Flow synthesis of oxadiazoles coupled with sequential in-line extraction and chromatography

Abstract

An efficient continuous flow process is reported for the synthesis of various 1,3,4-oxadiazoles via an iodine-mediated oxidative cyclisation approach. This entails the use of a heated packed-bed reactor filled with solid K₂CO₃ as a base. Using DMSO as solvent, this flow method generates the target heterocycles within short residence times of 10 minutes and in yields up to 93%. Scale-up of this flow process was achieved (34 mmol/h) and featured an integrated quenching and extraction step. Lastly, the use of an automated in-line chromatography system was exploited to realise a powerful flow platform for the generation of the heterocyclic targets.

Keywords: chromatography; flow synthesis; in-line purification; oxadiazole; reaction telescoping.

Scheme 1

Methods for accessing 1,3,4-oxadiazoles.

Scheme 2

Synthesis of acyl hydrazones 1a–j.

Scheme 3

Iodine-mediated cyclisation of hydrazones 1a–j yielding oxadiazoles 2a–j. Reaction conditions: 1a–j (1 mmol), iodine (1.5 mmol), DMSO (4 mL, 0.25 M), 100 °C, 0.2 mL/min. Reported yields are isolated yields following purification [35].

Scheme 4

Synthesis of complex oxadiazoles.

Scheme 5

Continuous flow scale-up reaction with in-line quench and extraction.

Scheme 6

Continuous flow setup equipped with in-line extraction and purification.