Synthesis of Isoxazolopyridines via Cyclization of 3-Acylpyridine N-Oxide Oximes
College
College of Arts and Sciences
Department
Chemistry, Physics, Geology, & the Environment
Faculty Mentor
Dr. James M. Hanna, Jr.
Abstract
Isoxazoles are associated with a wide spectrum of biological functions including antiviral, anthelmintic, anti-inflammatory, anticonvulsant and insecticidal activities. Derivatives of isoxazolopyridines are reported to have cholesterol lowering activities. Recently, the Hanna laboratory reported that tosylhydrazones formed using 3-acylpyridine N-oxides could be cyclized into pyrazolopyridines. Reaction of an N-oxide tosylhydrazone with a proper electrophile formed an activated intermediate that allowed nucleophilic attack at C-2 or C-4 on the pyridine N-oxide; a subsequent base-promoted E2 elimination gave the desired product. We envisioned that this same method could be applied to form isoxazolopyridines from 3-acylpyridines. Previous investigations had determined that the N-oxide tosylhydrazones cyclized smoothly only when the attacking atom was syn to the pyridine ring. Therefore we initially examined the cyclization of 3-pivaloylpyridine N-oxide oxime (1), since the bulky t-butyl group would ensure that the attacking oxime hydroxy group would be in the required position. Cyclization of 1 to 3-t-butylisoxazolo[5,4-b]pyridine (2) was accomplished using various electrophile/base combinations, the most effective of which was triisopropylbenzenesulfonyl chloride and diisopropylethylamine in dichloromethane, giving an 86% yield of 2 (derived from attack at C-2); 3-t-butylisoxazolo[4,5-c]pyridine (derived from attack at C-4) was also formed in 9% yield. We hoped we could apply these conditions to the cyclization of compounds where the oxime hydroxy group was anti to the pyridine ring, so we examined the cyclization of 3-acetylpyridine N-oxide oxime. Unfortunately, the standard reaction conditions afforded no detectable amounts of desired products. Altering the solvent polarity (i. e. use of acetonitrile or N,N-dimethylformamide) had no effect.
Previously Presented/Performed?
Joint 67th Southeast and 71st Southwest Regional Meeting of the American Chemical Society, Memphis, Tennessee, November 2015
Grant Support?
Supported by grants from the National Institutes of Health IDeA Networks for Biomedical Research Excellence (NIH INBRE) and the Winthrop University Research Council
Start Date
22-4-2016 2:15 PM
End Date
22-4-2016 2:30 PM
Synthesis of Isoxazolopyridines via Cyclization of 3-Acylpyridine N-Oxide Oximes
DiGorgio Campus Center, Room 220
Isoxazoles are associated with a wide spectrum of biological functions including antiviral, anthelmintic, anti-inflammatory, anticonvulsant and insecticidal activities. Derivatives of isoxazolopyridines are reported to have cholesterol lowering activities. Recently, the Hanna laboratory reported that tosylhydrazones formed using 3-acylpyridine N-oxides could be cyclized into pyrazolopyridines. Reaction of an N-oxide tosylhydrazone with a proper electrophile formed an activated intermediate that allowed nucleophilic attack at C-2 or C-4 on the pyridine N-oxide; a subsequent base-promoted E2 elimination gave the desired product. We envisioned that this same method could be applied to form isoxazolopyridines from 3-acylpyridines. Previous investigations had determined that the N-oxide tosylhydrazones cyclized smoothly only when the attacking atom was syn to the pyridine ring. Therefore we initially examined the cyclization of 3-pivaloylpyridine N-oxide oxime (1), since the bulky t-butyl group would ensure that the attacking oxime hydroxy group would be in the required position. Cyclization of 1 to 3-t-butylisoxazolo[5,4-b]pyridine (2) was accomplished using various electrophile/base combinations, the most effective of which was triisopropylbenzenesulfonyl chloride and diisopropylethylamine in dichloromethane, giving an 86% yield of 2 (derived from attack at C-2); 3-t-butylisoxazolo[4,5-c]pyridine (derived from attack at C-4) was also formed in 9% yield. We hoped we could apply these conditions to the cyclization of compounds where the oxime hydroxy group was anti to the pyridine ring, so we examined the cyclization of 3-acetylpyridine N-oxide oxime. Unfortunately, the standard reaction conditions afforded no detectable amounts of desired products. Altering the solvent polarity (i. e. use of acetonitrile or N,N-dimethylformamide) had no effect.
