Ethyl chloroformate, reaction with enamines

With enamines of cyclic ketones direct C alkylation occurs with allyl and propargyl as well as alkyl halides. The reaction is again sensitive to the polarity of the solvent (29). The pyrrolidine enamine of cyclohexanone on reaction with ethyl iodide in dioxane gave 25% of 2-ethylcyclohexanone on hydrolysis, while in chloroform the yield was increased to 32%. 

From a preparative point of view, the acylation of ketones via enamines is of particular interest. In comparison with pyrrolidine and piperidine enamines, the less reactive morpholine enamines give better yields, as found by Hiinig et al.2iZ j8-Diketones are the products of acylation with an acyl halide followed by acid hydrolysis, whereas with ethyl chloroformate, /J-ketoesters are obtained.212 Hiinig and his collaborators242-247 have used the acylation of 1-morpholino-l-cyclopentene and 1-morpholino-l-cyclohexene to lengthen the chains of acids by five and six carbon atoms, respectively. The reaction may... 

Keto esters can be obtained by acylation of enamines of acyclic and cyclic ketones with ethyl chloroform ate Surprisingly no -keto ester was obtained when the reaction was carried out in the presence of triethylamine and an extra mole of enamine or a tertiary aromatic amine must therefore be used to neutralize the acid liberated. The intermediate enamino ester can be isolated and reduced by hydride donors (Scheme 92). 

Reaction of the enamines with ethyl chloroformate gives good yields of ethyl j8-oxo carboxylates (R" = COOC2H5),465,467 and cyanogen chloride affords / -oxo nitriles (R" = CN) smoothly.470... 

Tetrachloropyrimidine is formed in quantitative yield by the cyclization (with FeCla, at 200 °C) of perchloro-l-cyano-3-azabutadiene (Cl2C=N—CC1=CC1CN), itself formed by successive treatment of cyanoethyl)formamide with phosphorus pentachloride and chlorine. j8-Iminoyl-enamines (222), prepared by the reaction of the appropriate anils with nitriles, condense with ethyl chloroformate and carbon disulphide to give excellent yields of 2-oxo- and 2-thioxo-pyrimidines (223 X = O or S). Aldehydes, acetals, and ketals (but not ketones) also react with these enamines (222) to give 1,2-dihydropyrimidines (224) (70—93%). In similar fashion, malondiamidines condense with a large variety of aromatic aldehydes to give 2-aryl-5-arylmethyl-4,6-diaminopyrimidines. °... 

Af -2,2-Bis(ethoxycarbonyl)vinyl-protected amino acids are prepared by reaction of commercially available diethyl 2-(ethoxymethylene)malonate (127) with the respective amino acid in methanolic KOH. This rapid reaction is complete within 5 minutes and leads to the potassium salts. Subsequent acidification with 1M HCl yields the amino acid derivative in 75-90% yield.f This intermediate enamine-type N-protection is of particular interest in chemistry to be performed on the carboxy groups of the amino acids such as esterification with alkyl bromides in the presence of a base. Since cleavage of the enamine entity is achieved by treatment with bromine in chloroform at room temperature, it cannot be used for amino acids sensitive to halogenation such as tyrosine, tryptophan, and methionine (Scheme 61). Based on the experience gained with the enamine-type protection the Al-2-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde) and N-2-(4,4-dimethyl-2,6-dioxocyclohex-ylidene)isovaleryl derivatives were developed as specific side-chain protecting groups (see Section 2.1.2.2.5.2). 

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