4-methylthiobenzaldehyde

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

Procedure: This compound was synthesized from 2′-hydroxy-4′-ethyloxycarbonyldimethylmethyloxyacetophenone (starting material 1) and 4-methylthiobenzaldehyde according to general method 2 described earlier.

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

Procedure: The title compound was prepared according to the procedure of step 1 in the Example 190 using (4-bromophenyl)acetone and 4-methylthiobenzaldehyde, instead of phenylacetone and 4-bromobenzaldehyde.

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl inden-3-ylacetate (2 g, 10.6 mmol) in dry THF (20 mL) at −70° C. was added dropwise a solution of LDA in THF (25.7 mL, 0.87 M, 2.1 eq.). The resulting orange solution was stirred 30 minutes at −70° C. and then 4-methylthiobenzaldehyde (1.6 mL, 11.7 mmol, 1.1 eq.) was added dropwise. The cooling bath was removed and the reaction mixture was left to warm up to room temperature while a precipitate appeared. The reaction mixture was then quenched with a saturated aqueous solution of ammonium chloride and extracted twice with ethyl acetate. The organic phase was washed twice with iN aqueous HCl, then with brine and dried over MgSO4 and evaporated to dryness. The residue was dissolved in methanol (5 mL) and a solution of benzyltrimethylammonium hydroxide in methanol (Triton B, 1.4 M) (6 mL) was added at room temperature. After 10 minutes the reaction mixture was added to 1N aqueous HCl and extracted with ethyl acetate. The organic layer was treated with etheral diazomethane, dried over MgSO4 and evaporated to dryness. The residue was chromatographed on silica gel eluting with a 95:5 mixture of hexane-ethyl acetate to afford the title compound, as an oil. The cooling bath was removed the reaction mixture was left to warm up to room temperature while a precipitate The reaction mixture was then quenched with a saturated aqueous solution of ammonium chloride extracted twice with ethyl acetate The organic phase was washed twice with iN aqueous HCl with brine and dried over MgSO4 evaporated to dryness The residue was dissolved in methanol (5 mL) a solution of benzyltrimethylammonium hydroxide in methanol (Triton B, 1.4 M) (6 mL) was added at room temperature After 10 minutes the reaction mixture was added to 1N aqueous HCl extracted with ethyl acetate The organic layer was treated with etheral diazomethane dried over MgSO4 evaporated to dryness The residue was chromatographed on silica gel eluting with a 95:5 mixture of hexane-ethyl acetate

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

Procedure: To a solution of dry diisopropylamine (5.0 mL, 35.7 mM) in dry tetrahydrofuran (150 mL) at -78° C., was added dropwise a 2.3N solution of n-butyllithium in hexane (15.5 mL, 35.7 mM). After the reaction solution was stirred for 15 minutes, a solution of 2,2,5-trimethyl-3(2H)-furanone (30 g, 23.8 mM) in tetrahydrofuran (25 mL) was added dropwise. Hexamethylphosphoramide (6.4 mL, 34.7 mM) was then added dropwise after 30 minutes. Finally, p-methylthiobenzaldehyde (43 g, 28.5 mM) in tetrahydrofuran (25 mL) was added in one portion. The reaction solution was stirred 15 minutes when trifluoroacetic anhydride (10.5 mL, 75 mM) was added in one portion. Again, the reaction solution was stirred 15 minutes when triethylamine (5.9 mL, 48 mM) was added and was allowed to warm to room temperature. Then the reaction mixture was partitioned between saturated aqueous sodium chloride (50 mL) and diethyl ether (50 mL). The organic layer was separated and washed with saturated aqueous sodium bicarbonate (2×25 mL) and saturated aqueous sodium chloride (25 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give an amber liquid. The crude product was purified by chromatography (silica gel, pet. ether-ethyl acetate) to afford yellow crystals (3.0 g, 48% yield), m.p. 98°-99.5° C. was added in one portion was added Then the reaction mixture was partitioned between saturated aqueous sodium chloride (50 mL) and diethyl ether (50 mL) The organic layer was separated washed with saturated aqueous sodium bicarbonate (2×25 mL) and saturated aqueous sodium chloride (25 mL) The organic layer was dried over magnesium sulfate filtered concentrated under reduced pressure to give an amber liquid The crude product was purified by chromatography (silica gel, pet. ether-ethyl acetate)

