Nitrogen heterocycle is one of the most important structural units in drug molecules. Lots of best-selling drug molecules contain nitrogen heterocyclic structures. Due to the special structural properties of pyrimidines and pyrazoles, the introduction of these nitrogen-containing heterocycles is of great significance for improving the activity and diversity of drug molecules, for example, they can improve drug activity by forming hydrogen bonds with biological targets. In addition, late-stage structural modifications targeting these heterocycles could also speed up the discovery of novel drugs and agrochemicals. In recent years, chemists have made great progress in molecular skeleton editing and functionalization, but the current focus is still on editing the C-H bonds of molecular skeletons, and there are few methods for direct editing of molecular skeletons. On the other hand, pyrimidine heterocycle is a good directing group in the field of C-H bond activation, while pyrazole heterocycle is a relatively poor directing group, so pyrazole-directed C-H bond activation cannot be achieved at present. If the conversion of pyrimidines to pyrazoles can be achieved through molecular backbone editing, it may provide a new form of pyrazole-directed C–H bond activation strategy.
Recently, researchers found that pyrimidine N-trifluoromethylsulfonylation can effectively reduce the LUMO energy of pyrimidine (−3.88 eV) through computational studies, enabling hydrazine to carry out nucleophilic attack under mild conditions (23 °C), and successfully condensed a series of substituted pyrimidines into the corresponding pyrazoles. The key to this reaction is room temperature triflation of the pyrimidine core, followed by hydrazine-mediated backbone remodeling.
First, the researchers tried to determine the conditions for activating the pyrimidines, but using either Brønsted or Lewis acids had no effect. Supported by calculations, they reasoned that successful activation might be achieved by N-acylation or N-sulfonylation. When the trifluoroformylation of the pyrimidine nitrogen was performed at 23 °C for 15 min, ring contraction was achieved in 37% yield by the addition of hydrazine. After optimizing the reaction temperature and solvent, the best reaction conditions were obtained: that is, 4-phenylpyrimidine and trifluoromethanesulfonic anhydride Tf2O were first reacted at 23 °C for 15 min, and then hydrazine hydrate was added to it, and under the condition of 1,4-dioxane as solvent at 35 ℃ for 18 h, the target product—5-phenyl-1H-pyrazole can be obtained in 90% yield.
With the optimal reaction conditions in hand, the researchers investigated the substrate scope of the reaction. This transformation can be achieved in moderate to good yields no matter the ortho or meta position of the aromatic ring has electron-withdrawing/donating groups. In addition, pyrimidine rings containing various heteroaryl substituents, naphthyl, cyclohexyl and even biaryl can also be reacted. Subsequently, the researchers explored the functional group compatibility of the core substitution pyrimidine, and the results showed that the reaction is compatible with various substituents, such as electron-donating groups, benzene rings, benzyl groups, halogens, cyano groups, and even fused pyrimidines. Finally, the researchers attempted to synthesize a series of pyrazole derivatives with substituents at the N-1 position. By comparison, it can be found that the reactivity of phenyl-substituted hydrazines tends to be much lower than that of unsubstituted hydrazines, which may be due to the presence of phenyl groups reducing the nucleophilicity of hydrazines.
At the same time, the researchers found that the reaction can also be compatible with free hydroxyl and amino groups by slightly optimizing the reaction conditions. In addition, substituted quinazolines (building blocks in drugs) were also able to achieve this transformation, and the corresponding products were obtained in 41% yield. In order to demonstrate the practicability of this reaction, the researchers directly edited the skeleton of drug molecules with relatively complex structures and transformed them into pyrazole-containing structures in good yields. Finally, the researchers successfully synthesized the precursors of Celecoxib derivatives through sequential pyrimidine-directed C-H bond activation and pyrimidine molecular backbone editing.
Finally, the researchers also investigated the possible mechanism of the reaction. The pyrimidine nitrogen atom with the least steric hindrance is easier to triflate (ΔG⧧ ≈ 0.99 kcal/mol), this selectivity was further confirmed by the methylation experiment of 4-phenylpyrimidine and the calculated Fukui indice. Subsequently, the nucleophilic hydrazine attacks the C-6 position of the activated pyrimidine to obtain an intermediate, and DFT calculations show that this step is the rate-determining step.
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Reference
- Skeletal Editing of Pyrimidines to Pyrazoles by Formal Carbon Deletion
G. Logan Bartholomew, Filippo Carpaneto, Richmond Sarpong
