Skeletal Editing of Pyrimidines to Pyrazoles by Formal Carbon Deletion

Abstract

A method for the conversion of pyrimidines into pyrazoles by a formal carbon deletion has been achieved guided by computational analysis. The pyrimidine heterocycle is the most common diazine in FDA-approved drugs, and pyrazoles are the most common diazole. An efficient method to convert pyrimidines into pyrazoles would therefore be valuable by leveraging the chemistries unique to pyrimidines to access diversified pyrazoles. One method for the conversion of pyrimidines into pyrazoles is known, though it proceeds in low yields and requires harsh conditions. The transformation reported here proceeds under milder conditions, tolerates a wide range of functional groups, and enables the simultaneous regioselective introduction of N-substitution on the resulting pyrazole. Key to the success of this formal one-carbon deletion method is a room-temperature triflylation of the pyrimidine core, followed by hydrazine-mediated skeletal remodeling.

Skeletal Editing: Interconversion of Arenes and Heteroarenes

“…C-Atom deletion of pyrimidines to pyrazoles by ring-opening/hydrazine condensation. [84] Scheme 13. Strategies for atom exchange.…”

“…Ring contraction through C‐atom deletion has also been reported by Sarpong and co‐workers ( Scheme 12). [84] This method transforms six‐membered pyrimidines to five‐membered pyrazoles by a ring opening/condensation strategy. Initial reaction with triflic anhydride activates the substrate towards nucleophilic attack from hydrazine.…”

Recent Applications of Trifluoromethanesulfonic Anhydride in Organic Synthesis

“…By employing triflic anhydride as activator, a formal carbon deletion of pyrimidines has been achieved by Sarpong and co‐workers, affording the corresponding pyrazoles under mild conditions (Scheme 8). [29] The reaction proceeded through initially activation of pyrimidine core with Tf 2 O to afford N‐ triflylpyrimidinium triflate species 25 and followed by hydrazine‐mediated skeletal remodeling. This methodology showed broad substrate scope and provided an alternative approach to N2‐substituted pyrazoles, which were not easily accessed by other mehods.…”

Nitrenium ions as new versatile reagents for electrophilic amination

“…We envision that the N-N bonds in these compounds should be relatively weak and could be cleaved under standard reduction conditions, providing primary amines via N-atom deletion from the triazane ring (Scheme 2b). Interestingly, carbon and nitrogen atom deletion from heterocycles for synthetic purposes, [44][45][46][47] including carbon atom deletion from N-heterocyclic carbenes, 48 have gained much current interest. If this hypothesis is successful, the NHN would serve as a novel robust and stable electrophilic aminating agent.…”