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

Procedure: To a solution of dry diisopropylamine (5.0 mL, 35.7 mM) in dry tetrahydrofuran (150 mL) at -78° C., was added dropwise a 2.3N solution of n-butyllithium in hexane (15.5 mL, 35.7 mM). After the reaction solution was stirred for 15 minutes, a solution of 2,2,5-trimethyl-3(2H)-furanone (30 g, 23.8 mM) in tetrahydrofuran (25 mL) was added dropwise. Hexamethylphosphoramide (6.4 mL, 34.7 mM) was then added dropwise after 30 minutes. Finally, p-methylthiobenzaldehyde (43 g, 28.5 mM) in tetrahydrofuran (25 mL) was added in one portion. The reaction solution was stirred 15 minutes when trifluoroacetic anhydride (10.5 mL, 75 mM) was added in one portion. Again, the reaction solution was stirred 15 minutes when triethylamine (5.9 mL, 48 mM) was added and was allowed to warm to room temperature. Then the reaction mixture was partitioned between saturated aqueous sodium chloride (50 mL) and diethyl ether (50 mL). The organic layer was separated and washed with saturated aqueous sodium bicarbonate (2×25 mL) and saturated aqueous sodium chloride (25 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give an amber liquid. The crude product was purified by chromatography (silica gel, pet. ether-ethyl acetate) to afford yellow crystals (3.0 g, 48% yield), m.p. 98°-99.5° C. was added in one portion was added Then the reaction mixture was partitioned between saturated aqueous sodium chloride (50 mL) and diethyl ether (50 mL) The organic layer was separated washed with saturated aqueous sodium bicarbonate (2×25 mL) and saturated aqueous sodium chloride (25 mL) The organic layer was dried over magnesium sulfate filtered concentrated under reduced pressure to give an amber liquid The crude product was purified by chromatography (silica gel, pet. ether-ethyl acetate)

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

Procedure: To a solution of dry diisopropylamine (5.0 mL, 35.7 mM) in dry tetrahydrofuran (150 mL) at -78° C., was added dropwise a 2.3N solution of n-butyllithium in hexane (15.5 mL, 35.7 mM). After the reaction solution was stirred for 15 minutes, a solution of 2,2,5-trimethyl-3(2H)-furanone (30 g, 23.8 mM) in tetrahydrofuran (25 mL) was added dropwise. Hexamethylphosphoramide (6.4 mL, 34.7 mM) was then added dropwise after 30 minutes. Finally, p-methylthiobenzaldehyde (43 g, 28.5 mM) in tetrahydrofuran (25 mL) was added in one portion. The reaction solution was stirred 15 minutes when trifluroacetic anhydride (10.5 mL, 75 mM) was added in one portion. Again, the reaction solution was stirred 15 minutes when triethylamine (5.9 mL, 48 mM) was added and was allowed to warm to room temperature. Then the reaction mixture was partitioned between saturated aqueous sodium chloride (50 mL) and diethyl ether (50 mL). The organic layer was separated and washed with saturated aqueous sodium bicarbonate (2×25 mL) and saturated aqueous sodium chloride (25 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give an amber liquid. The crude product was purified by chromatography (silica gel, pet. ether-ethyl acetate) to afford yellow crystals (3.0 g, 48% yield), m.p. 98°-99.5° C. was added in one portion was added Then the reaction mixture was partitioned between saturated aqueous sodium chloride (50 mL) and diethyl ether (50 mL) The organic layer was separated washed with saturated aqueous sodium bicarbonate (2×25 mL) and saturated aqueous sodium chloride (25 mL) The organic layer was dried over magnesium sulfate filtered concentrated under reduced pressure to give an amber liquid The crude product was purified by chromatography (silica gel, pet. ether-ethyl acetate)

