diphenylphosphino)propane ** o-tol : o-tolyl

Example 2

Optimisation of the hydroxycarbonylation temperature of reaction, palladium source, ratio precatalyst / Iigand and optional amount of LiCI additive

Under the conditions of example 1, N-tert-butoxycarbonyl~iV-rnethyl-4- bromobenzylamine was converted into the desired acid. The results are shown in Table 2.

Reaction conditions : 1 (or 2) mmol bromide, 2 equivalents acetic acid anhydride, 3 equivalents lithium formate, 2 equivalents Z-Pr ₂ EtN, in 5 (or 10) ml DMF. ^b The reaction was conducted in the presence of 3 equiv. LiCl. ^c NMR yield. After cooling the reaction mixture was diluted with ethyl acetate, washed with 2 N HCl, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was analysed via ¹ H and ¹³ C NMR. ^d HPLC yields. ^e Isolated yield. ^f NMP (N-methyl pyrrolidone) was used as solvent. ^g DMS0 (dimethylsulfoxyde) was used as solvent.

Table 2

The assays indicated that the temperature acts on the yield of the hydroxycarbonylation reaction, since both the oxidative addition of a bromide and the thermal decomposition of the intermediate acetic acid / formic acid anhydride is determined by this factor.

An improvement was achieved by a rise in temperature (Table 2, assays No. 1, 3, 4). When the reaction was carried out at 120 C, this resulted in a significant rise in the yield. In comparison to the details disclosed by Cacchi et al. no favourable effect of LiCl was observed, when dppf was used as ligand at 80°C or 12O ⁰ C (Table 2, assays No. 2 and 6 compared to 1 and 5). A change in the palladium source yielded only a moderate effect, Pd ₂ (dba) ₃ , Pd(OAc) ₂ and PdCl ₂ were effective pre-catalysts (Table 2, assays No. 6 to 8). If the pre-catalyst / ligands ratio was changed, slightly

better yields resulted from using an equimolar ratio of Pd(OAc) ₂ and dppf (Table 2, assays No. 8 to 10). The reaction ran well in polar solvents such as DMF and NMP (Table 2, No. 9, 11).

Example 3

Examination of the substrate concentration for the hydroxycarbonylation of bromide : iV-ferf-bntoxycarbonyl-iV-methyl-4-bromobenzvIamine.

Reaction conditions : 0.01-0.75 mol bromide, 2 equiv. acetic acid anhydride, 3 equiv. lithium formate, 2 equiv. base, 1 mol % Pd(OAc) ₂ , 1 mol % dppf

The product yield varies with the aryl bromide concentration. The hydroxycarbonylation reaction prodeeded smoothly in diluted solutions of aryl bromide in DMF (Table 3).

Table 3

Example 4

Application of hydroxycarbonylation reaction to different vinyl and aryl bromides

To understand the limits of this reaction, a series of bromides was examined. The reaction conditions used in examining different aryl bromides were : aryl bromide (1 equivalent, 0.18 M), Pd(OAc) ₂ / dppf (3-5 mol %), Z-Pr ₂ EtN (2 equivalents), LiO ₂ CH (3 equivalents), Ac ₂ O (2 equivalents) in DMF at 120°C. The results are specified in Table 4. The amount of the catalytic system was not optimized, and instead 3-5 mol-% of catalytic system were added to ensure complete conversion of the starting bromide.

Reaction conditions : 2 mmol bromide, 2 equiv. acetic acid anhydride, 3 equiv. lithium formate, 2 equiv. /-Pr ₂ EtN, Pd(OAc) ₂ : dppf ratio 1:1 in 9 ml DMF. ^b 33 % in

the presence of 1 mol% Pd(OAc) ₂ ^c 36 % in the presence of 3 mol% Pd(OAc) ₂ ^d 20% benzoic acid was obtained.

U

Table 4

Surprisingly, the hydroxycarbonylation reaction according to the invention can be applied to a substantial range of substrates and starting from neutral aryl bromides, electron-poor and electron-rich aryl bromides, produces the desired acids with good yields (Table 4, assays No. 1 to 8). 4-(trifluormethyl)-benzoic acid, which now has a series of industrial applications, can be produced for example with a yield

of 74% (Table 4, Assay No. 7). Tolerance relative to different functional groups such as keto, ester or ether groups is of particular advantage under these conditions. Bromonaphthalenes can be likewise converted with good yields in the corresponding acids (Table 4, Assay No. 9). The inventive hydroxycarbonylation reaction can surprisingly also be used for the synthesis of dicarboxylic acids. Under the inventive conditions terephthalic acid can be obtained from 1,4-dibromobenzol with a yield of 75% (together with 20% benzoic acid) (Table 4, Assay No. 10). The inventive hydroxycarbonylation can further be employed surprisingly for the conversion of vinyl bromides in the corresponding acids. 2-bromoindene produced the corresponding acid with a yield of 80% under standard conditions (Table 4, Assay No. 11).

