3-Methylfuran-2-carboxylic acid

white to beige powder

Commercial methyl 3-methyl-2-furoate, 4, (2.0 g, 14.3 mmol) was reacted under reflux with 3.8 mL of 30percent sodium hydroxide aqueous solution (28.5 mmol) and 3.6 mL of methanol (88.8 mmol) for 3.5 h. EXAMPLE 57; (αR, γS, 2S)-N-((3S, 4S)-3, 4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-γ-hydroxy-4-[1-methyl-1-[3-methyl-5-(4-pyridinyl)-2-furanyl]ethyl]-α-(phenylmethyl)-2-[[(2, 2, 2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide; To a solution of commercially available methyl 3-methylfuroate (20.0 g, 140 mmol) in 100 mL of MeOH, NaOH (11.43 g, 280 mmol) in 20 mL of water was added. The yellowish solution was stirred at room temperature for 3 hours. TLC (1:9 EtOAc/hexane) showed no starting material. MeOH was removed and the pH of the aqueous solution was adjusted to 4 with 1N HCl. The slurry was extracted with ethyl acetate (5.x.100 mL). The combined ethyl acetate layers were washed brine, and dried over sodium sulfate. 3-methyl furoic acid was obtained as a white solid (13.2 g, 73percent) after evaporation of the solvent. To a mixture of 3-methyl furoic acid (8.60 g, 68 mmol), N, O-dimethylhydroxylamine hydrochloride (8.0 g, 82 mmol), EDC (15.7 g, 82 mmol), and HOBT (11.07 g, 82 mmol) in dichloromethane (200 mL), triethylamine (14.4 mL, 100 mmol) was added. The solution was stirred at room temperature for 4 hours, and washed with 1N NaOH (50 mL), 1N HCl (50 mL), brine, and dried over sodium sulfate. The title compound was obtained as a colorless liquid upon removal of the solvent.To a stirred EtCommercial methyl 3-methyl-2-furoate, 4, (2.0 g, 14.3 mmol) was reacted under reflux with 3.8 mL of 30percent sodium hydroxide aqueous solution (28.5 mmol) and 3.6 mL of methanol (88.8 mmol) for 3.5 h. The solvent was removed and the resulting crude mixture was dissolved in 10 mL of water and acidified with concentrated hydrochloric acid until pH 1, and extracted with diethyl ether (4*3 mL). The organic phases were combined together, dried over magnesium sulfate, filtrated, and concentrated to dryness, giving 1.7 g of 3-methyl-2-furoic acid (13.6 mmol, yield 95percent). MP: 135 °C (ether). 1H NMR (400 MHz, CDCl3, delta, ppm): 2.40 (3H, s, CH3), 6.41 (1H, d, J4, 5=1.6 Hz, H4), 7.52 (1H, d, J5, 4=1.6 Hz, H5). 13C NMR (100 MHz, CDCl3, delta, ppm): 170.2 (COO), 150.1 (C5), 139.9 (C2), 125.3 (C3), 112.0 (C4), 13.3 (Me). IR (film, nu, cm-1): 1102 (st. C-O), 1136 (st. C-O), 1189 (st. C-O), 1488 (def. C-H), 1599 (st. C=C Ar.), 1670 (st. C=O), 2200-3200 (st. O-H). MS (EI, m/z, percent): 126.03 (M+, 100); 127.03 (7); 109.03 (M+-OH, 20); 81.03 (40, M+-CHO2). EA. Calculated for C6H6O3: C (57.14), H (4.80). Found: C (57.11), H (4.83).A. 3-Methyl-2-furanoic acid A mixture of 3-methyl-2-furoic acid, methyl ester [20.0 g, 0.14 mole, 0.14 mole, Organic Synthesis 39, 49 (1959)] and 20percent NaOH solution (46 mL) was refluxed under argon for 2 hours. The cooled mixture was acidified with concentrated HCl (28.5 mL). The resulting white precipitate was collected, washed with water and dried in vacuo to give the title acid (16.53 g, 94percent) as a white crystalline solid, mp 132°-134° C.EXAMPLE 57; (alphaR, gammaS, 2S)-N-((3S, 4S)-3, 4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-gamma-hydroxy-4-[1-methyl-1-[3-methyl-5-(4-pyridinyl)-2-furanyl]ethyl]-alpha-(phenylmethyl)-2-[[(2, 2, 2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide; To a solution of commercially available methyl 3-methylfuroate (20.0 g, 140 mmol) in 100 mL of MeOH, NaOH (11.43 g, 280 mmol) in 20 mL of water was added. The yellowish solution was stirred at room temperature for 3 hours. TLC (1:9 EtOAc/hexane) showed no starting material. MeOH was removed and the pH of the aqueous solution was adjusted to 4 with 1N HCl. The slurry was extracted with ethyl acetate (5.x.100 mL). The combined ethyl acetate layers were washed brine, and dried over sodium sulfate. 