Arylation of enolates

Enolizable compounds can be used for Meerwein reactions provided that the keto-enol equilibrium is not too far on the side of the ketone for example, P-dicar-bonyl compounds such as acetylacetone are suitable (Citterio and Ferrario, 1983). The arylation of enol esters or ethers (10.12) affords a convenient route for arylating aldehydes and ketones at the a-carbon atom (Scheme 10-48). Silyl enol ethers [10.12, R = Si(CH3)3] can be used instead of enol ethers (Sakakura et al., 1985). The reaction is carried out in pyridine. 

Palladium-Catalyzed Arylation of Enolates. Very substantial progress has been made in the use of Pd-catalyzed cross coupling for arylation of enolates and enolate equivalents. This reaction provides an important method for arylation of enolates, which is normally a difficult transformation to accomplish.171 A number of phosphine ligands have been found to promote these reactions. Bulky trialkyl phosphines such as /n. v-(/-butyl)phosphinc with a catalytic amount of Pd(OAc)2 results in phenylation of the enolates of aromatic ketones and diethyl malonate.172... 

Conditions for arylation of enolate equivalents have also been developed. In the presence of ZnF2, silyl enol ethers, silyl ketene acetals, and similar compounds react. For example, the TMS derivatives of /V-acyl oxazolidinones can be arylated. 

In Section 8.2.3.2, we discussed arylation of enolates and enolate equivalents using palladium catalysts. Related palladium-phosphine combinations are very effective catalysts for aromatic nucleophilic substitution reactions. For example, conversion of aryl iodides to nitriles can be done under mild conditions with Pd(PPh3)4 as a catalyst. 

Transition Metal-Catalyzed Asymmetric Arylation of Enolates. 167... 

The arylation of enol esters has also been improved (95). Previously a wide range of products were produced including j8-aryl carbonyls, arylated enol esters, styrene, and stilbene derivatives (96). It has also been found that arylated enol esters can be obtained as major products if the reactions are carried out with stoichiometric amounts of aryl mercuric acetate and palladium acetate in anhydrous acetonitrile or in excess enol ester solution. The products are those arising from addition of the phenyl group to the carbons not containing the ester. Thus, with vinyl acetate and phenyl mercuric acetate, the product is the enol acetate of phenyl acetaldehyde ... 

Benzofurans are available via ( -arylation of enolates as reported by Willis [187]. In the simplest example, tricyclic benzofuran 237 was prepared from bromoketone 236 upon treatment with cesium carbonate and DPEphos. In total, eight other benzofurans were prepared in good to excellent yield using this methodology. 

C-Arylation of enols and enolate anions 6.2.2.1 1,3-Dicarbonyl compounds... 

The scope of Pd-catalyzed a-arylation of enolates has been further expanded so as to include amides,malononitrile, a-cyanoesters, ° a-cyanophosphates, and a-cyanosulfones. " The metal countercations in these reactions are mostly alkali metals, such as Li, Na, K, and Cs. Some representative examples of these reactions are shown in Scheme 13. The Pd-catalyzed reaction of 2-methyl-l-propenyl chloride with NaCH(COOMe)2 in the presence of 2 mol% of Me2Pd(dcypb), where dcypb is Cy2P(CH2)3PCy2, led to 2-methylallylationf i (Scheme 14). 

Heck, R.F. (1968) The palladium-catalyzed arylation of enol esters, ethers, and halides. A new synthesis of 2-aryl aldehydes and ketones. J. Am. Chem. Soc., 90, 5535-8. 

The first attempts to use transition metal-catalyzed cross-coupling methodology to couple enolates with aryl halides were far from being broadly applicable, and involved less-attractive preformed zinc- or tin-enolates [210]. In addition, only ketones or acetates could be employed as enolate precursors. At that time, nickel was the predominant transition metal to mediate these couplings [211]. In an early contribution, CiufoHni arylated soft enolates in an intramolecular fashion with aryl halides using Pd(PPh3)4, along with NaH, in DMF at elevated temperatures [212]. This represented one of the first palladium-catalyzed arylations of enolates. 

Scheme 8.31 Pd-catalysed arylation of enolates derived from 79.

A remarkable reaction of pentavalent arylbismuth compounds is the arylation of enols and phenols. Three examples are shown below ... 

Ligand exchange of monoaryl-A -iodanes with an arylsilane or arylstannane leads to analogous diaryl reagents, which have unique uses. For example, diaryl-A -iodanes bring about a-arylation of enolates, as shown below ... 

The preceding reactions dealt with the use of chiral auxiliaries linked to the electrophilic arene partner. The entering nucleophile can also serve as a chiral controller in diastereoselective SjjAr reactions. This approach was successfully employed for the arylation of enolates derived from amino acids. To illustrate the potential of the method, two examples have been selected. Arylation of Schollkopf s bislactim ether 75 with aryne 77 as electrophilic arylation reagent was demonstrated by Barrett to provide substitution product 81 with good yield (Scheme 8.18) [62, 63]. Aryne 77 arises from the orf/jo-lithiation of 76 between the methoxy and the chlorine atom followed by elimination of LiCl. Nucleophilic attack of 77 by the lithiated species 78 occurs by the opposite face to that carrying the i-Pr substituent. Inter- or intramolecnlar proton transfer at the a-face of the newly formed carbanion 79 affords the anionic species 80. Subsequent diastereoselective reprotonation with the bulky weak acid 2,6-di-f-butyl-4-methyl-phenol (BHT) at the less hindered face provides the syn product 81. Hydrolysis and N-Boc protection give the unnatural arylated amino acid 82. The proposed mechanism is supported by a deuterium-labeling experiment. Unnatural arylated amino acids have found application as intermediates for the construction of pharmaceutically important products such as peptidomi-metics, enzyme inhibitors, etc. [64, 65]. 

The a-arylation of enol acetates was carried out following a related approach (Scheme 29.16)... 

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