Example 5

General experimental procedure.

A solution of HCOOLi (312 mg, 6 mmol), z-Pr ₂ NEt (697 μl, 4 mmol), acetic acid anhydride (377 μl, 4 mmol) in water-free DMF (9 ml) was stirred at room temperature for 1 hour in an inert atmosphere. Then aryl bromide (2 mmol), Pd(OAc) ₂ (22.5 mg, 0.10 mmol) and dppf (55.4 mg, 0.10 mmol) were added. The reaction mixture was stirred at 120°C until the bromide had reacted fully (via HPLC). After cooling, 20 ml ethyl acetate and 20 ml water were added and the reaction mixture was adjusted with concentrated HCl, to pH 1. Two phases were separated and the aqueous layer was extracted with ethyl acetate (2 x 10 ml). The pure acid was isolated through extraction of the combined organic phase, with aqueous sodium hydroxide (10%) (3 x 10 ml), acidification of the aqueous phase to pH 1 with concentrated HCl, and then repeated extraction with ethyl acetate (3 x 15 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure at 80 ⁰ C. hi a few cases (Table 4, Assays No. 3, 4, 11) the pure acids were isolated by chromatography (SiO ₂ ; n-heptane/ethyl acetate 50/50). The ¹ H- and ¹³ C NMR spectra of the isolated acids (Table 4) matched those mentioned in the literature [Aldrich Chemical spectra, FT-NMR ₃ I]. iV-(ter^-butoxycarbonyl)-methylbenzylamine-4-carboxyl acid (Table 3, Assay

No. 2) was obtained from 3.00 g (10 mmol) N-tør^butoxycarbonyl-N-methyl-4- brombenzylamine under the abovementioned conditions.

Mp 146 - 147°C

¹ H NMR (CDCl ₃ ) : δ = 1.28 (t, J = 7.9 Hz, 3 H), 1.35 (s, 9H), 4.56 (q, J = 7.9 Hz, IH), 7.39 (d, J = 7.8 Hz, 2H), 7.89 (d, J = 7.8 Hz, 2H), 10.5 (br s, IH).

¹³ C NMR (CDCl ₃ ): δ = 23.09, 28.70, 50.00, 78.30, 126.39, 129.56, 129.84, 151.10, 155.29, 167.68.

4-biphenylcarboxyl acid (Table 4, Assay No. 1) was obtained from 466 mg (2 mmol) 4-brombiphenyl under the abovementioned conditions. Mp 224 - 225°C; lit. Mp (Aldrich catalog) 225 - 226 ^° C.

¹ H NMR (DMSO-Λ5): δ = 7.45 (m, 3 H), 7.71 (d, J = 6.6 Hz, 2H), 7.78 (d, J =

8.2 Hz, 2H), 8.01 (d, J = 8.2 Hz, 2H), 11.5 (br s, IH).

¹³ C NMR : δ = 127.76, 127.90, 129.23, 130.02, 130.57, 130.92, 139.97, 145.25, 168.08. /7-toluic acid (Table 4, Assay No 2) was obtained from 855 mg (5 mmol) 4- bromotoluene under the abovementioned conditions.

Mp 180 - 181 °C; lit. Mp (Aldrich catalog) 180 - 182 ⁰ C

¹ H NMR (OUSO-d6): δ = 2.18 (s, 3 H), 7.25 (d, J = 8.1 Hz, 2H), 7.82 (d, J = 8.1 Hz, 2H), 11.5 (br s, I H) ¹³ C NMR (OMSO-d6): δ = 22.37, 129.93, 131.37, 132.36, 138.80, 168.85.

Terephthalic acid, monoethyl ester (Table 4, Assay No. 3) was obtained from 2.29 g (10 mmol) ethyl-4-bromobenzoate under the abovementioned conditions.

¹ H NMR (DMSO-dS): δ - 1.32 (t, J = 7.9 Hz, 3 H), 4.32 (q, J = 7.9 Hz, 2H),

8.03 (br s, 4H), 11.5 (br s, IH). ¹³ C NMR (OMSO-d6): δ = 19.83, 66.90, 135.02, 135.17, 139.10, 140.60,

170.84, 172.32.

4-acetylbenzoic acid (Table 4, Assay No. 4) was obtained from 796 mg (4 mmol) 4-bromoacetophenone under the abovementioned conditions.

Mp 208 - 209°C; lit. Mp (Aldrich catalog) 208 - 210 ⁰ C. ¹ H NMR (DMSO-Λ5): δ = 2.60 (s, 3 H), 8.02 (s, 4H), 13.2 (br s, IH).

¹³ C N MR (DMSO-Λ5): δ = 28.15, 129.47, 130.71, 135.71, 141.04, 167.81, 198.87.

