Lithiation Substitution of Unprotected Benzyltetrazoles

Abstract

1H-Tetrazoles occupy an important role in modern medicinal chemistry, but few methods for their modification exist. Many extant protocols require the use of a difficult to remove N-alkyl-protecting group, precluding the products from use as carboxylate bioisosteres, the major role of tetrazoles in pharmaceuticals. We herein report a convenient, protecting-group-free lithiation-substitution protocol for benzylic tetrazoles. Metalation with n-BuLi at 0 °C followed by electrophilic trapping gave a range of α-functionalized benzyltetrazoles in up to 91% yield.

Flash chemistry enables high productivity metalation-substitution of 5-alkyltetrazoles

“…We note that this requirement for an extra equivalent of base over the strict stoichiometric requirements during lithiation of tetrazoles appears to be a common issue, and has been encountered by our group during the lithiation of benzyltetrazoles, as well as Flippin during the ortho-lithiation of 5-aryltetrazoles. 15,18 Since no lithiation was observed when milder LDA was used as base (entries 14 and 15), the conditions in entry 11 and 13 were taken as optimal. It is hypothesised that the drop in yield at 0 °C when lengthening reaction time from 15 min to 1 h (entry 13 vs. 8) may arise from instability of the lithiated intermediate.…”

“…Recently, our group has developed a lithiation-substitution protocol for 5-benzyltetrazoles using n-BuLi at an industrially convenient temperature. 18 Unfortunately, 5-alkyltetrazoles proved not to be amenable to derivatisation using this approach, considerably limiting the substrate scope, and continuous flow conditions could not be optimised due to precipitation of an insoluble metalated intermediate, and the metalation-substitution of unprotected or readily deprotected 5-alkyltetrazoles in the αposition has not previously been described. Herein, we report a general and high-yielding strategy for the C-H functionalisation of 5alkyltetrazoles under both batch and continuous flow conditions.…”