Construction of novel spiroisoxazolines via intramolecular cyclization/methylation

Abstract

Improved yields for the syntheses of a variety of spiroisoxazolines were achieved through intramolecular cyclization/methylation reactions of functionalized 5,5-disubstituted isoxazolines in one reaction vessel. Aromatic ring containing nitrile oxides and disubstituted geminal alkenes reacted in a 1,3-dipolar fashion to afford the corresponding 5,5-isoxazoline. A comparison of the relative location of the nucleophile and electrophile on the isoxazoline and two different ester functional groups was performed in order to determine the best isoxazoline system for the intramolecular cyclization/methylation reaction.

Utilization of 2‐Chloronicotinonitrile in the Syntheses of Novel Fused Bicyclic and Polynuclear Heterocycles of Anticipated Antitumor Activity

“…Synthesis of five fused bicyclic ring systems was achieved via the alkylation of pyridinethiol derivative 3 with ethyl chloroacetate in the presence of sodium carbonate to afford the acetate ester derivative 4 (which is consistent with the published data [12]). Refluxing of a solution of acetate ester 4 with sodium hydride in THF gave ethyl 4,6-dimethyl-3-oxo-2,3-dihydrothieno[2,3-b]pyridine-2-carboxylate (5), with carefully working up at À20 C. Attempting for working up at 0 C causes the hydrolysis and decarboxylation of the b-ketoester derivative 5 to give the 4,6-dimethylthieno [2,3-b]pyridin-3(2H)-one (6).…”

“…A mixture of 3 (3.28 g, 0.02 mol), ethyl chloroacetate (2.44 g, 0.02 mol), and sodium carbonate (2.1 g, 0.02 mol) in DMF (50 mL) was refluxed with stirring for 4 h. After cooling, it was poured onto ice-cold water, and the solid formed was collected and recrystallized from methanol to give compound 4 (4.4 g, 88% yield), mp 90-92 C, Lit. [12]; IR (KBr) υ (cm A solution of 4 (2.5 g, 0.01 mol) in THF (20 mL) added to sodium hydride (0.8 g, 60%, 0.02 mol) under nitrogen in THF (40 mL) was refluxed for 3 h. The reaction mixture was cooled in ice bath at À20 C and then ethanol (10 mL) was added followed by cold water (50 mL) and acidified with dilute HCl. The formed solid product was collected and recrystallized from methanol to give compound 5 (1.83 g, 73% (6).…”

One pot spiropyrazoline synthesis via intramolecular cyclization/methylation

“…These spectroscopic observations are in correlation with previous results reported from our research laboratories. 13 Even though the isolated yields for the aforementioned spiropyrazolines were good, we decided to investigate the potential of improving the intramolecular cyclization/methylation yields by repositioning the electrophilic ester to a more remote location relative to the pyrazoline ring thereby potentially decreasing the steric environment of the ester.…”

“…Our recent report on spiroisoxazoline synthesis utilized intramolecular alkylation/methylation of a 5,5-disubstituted isoxazoline as the central spiroisoxazoline synthetic pathway. 13 In this paper, we extend the application of this practical synthetic methodology toward the synthesis of functionalized unsaturated carbocyclic spiropyrazolines while also determining the best pyrazoline system for the intramolecular cyclization/methylation reaction.…”

Synthesis of Novel 3‐aryl‐1‐oxa‐2,8‐diazaspiro[4.5]dec‐2‐ene Derivatives and Their Biological Evaluation Against Protein Tyrosine Phosphatase 1B

“…Many synthetic and naturally occurring spiroisoxazolines have been found as pharmacophores with a wide array of bioactivities (10)(11)(12). One such series is 3-aryl-1-oxa-2,8-diazaspiro [4.5]dec-2-ene derivatives, which are selective antagonists of the somatostatin subtype receptor 5 (SSTR5) and useful for the treatment of type 2 diabetes (13).…”