Translation of Microwave Methodology to Continuous Flow for the Synthesis of Diaryl Ethers via an SNAr Reaction

Diaryl ethers are a synthetically interesting sub-unit, with examples found in a series of medicinally significant natural products.
Installation of the diaryl ether can however be synthetically challenging, as illustrated by the wide number of techniques developed which include, Ullmann ether synthesis, Pummerer-type rearrangements, Buchwal-Hartig couplings, phenolic additions to amines, potassium fluoride/alumina mediated couplings and the use of solid-supports.
Recently Moseley and co-workers demonstrated the largely overlooked nucleophilic substitution reaction of aromatic halides to phenols, reporting that under microwave irradiation reaction times of the order of ten`s of minutes could be obtained for the synthesis of diaryl ethers.
Like microwave reactors, continuous flow systems can be readily heated and pressurised in order to access “extreme” reaction conditions. To demonstrate any advantages that continuous flow reactors may have compered to microwave reactors, the nucleophilic substitution reaction between 3,4-dichloronitrobenzene and 4-methoxyphenol was investigated under previously reported literature conditions.