A New Synthetic Approach to 4(1H)-Pyridone Derivatives. I. 1-Alkyl-3,5-diaryl-4(1H)-pyridones

Abstract

Recent developments1–3 in the synthesis of 4(1H)-pyridone derivatives have prompted us to communicate a highly versatile synthesis of this class of heterocycles. Acylation of the styrylamine (I)4 (R1 = C2H5) with a substituted arylacetyl halide (II) in ether at O[ddot]-30[ddot]C in the presence of triethylamine or pyridine gave in 2 to 24 hours the enaminoketone (III) (75%-85% trans-isomer together with 25%-15% cis-isomer based on chemical shift of CH methine proton). Enaminoketone (III) could be readily converted to (IIIa) with aqueous methylamine in ethanol or to the bis-enaminoketone (IV) with N,N-dimethylformamide dimethyl acetal. The enaminoketone (IIIa) could be cyclized to pyridone (V) by refluxing with N,N-dimethylformamide dimethyl acetal; alternatively, the bis-enaminoketone (IV) could be cyclized to pyridone (V) by overnight reflux with methylamine hydrochloride in ethanol. yields based on styrylamine were 30%-65%. These transformations are outlined in Scheme 1. As an example, the synthesis of 1-methyl-3-(4-nitrophenyl)-5-phenyl-4(1h)-pyridone (Va) is outlined. Addition of 4-nitrophenylacetyl cloride (0.08 mole) in chloroform (200 ml) to diethylstyrylamine5 (0.08 mole) in chloroform (400 ml) in the presence of triethylamine (0.09 mole, dried over KOH) over a period of 2 hr and under nitrogen atmosphere gave a reddish solution. After stirring an additional hour, the reaction was washed with 1N HC1, N/10 NaOH, and saturated aqueous NaC1, dried over MgSO4, and filtered through Darco-60G to afford on removal of solvent 8.8 g (32%) of the transenaminoketon6 as a crystalline solid from 2-propanol (III, R2 = 4-nitrophenyl, R1 = C2H5; v co 1655 cm−1; δ ppm, 0.97, t, 6H; 3.02, q, 4H; 3.55, s, 2H; 7.72, s, 1H; 7.0–8.1, m, 9H. Anal. Calcd. for C20H22N2O3, % C, 70.99; H, 6.55; N, 8.28. Found: C, 70.84; H, 6.42; N, 8.21 (mp 141°–142°). To 6.0 g of (III) g dissolved in 60 ml of methanol was added 12.0 g of methylamine hydrochloride, and the mixture was heated to reflux for 18 hr. Workup with chloroform gave a quantitative recovery of analytically pure compound (IIIa) as an oil (δ ppm 3.0, d, 3h; 3.53, s, 2H; 6.80, d, 1H; 7–8, m, 9H; Anal. Calcd. for C17H16N2O3, % C, 68.91; H. 5.44; N, 9.45. Found: C, 68.68; H, 5.24; N, 9.20). To 4.85 g of (IIIa) was added 2.14 g (1 equivalent of N,N-dimethylformamide dimethyl acetal and 20.0 ml of anhydrous DMF. The reaction mixture developed an intense blue-violet color which was discharged during refluxing for 16 hr. All volatile components were removed on a rotary evaporator at 80°C/8 Torr to giva a microcrystalline precipitate of the pyridone (Va), which was recrystallized from 2-propanol/DMF to give 3.3 g (66%) of (Va) as bright yellow needles. (v co 1652; δ ppm 3.86, s, 3H; 7.2–8.25, m, 11H; Anal. Calcd. for C18H14N2O3, % C, 70.58; H, 4.61; N, 9.15. Found: C, 70.79; H, 4.89; N, 8.86; mp 212°–214°).