Enolate anions condensation with methyl

This is an example of a Robinson annulation. The mechanism for the Robinson annulation involves a sequence of conjugate addition reactions and aldol condensations. As illustrated, the first step is deprotonation of cyclohexanedione with sodium hydride. The resulting anion then participates in a 1,4-addition to methyl vinyl ketone. The resulting enolate anion then tautomerizes through... 

Just occasionally it is possible to carry out cross-condensations between two different enolizable molecules under equilibrating conditions, A notable example is the base-catalysed reaction between methyl ketones and lactones. With sodium hydride—a strong base that can convert either starting material entirely into its enolate anion—good yields of products from the attack of the enolate of the ketone on the electrophilic lactone can be obtained. 

Addition of the anion of 2-methyl-l,3-cyclopentadione (348) to protoane-monin (349), easily prepared from levulinic acid in four steps (207), led to adduct 350 in low yield due to ready self-condensation (Scheme 39). Transesterification with acidic methanol set the alcohol free, which cyclized spontaneously to the 1 1 mixture of ketals 351 and 352. To enhance the yield of the ketal 352, ketal 351 was recycled by equilibration in acidic methanol. Under Kharash-Grignard conditions, the isopropenyl group added unselectively in 1,4-mode and the ester enolate 353... 

Another method of alkylation of A -3-ketones involves a Mannich-type condensation of the enolate anion with formaldehyde and a thiol [166]. The outcome is a selective thio-methylation at C(4>, probably involving nucleophilic attack... 

Geminal alkylation of ketones. Coates and Sowerby2 have reported a new method for site-selective geminal alkylation of ketones which involves reduction of the n-butyl-thiomethylene derivative of the ketone by lithium-ammonia to give a methyl-substituted enolate anion which can be alkylated in situ. The ketone, for example cyclohexanone (1), is condensed with ethyl formate and then transformed into the n-butyl-thiomethylene derivative (2) by reaction with n-butyl mercaptan (2, 53-54). This is then reduced with excess lithium in liquid ammonia at -33° with 2 eq. of a proton donor (water is usually used to avoid overalkylation). The lithium enolate is then... 

The same year, Gerlach described a synthesis of optically active 1 from (/ )- ,3-butanediol (7) (Scheme 1.2). The diastereomeric esters produced from (-) camphorsulfonyl chloride and racemic 1,3-butanediol were fractionally recrystallized and then hydrolized to afford enantiomerically pure 7. Tosylation of the primary alcohol, displacement with sodium iodide, and conversion to the phosphonium salt 8 proceeded in 58% yield. Methyl-8-oxo-octanoate (10), the ozonolysis product of the enol ether of cyclooctanone (9), was subjected to Wittig condensation with the dilithio anion of 8 to give 11 as a mixture of olefin isomers in 32% yield. The ratio, initially 68 32 (E-.Z), was easily enriched further to 83 17 (E Z) by photolysis in the presence of diphenyl disulfide. The synthesis was then completed by hydrolysis of the ester to the seco acid, conversion to the 2-thiopyridyl ester, and silver-mediated ring closure to afford 1 (70%). Gerlach s synthesis, while producing the optically active natural product, still did not address the problem posed by the olefin geometry. 

A second major class of acyl anion equivalents are the enol ethers such as methyl 1-propenyl ether (359). When 359 was treated with tert-butyllithium (note the need for a stronger base with the less acidic vinyl hydrogen) and then condensed with benzaldehyde, the product was 260. Lithiation of vinyl derivatives was described in Section 8.5. Facile hydrolysis with aqueous acid liberated the corresponding ketone (361), completing the acyl anion equivalency. Schlosser co-workers found that a mixture of 5ec-butyllithium and potassium tert-butoxide could be used to generate the lithium anion of O-tetrahydropyranyl enol ethers.360 This modification generates a product that is more easily hydrolyzed to the ketone. 

There are countless synthetic examples of the aldol condensation. In one example taken from Massanet s synthesis of eudesmanolides, diketone 134 was converted to the enolate anion with LDA. In a second step, methyl pyruvate was added to give a 98% yield of 135 and 136 in about a 1 1 ratio. 

The preference for the lowest energy conformation of the enolate anion is seen in larger ring systems as well (sec. 1.5.B,C), leading to good selectivity in alkylation and condensation reactions. The methyl group provides only small steric encumbrance to approach of the electrophile in enolate 505 (derived from lactone 504 and LDA). The preferred mode of attack for this relatively stable conformation was from the top face (path a, pseudoequatorial attack) and gave the syn diastereomer (506) with >99 1 selectivity.- ... 

The synthesis of the 10-methoxytetracyclic ketone 353 (Scheme 26) started from the readily available 3-methyl-5-methoxyindole 355, which after Boc protection, was brominated, and then condensed with the anion of the Schollkopf auxiliary 356 (from l-valine). Removal of the Boc-protecting group, followed in succession by A -methylation and hydrolysis, gave the required A -methyl-5-methoxy-D-tryptophan ethyl ester 357, which was then transformed into the key 10-methoxytetracyclic ketone 353, via N-benzylation, Pictet-Spengler condensation, and Dieckmann cyclization. Subsequent N-alkylation by the vinyl iodide 358 followed by Pd-catalyzed (enolate-driven)... 

In the late nineteenth century, Ludwig Claisen (Germany 1851-1930) treated an ester with a base the isolated product was a P-keto ester. This product results from the enolate anion of one molecule of the ester condensing with a second molecule via an acyl substitution reaction (Chapter 16, Section 16.8). In a typical experiment, ethyl 2-methyl propionate (60) is treated with a specialized base (sodium triphenylmethide, 19) in diethyl ether and stirred at room temperature for 60 hours. This reaction mixture is then acidified with glacial acetic acid (i.e., 100% acetic acid) the final isolated product is ethyl 2,2,4-tri-methyl-3-oxopentanone (61) in 74% yield. It is clear that when an ester enolate reacts with another ester, the product is a -keto ester and the reaction is now called the Claisen condensation. 

The synthesis begins with an Sn2 reaction (Chapter 10, Section 10.2) of bromide 141 with potassium cyanide to give 144. Note the use of the aprotic solvent DMF to facilitate the 8 2 reaction. A Grignard reaction of the nitrile with methylmagnesium bromide followed by hydrolysis leads to the requisite ketone (see Chapter 20, Section 20.9.3). The final step simply reacts the methyl ketone with LDA under kinetic control conditions to give the enolate anion (143), which is condensed with the ester (142) to give the diketone target, 140 (Section 22.7.2). 

A classical reaction of an enolate anion with a conjugated carbonyl leads to a bicyclic derivative. When cyclohexanone (58) is heated with methyl vinyl ketone (10) in the presence of ethanoUc KOH, the final product (after hydrolysis) is bicyclic ketone 64. This process is called the Robinson annulation, after Sir Robert Robinson (England 1886-1975). It begins with the reaction of 58 with KOH to form the enolate anion (59). Under these conditions, Michael addition to 10 is faster than self-condensation of the ketone (see Chapter 22, Section 22.2), and the product is enolate anion 60. 

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