Student Research Paper
Chemistry and Biochemistry
James A. MacKay
The research presented here demonstrates a halogenation reaction for pyrazoles from the generation of electrophilic halogens through a reaction between halide anions and Oxone®. Halogenation occurs at the 4-position, which is the most nucleophilic atom of the heterocycle. The sodium halide salt and Oxone serve as the halogen source in an electrophilic aromatic substitution. Oxone is a water-soluble, relatively innocuous reagent produced by DuPont that makes this reaction environmentally friendly. The reaction functions with good yields on a wide scope of substrates, works best without a co-solvent, is performed at room temperature, and requires short reaction times. These factors, along with its operational simplicity and ease of purification make this reaction highly valuable. To demonstrate the utility of the reaction, a concise synthesis of the natural product withasomnine was undertaken. Withasomnine is a compound isolated from the flower withania somnifera and is a popular target for total syntheses involving pyrazoles. Our synthesis is completed in five steps from pyrazole. A halogenation and subsequent Suzuki-Miyaura cross-coupling reaction couples a phenyl ring to the 4-position. Alkylation at position 1 using 3-bromopropanol followed by formation of the xanthate ester enables a radical-initiated cyclization that forms the fused ring connecting to the 5-position of pyrazole. Reaction sequence and conditions were explored and optimized and are presented here.
Jensen, Matthew R., "A Green Halogenation of Pyrazoles using NaX/Oxone® and the Total Synthesis of the Natural Product Withasomnine" (2016). Chemistry: Student Scholarship & Creative Works. 3.