Domino Sequences Involving Stereoselective Hydrazone-Type Heck Reaction and Denitrogenative [1,5]-Sigmatropic Rearrangement

Although the Heck reactions of alkene partners with various electrophiles have achieved great success, the variant focused on carbon═heteroatom counterparts still remains elusive. Herein, we report a Pd(0)-catalyzed asymmetric intramolecular hydrazone-type Heck reaction of N-[(Z)-3-iodoallyl]-aminoacetaldehyde and hydrazine hydrate (NH2NH2–H2O), wherein the required hydrazone is in situ generated via an acid-promoted condensation. A key strategic advantage of this Heck paradigm is that the resultant Heck product allylic diazene rapidly undergoes stereospecific denitrogenative [1,5]-sigmatropic rearrangement, eventually furnishing a domino sequence toward 3-substituted tetrahydropyridine (THP) with high enantioselectivity. The substrate-induced diastereoselective version has also been realized, exclusively giving cis-2,5-disubstituted THPs. The utility of this sequence is demonstrated by the formal synthesis of multiple valuable bioactive targets, including 3-ethylindoloquinolizine, preclamol, and niraparib.