2,2-diethylpropane-1,3-diol

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: Twenty g. of 3,6-dichloropyridazine, 2.3 g. of silver nitrate and 44.4 g. of 2,2-diethyl-1,3-propanediol were slurried in 280 ml. of water and 19.7 g. of sulfuric acid. To the mixture were added, simultaneously, solutions of 61.3 g. of ammonium persulfate in 200 ml. of water and 20 g. of silver nitrate in 40 ml. of water, over a period of 20 minutes at 55°. The mixture heated exothermically to 70°, and it was cooled to ambient temperature after the addition was complete. The aqueous layer was then decanted off, and the solids remaining were slurried twice in 800 ml. of diethyl ether. The resulting solution was shaken with the aqueous layer, and the layers were separated again. The aqueous layer was then made basic to pH 9 with ammonium hydroxide, and was re-extracted with 500 ml. of diethyl ether. The ether was evaporated under vacuum to obtain 46 g. of brown oil, which was purified by high performance liquid chromatography, eluting with 6:1 heptane:ethyl acetate. The product-containing fractions were combined and evaporated under vacuum to obtain, after recrystallization from diethyl ether/heptane, 0.54 g. of the desired product, m.p. 85°-87°. To the mixture were added The mixture heated exothermically to 70° after the addition The aqueous layer was then decanted off the layers were separated again was re-extracted with 500 ml The ether was evaporated under vacuum to obtain 46 g of brown oil, which was purified by high performance liquid chromatography eluting with 6:1 heptane evaporated under vacuum to obtain after recrystallization from diethyl ether/heptane, 0.54 g

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

Procedure: 30 g (0.27 mmol) of cyclohexane-1,4-dione, 35.4 g (0.27 mol) of 2,2-diethylpropane-1,3-diol and 360 mg of para-toluenesulfonic acid were heated in 200 ml of toluene on a water separator. After the mixture had been cooled to room temperature and the water of reaction separated off, the organic phase was washed with a semisaturated sodium hydrogen carbonate solution and dried over magnesium sulfate. After the solvent had been evaporated, 65 g of crude product were obtained which was purified by flash chromatography (ethyl acetate/petroleum ether=1:4). The first fraction contained the 1,4-diketal which was formed as secondary product (10 g). The main fraction contained 28.5 g (47%) of a yellow oil. separated off the organic phase was washed with a semisaturated sodium hydrogen carbonate solution dried over magnesium sulfate After the solvent had been evaporated 65 g of crude product were obtained which was purified by flash chromatography (ethyl acetate/petroleum ether=1:4)

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: 2-Fluoro-5-formylbenzonitrile (250 mg, 1.68 mmol), 2,2-diethyl-1,3-propanediol (776 mg, 5.87 mmol) and a catalytic amount of p-toluenesulfonic acid monohydrate were refluxed in toluene (25 mL) overnight in a Dean-Stark apparatus. The reaction mixture was then concentrated and the residue dissolved in chloroform (50 mL) and washed with saturated sodium bicarbonate solution (2×25 mL) then brine (1×25 mL). The organic phase was dried (Na2SO4) and evaporated to give an oil. The oil was then chromatographed on silica gel (4:1 hexane/ethyl acetate) to give 5-(5,5-diethyl-1,3-dioxan-2-yl)-2-fluorobenzenecarbonitrile (43) as a light yellow oil (401 mg, 91%). 1H NMR (MeOD, 300 MHz): δ 0.90, t (7.7 Hz), CH2CH3; 0.97, t (7.5 Hz), CH2CH3; 1.25, q (7.6 Hz), CH2CH3; 1.86, q (7.6 Hz), CH2CH3; 3.72, d (11.5 Hz), CH2O; 4.02, d (11.4 Hz), CH2O; 5.52, s, H2; 7.42, t (9.3 Hz), H3; 7.86, m, H4,6. ESI (+ve) MS: m/z 264 (M+H, 11%). The reaction mixture was then concentrated the residue dissolved in chloroform (50 mL) washed with saturated sodium bicarbonate solution (2×25 mL) The organic phase was dried (Na2SO4) evaporated to give an oil The oil was then chromatographed on silica gel (4:1 hexane/ethyl acetate)

