Enamine hydrochlorides esters

Ethyl 2-oxocyclohexanecarboxylate Ethyl chloroformate (7.2 g, 0.066 mole) is added to a well stirred solution of 4-(l-cyclohexenyl)morphoIine (20.0 g, 0.12 mole) in anhydrous benzene (100 ml) under nitrogen, and the mixture is boiled under reflux for 10 h, then cooled and filtered. The precipitate of enamine hydrochloride is washed with anhydrous ether. The united filtrates are treated with 10% aqueous hydrochloric acid (22 ml) and the mixture is stirred vigorously for 15-30 min. The layers are separated, the aqueous phase is extracted with benzene, the organic phases are united, and the solvent is distilled off under reduced pressure. Fractionation of the residue gives 62% (6.2 g) of the /S-oxo ester, b.p. 112-115°/ 10 mm. 

A structurally unrelated agent is tazadolene (40). The synthesis of tazadolene begins with P-keto ester 37 and subsequent enamine formation with 3-amino-1-propanol followed by hydrogenolysis to give 38. This phenylhydroxymethyl compound is then dehydrated with hydrochloride acid to form olefin 39. Treatment with bromine and triphenylphosphine effects cycliza-tion to form the azetidine ring of tazadolene [10]. 

The groups of Giacomelli and Taddei have developed a rapid solution-phase protocol for the synthesis of 1,4,5-trisubstituted pyrazole libraries (Scheme 6.194) [356]. The transformations involved the cyclization of a monosubstituted hydrazine with an enamino-/8-ketoester derived from a /8-ketoester and N,N-dimethylformamide dimethyl acetal (DMFDMA). The sites for molecular diversity in this approach are the substituents on the hydrazine (R3) and on the starting j3-keto ester (R1, R2). Subjecting a solution of the /8-keto ester in DMFDMA as solvent to 5 min of microwave irradiation (domestic oven) led to full and clean conversion to the corresponding enamine. After evaporation of the excess DMFDMA, ethanol was added to the crude reaction mixture followed by 1 equivalent of the hydrazine hydrochloride and 1.5 equivalents of triethylamine base. Further microwave irradiation for 8 min provided - after purification by filtration through a short silica gel column - the desired pyrazoles in >90% purity. 

Biginelli synthesis of 3,4-dihydropyrimidin-2( 1 //)-oncs (99) from an aldehyde, a /3-diketone, and urea is catalysed by L-proline methyl ester hydrochloride.276 Although evidence strongly supports an enamine mechanism, the products were essentially racemic. 

Hydrochlorides of enamines add as iminium salts to dialkyl phosphites with formation of a-amino phosphonic esters.132... 

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