Targeted covalent inhibitors (TCIs) have increased in popularity among drug candidates and chemical probes. Among current TCIs, the chemistry employed is largely limited to labeling cysteine and lysine side chains. Tyrosine is an attractive residue for TCIs due to its enrichment at protein-protein interfaces. Here, we investigate the utility of cyclic imine Mannich electrophiles as covalent warheads to specifically target a pro-tein tyrosine adjacent to an inhibitor binding pocket. We characterized the intrinsic reaction rates of several cyclic imines to tyrosine and identified the iminolactone to be suitable for a covalent inhibitor (second order rate constant of 0.0029 M-1 s-1). We appended the cyclic imine warheads to a CBX8 chromodomain inhibitor to label a non-conserved tyrosine, which markedly improves both the potency and selectivity of the inhibitor for CBX8 in vitro and in cells. These results indicate that Mannich electrophiles are promising and robust chemical warheads for tyrosine bioconjugation and covalent inhibitors.