Arylation and a-Alkenylation of Carbon Nucleophiles

In contrast to facile a-alkylation of carbonyl compounds, a-arylation or alkenylation of carbonyl compounds has been considered to be a difficult reaction. Recently, a big breakthrough has occurred, and methods for the smooth a-arylation or alkenylation of carbonyl compounds have been developed [1]. Active methylene compounds, ketones, aldehydes, esters, amides and nitriles are now a-arylated easily not only with aryl iodides, but also with bromides and even chlorides. These reactions will lead to wide-ranging applications. A typical example of a synthetic application of the innovative reactions is a new preparative method for a-arylated carboxylic acids, such as ibuprofen (1) and naproxen, by direct a-arylation of acetate or propionate. 

The breakthrough became possible by the emergence of new ligands, particularly bulky and electron-rich ligands. The selection of bases is also important, and stable 

Arylation of active methylene compounds has been carried out using Cu salts as promoters under severe conditions [2], Recently it was discovered that the reaction can be carried out much more smoothly using Pd catalysts. The first Pd-catalyzed intermolecular arylation of cyanoacetate and malononitrile with aryl iodides was carried out by Takahashi using PPhs as a ligand, and was applied to a simple synthesis of tetracyanoquinodimethane (2) by the reaction of p-diiodobenzene with malononitrile [3], The intramolecular arylation of malonates and -diketones with aryl iodides proceeds smoothly. Presence of a cyano group seemed to be important [4,5], The arylation has been successfully extended to halides of heterocycles, such as pyridine, quinoline and isoquinoline. The reaction of bromoxazole 3 with sulfone 4 is an example [6]. 

Di- -butyl malonate can be arylated with electron-rich aryl chlorides using NaH and P(r-Bu)3 [11], The arylation suffers steric effects, and no arylation takes place with diethyl methylmalonate (9). Thus, diethyl methylphenylmalonate (10) can be prepared via arylation of malonate to give 11, followed by methylation as a one-pot reaction. When the arylation of diethyl malonate is carried out at 120 C, phenylacetate (12) is obtained as a one-pot reaction product [12], 

Hartwig and Wolkowski have synthesized arylpalladium complexes of mal-onates, and have shown that the greater steric hindrance of bulky ligand FcP(t-Bu)2 (VIII-2), relative to that of phenylphosphines, induces reductive elimination from 

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