Efficient copper-catalyzed trifluoromethylation of aromatic iodides was achieved with TMSCF 3 in the presence of trimethoxyborane. The Lewis acid was used to anchor the in situ generated trifluoromethyl anion and suppress its rapid decomposition. Broad applicability of the new trifluoromethylating reaction was demonstrated in the functionalization of different aromatic and heteroaromatic iodides.

A new electrophilic difluoromethylating reagent has been developed. The S-(difluoromethyl)diarylsulfonium tetrafluoroborate has been shown to be effective for the introduction of an electrophilic difluoromethyl group into the following nucleophiles: sulfonic acids, tertiary amines, imidazole derivatives, and phosphines. The reagent failed to transfer the difluoromethyl group to phenols, carbon nucleophiles, and primary and secondary amines.

Dual‐specificity tyrosine‐phosphorylation‐regulated kinase 1A (DYRK1A) is an emerging biological target with implications in diverse therapeutic areas such as neurological disorders (Down syndrome, in particular), metabolism, and oncology. Harmine, a natural product that selectively inhibits DYRK1A amongst kinases, could serve as a tool compound to better understand the biological processes that arise from DYRK1A inhibition. On the other hand, harmine is also a potent inhibitor of monoamine oxidase A (MAO‐A). Using structure‐based design, we synthesized a collection of harmine analogues with tunable selectivity toward these two enzymes. Modifications at the 7‐position typically decreased affinity for DYRK1A, whereas substitution at the 9‐position had a similar effect on MAO‐A inhibition but DYRK1A inhibition was maintained. The resulting collection of compounds can help to understand the biological role of DYRK1A and also to assess the interference in the biological effect originating in MAO‐A inhibition.

The kinase DYRK1A is an attractive target for drug discovery programs due to its implication in multiple diseases. Through a fragment screen, we identified a simple biaryl compound that is bound to the DYRK1A ATP site with very high efficiency, although with limited selectivity. Structure-guided optimization cycles enabled us to convert this fragment hit into potent and selective DYRK1A inhibitors. Exploiting the structural differences in DYRK1A and its close homologue DYRK2, we were able to fine-tune the selectivity of our inhibitors. Our best compounds potently inhibited DYRK1A in the cell culture and in vivo and demonstrated drug-like properties. The inhibition of DYRK1A in vivo translated into dose-dependent tumor growth inhibition in a model of ovarian carcinoma.

NMR studies showed that, in addition to the expected N(1) protonation, 2,4,6-pyrimidinetriamine, N,N,N',N',N",N"-hexamethyl- (1) could also be protonated at the C(5) position in water, leading to an equilibrium between the C(5) and N(1) protonated forms. Analysis of the NMR titration data gives 6.87 and 6.89 for the pK(a) of the C(5) and N(1) protonation equilibria. Moreover, the reaction of 1 with chloroacetyl chloride leads to a novel 1,1-bis(pyrimidin-5-yl)-2-chloroethene type derivative (4) that is, peculiarly, fully monoprotonated at the C(5) position in either of the pyrimidine rings, forming a stable cationic sigma-complex.