Ketone-ester coupling

Fig. 14.50. Crossed McMurry reactions ketone/ester coupling (top) and ketone/amide coupling (bottom).

Stetter expanded Umpolung reactivity to include the addition of acyl anion equivalents to a,P-unsaturated acceptors to afford 1,4-dicarbonyls Eq. 5a [57-60]. Utilizing cyanide or thiazolylidene carbenes as catalysts, Stetter showed that a variety of aromatic and aliphatic aldehydes act as competent nucleophilic coupling partners with a wide range of a,p-unsaturated ketones, esters, and nitriles [61]. The ability to bring two different electrophilic partners... 

Alkynes are usually alkylated under strongly basic conditions. Gregory Fu of MIT recently reported (J. Am. Chem. Soc. 125 13642, 2003) a much milder Pd and Cu mediated coupling, illustrated by the reaction of the terminal alkyne 7 with the alkyl iodide 8 to give 9. Alkyl bromides work equally well. It is exciting that ketones, esters, alkyl chlorides, alkenes, nitriles and acetals are compatible with the procedure. The key to the reaction is the use of the supporting carbene ligand 10. 

Thiane oxides have been shown to be reduced cleanly back to the thiane with phosphorus pentasulfide under conditions to which sulfones, sulfinates, ketones, esters and amides are inert (78CJC1423) the potential of this reaction, though not yet applied, is obviously considerable, especially when coupled with the old-established Raney nickel desulfurization technique. Thiane itself is desulfurized to pentane (with traces of cyclopentane) but the opportunity to construct alkyl chains of great complexity regio- and stereo-specifically is there. At the very least, the reduction to tetrahydrothiopyrans presents a very useful entree into a wide range of 2-substituted thianes (Scheme 2). 

Analogous intramolecular chelation-controlled ketone/olefin couplings with Sml2, in which Sm+3 was complexed in a cyclic manner to the ketyl anion and a /1-carbonyl of an ester or amide functionalilty, were reported as early as 1987 (Scheme 31)86. The cyclized samarium intermediate 49 could be further reacted with added electrophiles such... 

Palladium catalysts have high tolerance for several functional groups irrespective of their gem- or fc -sclcctivity [4, 6, 7]. Aldehydes, alcohols, saturated or conjugated ketones, esters, sulfones, malonates and silyl ethers have proved to be compatible. The presence of an additional double bond does not modify the coupling, enabling self-dimerization of non-conjugated enynes as depicted in Scheme 8. 

The use of solid supported, recyclable catalysts, is a well-assessed technique in classic organic chemistry, and many exhaustive reviews dealing with this subject are available [105, 115]. The use of solid supported catalysts for library synthesis in solution has also been reported. Among others, Kobayashi et al. presented the use of a new supported scandium catalyst for 3CC reactions leading to solution libraries of amino ketones, esters, and nitriles (24-member model discrete library) [116], or to quinolines (15-member model discrete library) [117], and Jang [118] presented a polymer bound Pd-catalyzed Suzuki coupling of organoboron compounds with halides and triflates. This area was also briefly reviewed recently [119]. 

Substituted 3-aminofuran-2-carboxylate esters can be prepared following a simple two-step procedure (Scheme 10) <20000L2061>. n-Cyano ketones are coupled with ethyl glyoxylate under Mitsunobu conditions to provide a-cyanovinyl ethers in good yield. Subsequent treatment of the vinyl ether with sodium hydride affords the 3-aminofuran. It was found that carrying out the reaction sequence in a one-pot procedure afforded the 3-aminofuran in comparable yields. 

Murai found that C-H bonds in imidazoles also undergo carbonylation (Eq. 9.23). The coupling occurred regioselectively at the 4-position (a to the sp nitrogen), with no 5 -isomer being detected [3 5]. A variety of functional groups, such as ketone, ester, cyano, acetal, N, 0-acetal, ketal, and silyl groups, were tolerated under the reaction conditions. 

The reductive coupling of carbonyl compounds with formation of C-C double bonds was developed in the early seventies and is now known as McMurry reaction [38, 39]. The active metal in these reactions is titanium in a low-valent oxidation state. The reactive Ti species is usually generated from Ti(IV) or Ti(III) substrates by reduction with Zn, a Zn-Cu couple, or lithium aluminum hydride. A broad variety of dicarbonyl compounds can be cyclized by means of this reaction, unfunctionalized cycloalkenes can be synthesized from diketones, enolethers from ketone-ester substrates, enamines from ketone-amide substrates [40-42], Cycloalkanones can be synthesized from external keto esters (X = OR ) by subsequent hydrolysis of the primary formed enol ethers (Scheme 9). 

Another important coupling reaction uses esters as the electron-accepting species and leads to a-hydroxy ketones (acyloin coupling). Sodium, potassium (less frequently) or sodium-potassium alloys are commonly used as electron donors in nonpolar solvents such as toluene or xylene. The first detectable reaction intermediate after the primary reductive step is the enediolate which can be trapped with tri-alkylsilyl chloride. This method is widely used to synthesize highly nucleophilic alkenes and/or protected acyloins (Scheme 12) [50, 51]. 

For the one-step conversion of oxiranes to alkenes a variety of reducing metals have been used, including Li, Ti°, low-valent Nb, Cr , and Sm . ° In the latter case, HMPA and N,N-dimethylami-noethanol facilitate the reaction. Reaction of 2 equiv. of Bu"Li with WCle produces a reagent which effects efficient deoxygenation of oxiranes, as exemplified in equation (8). This reagent is particularly valuable for the deoxygenation of tri- and tetra-substituted oxiranes and is compatible with ethers and esters, although aldehydes and ketones reductively couple with it. 

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