Ritter reaction reversed

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. 

To favor the coupling reaction, the competing side reaction of the radical cation with nucleophiles must be suppressed by the use of a medium of low nucleophilicity. The solvent of choice is dichloromethane. Especially in electroanalytic studies, neutral alumina is frequently added to suppress hydroxylation of the radical cation [20]. The reversible cyclic voltammetric behavior of radical cations is also enhanced in mixtures of methylene dichloride, trifluoroacetic acid, and trifluoroacetic anhydride (TFAn) with TBABF4 as supporting electrolyte. With acetonitrile as solvent, acetamides, formed in a Ritter reaction, are often the major products. The selective dimerization of mesitylene in acetonitrile is exceptional (Table 1, number 3). Dichloromethane, however, is reducible at the cathode. 

Retro-Ritter reaction amide into alkene reverse sequence to above SOCI2 or P4O10. Intramolecular Ritter reaction alkene (etc.) into heterocycle sequence (130) -> carbenium ion - (129) - (131) (where Y is a nucleophilic substituent) H2SO4 then H2O. 

The benzamido-group is readily eliminated to give olefins by the action of P2O5 in boiling benzene. In some cases SOClj and pyridine in ether can be employed. The elimination, which formally reverses the Ritter reaction, is illustrated by examples in Scheme 14. A transition state with carbonium ion character is indicated by the rearrangement of (436) into (438) and (439). 

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