One-pot synthesis of N-heterocycles and enimino carbocycles by tandem dehydrative coupling–reductive cyclization of halo-sec-amides and dehydrative cyclization of olefinic sec-amides

Abstract

We report two efficient and versatile alkenylative cyclization methods for the one-pot synthesis of substituted pyrrolidine, piperidine, indolizidine, and quinolizidine ring systems, and enimino carbocycles, respectively. The first method consists of amide activation (Tf₂O) induced dehydrative coupling of halogenated secondary amides with alkenes and the NaBH₄ reduction triggered tandem cyclization reaction, while the second one features the Tf₂O-promoted novel modes of extended Bischler–Napieralski cyclization reactions of olefinic secondary amides. Taking advantage of triflic anhydride (Tf₂O) as the amide activating reagent, the hitherto failed two-step process for the construction of the quinolizidine ring system via intramolecular vinylogous Bischler–Napieralski cyclization has been realized in one pot. The first method was applied to the protecting-group-free one-pot synthesis of the cytotoxic natural product caulophyllumine B (5) and its bioactive derivatives, and to the synthesis of δ-coniceine and 6-styrylpiperidin-2-one. When ethyl vinyl ether and enamides were used as functionalized alkenes, saturated 1,3-amino-ether/amido products 4A₁–4A₃ were obtained in 73%–74% yields.