Arylation of Enolates and Equivalents

Arylation of Enolates and Equivalents 381 Table 8.1 Palladium-catalyzed a-arylation of ketones with aryl chlorides. 

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... 

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. 

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. 

Cycloadditions of ketenes with alkenes and alkynes constitute the most popular method for the synthesis of cyclobutanones and cyclobutenones. Unfoitunately, however, this process is truly general only for highly nucleophilic ketenophiles such as conjugated dienes and enol ethers. In general, unactivated alkenes and alkynes fail to react in good yield with either alkyl- or aryl-substituted ketenes, or with ketene itself To circumvent this limitation, dichloroketene is usually employed as a ketene equivalent, since this electrophilic ketene reacts well with many types of unactivated multiple bonds, and the resultant cycloadducts undergo facile dechlorination under mild conditions. ... 

Enolate Arylation Reactions. The direct coupling of aryl halides with enolates (or enolate equivalents) of ketones, esters, and amides is now well established. Malonic esters, cyanoacetates, and malononitrile can be arylated upon treatment with aryl halides in the presence of Pd(dba)2 and electron-rich phosphines or N-heterocyclic carbenes. Carbene ligands have also proven effective in promoting the a-arylation of protected amino acids. As a caveat to the use of Pd(dba)2, the arylation of azlactones in the presence of this palladium source and phosphines was less efficient than that with Pd(OAc)2. The dba ligands were found to react with azlactone substrates to form catalytically inactive palladium complexes. Diastereoselective enolate arylation has been achieved through the use of chiral auxiliaries appended to preformed enol silyl ethers (eq 23). The role of the zinc additive is not clear, however, it appears that discrete zinc enolates are not involved. 

Hydrosilylations by complexed CuH have been applied to several substrate types (Scheme 1-17). As illustrated by the following examples, the stereochemical outcomes from both 1,2-additions (to aryl ketones and aryl imines ) and 1,4-conjugate additions (cyclic ketones, P-aryl and/or P-silyl enoates, and unsaturated lactones) can be controlled by these ligand-accelerated reactions. One of the key tricks to this chemistry is to take advantage of the tolerance of CuH complexes to alcohols and water.In fact, several methods rely on the presence of a bulky alcohol (e.g., t-BuOH) to significantly enhance reaction rates. It takes relatively little added alcohol (volume-wise) to accelerate the hydrosilylation, usually on the order of 1-3 equivalents. The role of this additive is usually ascribed to the more rapid quenching of an intermediate copper alkoxide or enolate, which necessarily generates a copper alkoxide, an ideal precursor to rapid reformation of CuH in the presence of excess silane. Thus, the rate increase is presumably due to... 

The fourth item in the table, phenol (hydroxybenzene), is alkylated on oxygen, forming an ether, methoxybenzene (anisol), with the powerful alkylating agent trimethyloxonium tetrafluoroborate [(CH30)3 BFt]. Other alkoxonium tetrafluo-roborates are also commercially available and can be used to the same end with phenols, enols, and alcohols, forming aryl ethers, enol ethers, and dialkyl ethers, respectively. In contrast to dialkyl, diaryl, and aralkyl ethers, which are quite inert and are often used as solvents, enol ethers are capable of acid-catalyzed hydrolysis to produce ketones (or their equivalent enol) and the alcohol from which the enol ether is formed (Scheme 8.47). 

In 2011, an elegant report by Gaunt and coworkers [122] described a related catalytic enan-tioselective process, which involves a copper-catdyzed enantioselective arylation of an enolate equivalent with diaryliodonium trrflates to form a-arylcarbonyl products in excellent yields and... 

In addition, unstabilized enolate nucleophiles have been generated by decarboxylation of (3-ketocarboxylates. In this case, no additives are required to activate the nucleophile, but the highest yields and selectivities were obtained in the presence of two equivalents of DBU [82]. Although reactions of allylic carbonates containing aromatic, heteroaromatic, and aliphatic substituents occurred, only reactions to form aryl ketone products were published. 

Bromination of the enol ether product with two equivalents of bromine followed by dehydrobromination afforded the Z-bromoenol ether (Eq. 79) which could be converted to the zinc reagent and cross-coupled with aryl halides [242]. Dehydrobromination in the presence of thiophenol followed by bromination/dehydrobromination affords an enol thioether [243]. Oxidation to the sulfone, followed by exposure to triethylamine in ether, resulted in dehydrobromination to the unstable alkynyl sulfone which could be trapped with dienes in situ. Alternatively, dehydrobromination of the sulfide in the presence of allylic alcohols results in the formation of allyl vinyl ethers which undergo Claisen rearrangements [244]. Further oxidation followed by sulfoxide elimination results in highly unsaturated trifluoromethyl ketonic products (Eq. 80). 

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