Microwave‐Assisted Decarboxylation of Bicyclic 2‐Pyridone Scaffolds and Identification of Aβ‐Peptide Aggregation Inhibitors.

Abstract

Decarboxylation O 0296Microwave-Assisted Decarboxylation of Bicyclic 2-Pyridone Scaffolds and Identification of Aβ-Peptide Aggregation Inhibitors. -The lithium salts of pyridone derivatives (Ia) and (Ib) are found to inhibit the amyloid formation of the Alzheimer Aβ(1-40) peptide. -(AABERG, V.; NORMAN, F.; CHORELL, E.; WESTERMARK, A.; OLOFSSON, A.; SAUER-ERIKSSON, A. E.; ALMQUIST*, F.; Org. Biomol. Chem. 3 (2005) 15, 2817-2823; Dep. Chem., Org. Chem., Umea Univ., S-901 87 Umea, Swed.; Eng.) -Nuesgen 49-055

Synthesis of N-Alkylpyridin-4-ones and Thiazolo[3,2-A]pyridin-5-ones Through Pummerer-Type Reactions

“…The reaction was quenched with saturated sodium bicarbonate solution, stir vigorously for about 20 minutes (3ab、3cb and 3db、3ac、3cc and 3dc, stir vigorously for about 12 hour), diluted with water, extracted with dichloromethane, dried over sodium sulfate, and purified with flash column chromatography (petroleum ether/ethyl acetate/dichloromethane 6:3:1to 3:3:1) to give 61 mg product 3aa as a solid in 80% yield. 13 1-(((4-Bromophenyl)thio)methyl)-2-methylpyridin-4(1H)-one (3cb) was synthesized according to General Procedure A from 4bromophenyl methyl sulfoxide (1c) (66 mg, 0.3 mmol), 2.4 eq 2methyl-4-fluoropyedine (2b) (80 mg, 0.72 mmol), eluted by 6:3:1 petroleum ether/ethyl acetate/dichloromethane to 3:3:1 petroleum ether/ethyl acetate/dichloromethane, to give 75 mg product 3cb as a red liquid in 80% yield. 3cb: Rf = 0.40 (10:1 dichloromethane/methanol).…”

“…3ac: Rf = 0.46 (10:1 dichloromethane/methanol). 1 13 2-(Phenylthio)-1-((phenylthio)methyl)pyridin-4(1H)-one (4a) To a 5 mL flame dried flask, 1.5 eq sodium hydride (60%, 6 mg, 0.15 mmol), 1.5 eq thiophenol (16 mg, 0.15 mmol), and tetrahydrofuran (2.0 mL) were added, and the mixture was stirred at room tempreture for 15 minutes, then added 1eq pyrdin-4-one 3aa (25mg, 0.1 mmol), the mixture was heated to 60 o C and reacted at 60 o C for 4 hours. The mixture was cooled to room temperature, and then extracted by dichloromethane (8 mL × 3).…”

“…After drying with anhydrous sodium sulfate, it was concentrated and purified with flash column chromatography, eluted by petroleum ether/ethyl acetate (5/1), to give 32 mg product as a viscosity oil in 99% yield. 1 H NMR (400 MHz, CDCl3) δ 7.46 -7.37 (m, 8H), 7.33 (m, 2H), 6.91 (d, J = 7.6 Hz, 1H), 6.07 (m, 2H), 5.25 (s, 2H); 13 2-Phenoxy-1-((phenylthio)methyl)pyridin-4(1H)-one (4b) To a 5 mL flame dried flask, 1.5 eq sodium hydride (60%, 6 mg, 0.15 mmol), 1.5 eq phenol (14 mg, 0.15 mmol), and N,N-Dimethyformamide (2.0 mL) were added, and the mixture was stirred at room tempreture for 15 minutes, then added 1eq pyrdin-4-one 3aa (25mg, 0.1 mmol), the mixture was heated to 100 o C and reacted at 100 o C for 4 hours. The mixture was cooled to room temperature, and then extracted by dichloromethane (8 mL × 3).…”

“…[1][2][3] For example, a number of N-alkylpyridin-4one or thiazolo[3,2-a]pyridin-5-one structures were reported to have interesting pharmaceutical activities (Scheme 1). [4][5][6][7][8][9][10][11][12][13][14][15] Scheme 1. Pharmaceutically active pyridin-4-one and thiazolo[3,2-a]pyridin-5-one derivatives…”

“…H NMR (400 MHz, CDCl3) δ 7.50− 7.11 (m, 5H), 6.79 (d, J = 7.6 Hz, 1H), 6.01 (d, J = 6.0 Hz, 1H), 5.77 (s, 1H), 5.00 (s, 2H), 3.58 (s, 3H);13 C NMR (101 MHz, CDCl3) δ 181.1, 158.50, 137.5, 134.8, 131.1, 129.3, 129.2, 114.5, 96.0, 56.3, 55.0; IR (neat) ν 3053, 2942, 1637, 1570, 1481, 1323, 1181, 1097, 1024, 836 cm -1 ; HRMS[ESI]: calculated for C13H14NO2S + [M+H] + : 248.0740, found 248.0744.1-(((4-Bromophenyl)thio)methyl)-2-methoxypyridin-4(1H)-one (3cc) was synthesized according to General Procedure A from 4bromophenyl methyl sulfoxide (1c) (42 mg, 0.3 mmol), 2.4 eq 4fluoro-2-methoxypyridine (2c) (91 mg, 0.72 mmol), eluted by 6:3:1 petroleum ether/ethyl acetate/dichloromethane to 3:3:1 petroleum ether/ethyl acetate/dichloromethane, to give 87 mg product 3cc as a colorless liquid in 89% yield. 3cc: Rf = 0.46 (10:1 dichloromethane/methanol).…”