Enamino ketones basicity

Addition of nucleophiles to the cyano group of cyanothiadiazole under basic conditions takes place with unusual ease <88AG(E)434,94ACS372). Hydrolysis to the amide, for example, can be effected at 0°C in the presence of a catalytic amount of sodium hydroxide or basic ion-exchange resin. At reflux temperature, hydrazine and monosubstituted hydrazines convert 3,4-dicyano-l,2,5-thia-diazole into the l,2,5-thiadiazole[3,4-. The base-catalyzed addition of acetone to cyanothiadiazole forms an enamino ketone, used as a key intermediate for the synthesis of a number of heterocyclic ring systems, e.g. isothiazole, isoxazole, pyrazole, pyrimidine, and thiazole <77H(6)1985>. 

Lewis and Bronsted basicities of enamino ketones, which present the possibility of O, C or N protonation, have been determined experimentally by Geribaldi and coworkers290 and additional STO-3G calculations for 4-Af,Af-dimethylaminopent-3-en-2-one and its protonated forms have been performed. 

There is one example in which part of the amidine system is a C—N bond in a heterocyclic ring. The enamino ketone condensation products (42) of 3-amino-l,2,4-oxadiazoles and 1,3-dicarbonyl compounds cyclize in basic medium to form 60-80% yields of imidazoles. The driving force for this reaction is provided by the well-established, general attack of a nucleophilic centre in the side-chain at N-2 of the heterocyclic ring, but it is unusual in that a carbon nucleophile (rather than an oxygen or nitrogen species) is implicated (Scheme 23). 

P-Enamino ketones or esters 30, readily accessible from 1,3-diketones or P-ketoesters, are susceptible to diazo transfer (Regitz reaction [499]) with mesyl or tosyl azide in basic medium at room temperature and subsequent cyclization to give 4-acyl-(or 4-carbalkoxy-) 1,5-substituted 1,2,3-triazoles 32 [500] ... 

These tautomeric equilibria support the view that in enamino-aldehyde, -ketone and -ester systems generally the relative basicities of the C- and O-protonation sites are comparable, whereas N-protonation is encountered only when steric hindrance to meso-merism is present and, exceptionally, in some solid salts. 

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