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

Procedure: A stirred mixture consisting of 2.60 g (17.2 mmol) of 4-methylthiobenzaldehyde, 2.70 g (17.2 mmol) of benzenesulfonamide and 20 mg of p-toluenesulfonic acid monohydrate in 150 mL of toluene was heated to reflux. The reaction vessel was equipped with a Soxhlet extractor containing 4A molecular sieves. After heating 8 hours, the mixture was allowed to cool to room temperature and was concentrated to afford 4.60 g (92%) of sulfonimine as light tan crystals: mp 150°-155 ° C.; 1H NMR (CDCl3, TMS ext std) δ9.15 (s, 1), 8.27-7.18 (m, 9), 2.53 (s, 3). was heated to reflux The reaction vessel was equipped with a Soxhlet extractor After heating 8 hours was concentrated to afford 4.60 g (92%) of sulfonimine as light tan crystals

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

Procedure: To a solution of 4-bromothioanisole (1.06 g, 5.2 mmol) in THF (20 mL) at −78° C. was added BuLi (2.3M, hexane, 2.2 mL, 5 mmol) dropwise. After 30 min at −78° C., 4-methylthiobenzaldehyde (685 mg, 4.5 mmol) was added. After 20 min., the resulting reaction mixture was diluted with a saturated ammonium chloride solution and ethyl acetate. The organic extracts were washed (H2O, brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (eluting with hexane/ethyl acetate, 80:20) provided the bis-(4-methylsulfanyl-phenyl)-methanol compound. After 20 min. the resulting reaction mixture The organic extracts were washed (H2O, brine) dried (MgSO4) filtered concentrated Purification by flash chromatography (eluting with hexane/ethyl acetate, 80:20)

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

Procedure: A stirred mixture consisting of 2.60 g (17.2 mmol) of 4-methylthiobenzaldehyde, 2.70 g (17.2 mmol) cf benzenesulfonamide and 20 mg of p-toluenesulfonic acid monohydrate in 150 mL of toluene was heated to reflux. The reaction vessel was equipped with a Soxhlet extractor containing 4A molecular sieves. After heating 8 hours, the mixture was allowed to cool to room temperature and was concentrated to afford 4.60 g (92%) of sulfonimine as light tan crystals: mp 1.50°-155° C.; 1H NMR (CDCl3, TMS ext std) δ9.15 (s, 1), 8.27-7.18 (m, 9), 2.53 (s, 3). was heated to reflux The reaction vessel was equipped with a Soxhlet extractor After heating 8 hours was concentrated to afford 4.60 g (92%) of sulfonimine as light tan crystals

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

Procedure: A stirred mixture consisting of 2.60 g (17.2 mmol) of 4-methylthiobenzaldehyde, 2.70 g (17.2 mmol) cf benzenesulfonamide and 20 mg of p-toluenesulfonic acid monohydrate in 150 mL of toluene was heated to reflux. The reaction vessel was equipped with a Soxhlet extractor containing 4A molecular sieves. After heating 8 hours, the mixture was allowed to cool to room temperature and was concentrated to afford 4.60 g (92%) of sulfonimine as light tan crystals: mp 1.50°-155° C.; 1H NMR (CDCl3, TMS ext std) δ9.15 (s, 1), 8.27-7.18 (m, 9), 2.53 (s, 3). was heated to reflux The reaction vessel was equipped with a Soxhlet extractor After heating 8 hours was concentrated to afford 4.60 g (92%) of sulfonimine as light tan crystals

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

Procedure: This compound was synthesized from 2′-hydroxy-4′-ethyloxycarbonyldimethylmethyloxyacetophenone (starting material 1) and 4-methylthiobenzaldehyde according to general method 2 described earlier.

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

Procedure: This compound was synthesized from 2′-hydroxy-4′-ethyloxycarbonyldimethylmethyloxyacetophenone (starting material 1) and 4-methylthiobenzaldehyde according to general method 2 described earlier.