The 1,2,3‐triazole has been successfully utilized as an amide bioisostere in multiple therapeutic contexts. Based on this precedent, triazole analogues derived from VX‐809 and VX‐770, prominent amide‐containing modulators of the cystic fibrosis transmembrane conductance regulator (CFTR), were synthesized and evaluated for CFTR modulation. Triazole 11, derived from VX‐809, displayed markedly reduced efficacy in F508del‐CFTR correction in cellular TECC assays in comparison to VX‐809. Surprisingly, triazole analogues derived from potentiator VX‐770 displayed no potentiation of F508del, G551D, or WT‐CFTR in cellular Ussing chamber assays. However, patch clamp analysis revealed that triazole 60 potentiates WT‐CFTR similarly to VX‐770. The efficacy of 60 in the cell‐free patch clamp experiment suggests that the loss of activity in the cellular assay could be due to the inability of VX‐770 triazole derivatives to reach the CFTR binding site. Moreover, in addition to the negative impact on biological activity, triazoles in both structural classes displayed decreased metabolic stability in human microsomes relative to the analogous amides. In contrast to the many studies that demonstrate the advantages of using the 1,2,3‐triazole, these findings highlight the negative impacts that can arise from replacement of the amide with the triazole and suggest that caution is warranted when considering use of the 1,2,3‐triazole as an amide bioisostere.

A Pd 0 -catalyzed formal (4 + 1)-cycloaddition approach to 2,3-disubstituted dihydroindoles is described. The diastereoselective formation of dihydroindoles that is highlighted by a carbene migratory insertion/reductive elimination sequence proceeding via a π-allyl Pd II -species compliments existing methods of indoline assembly.

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An intermolecular RhII-catalyzed, formal (4 + 3)-cycloaddition between vinyl ketenes and N-sulfonyl-1,2,3-triazoles for the construction of azepinone products is described. Employing vinyl ketenes as a 1,4-dipolar surrogate, instead of the more commonly used dienyl moieties, allows for the intermolecular and selective formation of azepinone products over a potential (3 + 2)-cycloadduct under mild reaction conditions allows for the generation of azepinone products in up to 98% yield.