diethoxyphosphorylmethylsulfonylbenzene

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

Procedure: Combine diethyl phenylsulphonylmethylphosphonate (T. A. Blumenkopf Synth. Commun. 26, 139-147, (1986)) (117.0 g, 400 mmol) and tetrahydrofuran (500 mL). Cool in an ice-bath. Add lithium bis(trimethylsilyl)amide (480 mL, 1M in tetrahydrofuran, 480 mmol). Stir for 30 minutes after the addition of lithium bis(trimethylsilyl)amide, then add methyl benzoylformate (72.0 g, 439 mmol). Warm to ambient temperature and stir for 2 hours. Partition between water and ethyl acetate. Extract the aqueous layer with ethyl acetate. Combine the organic layers, dry over magnesium sulfate and evaporate in vacuo to give an oil. Triturate with cyclohexane to give a solid. Chromatograph the solid on silica gel eluting sequentially with 10% ethyl acetate/hexane, 15% ethyl acetate/hexane, and 33% ethyl acetate/hexane. Evaporation of the product containing fractions give a solid. Recrystallize form ethyl acetate/hexane to give 2-phenyl-3-sulfonylphenyl-propenoic acid, methyl ester as a solid. Elem. Anal calculated for C16H14O4S: C, 63.56; H, 4.67. Found: C, 63.25; H, 4.70. Cool in an ice-bath stir for 2 hours Partition between water and ethyl acetate Extract the aqueous layer with ethyl acetate dry over magnesium sulfate evaporate in vacuo to give an oil Triturate with cyclohexane to give a solid Evaporation of the product containing fractions give a solid Recrystallize form ethyl acetate/hexane

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

Procedure: Combine diethyl phenylsulphonylmethylphosphonate (T. A. Blumenkopf Synth. Commun. 26, 139-147, (1986)) (117.0 g, 400 mmol) and tetrahydrofuran (500 mL). Cool in an ice-bath. Add lithium bis(trimethylsilyl)amide (480 mL, 1M in tetrahydrofuran, 480 mmol). Stir for 30 minutes after the addition of lithium bis(trimethylsilyl)amide, then add methyl benzoylformate (72.0 g, 439 mmol). Warm to ambient temperature and stir for 2 hours. Partition between water and ethyl acetate. Extract the aqueous layer with ethyl acetate. Combine the organic layers, dry over magnesium sulfate and evaporate in vacuo to give an oil. Triturate with cyclohexane to give a solid. Chromatograph the solid on silica gel eluting sequentially with 10% ethyl acetate/hexane, 15% ethyl acetate/hexane, and 33% ethyl acetate/hexane. Evaporation of the product containing fractions give a solid. Recrystallize form ethyl acetate/hexane to give 2-phenyl-3-sulfonylphenyl-propenoic acid, methyl ester as a solid. Elem. Anal calculated for C16H14O4S: C, 63.56; H, 4.67. Found: C, 63.25; H, 4.70. Cool in an ice-bath stir for 2 hours Partition between water and ethyl acetate Extract the aqueous layer with ethyl acetate dry over magnesium sulfate evaporate in vacuo to give an oil Triturate with cyclohexane to give a solid Evaporation of the product containing fractions give a solid Recrystallize form ethyl acetate/hexane

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

Procedure: Magnesium chloride (dry, 3.16 g, 33.2 mmol) was put in a flask under a nitrogen atmosphere and acetonitrile (100 mL) was added. The mixture was stirred for five minutes at room temperature. Diethyl [(phenylsulfonyl)methyl]phosphonate (10.0 g, 89% purity, 30.4 mmol) was added. After 5 minutes stirring the magnesium chloride was nearly dissolved. Triethylamine (5.01 mL, 35.9 mmol) was added and after 10 minutes at room temperature a yellow solution was obtained. Then 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanone (6.89 mg, 98% purity, 27.7 mmol) was added. After stirring for one hour additional magnesium chloride (0.1 eq.) and triethylamine (0.1 eq.) were added and the mixture was stirred for additional 30 minutes. Then, additional triethylamine (0.1 eq.) was added. Water (100 mL) and ethyl acetate (200 mL) were added and the phases were separated. After extracting the aqueous phase twice with ethyl acetate (100 mL) the combined organic phases were washed three times with water (100 mL), three times with saturated sodium bicarbonate solution (100 mL), dried over sodium sulfate, filtered and the solvents evaporated. The yellow oil was recrystallized from n-heptane. 2-(3,5-dichlorophenyl)-3,3,3-trifluoroprop-1-en-1-yl phenyl sulfone was obtained (10.5 g, 97% purity, 98% yield, E/Z (not assigned)=64/36). was nearly dissolved was obtained were added the mixture was stirred for additional 30 minutes the phases were separated After extracting the aqueous phase twice with ethyl acetate (100 mL) the combined organic phases were washed three times with water (100 mL), three times with saturated sodium bicarbonate solution (100 mL) dried over sodium sulfate filtered the solvents evaporated The yellow oil was recrystallized from n-heptane