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

Procedure: 2-Fluoro-5-formylbenzonitrile (250 mg, 1.68 mmol), 2,2-diethyl-1,3-propanediol (776 mg, 5.87 mmol) and a catalytic amount of p-toluenesulfonic acid monohydrate were refluxed in toluene (25 mL) overnight in a Dean-Stark apparatus. The reaction mixture was then concentrated and the residue dissolved in chloroform (50 mL) and washed with saturated sodium bicarbonate solution (2×25 mL) then brine (1×25 mL). The organic phase was dried (Na2SO4) and evaporated to give an oil. The oil was then chromatographed on silica gel (4:1 hexane/ethyl acetate) to give 5-(5,5-diethyl-1,3-dioxan-2-yl)-2-fluorobenzenecarbonitrile (43) as a light yellow oil (401 mg, 91%). 1H NMR (MeOD, 300 MHz): δ 0.90, t (7.7 Hz), CH2CH3; 0.97, t (7.5 Hz), CH2CH3; 1.25, q (7.6 Hz), CH2CH3; 1.86, q (7.6 Hz), CH2CH3; 3.72, d (11.5 Hz), CH2O; 4.02, d (11.4 Hz), CH2O; 5.52, s, H2; 7.42, t (9.3 Hz), H3; 7.86, m, H4,6. ESI (+ve) MS: m/z 264 (M+H, 11%). The reaction mixture was then concentrated the residue dissolved in chloroform (50 mL) washed with saturated sodium bicarbonate solution (2×25 mL) The organic phase was dried (Na2SO4) evaporated to give an oil The oil was then chromatographed on silica gel (4:1 hexane/ethyl acetate)

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

Procedure: With 4-nitrobenzylphosphonic acid and 2,2-diethyl-1,3-propanediol, the same procedure as in Reference Example 11 was followed, to yield 5,5-diethyl-2-(4-nitrobenzyl)-1,3,2-dioxaphosphorinane-2-oxide, which was then recrystallized from ethanol-hexane to yield colorless prisms having a melting point of159° to 160° C.

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

Procedure: The thiocarbonate 1 was prepared by a variation of the thiocarbonylation procedure developed by Corey and Hopkins. To a three-necked round-bottomed flask, equipped with a mechanical stirrer and an additional funnel, was placed 2,2-diethyl-1,3-propanediol (15.86 g, 120 mmol), 4-dimethylaminopyridine (DMAP, 29.32 g, 240 mmol) and 120 mL of toluene under an atmosphere of nitrogen. The mixture was allowed to stir at room temperature until a homogeneous solution was reached. The mixture was cooled to 0-5° C. and then a solution of thiophosgene (9.43 mL, 120 mmol) in 90 mL of toluene was added dropwise via the additional funnel over a period of 90 min. This resulted in the formation of a bright orange DMAP-thiophosgene complex. After the completion of addition, the reaction mixture was allowed to stir for an hour at 0-5° C. and then slowly warmed to room temperature. The reaction mixture was allowed to stir at room temperature for an additional hour and then the precipitated DMAP-HCl salt was removed by filtration. The filtrate was concentrated under reduced pressure using a rotary evaporator. The crude material was purified by recrystallization (the crude material was dissolved in refluxing ether, allowed to cool to room temperature and slowly evaporated) or by column chromatography (silica gel, 2:1 methylene chloride/hexanes). The desired thiocarbonate 1 was obtained as white crystalline in 70% yield. Mp (DSC) 64.4° C. 1H-NMR (CDCl3, 300 MHz) δ4.17 (s, 4H), 1.51-1.43 (q, 4H, J=7.5 Hz), 0.92-0.87 (t, 6H, J=7.5 Hz); 13C-NMR (CDCl3, 75 MHz) δ189.53, 76.08, 33.67, 23.09, 6.97; IR (KBr pellet) (cm−1) 2960, 2920, 1455, 1395, 1380, 1290, 1240, 1200, 1180, 1060, 990, 930, 720. The thiocarbonate 1 was prepared by a variation of the thiocarbonylation procedure To a three-necked round-bottomed flask, equipped with a mechanical stirrer and an additional funnel The mixture was cooled to 0-5° C. This resulted in the formation of a bright orange DMAP-thiophosgene complex After the completion of addition to stir for an hour at 0-5° C. slowly warmed to room temperature to stir at room temperature for an additional hour the precipitated DMAP-HCl salt was removed by filtration The filtrate was concentrated under reduced pressure a rotary evaporator The crude material was purified by recrystallization (the crude material was dissolved in refluxing ether to cool to room temperature slowly evaporated) or by column chromatography (silica gel, 2:1 methylene chloride/hexanes)