The formation of reversible‐covalent interactions between a small‐molecule ligand and its protein target is emerging as a general strategy to design binders with increased affinity. In this context, 2‐hydroxybenzaldehyde (2HB) has been recently proposed as suitable electrophilic tag to engage primary amines, such as the ϵ‐amino group of lysine residues, in remarkably stable imines. Lys residues are often expressed in high amounts on protein surfaces and in the proximity of ligand binding sites, and a fine‐tuning of the chemical connection between the ligand and 2HB is fundamental for the affinity gain. Herein we report the synthesis of four 2HB tags functionalized with a short polyethylene glycol (PEG) spacer and a suitable reactive ‘handle’ (alkyne, azide, carboxylic acid and amine, respectively) for their conjugation to virtually any type of small molecule ligand.

A palladium-catalyzed intramolecular formal anti-carboamination of internal alkynes for the synthesis of tetrasubstituted enamines and pyrroles is reported. A broad range of different aniline derivatives, and also alkylated and benzylated amines, were used for the termination of the cascade. In the follow-up chemistry, we demonstrate that the TBS-protected pyrrole can be converted to a variety of other substituted pyrroles.