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To a solution of tetrahydro-3-furancarboxylic acid (20.00 g, 172 mmol) in MeOH (350 mL) was added sulfuric acid (27.54 mL, 517 mmol). The reaction was heated to reflux for 18 h. The reaction was then cooled to rt and concentrated. The residue was partitioned between water (500 mL) and DCM (200 mL). The phases were separated and the aqueous fraction was extracted with DCM (200 mL). The combined organic fractions were washed with saturated aqueous NaHCO3 (200 mL) and brine (200 mL), dried over Na2SO4, filtered, and concentrated to afford methyl tetrahydro-3-furancarboxylate (15.0 g, 67percent yield) as a pale yellow oil. 1H NMR (400 MHz, DMSO-d) δ ppm 3.85 (t, J=8.4 Hz, 1H), 3.77-3.66 (m, 3H), 3.62 (s, 3H), 3.07-3.22 (m, 1H), 1.97-2.12 (m, 2H).
Reference:
[1] Journal of Organic Chemistry, 1996, vol. 61, # 8, p. 2690 - 2694
[2] Patent: US2018/201610, 2018, A1, . Location in patent: Paragraph 0076; 0077
[3] Advanced Synthesis and Catalysis, 2010, vol. 352, # 2-3, p. 463 - 477
To a solution of tetrahydro-3-furancarboxylic acid (20.00 g, 172 mmol) in MeOH (350 mL) was added sulfuric acid (27.54 mL, 517 mmol). The reaction was heated to reflux for 18 h. The reaction was then cooled to rt and concentrated. The residue was partitioned between water (500 mL) and DCM (200 mL). The phases were separated and the aqueous fraction was extracted with DCM (200 mL). The combined organic fractions were washed with saturated aqueous NaHCO3 (200 mL) and brine (200 mL), dried over Na2SO4, filtered, and concentrated to afford methyl tetrahydro-3-furancarboxylate (15.0 g, 67% yield) as a pale yellow oil. 1H NMR (400 MHz, DMSO-d) delta ppm 3.85 (t, J=8.4 Hz, 1H), 3.77-3.66 (m, 3H), 3.62 (s, 3H), 3.07-3.22 (m, 1H), 1.97-2.12 (m, 2H).
Intermediate 4: 3-Oxo-3-(tetrahydro-furan-3-yl)-propionic acid ethyl ester To a solution of lithium bis(trimethylsilyl)amide (1 M in hexanes; 100 mL) in THF (200 mL) at -78 C. was added dry ethyl acetate (10.8 g, 12 mL, 122.5 mmol) dropwise. After 30 min at -78 C., the mixture was treated with a solution of <strong>[53662-85-4]tetrahydro-furan-3-carboxylic acid methyl ester</strong> (6.0 g, 46.1 mmol) in THF (50 mL). After 4 h at -78 C., the reaction was quenched with satd. aq. NH4Cl, warmed to rt, and extracted with EtOAc (5*75 mL). The combined organic layers were washed with satd. aq. NaCl, dried, and concentrated to give a colorless oil. Chromatography on SiO2 (EtOAc/CH2Cl2) afforded the title compound (3.3 g).
With potassium tert-butylate; In tetrahydrofuran; at 20℃; for 1h;Cooling with ice;
To an ice-cooled solution of <strong>[53662-85-4]methyl tetrahydrofuran-3-carboxylate</strong> (50 g, 0.385 mol) and acetonitrile (47 g, 1.154 mol) in tetrahydrofuran (500 mL) was added potassium ieri-butoxide (129 g, 1.15 mol) portion- wise. The resulting mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was poured into saturated aqueous ammonium chloride solution (1 L) and extracted with ethyl acetate (3 x 400 mL). The collected organic layers were washed with saturated aqueous sodium chloride solution (400 mL), dried over sodium sulfate, and concentrated in vacuo to afford product (41 g, crude, 76.6% yield).
