Esters from chloro ketones

Many synthetic routes have been developed to access the saturated oxazolo[3,2- ]pyridine ring system. Among those, the most efficient ones rely on a similar strategy starting from an amino alcohol 360 and a bis-electrophile 361, the latter being either a bis-aldehyde, a keto-ester, a chloro-ketone, or a chloroalkyne (Scheme 96). Among these electrophiles, the first two have demonstrated their utility and generality over the years and have been used for the preparation of many saturated oxazolo[3,2- ]pyridines 362. 

The cyclopropanols 13 were separated from the ketone by column chromatography and rearranged to eucarvone. In a closely related process, the addition of chloro(methyl)carbene to ketene alkyl silyl acetals afforded adducts 14 which were transformed without isolation into esters of 2-methyl-substituted a,/i-unsaturated acids 15. ... 

Hydrophobic interactions may also serve to purify products of combinatorial syntheses. As an example, penta-O-lauroyl-l-thio-p-galactose was subjected to a Michael addition to a,p-unsaturated ketones or to alkylation by a-chloro ketones followed by reduction of the keto groups or by reductive alkylation with amino acid esters. The reaction mixtures were passed through Cl8 silica gel, whereby the desired products were adsorbed while unwanted products were washed away. Desorption was carried out with pentane, and the hydrophobic labels were removed with methanolic sodium methoxide.The methyl laurates were finally separated from the desired products by chromatography on silica... 

The Cs-phosphonium ester salts 95 + 99 and the Cs-phosphonate ester 100 (Scheme 11), as well as their corresponding methyl esters, are key building blocks for the manufacture of various polyenecarboxylic acid esters for use in the carotenoid field [34-36]. An efficient route uses as an intermediate 2-hydroxy-2-methylbut-3-enoic acid ethyl ester (101) [37,38], which can be prepared from methylvinyl ketone (102) by acidic ethanolysis of the cyanohydrin 103, prepared by reaction of 102 with HCN (104). Reaction of 101 with thionyl chloride under reflux conditions led to a 76% yield of distilled 4-chloro-2-methyl-but-2-enoic acid ethyl ester (105), from which the phosphonium chloride 98 was obtained in good yield [36]. 

Several approaches to cyclic thio- and dithio-lactones have been described thus, the reaction of y-oxo-esters with HjS gave 5-mercaptothiolan-2-ones (123) (see Vol. 5, p. 249). A general approach to y- and -thiolactones, e.g. (124), involves the reaction of a bis-metallated thioacid with a- or /6-chloro-ketones and cyclization of the resulting y- or <5-chloro-y6-hydroxy-thioacids. Reactions of cyclic lactones with the dimeric phenylthionophosphine sulphide (125) gave dithiolactones. y-Dithiolactones, e.g. (126), were obtained from 2-alkenyl alkanedithioates, which... 

Ketones from carboxylic acid esters oc-Chloro-a,/9-oxidoketones... 

Manganese metal (commercial quality) without any special preparation allows Barbier or Reformatsky reactions, respectively, to be performed from allylic bromides and a-halogenoesters. The use of manganese is of real preparative interest since these reactions have a large scope of application and occur under mild conditions to give high yields of 1,2-addition products (16]. It should be noted that numerous functional ketones (keto-esters, keto-acetals, w-chloro-ketones) were converted into the corresponding functional alcohols very efficiently (Schemes 13.13 and 13.15). 

The possible presence in the 4-chloro-4-hexenyl trifluoroacetate of small amounts of two cis-trans pairs of products of addition of trifluoroacetic to the triple bond without concomitant halogen shift remains speculative. In any event these compounds would be removed as ketones upon hydrolysis of the trifluoroacetate. Both the 4-chloro-4-hexenyl trifluoroacetate and the alcohol resulting from its hydrolysis have been shown to contain 9% of the (E) isomer. In the present study the hydrogen decoupled magnetic resonance spectra of the ester and alcohol were shown to contain peaks attributable to approximately 9% of E) isomer. 

A thioamide of isonicotinic acid has also shown tuberculostatic activity in the clinic. The additional substitution on the pyridine ring precludes its preparation from simple starting materials. Reaction of ethyl methyl ketone with ethyl oxalate leads to the ester-diketone, 12 (shown as its enol). Condensation of this with cyanoacetamide gives the substituted pyridone, 13, which contains both the ethyl and carboxyl groups in the desired position. The nitrile group is then excised by means of decarboxylative hydrolysis. Treatment of the pyridone (14) with phosphorus oxychloride converts that compound (after exposure to ethanol to take the acid chloride to the ester) to the chloro-pyridine, 15. The halogen is then removed by catalytic reduction (16). The ester at the 4 position is converted to the desired functionality by successive conversion to the amide (17), dehydration to the nitrile (18), and finally addition of hydrogen sulfide. There is thus obtained ethionamide (19)... 

Baker s yeast has been widely used for the reduction of ketones. The substrate specificity and enantioselectivity of the carbonyl reductase from baker s yeast, which is known to catalyze the reduction of P-keto ester to L-hydroxyester (L2-enzyme) [15], was investigated, and the enzyme was found to reduce chloro-, acetoxy ketones with high enantioselectivity (Figure 8.32) [24aj. 

The intermediate Michael adducts have been isolated from the reaction of a-chloro-a-nitroalkanes with a, 3-unsaturated aldehydes, ketones, nitriles and esters... 

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