Introduction
2,5-Dihydro-2-oxofuran derivatives are a large family of heterocycles that include synthetically useful compounds, several natural products [1–14], and a number of drugs with diverse biological activities such as antifungal, antibacterial, and anti-inflammatory properties [15–19]. There has been a continuous interest in the development of efficient and convenient methods for the preparation of these heterocycles [10–14, 20–22]. In an extension of our synthetic studies on 2,5-dihydro-2-oxofurans, here we report a convenient and efficient synthesis of the title compounds starting from readily available tertiary α-hydroxyketones 1a,b (Scheme 1).
Citation: Heterocyclic Communications 20, 2; 10.1515/hc-2014-0023
The condensation of α-hydroxyketones 1a,b with cyanoacetamides 2a–d in the presence of a catalytic amount of sodium methoxide afforded 2-imino-2,5-dihydrofuran-3-carboxamides 3a–f that, without isolation, were hydrolized to 2,5-dihydro-2-oxofuran-3-carboxamides 4a–f in good yields. The products 4a–f are unsubstituted or substituted at the carboxamide nitrogen atom.
Several syntheses of 2,5-dihydro-2-oxofuran-3-carboxamides have been reported in the literature [23–30]. These authors have previously synthesized compounds 4a–f by related reactions [24–29]. The key step in the current synthesis is the preparation of 2,5-dihydro-2-oxofuran-3-carboxamides 4a–f by Knoevenagel condensation of compounds 1a,b with 2a–d. After hydrolysis of the resultant product 3a–f, without isolation, the overall yield of this one-pot two-step synthesis is 74–79%. This method is simpler and more convenient than the methods described earlier.
Experimental
General procedure for 4a–f
A mixture of an α-hydroxyketone 1a,b (10 mmol), a cyanoacetamide 2a–d (10 mmol), and sodium methoxide (1 mmol) in absolute methanol (15 mL) was heated at 35–40°C for 5 h. After concentration, the residue was acidified with (1:1) aqueous HCl to pH 1–2 and kept at room temperature for 24 h. The solution was extracted with ethyl ether (3 × 20 mL), and the combined organic layers were dried with anhydrous Na2SO4, filtered, and concentrated. The product 4a–f was crystallized as indicated below.
4,5,5-Trimethyl-2,5-dihydro-2-oxofuran-3-carboxamide (4a)
Yield 77%; mp 125–126°C (from petroleum ether), Refs. [23, 24] mp 125–126°C.
N-Methyl-(4,5,5-trimethyl-2,5-dihydro-2-oxofuran)-3-carboxamide (4b)
Yield 79%; mp 65–66°C (from petroleum ether), Refs. [23, 24] mp 65–66°C.
N-Benzyl-(4,5,5-trimethyl-2,5-dihydro-2-oxofuran)-3-carboxamide (4c)
Yield 76%; mp 84–85.5°C (from petroleum ether), Ref. [23] mp 86–88°C (from petroleum ether), Ref. [24] mp 84–85°C, Ref. [30] mp 83–84°C.
N-Phenyl-(4,5,5-trimethyl-2,5-dihydro-2-oxofuran)-3-carboxamide (4d)
Yield 75%; mp 97–98°C (from petroleum ether), Ref. [23] mp 96.5–98°C.
4-Methyl-5,5-pentamethylene-2,5-dihydro-2-oxofuran-3-carboxamide (4e)
Yield 79%; mp 161–163°C (from octane), Ref. [23] mp 161–162.5°C.
N-Methyl-(4-methyl-5,5-pentamethylene-2,5-dihydro-2-oxofuran)-3-carboxamide (4f)
Yield 79%; mp 108–109°C (from octane), Ref. [23] mp 108–109°C.
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