Nitrogen-containing heterocycles make up about 60% of FDA-approved small-molecule drugs, with piperidines being the most common. With the aim of synthesizing new functionalized piperidines, UCLA’s Neil K. Garg, Kendall N. Houk, and coworkers wondered if the unusual molecule 3,4-piperidyne could be generated and used as a synthetic building block. Although aromatic 2,3- and 3,4-pyridynes are common and aliphatic 2,3-piperidynes are known, a 3,4-piperidyne has not been reported before now. The researchers first developed a three-step synthesis of a carboxybenzyl-protected trimethylsilyl-triflate piperidine derivative as a starting material. Treating this compound with cesium fluoride generates the reactive 3,4-piperidyne in situ. By including a nucleophile or cycloaddition partner in the mixture, the UCLA team can trap the 3,4-piperidyne as a piperidine derivative. The team used a computational model to predict and explain regioselectivities and made an array of new functionalized piperidine products (J. Am. Chem. Soc. 2015, DOI: 10.1021/jacs.5b01589). The silyltriflate precursor has proven so useful that it is in the process of being commercialized by Sigma-Aldrich.