Refoimatsky reaction

Scheme 79 Refoimatsky reaction of imines and a-bromoesters affording P-lactams and P-aminoesters...

Refoimatsky Reactions. The Reformatsky reaction of a-halooxazolidinones provides an alternative to the more conventional aldol reaction. Although the traditional zinc-mediated Reformatsky using valine-derived compounds proceeds nonselectively, the Sn modification with 2-bromo-2-methylpropionyloxazolidinone proceeds well (eq 46). In this particular case, however, the geminal dialkyl substiments favor the endocyclic carbonyl acyl transfer of the auxiliary by the aldolate oxygen. 

Enolates lype Anions. The well-known Refoimatsky reaction allows the introduction of a functionalized two-carbon chain. Modified experimental procedures have now been proposed, such as the reaction of ethylbromoacetate with ketosugar 18 (Scheme 10) in the presence of zinc/silver graphite prepared from CgK, giving 19 in excellent yield [32],... 

Aluminum enolates can be obtained also by transmetallation of lithium enolates (Scheme 31 ). 3 Diethylaluminum enolates can be produced regiospecifically through reaction of diethylaluminum chloride and zinc dust with a-bromo ketones and esters (Scheme 32). Obviously zinc is involved in this reaction, but the mild conditions are in sharp contrast to the Refoimatsky reaction and support the existence of an aluminum enolate in this process. The same type of enolate can be obtained from r-butyi acetates and diethylaluminum 2,2,6,6-tetramethylpiperidide (DATMP), which is generated in situ from diethylaluminum chloride and LITMP (Scheme 33). ... 

Thomas and cowoikers examined the reaction of 2-phenylcyclohexanone with a number of nucleophiles. The highest stereoselectivity was observed with a Refoimatsky reaction of ethyl a-bromopropionate (equation 3S). The exclusive product (25) corresponds to that expected from the most stable zinc aldolate (26) with the a-methyl away from the phenyl group. 

Dehydration of the aldol products of a Refoimatsky reaction does not normally occur under the usual reaction conditions but is often accomplished in a separate step to prepare unsaturated esters. Acid-promoted dehydration of -hydroxy esters can give significant amounts of nonconjugated unsaturated esters by either kinetic or thermodynamic control. Mirrington and cowoikers found that acetates can be prepared directly from Refoimatsky reaction mixtures by addition of acetyl chloride. Base-promoted elimination of the acetates produced conjugated esters in high yield. For the reaction shown in Scheme 14, the thermodynamic ratio of products (32) (33) is 40 60 and four different acid-promoted dehydration procedures gave at best a 68 32 ratio of products. ... 

Refoimatsky reactions of a-trimethylsilyl esters have been used to obtain a,3-unsaturated esters directly from carbonyl substrates in a Peterson-type alkenation, as shown in equation (40). 

The corresponding enol ether from cyclohexane>l,2 dione is obtained in the same way from the hydrated diketone dimer as obtained from the nitric acid oxidation of cyclo-hexanol this enol ether was used in a Refoimatski reaction... 

Other studies of the Refoimatsky reaction in refluxing benzene with ketone substrates are readily explained in teims of equilibrated zinc aldolates, although direct evidence for equilibration was not obtained. Matsumoto and coworkers examined the reaction of 3-phenyl-2-butanone with methyl a-bromopropionate and observed a net syn anti ratio [(21 + 22) (23 + 24)] of 10 90, in harmony with equilibrated zinc aldolates (equation 34). 

The reaction of imines with Refoimatsky reagents was flrst examined by Gilman and Speetei in 1943 with benzalaniline. The product of the reaction was a -lactam, formed by cyclization of an intermediate zinc salt (Scheme 15). The stereoselectivity of the reaction of a-alkyl-substituted bromo esters with a variety of benzalanilines was examined by both Luche and Kagan, and Gaudemar and coworkers. Condensations conducted at reflux temperatures gave a mixture of cis and trans -lactams (equation 41). 

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