Synthesis and Structure of Novel Pyrimidine‐Thioethers: Structural Effects on Reactivity along with an Unpredicted Dimethylamination Reaction

When applying the Buchwald–Hartwig approach to synthesize aminopyrimidine-arylsulfide conjugates designed to inhibit trypanothione reductase, a key enzyme in the redox pathway of trypanosomatids, we witnessed that reactivity and regioselectivity depend on reaction time and Boc-protection of the starting 2,6-dichloropyrimidin-4-amine. The electron-withdrawing protecting group increases the susceptibility of the pyrimidine for reaction with DMF, yielding novel diaminopyrimidine-based conjugates.

Buchwald–Hartwig reactions have been in the spotlight over the past years due to their usefulness in creating a wide range of chemical skeletons applied in drug discovery. Aminopyrimidines are heterocyclic structures with significant biological relevance and compounds bearing the amino- and diaminopyrimidine motifs have been associated with antiviral, antibacterial, antiparasitic, antifungal, anticancer, and anti-inflammatory properties. Given the notable status of aminopyrimidines in the design of target-specific drug candidates, the synthesis and structure of four aminopyrimidine-arylsulfide conjugates (3, 4, 5, and 6) are reported that are designed to inhibit trypanothione reductase, a key enzyme in the redox pathway of trypanosomatids. When applying the Buchwald–Hartwig synthetic approach, the formation of different products is witnessed by altering the reaction conditions, observing that regioselectivity is conditioned by reaction time and by Boc-protection of the starting 2,6-dichloropyrimidin-4-amine. The electron-withdrawing character of the protecting group appears to increase the susceptibility of the pyrimidine at C2 for further reaction with the solvent, DMF, yielding the corresponding diaminopyrimidine-based conjugates. The crystal structures of the novel aminopyrimidine-arylsulfide conjugate and their Boc-protected 2,6-dichloropyrimidin-4-amine precursors are disclosed and discussed.

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