C-Acylaminomethylation

Conversion of the C-2 amide to a biologically inactive nitrile, which can be further taken via a Ritter reaction (29) to the corresponding alkylated amide, has been accomphshed. When the 6-hydroxyl derivatives are used, dehydration occurs at this step to give the anhydro amide. Substituting an A/-hydroxymethylimide for isobutylene in the Ritter reaction yields the acylaminomethyl derivative (30). Hydrolysis affords an aminomethyl compound. Numerous examples (31—35) have been reported of the conversion of a C-2 amide to active Mannich adducts which are extremely labile and easily undergo hydrolysis to the parent tetracycline. This reverse reaction probably accounts for the antibacterial activity of these tetracyclines. 

Imidazole ring annulation according to variant Alg can be a result of the nucleophilic attack of the nitrogen atom in the 1- or 4-position of quinoxaline at the electrophilic carbon atom of the C-N-C moiety of the substituent at the C(2) or C(3) atom. Such substituents are acylaminomethyl, isocyanatomethyl, benzylaminomethyl, etc. 

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