Aldehyde N,N-Dialkylhydrazones as Neutral Acyl Anion Equivalents: Umpolung of the Imine Reactivity

Abstract

The isoelectronic replacement of the α-carbon of enamines by nitrogen leads to the corresponding hydrazones, and thus, they can be termed “aza-enamines”. Hence, aldehyde N,N-dialkylhydrazones enable analogous electrophilic substitutions at the imine carbon that corresponds to the β-carbon of enamines. In addition, after hydrolysis of the product hydrazones to the parent ketones or aldehydes, these reactions constitute an umpolung of the classical carbonyl reactivity and overall a nucleophilic acylation or formylation. This review covers the aza-enamine chemistry from its very beginning in the late 1960s up to this year. In the first part, reactions of aromatic, aliphatic, and heterocyclic aldehyde N,N-dialkylhydrazones with highly reactive substrates such as the Vilsmeier and Mannich reagents, sulfonyl isocyanates, perfluoroacetic anhydride, and inorganic electrophiles such as halogens and phosphorus tribromide are described. The hydrazones of α,β-unsaturated aldehydes react as vinylogous aza-enamines at the terminal carbon providing unsaturated aldehydes. As electron-rich dienes and dienophiles, they also form Diels–Alder adducts and thus interesting N-heterocycles. The second part covers carbon–carbon bond formations of the sterically less-demanding formaldehyde N,N-dialkylhydrazones with synthetically very useful electrophiles such as various Michael acceptors and carbonyl compounds. Formaldehyde SAMP-hydrazone and related derivatives generally give excellent asymmetric inductions. Finally, first organocatalytic versions of the aza-enamine chemistry are presented. In summary, the rich chemistry of aldehyde N,N-dialkylhydrazones as neutral acyl anion, formyl anion, and cyanide equivalents is demonstrated.