ethyl oxane-4-carboxylate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: It is known that 4-hydroxymethyltetrahydropyran can be prepared in three steps: reaction of ethyl acetoacetate with ethylene oxide to form 3-(2-hydroxyethyl)gamma-butyrolactone (EP-A-246 581), rearrangement to ethyl tetrahydropyran-4-carboxylate (EP-A-284 969), and subsequent catalytic hydrogenation to form 4-hydroxymethyltetrahydropyran (DE-A-4 141 222). can be prepared in three steps

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: It is known that 4-hydroxymethyltetrahydropyran can be prepared in three steps: reaction of ethyl acetoacetate with ethylene oxide to form 3-(2-hydroxyethyl)gamma-butyrolactone (EP-A-246 581), rearrangement to ethyl tetrahydropyran-4-carboxylate (EP-A-284 969), and subsequent catalytic hydrogenation to form 4-hydroxymethyltetrahydropyran (DE-A-4 141 222). can be prepared in three steps

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: It is known that 4-hydroxymethyltetrahydropyran can be prepared in three steps: reaction of ethyl acetoacetate with ethylene oxide to form 3-(2-hydroxyethyl)gamma-butyrolactone (EP-A-246 581), rearrangement to ethyl tetrahydropyran-4-carboxylate (EP-A-284 969), and subsequent catalytic hydrogenation to form 4-hydroxymethyltetrahydropyran (DE-A-4 141 222). can be prepared in three steps

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Lithium diisopropylamide was prepared by the addition of 2.5M N-butyl lithium (5.6 mL, 13.9 mmol) in hexanes to a solution of diisopropylamine (1.95 mL, 13.9 mmmol) in tetrahydrofuran (30 mL) at 0° C. with stirring for 20 minutes. Then a solution of tetrahydropyran-4-carboxylic acid ethyl ester (2 g, 12.7 mmol) in tetrahydrofuran (8 mL) was added to the solution of lithium diisopropylamide at a temperature of -78° C. over 15 minutes. The resulting solution was stirred an additional 50 minutes, and diiodomethane (1.14 mL, 14.2 mmol) was added. The resulting mixture was stirred an additional 50 minutes, warmed to room temperature over 30 minutes, then recooled to 0° C. The mixture was diluted with 1M aqueous hydrochloric acid (25 ml), extracted with diethyl ether (2×100 mL), and washed with additional portions of diethyl ether (2×50 mL). The combined organic layers were washed once with 1M aqueous hydrochloric acid (100 mL), saturated aqueous sodium bisulfite (100 mL), saturated aqueous sodium bicarbonate (100 mL), and dried over magnesium sulfate, and concentrated in vacuo. The residue was filtered over a plug of silica gel, eluting successively with hexanes and ethyl acetate, removing excess alkylating agent with the hexane wash, to afford pure 4-(iodomethyl)tetrahydropyran-4-carboxylic acid ethyl ester as a pale yellow oil which was taken directly into the next reaction without further purification (3.20 g, 85%). IR (KBr) 1732 cm-1 ; 1HNMR (CDCl3) 1.31 (q, J=7.3 Hz, 3H), 1.56 (ddd, J=14.6, 10.9, 4.5, 2H), 2.17 (ddd, J=14.6, 5.7, 3.3, 2H), 3.31 (s, 2H), 3.51 (ddd, J=11.7, 11.1, 2.5 Hz, 2H), 3.51 (td, J=11.7, 4.3 Hz, 2H), 4.24 (q, J=7.1 Hz, 2H); 13CNMR (CDCl3) δ 14.33 (q) , 15.04 (t), 34.70 (t), 45.26 (s), 61.34 (t), 65.22 (t), 172.89 (s); EIHRMS Calcd. for C9H15IO3 (M+): 298.0066. Found: 298.0066. Anal. Calcd. for C9H15IO3 : C, 36.26; H, 5.07. Found: C, 36.56; H, 5.09. The resulting solution was stirred an additional 50 minutes The resulting mixture was stirred an additional 50 minutes recooled to 0° C extracted with diethyl ether (2×100 mL) washed with additional portions of diethyl ether (2×50 mL) The combined organic layers were washed once with 1M aqueous hydrochloric acid (100 mL), saturated aqueous sodium bisulfite (100 mL), saturated aqueous sodium bicarbonate (100 mL) dried over magnesium sulfate concentrated in vacuo The residue was filtered over a plug of silica gel eluting successively with hexanes and ethyl acetate removing excess alkylating agent with the hexane wash

