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
James M. Hanna, Jr., Ph.D.
Abstract
Isoxazoles are associated with a wide spectrum of biological functions, including antiviral, anthelmintic, anti-inflammatory, anticonvulsant and insecticidal activities. Derivatives of isoxazolopyridines are also reported to have cholesterol-lowering activities. Recently, the Hanna laboratory reported that tosylhydrazones formed using 3-acylpyridine N-oxides could be cyclized into pyrazolopyridines. Through the reaction of N-oxide tosylhydrazone with a proper electrophile, they were able to form an activated intermediate that allowed nucleophilic attack at C2 on the pyridine N-oxide; in the presence of a base, an E2 elimination then formed the desired cyclized product. We envisioned that this same method could be applied to form isoxazolopyridines from 3-acylpyridines. Previously, it had been discovered that the N-oxide tosylhydrazones in the Z-configuration cyclized smoothly, but those in the E-configuration did not. We reasoned that formation of the oxime of 3-pivaloylpyridine N-oxide would force the oxime into the Z-configuration; thus, we initially studied the cyclization of 3-pivaloylpyridine N-oxide oxime (1). Cyclization of 1 to 3-t-butylisoxazolo[5,4-b]pyridine (2) was accomplished using the electrophile/base combination of PyBroP and Et3N. The resulting isoxazolopyridine was isolated in 51 % yield and characterized using 1H- and 13C-NMR. Several different electrophiles and bases were subsequently tested and product yields determined by 1H-NMR using an internal standard. The most effective combination was triisopropylbenzenesulfonyl chloride (electrophile) with diisopropylethylamine (base), which gave an 86 % yield of 2 and a 9 % yield of 3-t-butylisoxazolo[4,5-c]pyridine (2ʹ), as determined by 1H-NMR.
Start Date
24-4-2015 3:35 PM
Synthesis of Isoxazolopyridines via Cyclization of 3-Acylpyridine N-Oxide Oximes
DiGiorgio Campus Center, Room 114
Isoxazoles are associated with a wide spectrum of biological functions, including antiviral, anthelmintic, anti-inflammatory, anticonvulsant and insecticidal activities. Derivatives of isoxazolopyridines are also reported to have cholesterol-lowering activities. Recently, the Hanna laboratory reported that tosylhydrazones formed using 3-acylpyridine N-oxides could be cyclized into pyrazolopyridines. Through the reaction of N-oxide tosylhydrazone with a proper electrophile, they were able to form an activated intermediate that allowed nucleophilic attack at C2 on the pyridine N-oxide; in the presence of a base, an E2 elimination then formed the desired cyclized product. We envisioned that this same method could be applied to form isoxazolopyridines from 3-acylpyridines. Previously, it had been discovered that the N-oxide tosylhydrazones in the Z-configuration cyclized smoothly, but those in the E-configuration did not. We reasoned that formation of the oxime of 3-pivaloylpyridine N-oxide would force the oxime into the Z-configuration; thus, we initially studied the cyclization of 3-pivaloylpyridine N-oxide oxime (1). Cyclization of 1 to 3-t-butylisoxazolo[5,4-b]pyridine (2) was accomplished using the electrophile/base combination of PyBroP and Et3N. The resulting isoxazolopyridine was isolated in 51 % yield and characterized using 1H- and 13C-NMR. Several different electrophiles and bases were subsequently tested and product yields determined by 1H-NMR using an internal standard. The most effective combination was triisopropylbenzenesulfonyl chloride (electrophile) with diisopropylethylamine (base), which gave an 86 % yield of 2 and a 9 % yield of 3-t-butylisoxazolo[4,5-c]pyridine (2ʹ), as determined by 1H-NMR.
