Quaternary N‑(2-Pyridyl)-DABCO Salts: One-Pot in Situ Formation from Pyridine‑N‑oxides and Reactions with Nucleophiles: A Mild and Selective Route to Substituted N‑(2-Pyridyl)‑N′‑ethylpiperazines

• Published in: Journal of organic chemistry 2017-02, Vol.82 (4), p.2136-2149
• Main Authors: Bugaenko, Dmitry I, Yurovskaya, Marina A, Karchava, Alexander V
• Format: Article
• Language: English
• Subjects: Molecular Structure; Piperazines - chemistry; Pyridines - chemistry; Salts - chemical synthesis; Salts - chemistry
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/acs.joc.6b02952

The N-(2-pyridyl)-N′-ethylpiperazines are important structural motifs in several medicinally relevant compounds. Known synthetic methods toward these structures are multistep and generally based on the SNAr-chemistry; their applicability is significantly limited to substrates containing electron-withdrawing groups. Here, we describe a new methodology for a rapid and modular access to this privileged scaffold. Importantly, the developed protocol proved to be very general and efficient for the substrates containing substituents of different electronic nature. An operationally simple, metal-free, one-pot synthetic procedure involves the initial reaction of activated heterocyclic N-oxides with DABCO, followed by in situ treatment of the resultant quaternary N-(2-pyridyl)-DABCO salts with nucleophiles, resulting in ring-opening. The method features mild reaction conditions, high positional selectivity, and excellent functional-group tolerance. The utility of our approach is demonstrated by the late-stage site-selective functionalizations of complex molecules; a rapid modular assembly of MC2050, a potent PARP-1 inhibitor; and gram-scale preparations.