triethoxymethoxyethane

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 0.17 g of biphenyl-4-yl-(3-hydroxyoxetan-3-yl)methanesulfonamide in 4 ml of tetraethoxymethane and 1 ml of acetic acid was stirred at 90° C. for 3 hours. The solvent was removed under reduced pressure. This gave the crude product, which was used without further purification. The solvent was removed under reduced pressure

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 14.40 g of 2-(3-bromophenyl)-3-hydroxy-3-methylbutane-2-sulfonamide (50%, contaminated with 1-(3-bromophenyl)ethanesulfonamide)) in 100 ml of tetraethoxymethane was admixed with 12 ml of acetic acid and stirred at 100° C. under a strong argon stream for 6 hours. After the removal of the solvent under reduced pressure (bath temperature 70° C.), the viscous residue was dried at 50° C. in a vacuum drying cabinet for 16 hours. The conversion was checked by LCMS and found to be incomplete. Therefore, the oily residue was left to react on the rotary evaporator under reduced pressure (bath temperature 80° C.) for 4 hours. After the addition of 10 ml of acetic acid, the bath temperature was increased to 85° C. and the pressure was adjusted to 150 mbar. Subsequently, the volatile constituents were removed, again under reduced pressure, and the crude product was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (5.97 g) with a molecular weight of 376.3 g/mol (C14H18BrNO4S). After the removal of the solvent under reduced pressure (bath temperature 70° C.) the viscous residue was dried at 50° C. in a vacuum drying cabinet for 16 hours Therefore, the oily residue was left to react on the rotary evaporator under reduced pressure (bath temperature 80° C.) for 4 hours the bath temperature was increased to 85° C. Subsequently, the volatile constituents were removed, again under reduced pressure the crude product was purified by means of normal phase chromatography concentrated by rotary evaporation

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3.14 g of 1-biphenyl-4-yl-2-hydroxy-2-methylpropane-1-sulfonamide in 75 ml of tetraethoxymethane and 15 ml of acetic acid was stirred at 100° C. for 24 hours. The conversion was checked by LCMS. Since it was incomplete, the reaction mixture was admixed with a further 15 ml of acetic acid and stirred at 120° C. for 4 hours. Subsequently, a further 20 ml of tetraethoxymethane were added and the reaction mixture was stirred at 120° C. for 5 hours. Since, by checking with LCMS, no further conversion had been achieved, the solvent was removed under reduced pressure and the residue was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (1.04 g) with a molecular weight of 359.5 g/mol (C19H21NO4S). stirred at 120° C. for 4 hours the reaction mixture was stirred at 120° C. for 5 hours the solvent was removed under reduced pressure the residue was purified by means of normal phase chromatography concentrated by rotary evaporation

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 75 mg of 1-(3-bromophenyl)-1-fluoro-2-hydroxy-2-methylpropane-1-sulfonamide in 5 ml of tetraethoxymethane and 1 ml of acetic acid was stirred at 100° C. for 1.5 hours. The conversion was checked by LCMS. Since it was incomplete, the reaction mixture was stirred at 100° C. for a further 3.5 hours. After the removal of the solvents under reduced pressure, the residue was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (45.6 mg) with a molecular weight of 380.2 g/mol (C13H15BrFNO4S). the reaction mixture was stirred at 100° C. for a further 3.5 hours After the removal of the solvents under reduced pressure the residue was purified by means of normal phase chromatography concentrated by rotary evaporation

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

Procedure: Prepared in a similar manner to example 41 using 3-amino-4-hydroxy-N-(1-propylbutyl)benzamide (example 41a) and tetraethoxymethane: mp 128-129° C.; MS (M+H, 305.1).

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

Procedure: 200 mg of 6-(3-phenylamino-4-aminophenyl)oxyhexanoic acid methyl ester was mixed with 0.19 ml of tetraethylorthocarbonate and 40 μl of acetic acid, and the mixture was heated for 4 hours to 80° C. After cooling, it was mixed with 1N sodium hydroxide solution, extracted three times with ethyl acetate, the combined organic phases were washed with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel. 124 mg was obtained. the mixture was heated for 4 hours to 80° C After cooling extracted three times with ethyl acetate the combined organic phases were washed with saturated sodium chloride solution dried on sodium sulfate concentrated by evaporation in a vacuum The residue was purified by column chromatography on silica gel 124 mg was obtained

