Unsaturated ketoesters, reaction with

A reaction related to the Michael addition reactions of enamines to unsaturated esters, which leads to S-ketoesters, is the reaction with 1-carb-ethoxy-l-cyanocyclopropane (318). This gives access to ketones substituted with the next higher homologous acid chain. 

Further studies by Bode and co-workers have shown that enolate formation from a-chloroaldehydes and subsequent reaction with 4-oxo-enoates or unsaturated a-ketoesters 232 generates dihydropyranones 233 in excellent diastereo- and enantio-selectivities, and with impressively low catalyst loadings [90], This work has been extended to the generation of enolate equivalents from bisulfite adducts of a-haloaldehydes 234 under aqueous conditions (Scheme 12.50) [91]. 

In the Diels-Alder reaction with inverse electron demand, the overlap of the LUMO of the 1-oxa-l,3-butadiene with the HOMO of the dienophile is dominant. Since the electron-withdrawing group at the oxabutadiene at the 3-position lowers its LUMO dramatically, the cycloaddition as well as the condensation usually take place at room or slightly elevated temperature. There is actually no restriction for the aldehydes. Thus, aromatic, heteroaromatic, saturated aliphatic and unsaturated aliphatic aldehydes may be used. For example, a-oxocarbocylic esters or 1,2-dike-tones for instance have been employed as ketones. Furthermore, 1,3-dicarbonyl compounds cyclic and acyclic substances such as Meldmm s acid, barbituric acid and derivates, coumarins, any type of cycloalkane-1,3-dione, (1-ketoesters, and 1,3-diones as well as their phosphorus, nitrogen and sulfur analogues, can also be ap-... 

Reactions of this type have been widely used for the synthesis of 1,5-benzoxazepines by the reactions of o-aminophenols and their derivatives with a variety of functionalized three-carbon chains. Thus reaction with 3-bromo-l-chloropropane gives (360) and reaction with 3-chloropropionyl chloride gives the analogous 4-oxo derivative. Similarly a,/3-unsatur-ated Icetones give (361), /3-ketoesters give (362), l,3-oxazolid-5-ones give (363), and the reaction of the sodium salt of N-methanesulfonyl-o-aminophenol with epichlorohydrin gives... 

The reaction process can be monitored by TLC or GC. The unsaturated ketoester is generally consumed within 1 h. Once the starting material is consumed, the reaction can be quenched with 1 N HCl. The double bond in the product will be slowly reduced at elevated temperature (80 °C) and prolonged reaction time. However, it is relatively stable at room temperature under the catalysis of Ru(p-cymene)(TsDPEN) no significant amount (<1 %) of double bond reduced product was detected 5h after the consumption of the starting material. 

Friedel-Crafts Alkylation Reactions. The activation of glyoxylate esters,trifluoromethyl pyruvate esters, and unsaturated a-ketoesters by catalyst 2 converts these materials into effective electrophiles for asymmetric Friedel-Crafts alkylation reactions with activated arenes (eqs 16 and 17). In fact, bis(triflate) (2) is far superior to tbe bis(hexafluoroantimonate) complex at catalyzing the enantioselective alkylation of benzene derivatives. Aniline and anisole derivatives both give the reaction, as do heterocyclic aromatic compounds such as indole and furan. 

In 2006, Deng and coworkers reported that quinine/quinidine-derived catalysts (64a,b) bearing a free OH group at the C6 -position and bulky phenanthryl moiety at the 9( Opposition quite efficiently promoted the Michael addition of the a-substituted P-ketoesters 65 to the a,P-unsaturated ketones 66 (Scheme 9.21) [18]. The reaction with as little as 1.0mol% of catalyst 64 afforded excellent stereoselectivity and chemical yields (up to 98% ee with quantitative yield) for a wide range of both donors and acceptors. 

Enders and coworkers [300] used the lithiated carbanion of the chiral ami-nonitrile 1.70 as a Michael donor. Additions of this species to a,P-unsaturated esters are performed at -100°C. After removal of the chiral residue with aqueous CuS04, 3-branched-4-ketoesters are obtained with a high enantiomeric excess (Figure 7.66). 2-Cyclohexenone can also be used as an acceptor with equally good results [1453], Dienolate 7.100 has also been proposed as a chiral Michael donor [1454], but its reactions with a,p-unsaturated aldehydes give low chemical yields. 

In a similar context, y,5-unsaturated p-ketoesters (Nazarov reagents) have also been employed as suitable functionalized Michael donor substrates for a Michael/Michael cascade reaction with nitroalkenes using, in this case, Takemoto s catalyst 68a (Scheme 7.65). This reaction proceeded in a tandem... 

The synthesis of six-membered all-carbon rings have been extensively studied in the literature, mainly because of their importance as constituents in natural products and biologically relevant compounds. The first example of an enantioselective organocatalytic domino reaction with nitroalkenes to furnish cyclohexanes was disclosed by Takemoto and co-workers [38] in 2004. In this work, a domino Michael addition of 7,8-unsaturated-(3-ketoesters (58) to nitroalkenes (28) catalyzed by a bifunctional amino-thiourea (Takemoto s catalyst, XVIII) and 1,1,3,3-tetramethylguanidine (TMG) was reported with excellent results and diastereoselectivities (up to 71% yield, up to >99% ee) and was recently applied to the synthesis of (-)-epibatidine. 

Michael reaction with an o , S-unsaturated ketone followed by an intramolecular aldol reaction has proven to be a valuable method for the synthesis of 2-cyclohexenones. An especially important example of a Michael-aldol sequence is the Robinson annulation, in which treatment of a cyclic ketone, 8-ketoester, or S-diketone with an a,)8-unsaturated ketone in the presence of a base catalyst forms a cyclohexenone ring fused to the original ring. When the following racemic 8-ketoester, for example, is treated with methyl vinyl ketone in the presence of sodium ethoxide in ethanol, the Michael adduct forms and then, in the presence of sodium ethoxide, undergoes a base-catalyzed intramolecular aldol reaction followed by dehydration to give a racemic substituted cyclohexenone. 

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