A two-step telescoped continuous flow switchable process leading to nitriles, diaziridine or hydrazine derivatives

Abstract

Primary and benzylic alcohols were cost-effectively transformed into their corresponding nitriles using a classical batch approach and a continuous flow process implemented on a multi-jet oscillating disk (MJOD) reactor platform. The alcohols as substrates were treated with a (2,2,6,6-tetra-methylpiperidin-1-yl)oxidanyl (TEMPO) free radical as the pre-catalyst with 1,3-dichloro-5,5-dimethylhydantoin (DCH) as the terminal oxidant to produce their corresponding carbonyl compounds. The reaction was conducted at a reaction temperature of 35 °C and a flow reactor residence time of 5 min. This alcohol to carbonyl oxidation step was telescoped with a subsequent step that involved treatment with aqueous ammonium hydroxide and 1,3-diiodo-5,5-dimethylhydantoin (DIH) at a reaction temperature of 65 °C with concomitant oxidation to nitrile using a flow reactor residence time of 15 min. A solvent exchange process was conducted in-between the two synthetic reaction steps by means of an in-line extraction process with ethyl acetate, a step that was concatenated by using an in-line liquid–liquid separation process using a hold-up tank. The second synthetic step was revealed to be tuneable, since four distinct products might be produced at varying degrees of selectivity. When DIH was used as the terminal oxidant, a high selectivity towards the original target nitrile was achieved, but if DIH was replaced with DCH as the terminal oxidant, 1,2-di((E)-benzylidene)hydrazine and two different stereoisomers of the 1,3,5-triazabicyclo[3.1.0]hexane scaffold were produced. The selectivity towards the various products was highly influenced by the reaction temperature. A scope and limitation study of the nitrile process with an assortment of primary alcohols as substrates provided excellent yields which revealed good functional group tolerance.