4-chlorobenzoic acid (Table 4, Assay No. 5) was obtained from 383 mg (2 mmol) 4-bromochlorbenzol under the abovementioned conditions. Mp 238 - 240°C; lit. Mp (Aldrich catalog) 239 - 241°C.

¹ H NMR (DMSO-ctø): δ = 7.54 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.4 Hz, 2H), 7.93 (br s, 1 H).

¹³ C NMR (DMSCM6): δ = 129.37, 130.38, 130.65, 144.29, 168.66.

4-fluorobenzoic acid (Table 4, Assay No. 6) was obtained from 383 mg (2 mmol) 4-bromofluorobenzol under the abovementioned conditions.

Mp 183 - 184°C; lit. Mp (Aldrich catalog) 182 - 184°C. ¹ H NMR (OMSO-d6): δ = 7.54 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.4 Hz, 2H),

7.93 (br s, 1 H).

¹³ C NMR (DMSO-d6): δ = 116.95 (d, J = 22.6 Hz), 129.10, 133.65 (d, J = 10.3 Hz), 166.65 (d, J - 250.6 Hz), 168.14.

4-(trifluoromethyl)-benzoic acid (Table 4, Assay No. 7) was obtained from 383 mg (2 mmol) 4-bromochlorbenzol under the abovementioned conditions.

Mp 218 - 220 ⁰ C; lit. Mp (Aldrich catalog) 219 - 220°C.

¹ H NMR (DMSO-d6): δ = 7.85 (d, J = 8.2 Hz, 2H), 8.12 (d, J = 8.2 Hz, 2H), 12.3 (br s, 1 H).

¹³ C NMR (DMSO-J6): δ = 124.97 (q, J = 270.5 Hz), 126.69 (q, J - 3.2 Hz), 131.25, 133.34(q, J - 31.5 Hz), 135.82, 167.35. jo-anisic acid (Table 4, Assay No. 8) was obtained from 718 mg (4 mmol) 4- anisole bromide under the abovementioned conditions.

Mp 183 - 184°C; lit. Mp (Aldrich catalog) 182 - 185°C.

¹ H NMR (DMSO-tfό): δ = 3.81 (s, 3H), 7.01 (d, J = 8.1 Hz, 2H), 7.88 (d, J = 8.1 Hz, 2H), 12.61 (br s, 1 H).

¹³ C NMR (DMSO-rftf): δ = 56.60, 114.98, 124.17, 132.50, 164.025, 168.15.

4-methyl-l -naphthoic acid (Table 4, Assay No. 9) was obtained from 442 mg (2 mmol) l-bromo-4-methylnaphthalene.

Mp 179 - 181 ⁰ C; lit. Mp (Aldrich catalog) 179 - 180 ⁰ C. ¹ H NMR (DMSO-Λ5): δ = 2.71 (s, 3 H), 7.45 (d, J = 8.1 Hz, 1 H), 7.65 (m,

2H), 8.06 (d, J = 8.1 Hz, 1 H), 8.09 (m, 1 H), 8.94 (m, 1 H), 12.9 (br s, 1 H).

¹³ C NMR (DMSO~d6): δ - 22.82, 125.85, 126.88, 127.31, 128.38, 131.05, 132.17, 133.63, 140.98, 170.01.

Terephthalic acid (Table 4, Assay No. 10) was obtained from 472 mg (2 mmol) 1,4-dibromobenzol under the abovementioned conditions together with benzoic acid (20%).

Mp >300°C; lit. Mp (Aldrich catalog) >300°C.

¹ H NMR (DMSO-c/6): δ = 8.15 (s, 4 H), 13.41 (s, 2H). ¹³ C NMR (DMSO-d<5): δ = 130.76, 135.93, 167.15.

Indene-2-carboxylic acid (Table 4, Assay No. 11) was obtained from 780 mg (4 mmol) 2-bromoindene under the abovementioned conditions. ¹ H NMR (DMSO-Λ5): δ = 3.62 (d, J = 1.6 Hz, 2H), 7.32 (m, 2H), 7.53 (m, 2H),

7.68 (m, I H), 12.9 (br s, I H).

¹³ C NMR (DMSO-rfό): δ = 39.06, 122.85, 123.88, 126.49, 126.83, 137.95, 139.69, 142.12, 144.18, 165.23.

Various ligaπds containing a free ferrocene fragment were tested for hydroxycarbonylation of 4-bromobiphenyl. l,l'-bis(di-isopropylphosphine)- ferrocene proved efficient. On the other hand low yields of acid in the presence of ferrocenes were obtained, which contained an attached heteroatom group such as (-)- (R)-l-[(S)-2-(diρhenylphosphine)ferroceneyl]-ethylmethyleth er or (R)-(-)-l-[(S)-2- (dicyclohexylphosphine)ferroceneyl]-ethyldicyclohexylphosphi ne.