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1,3,4‐Oxadiazoles are a common motif in pharmaceutical chemistry, but few convenient methods for their modification exist. This application note illustrates the use of Vapourtec E-series flow reactor for a fast, convenient, high yielding and general α‐substitution of 1,3,4‐oxadiazoles via a lithiation-substitution approach. Under continuous flow conditions, metalation is carried out at room temperature, and subsequent in-flow electrophilic trapping gave up to quantitative isolated yields. Notably, lithiation in batch at room temperature results only in ring fragmentation and we propose that the superior mixing in flow allows interception and exploitation of an unstable intermediate before decomposition can occur. This is the first reported example of the formation of otherwise unstable intermediate via organolithium reagents followed by trapping at room temperature in flow.