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Lithium diisopropylamide was prepared by the addition of 2.5M N-butyl lithium (30.3 mL, 75.6 mmol) in hexanes to a solution of diisopropylamine (10.6 mL, 75.6 mmmol) in tetrahydrofuran (244 mL) at 0° C. and stirring for 20 minutes. Then a solution of tetrahydropyran-4-carboxylic acid ethyl ester (10 g, 63.2 mmol) in tetrahydrofuran (50 mL) was added to the solution of lithium diisopropylamide over 15 minutes at -78° C. The resulting solution was stirred an additional 50 minutes, and solid paraformaldehyde (10 g) was added in one portion. The mixture was slowly allowed to warm to room temperature over 9 hours, diluted with 2M aqueous hydrochloric acid (100 mL), and filtered over a pad of celite pad which was washed with diethyl ether (2×200 mL). The aqueous layer of the filtrate was washed with additional portions of diethyl ether (2×200 mL). The combined organic layers were washed once with 2M aqueous hydrochloric acid (100 mL), saturated aqueous sodium bicarbonate (100 mL), dried over magnesium sulfate, and concentrated in vacuo to afford a slightly impure product 4-(hydroxymethyl)tetrahydropyran-4-carboxylic acid ethyl ester (11.5 g, 97%), which was taken into the next reaction without further purification. IR (neat) 3433 (br), 1726 cm-1 ; 1HNMR (CDCl3) δ 1.30 (t, J=7.1 Hz, 3H), 1.57 (ddd, J=13.8, 10.1, 4.4 Hz, 2H), 2.07 (dm, J=13.8 Hz, 2H), 2.30-2.45 (br s, 1H), 3.56 (ddd, J=11.9, 10.3, 2.7 Hz, 2H), 3.66 (s, 2H), 3.82 (dt, J=11.9, 4.2 Hz, 2H), 4.24 (q, J=7.2 Hz, 2H); 13CNMR (CDCl3) δ 14.25 (q), 30.54 (t), 46.63 (s), 61.04 (t), 64.79 (t), 69.02 (t), 175.24 (s); HRMS Calcd for C9H16O4 : 188.1049. Found: 188.1053. The resulting solution was stirred an additional 50 minutes filtered over a pad of celite pad which was washed with diethyl ether (2×200 mL) The aqueous layer of the filtrate was washed with additional portions of diethyl ether (2×200 mL) The combined organic layers were washed once with 2M aqueous hydrochloric acid (100 mL), saturated aqueous sodium bicarbonate (100 mL) dried over magnesium sulfate concentrated in vacuo

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tetrahydropyran-4,4-dicarboxylic acid diethyl ester (400 mg, 1.74 mmol) in N,N-dimethylformamide (4 mL), was added lithium iodide (1.16 g, 8.66 mmol), followed by sodium cyanide (94 mg, 1.91 mmol). The mixture was heated at 130° C. for 7 hours, 140° C. for 25 hours, after which GC analysis indicated the reaction to be >95% complete. The mixture was partitioned between 33% diethyl ether/hexanes (100 mL) and brine (25 mL). The organic layer was washed with additional brine (25 mL), dried (MgSO4) and concentrated in vacuo to afford the tetrahydropyran-4-carboxylic acid ethyl ester (253 mg, 92%). Note: Substitution of 2 equivalents of sodium acetate for 1.1 equivalents of sodium cyanide in this reaction and heating 12 hours longer provides identical results. the reaction The mixture was partitioned between 33% diethyl ether/hexanes (100 mL) and brine (25 mL) The organic layer was washed with additional brine (25 mL) dried (MgSO4) concentrated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a 500-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of ethyl tetrahydro-2H-pyran-4-carboxylate (8 g, 50.6 mmol) in tetrahydrofuran (100 mL). This was followed by the addition of LDA (50 mL, 101.1 mmol, 2M in THF) dropwise at −78° C. and stirred for 3 h. To this was added a solution of CH3I (9.5 mL, 151.9 mmol) in tetrahydrofuran (50 mL) dropwise at −78° C. The reaction mixture was stirred for 3 h at −78° C., then carefully quenched with 400 mL of NH4Cl (sat.). The aqueous phase was extracted with 300 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 8 g (92%) of the title compound as a yellow oil. Into a 500-mL three neck round-bottom flask, which was purged maintained with an inert atmosphere of nitrogen The reaction mixture was stirred for 3 h at −78° C. carefully quenched with 400 mL of NH4Cl (sat.) The aqueous phase was extracted with 300 mL of ethyl acetate the combined organic layers were dried over anhydrous sodium sulfate concentrated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: It is known that 4-hydroxymethyltetrahydropyran can be prepared in three steps: reaction of ethyl acetoacetate with ethylene oxide to form 3-(2-hydroxyethyl)gamma-butyrolactone (EP-A-246 581), rearrangement to ethyl tetrahydropyran-4-carboxylate (EP-A-284 969), and subsequent catalytic hydrogenation to form 4-hydroxymethyltetrahydropyran (DE-A-4 141 222). can be prepared in three steps