1‐Azaspiro[3.3]heptane as a Bioisostere of Piperidine

1‐Azaspiro[3.3]heptanes were synthesized, characterized, and validated biologically as bioisosteres of piperidine. The key synthesis step was thermal [2+2] cycloaddition between endocyclic alkenes and Graf's isocyanate, ClO2S‐NCO, into spirocyclic β‑lactams. Reduction of the β‐lactam ring with alane produced 1‑azaspiro[3.3]heptanes. Incorporation of this core into the anesthetic drug Bupivacaine instead of the piperidine fragment resulted in the new patent‐free analogue with high activity.