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Skeletal Editing of Pyrimidines to Pyrazoles by Formal Carbon Deletion

G. Logan Bartholomew, Filippo Carpaneto and Richmond Sarpong*

*Department of Chemistry, University of California, Berkeley, Berkeley, California 94720, United States, Email:

G. L. Bartholomew, F. Carpaneto, R. Sarpong, J. Am. Chem. Soc., 2022, 144, 22309-22315.

DOI: 10.1021/jacs.2c10746

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A room-temperature triflylation of the pyrimidine core, followed by hydrazine-mediated skeletal remodeling provides pyrazoles under mild conditions. This formal one-carbon deletion method tolerates a wide range of functional groups and enables the simultaneous regioselective introduction of N-substitution on the resulting pyrazole.

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General Procedure for the hydrazine-mediated contraction of 4-arylpyrimidines

To an oven-dried 1 dram vial was added pyrimidine substrate (0.10 mmol, 1.0 equiv) at 23 ˚C. The vial was evacuated and backfilled with nitrogen thrice before anhydrous 1,4-dioxane (1.30 mL, 0.05 M) was added at 23 ˚C. The vial was sealed with a PTFE-lined cap and transferred into a glove box, after which trifluoromethylsulfonic anhydride (19 ÁL, 0.11 mmol, 1.1 equiv) was added in the glove box under nitrogen atmosphere. The vials were sealed in the glove box, removed, affixed with a rubber septum, and placed under a positive pressure of nitrogen. The resulting mixtures were allowed to stir under nitrogen at 23 ˚C for 15 min, at which point anhydrous hydrazine (9 ÁL, 0.30 mmol, 3.0 equiv) was added at 23 ˚C. The vials were then sealed with a PTFE-lined cap and the resulting mixtures were then warmed to 35 ˚C and allowed to stir at that temperature overnight under nitrogen atmosphere. The mixtures were allowed to cool to 23 ˚C, diluted with ethyl acetate (10 mL), passed through a 1-inch plug of silica in a large glass pipette, concentrated in vacuo, and the resulting crude residues were purified by preparative TLC (hexanes:acetone) to give the desired 5-arylpyrazole products.

Key Words


ID: J48-Y2022