Formation of carboxylic acids and their derivatives

1 Formation of carboxylic acids ami their derivatives. Aryl and alkenyl halides undergo Pd-catalyzed carbonylation under mild conditions, offering useful synthetic methods for carbonyl compounds. The facile CO insertion into aryl- or alkenylpalladium complexes, followed by the nucleophilic attack of alcohol or water affords esters or carboxylic acids. Aromatic and a,/ -unsaturated carboxylic acids or esters are prepared by the carbonylation of aryl and alkenyl halides in water or alcohols[30l-305]. 

In the total synthesis of zearaienone (451), the ester 450 was prepared by the carbonylation of the crowded aryl iodide 448. The alkyl iodide moiety in the alcohol molecule 449 is not attacked[306]. Methyl trifluoromethacrylate (453) was prepared by the carbonylation of 3,3,3-trifluoro-2-bromopropylcne (452), The carbonylation in the presence of alkylurea affords 454. which is converted into the trifluoromethyluracil 455[307], 

Usually, iodides and bromides are used for the carbonylation, and chlorides are inert. I lowever, oxidative addition of aryl chlorides can be facilitated by use of bidcntatc phosphine, which forms a six-membered chelate structure and increa.scs (he electron density of Pd. For example, benzoate is prepared by the carbonylation of chlorobenzene using bis(diisopropylphosphino)propane (dippp) (456) as a ligand at 150 [308]. The use of tricyclohexylphosphine for the carbonylation of neat aryl chlorides in aqueous KOH under biphasic conditions is also recommended[309,310]. 

The benzoic acid derivative 457 is formed by the carbonylation of iodoben-zene in aqueous DMF (1 1) without using a phosphine ligand at room temperature and 1 atm[311]. As optimum conditions for the technical synthesis of the anthranilic acid derivative 458, it has been found that A-acetyl protection, which has a chelating effect, is important[312]. Phase-transfer catalysis is combined with the Pd-catalyzed carbonylation of halides[3l3]. Carbonylation of 1,1-dibromoalkenes in the presence of a phase-transfer catalyst gives the gem-inal dicarboxylic acid 459. Use of a polar solvent is important[314]. Interestingly, addition of trimethylsilyl chloride (2 equiv.) increased yield of the lactone 460 remarkabiy[3l5]. Formate esters as a CO source and NaOR are used for the carbonylation of aryl iodides under a nitrogen atmosphere without using CO[316]. Chlorobenzene coordinated by Cr(CO)j is carbonylated with ethyl formate[3l7]. 

The phenylacetic acid derivative 469 is produced by the carbonylation of the aromatic aldehyde 468 having electron-donating groups[jl26]. The reaction proceeds at 110 C under 50-100 atm of CO with the catalytic system Pd-Ph3P-HCl. The reaction is explained by the successive dicarbonylation of the benzylic chlorides 470 and 471 formed in situ by the addition of HCl to aldehyde to form the malonate 472, followed by decarboxylation. As supporting evidence, mandelic acid is converted into phenylacetic acid under the same reaction conditions[327]. 

---