With potassium 2-methylbutan-2-olate; In tetrahydrofuran; at 20℃;
A solution of KOt-Amyl (1.7M in toluene, 7.47 mL, 12.7 mmol) was added slowly to a solution of acetonitrile (276 muL, 5.28 mmol) in THF (14 mL, 0.3M). Methyl tetrahydrofuran-3-carboxylate (550 mg, 4.23 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was then quenched with 0.5M HCl (30 mL) and extracted with EtOAc (100 mL). The organic layer was washed with water (3 X 25 mL) and brine (25 mL), dried (Na2SO4), filtered, and concentrated. The crude product 3-oxo-3-(tetrahydrofuran-3-yl)propanenitrile was taken directly on to Step B.
To a solution of <strong>[53662-85-4]methyl tetrahydrofuran-3-carboxylate</strong> (15 g) in ammonia (7 N solution in MeOH, 110 mL) was heated to 80 C. for 72 h. The reaction mixture was then concentrated and dried under high vacuum to afford tetrahydrofuran-3-carboxamide (15 g, quantitative yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d) delta ppm 7.38 (brs, 1H), 6.87 (brs, 1H), 3.84 (t, J=8.0 Hz, 1H), 3.72-3.62 (m, 3H), 2.92 (m, 1H), 1.98 (m, 2H).
Example 11A methyl 3-bromotetrahydrofuran-3-carboxylate 5.0 g (38.419 mmol) of <strong>[53662-85-4]methyl tetrahydrofuran-3-carboxylate</strong> (prepared analogously to: J. Org. Chem. 1996, 2690) were dissolved in 200 ml of THF and cooled to -78 C., and then 76.83 ml of a 1M solution of lithium bis(trimethylsilyl)amide in THF were added. After 30 min at -78 C., 10.26 g (57.63 mmol) of N-bromosuccinimide suspended in 50 ml of THF were added gradually. Thereafter, the mixture was left to warm up to RT overnight. The mixture was then admixed with water and extracted with ethyl acetate. The phases were separated and the aqueous phase was extracted twice more with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution and then dried over sodium sulfate, filtered and concentrated. The crude product was purified by means of chromatography on silica gel (eluent: dichloromethane). This gave 491 mg (6% of theory) of the target compound. 1H NMR (400 MHz, CDCl3): delta [ppm]=2.49 (ddd, 1H), 2.74 (ddd, 1H), 3.83 (s, 3H), 4.03-4.10 (m, 1H), 4.11-4.17 (m, 2H), 4.31 (d, 1H).
6%
10447] 5.0 g (38.419 mmol) of methyl tetrahydrothran-3- carboxylate (Journal of Organic Chemistry; 1996; 2690) were dissolved in 200 ml of THF and cooled to -78 C., and 76.83 ml (76.83 mmol) ofbis(trimethylsilyl)lithium amide (1 M in THF) were then added. After 30 mm at -78 C., 10.26 g (57.63 mmol) ofN-bromosuccinimide, suspended in 50 ml of THF, were added slowly. The mixture was then allowed to warm to RT overnight. Water was added, and the mixture was extracted with ethyl acetate. The phases were separated and the aqueous phase was extracted two more times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution and then dried with sodium sulphate, filtered and concentrated. The crude product was purified by chromatography on silica gel (mobile phase:dichloromethane). This gave 491 mg (6% of theory) of the title compound.10448] 1H NMR (400 MHz, CDC13): oe [ppm]=2.49 (ddd,1H), 2.74 (ddd, 1H), 3.83 (s, 3H), 4.03-4.10 (m, 1H), 4.11-4.17 (m, 2H), 4.31 (d, 1H).
With potassium carbonate; In N,N-dimethyl-formamide; at 32℃; for 5h;
To a solution of tetrahydrofuran-3-carboxylic acid (50 g, 0.431 mol) and potassium carbonate (89.2 g, 0.647 mol) in A^N-dimethylformamide (500 mL) was added iodomethane (73.4 g, 0.517 mol) at 32 C and stirred for 5 h. The reaction solution was filtered, and the filtrate was concentrated in vacuo to afford crude product (53 g, 95% yield). NMR (400 MHz, CDC13): delta 3.98 - 3.76 (m, 4 H), 3.69 (s, 3 H), 3.11 - 3.04 (m, 1 H), 2.23 - 2.09 (m, 2 H).