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

Procedure: To a three-necked round-bottomed flask, equipped with a Dean-Stark trap (20 mL), a reflux condenser, a thermometer and a magnetic stir bar, was placed diol 1 (14.8 g, 115.5 mmol) and 370 mL of toluene under an atmosphere of N2. The mixture was brought to reflux and maintained at reflux temperature for 2 hours to azeotropically remove any moisture. About 100 mL (5×20 mL) of azeotropic mixture was collected in the Dean-Stark trap. The mixture was then allowed to slowly cool to room temperature and 0.2 g of anhydrous para-toluenesulfonic acid (PTSA) was added, followed by dropwise addition of tetraethylorthocarbonate (TEOC, 4563-91-2, 99.1%, 12.2 mL, 57.8 mmol). The resulting mixture was brought to reflux to azeotropically remove ethanol generated during this reaction. The azeotropic mixture was shaken with sale water to determine the amount (volume) of ethanol collected. After a total of 140 mL of azeotropic mixture (12.5 mL of ethanol) was collected, the reaction mixture was allowed to reflux for an additional 2 hours and then allowed to stir at 102° C. overnight. The reaction mixture was allowed to slowly cool to room temperature and then neutralized by the addition of 1 mL of triethylamine. The resulting mixture was allowed to stir at room temperature for an additional 30 min, and was stripped off solvents to give an off white solid. The crude material was then purified by flash chromatography (silica gel, CH2Cl2/hexanes 2/1 v/v) or by recrystallization from refluxing toluene. The desired product 7,9,17,18-tetraoxatrispiro[4.2.2.4.2.2]nonadeca-2,13-diene (DCP 3) was obtained as white crystals in 62% yield. Mp (DSC) 174.53° C.; 1H-NMR (CDCl3, 300 MHz) δ5.61 (s, 2H), 3.82 (s, 4H), 2.29 (s, 4H); 13C-NMR (CDCl3, 300 MHz) δ128.53, 114.14, 71.07, 39.79; FT-IR (CH2Cl2) (cm−1) 3052, 2947, 2928, 2880, 2842, 1614, 1481, 1267, 1210, 1171, 1014, 990, 738, 671; Anal. Calcd for C15H20O4: C, 68.16; H, 763; Found: C, 68.18; H, 7.81. To a three-necked round-bottomed flask, equipped with a Dean-Stark trap (20 mL), a reflux condenser to reflux maintained at reflux temperature for 2 hours to azeotropically remove any moisture About 100 mL (5×20 mL) of azeotropic mixture was collected in the Dean-Stark trap 0.2 g of anhydrous para-toluenesulfonic acid (PTSA) was added generated during this reaction collected After a total of 140 mL of azeotropic mixture (12.5 mL of ethanol) was collected to reflux for an additional 2 hours to slowly cool to room temperature neutralized by the addition of 1 mL of triethylamine to stir at room temperature for an additional 30 min to give an off white solid The crude material was then purified by flash chromatography (silica gel, CH2Cl2/hexanes 2/1 v/v) or by recrystallization from refluxing toluene