3-methyl furoic acid was obtained as a white solid (13.2 g, 73percent) after evaporation of the solvent. To a mixture of 3-methyl furoic acid (8.60 g, 68 mmol), N, O-dimethylhydroxylamine hydrochloride (8.0 g, 82 mmol), EDC (15.7 g, 82 mmol), and HOBT (11.07 g, 82 mmol) in dichloromethane (200 mL), triethylamine (14.4 mL, 100 mmol) was added. The solution was stirred at room temperature for 4 hours, and washed with 1N NaOH (50 mL), 1N HCl (50 mL), brine, and dried over sodium sulfate. The title compound was obtained as a colorless liquid upon removal of the solvent.To a stirred Et2O (500mL) solution of 4, 4-dimethoxy-2-butanone (80mL, 0.60mol) and methyl chloroacetate (90mL, 1.03mol) was added MeONa (54g, 1.00mol) at '5°C under a N2 atmosphere, and the resulting solution was stirred at '5°C for 2h, and at room temperature overnight. To the solution was slowly added a mixture of glacial acetic acid (7mL) and H2O (93mL) at 0°C. The organic layer was decantated. Aqueous phase was washed with Et2O. The combined organic layers were washed with sat. NaHCO3 aq. and brine, separated, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was distilled (bp 72'78°C/8mmHg) to give 2-methoxycarbonyl-3-methylfuran (71g, 0.51mol, 85percent yield). (0033) A mixture of 2-methoxycarbonyl-3-methylfuran (26g, 0.19mol) and 20percent NaOH aq. (60mL) was stirred at reflux for 2h. After the solution was cooled to 0°C, conc HCl (35mL) was slowly added to give colorless crystals of The 3-Methyl-furan-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2, 3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide was prepared from 3-nitrobenzoyl chloride using the following multiple step procedure: Step 1: 3-Methyl-furan-2-carboxylic acid [3-(2-oxo-2, 3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide.; A dry flask was charged with 3-Methyl-furan-2-carboxylic acid (0.500 g, 3.96 mmol) and thionyl chloride (10 mL) and allowed to stir at 79 C. for 3 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (40 mL). 6-(3-Amino-benzoyl)-1, 3-dihydro-indol-2-one (as prepared in Example 40, 1.00 g, 3.96 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and filtered. The solid residue was washed with 0 C. THF and collected to afford the 3-Methyl-furan-2-carboxylic acid [3-(2-oxo-2, 3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (1.242 g, 3.45 mmol, 87%).Example 461(S)-N-[methyl(oxo)phenyl-lambda6-sulfanylidene]-5-({3-[(3-methylruryl-2- carbonyl)amino]phenyl}ethynyl)nicotinamideStep 1N-(3-ethynylphenyl)-3-methylfuran-2-carboxamide.A dry 25 mL flask was charged with To a stirred Et2O (500mL) solution of 4, 4-dimethoxy-2-butanone (80mL, 0.60mol) and methyl chloroacetate (90mL, 1.03mol) was added MeONa (54g, 1.00mol) at '5°C under a N2 atmosphere, and the resulting solution was stirred at '5°C for 2h, and at room temperature overnight. To the solution was slowly added a mixture of glacial acetic acid (7mL) and H2O (93mL) at 0°C. The organic layer was decantated. Aqueous phase was washed with Et2O. The combined organic layers were washed with sat. NaHCO3 aq. and brine, separated, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was distilled (bp 72'78°C/8mmHg) to give 2-methoxycarbonyl-3-methylfuran (71g, 0.51mol, 85percent yield). (0033) A mixture of 2-methoxycarbonyl-3-methylfuran (26g, 0.19mol) and 20percent NaOH aq. (60mL) was stirred at reflux for 2h. After the solution was cooled to 0°C, conc HCl (35mL) was slowly added to give colorless crystals of A mixture of 3-methyl-2-furoic acid, 5, (1.7 g, 13.5 mmol), quinoline (5.7 mL, 27 mmol), and copper powder (0.33 g, 5.2 mmol) was heated in a one-piece microdistillation setup (fitted with a condenser with an ice-water circulating system) during 2.5 h at 165'180 °C. As a result, 0.75 g (9.2 mmol, 68percent yield) of 3-methylfuran vapor was condensed in the receiving flask cooled with an ice bath. 1H NMR (400 MHz, CDCl3, delta, ppm): 2.04 (3H, br s, CH3), 6.23'6.25 (1H, m, H4), 7.19'7.21 (1H, m, H2), 7.32'7.34 (1H, m, H5). 13C NMR (100 MHz, CDCl3, delta, ppm): 142.7 (C5), 139.3 (C2), 119.8 (C3), 112.2 (C4), 9.6 (Me). IR (film, nu, cm'1): 1100 (st. C'O), 1130 (st. C'O), 1200 (st. C'O), 1480 (def. C'H), 1588 (st. C=C Ar.). MS (DIP, EI, m/z, percent): 82.04 (M+, 100); 83.04 (6). EA. Calculated for C5H6O: C (73.15), H (7.37). Found: C (73.10), H (7.41).

3-Methyl-2-furoic acid can be used in a palladium-catalyzed cross-coupling between heteroaryl carboxylic acids and aryl bromides leading to arylated heterocycles.1 Also used in a palladium-catalyzed asymmetric hydrogenation.

Molecular Weight:126.11
XLogP3:1.2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:126.031694049
Monoisotopic Mass:126.031694049
Topological Polar Surface Area:50.4
Heavy Atom Count:9
Complexity:122
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes