“Privileged” structures such as 1,4-diazacycles play an important role in medicinal chemistry. Piperazines and homopiperazines are respectively six- and seven-membered 1,4-diazacycles that are especially ubiquitous in the structures of many pharmaceutical drugs. Our project aims to apply hydrogen-borrowing amine alkylation to synthesize (homo)piperazines from diols and diamines using a novel ruthenium catalyst and base and solvent-free conditions that only generate water as a byproduct (Scheme 1). This reaction works well for a variety of aliphatic substituents on nitrogen or the carbon chains of the diamine and the diol. Cyclizine, an anti-nausea drug containing a piperazine ring, and homochlorcyclizine, an antihistamine with a homopiperazine ring, were both successfully synthesized in good yields using our synthetic strategy (Scheme 1). To the best of our knowledge, this work is the first example of seven-membered 1,4-diazacycle synthesis from substituted diamines and diols using a hydrogen borrowing mechanism.

Synthesis of 1,4-diazacycles from diols and diamines via hydrogen-borrowing N-alkylation

ACS Spring 2022

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