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

Procedure: To a three-necked round-bottomed flask, equipped with a Dean-Stark trap (20 mL), a reflux condenser, a thermometer and a magnetic stir bar, was placed 2,2-cyclohexene-dimethanol 1 (15.78 g, 111 mmol) and 400 mL of toluene under an atmosphere of N2. The mixture was brought to reflux and maintained at reflux temperature for 2 hours to azeotropically remove any moisture. About 100 mL (5×20 mL) of azeotropic mixture was collected in the Dean-Stark trap. The mixture was then allowed to slowly cool to room temperature and 0.3 g of anhydrous para-toluenesulfonic acid (PTSA) was added, followed by dropwise addition of tetraethylorthocarbonate (TEOC, 11.7 mL, 56 mmol). The resulting mixture was brought to reflux to azeotropically remove ethanol generated during the reaction. The azeotropic mixture was shaken with salt water to determine the amount (volume) of ethanol collected. The reaction was monitored by GC (5 min at 105° C., a 20° C./min rise to 225° C.) and/or by TLC (silica gel, 15% ether/hexanes). After a total of 160 m L of azeotropic mixture (12.3 mL of ethanol) was collected, the reaction mixture was allowed to reflux for an additional 2 hours and then allowed to stir at 102° C. overnight. The reaction mixture was allowed to slowly cool to room temperature and then neutralized by the addition of 1 mL of triethylamine. The resulting mixture was allowed to stir at room temperature for an additional 30 min, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a light yellowish solid. The crude material was then purified by flash chromatography (silica gel, 15-25% ether/hexanes) or by recrystallization from refluxing ethyl ether/hexanes (v/v 1:1). The desired product 8,10,19,20-tetraoxatrispiro[5.2.2.5.2.2]henicosa-2,14-diene 2 (DCH) was obtained as white crystals in 80% yield. Mp (DSC) 118° C.; 1H-NMR (CDCl3, 300 MHz) δ126.20, 124.29, 114.82, 70.21, 30.62, 26.56, 21.42; IR (KBr pellet) (cm−1) 3020, 2920, 2850, 1630, 1440, 1365, 1250, 1225, 1190, 1100, 1025, 1000, 935, 920, 650; Anal. Calcd for C16H26O5: C, 69.84; H, 8.27; Found: C, 69.68; H, 8.42. To a three-necked round-bottomed flask, equipped with a Dean-Stark trap (20 mL), a reflux condenser to reflux maintained at reflux temperature for 2 hours to azeotropically remove any moisture About 100 mL (5×20 mL) of azeotropic mixture was collected in the Dean-Stark trap 0.3 g of anhydrous para-toluenesulfonic acid (PTSA) was added generated during the reaction collected 5 min at 105° C. to 225° C. After a total of 160 m L of azeotropic mixture (12.3 mL of ethanol) was collected to reflux for an additional 2 hours to slowly cool to room temperature neutralized by the addition of 1 mL of triethylamine to stir at room temperature for an additional 30 min dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure to give a light yellowish solid The crude material was then purified by flash chromatography (silica gel, 15-25% ether/hexanes) or by recrystallization from refluxing ethyl ether/hexanes (v/v 1:1)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The keto-ester was prepared by the sodium hydride induced acylation of cyclooctanone (1 using diethyl carbonate). A 1-L round bottom flask was charged with NaH (60% dispersion in mineral oil, 17.0 g, 708 mmol). The NaH was washed with three portions of toluene (200 mL), diethyl carbonate (36 mL, 207 mmol) was charged to the flask, and the reaction mixture warmed to 80° C. A solution of cyclooctanone (18.76 g, 149 mmol) in toluene (50 mL) was added dropwise over 1 hr. The temperature was maintained at 80° C. for 1.5 hr after the addition of cyclooctanone. Upon cooling to room temperature, glacial acetic acid (30 mL) was added dropwise, followed by ice water (200 mL). The reaction mixture was stirred until all the solid was in solution (additional water may be necessary). The layers were separated, and the aqueous layer was extracted with toluene (3×100 mL). The organic layer was dried over MgSO4, filtered, and evaporated in vacuo to yield an oil. Purification was achieved by simple high vacuum distillation (91°-93° C. 0.5 to 0.6 mmHg) to yield 20.8 g, 71% of 6; IR (neat) 2950, 2870, 1745, 1710, 1640, 1617, 1468, 1382, 1330, 1250, 1230, 1185, 1100 cm−1; 1H NMR (CDCl3, 300 MHz) δ(keto-enol mix) 1.23 (t), 1.29 (t), 1.33 to 1.58 (m), 1.62 to 1.76 (m), 1.85 to 1.95 (m), 2.32 to 2.68 (m), 3.5 to 3.6 (m), 4.1 to 4.25 (m), 12.6 (s, enol H). was charged to the flask The temperature was maintained at 80° C. for 1.5 hr Upon cooling to room temperature The layers were separated the aqueous layer was extracted with toluene (3×100 mL) The organic layer was dried over MgSO4 filtered evaporated in vacuo to yield an oil Purification was achieved by simple high vacuum distillation (91°-93° C. 0.5 to 0.6 mmHg)

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

Procedure: 3.60 g (18.4 mmol) 2-cyano-3-methyl-benzenesulfonamide and 5.29 g tetraethoxymethane (27.5 mmol) were heated to 160° C. slowly with stirring under removal of ethanol from the mixture. The mixture was cooled to room temperature. The residue was digerated with petrol ether, filtered and dried to afford 4.91 g (90% of theory) 2-Cyano-N-diethoxymethylene-3-methyl-benzene-sulfon-amide. filtered dried

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

Procedure: 3.60 g (18.4 mmol) 2-cyano-3-methyl-benzenesulfonamide and 5.29 g tetraethoxymethane (27.5 mmol) were heated to 160° C. slowly with stirring under removal of ethanol from the mixture. The mixture was cooled to room temperature. The residue was digerated with petrol ether, filtered and dried to afford 4.91 g (90% of theory) 2-Cyano-N-diethoxymethylene-3-methyl-benzene-sulfon-amide. filtered dried

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,3-Diaminotoluene (6.09 g, 49.8 mmol) and tetraethoxymethane (25 mL, 119 mmol) were mixed, and the mixture was stirred at 130° C. for 16 hr. The mixture was cooled to room temperature, diluted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30) to give the title compound (6.89 g, 78%). The mixture was cooled to room temperature washed with brine dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30)