Amino esters, enolates, reaction with halides

Synthesis and Reaction.—No less than three different groups " have described various extensions to the general method for the homolagation of a-amino-acids by the reactions of electrophiles with enolates derived from Schiff s bases of a-amino-esters, originally reported by Stork s group last year. A full report has appeared on the electro-reductive coupling of Schiff s bases of a-amino-esters with alkyl halides yields of a-alkylated amino-acids are between 36 and 86%... 

A typical reaction that uses an amino acid derivative involves initial conversion to an enolate anion. This nucleophilic species is then reacted with an alkyl halide or a carbonyl derivative. An example that produces a new amino acid is the reaction of the ethyl ester of n-benzyl glycine with lithium diisopropylamide to give the enolate. Subsequent reaction with the mixed anhydride shown below proceeded with displacement of acetate to give /.22J.13 Acid hydrolysis generated a P-keto amino acid, which decarboxylated under the reaction conditions to give 4-oxo-5-aminopen-tanoic acid 1.156, also known as 5-aminolevulinic acid). 

The common methods for the S5mthesis of p-lactams are cycloaddition reactions such as the Staudinger s ketene-imine cycloadditions, ester enolate-imine cycloadditions, alkyne-nitrone cycloadditions (Kinugasa reaction), alkene-isocyanate cycloadditions, and Torii s cyclocarbonylation of allyl halides with imines. Several cyclizahon reactions of p-amino esters, p-amino acids, p-hydroxamate esters, and a-diazocarbonyls have been developed for the formation of p-lactam ring. N,N-Disubstituted a-haloamides cyclize by C3-C4 bond formation leading to the formation of P-lactam ring. 

The most general method of preparation for a amino acids is the amido-malonate synthesis, a straightforward extension of the malonic ester synthesis (Section 22.8). The reaction begins with conversion of diethyl acetamidomalonate into an enolate ion by treatment with base, followed by Sf 2 alkylation with a primary alkyl halide. Hydrolysis of both the amidel protecting group and the esters occurs when the alkylated product is warmed 1 with aqueous acid, and decarboxylation then takes place to yield an a-amiaOj acid. For example, aspartic acid can be prepared from ethyl bromoacetate ... 

The preparation of indoles by the benzyne route is illustrated by the base-induced cyclization of the amino-alcohols (171 R = H or Me) to indole and 3-methylin-dole, respectively/ The photochemical reaction of o-bromo- or o-iodo-aniline with the enolates (172 R = H, Me, or PrO leads to indoles (173)/ The salt (174), generated by the action of lithium di-isopropylamide on o-tolyl isocyanide, serves as a source of diverse indole derivatives (i) it cyclizes spontaneously to 1-lithioindole, which forms 3-alkyl-indoles on treatment with alkyl halides in the presence of magnesium iodide, (ii) it reacts with allyl esters RC02CH2CH=CH2 (R = alkyl or aryl) to give the ketones (175), which cyclize... 

Enolate Arylation Reactions. The direct coupling of aryl halides with enolates (or enolate equivalents) of ketones, esters, and amides is now well established. Malonic esters, cyanoacetates, and malononitrile can be arylated upon treatment with aryl halides in the presence of Pd(dba)2 and electron-rich phosphines or N-heterocyclic carbenes. Carbene ligands have also proven effective in promoting the a-arylation of protected amino acids. As a caveat to the use of Pd(dba)2, the arylation of azlactones in the presence of this palladium source and phosphines was less efficient than that with Pd(OAc)2. The dba ligands were found to react with azlactone substrates to form catalytically inactive palladium complexes. Diastereoselective enolate arylation has been achieved through the use of chiral auxiliaries appended to preformed enol silyl ethers (eq 23). The role of the zinc additive is not clear, however, it appears that discrete zinc enolates are not involved. 

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