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

Procedure: Magnesium chloride (dry, 3.16 g, 33.2 mmol) was put in a flask under a nitrogen atmosphere and acetonitrile (100 mL) was added. The mixture was stirred for five minutes at room temperature. Diethyl [(phenylsulfonyl)methyl]phosphonate (10.0 g, 89% purity, 30.4 mmol) was added. After 5 minutes stirring the magnesium chloride was nearly dissolved. Triethylamine (5.01 mL, 35.9 mmol) was added and after 10 minutes at room temperature a yellow solution was obtained. Then 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanone (6.89 mg, 98% purity, 27.7 mmol) was added. After stirring for one hour additional magnesium chloride (0.1 eq.) and triethylamine (0.1 eq.) were added and the mixture was stirred for additional 30 minutes. Then, additional triethylamine (0.1 eq.) was added. Water (100 mL) and ethyl acetate (200 mL) were added and the phases were separated. After extracting the aqueous phase twice with ethyl acetate (100 mL) the combined organic phases were washed three times with water (100 mL), three times with saturated sodium bicarbonate solution (100 mL), dried over sodium sulfate, filtered and the solvents evaporated. The yellow oil was recrystallized from n-heptane. 2-(3,5-dichlorophenyl)-3,3,3-trifluoroprop-1-en-1-yl phenyl sulfone was obtained (10.5 g, 97% purity, 98% yield, E/Z (not assigned)=64/36). was nearly dissolved was obtained were added the mixture was stirred for additional 30 minutes the phases were separated After extracting the aqueous phase twice with ethyl acetate (100 mL) the combined organic phases were washed three times with water (100 mL), three times with saturated sodium bicarbonate solution (100 mL) dried over sodium sulfate filtered the solvents evaporated The yellow oil was recrystallized from n-heptane

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

Procedure: Sodium hydride (40 mg (60%), 1.09 eq) was added to a solution of diethyl phenylsulfonylmethylphosphonate (0.279 g, 1.09 eq) in dry THF (5.6 ml) at O° C. The mixture was stirred for 20 minutes before adding, drop-wise, a solution of Boc-L-Asp(O-t-Bu)-H (0.24 g, 0.876 mmol) in 1.6 ml of THF. The mixture was stirred for 1.15 h at RT, then poured into a mix of ethyl acetate and ammonium chloride saturated solution (45/15 ml). The organic layer was dried over magnesium sulfate and the solvent was evaporated to dryness. The crude material was purified on silica gel (gradient: ethyl acetate/hexane) to make the desired compound with a high chemical yield. before adding The mixture was stirred for 1.15 h at RT poured into The organic layer was dried over magnesium sulfate the solvent was evaporated to dryness The crude material was purified on silica gel (gradient: ethyl acetate/hexane) yield

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

Procedure: Boc-D-Phe-VS-Ph was prepared by reaction of Boc-D-Phe-H with diethyl phenylsulfonylmethanephosphonate in the presence of 2 N sodium methoxide, yield 85%. 1H-NMR (CDCl3) δ 1.3-1.4 (s, 9H, Boc), 2.9 (d, 2H, CH2-Phe), 4.4-4.5 (b, 1H, α-H), 4.6-4.7 (b, 1H, NH), 6.3 (d, 1H, CH═), 6.9-7.0 (dd, 1H, CH═), 7.1-7.3 (m, 5H, Ph), 7.5-7.8 (m, 5H, SO2-Ph). MS (FAB+) m/z 388 (M+1, 15%), 288 (M−Boc+1, 100%). Boc-D-Phe-VS-Ph was deblocked with 6.7 N HCl in EtOAc to give D-Phe-VS-Ph.HCl, yield 88%. 1H-NMR (DMSO-d6) δ 2.9-3.0 (m, 1H, CH2-Phe), 3.1-3.2 (m, 1H), 4.2 (b, 1H, α-H), 6.7-6.8 (m, 2H, CH═), 7.1-7.3 (m, 6H, CH═ and Ph), 7.6-7.8 (m, 5H, SO2-Ph), 8.6-8.8 (b, 2H, NH2). MS (FAB+) m/z 288 (M−Cl, 100%).

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

Procedure: Boc-Phe-VS-Ph was prepared by reaction of Boc-Phe-H with diethyl phenylsulfonylmethanephosphonate in the presence of 2 N sodium methoxide, yield 85%. 1H-NMR (CDCl3) δ 1.3-1.4 (s, 9H, Boc), 2.9 (d, 2H, CH2-Phe), 4.4-4.5 (b, 1H, α-H), 4.6-4.7 (b, 1H, NH), 6.3 (d, 1H, CH═), 6.9-7.0 (dd, 1H, CH═), 7.1-7.3 (m, 5H, Ph), 7.5-7.8 (m, 5H, SO2-Ph). MS (FAB+) m/z 388 (M+1, 15%), 288 (M−Boc+1, 100%). Boc-Phe-VS-Ph was deblocked with 6.7 N HCl in EtOAc to give Phe-VS-Ph.HCl, yield 88%. 1H-NMR (DMSO-d6) δ 2.9-3.0 (m, 1H, CH2-Phe), 3.1-3.2 (m, 1H, CH2-Phe), 4.2 (b, 1H, α-H), 6.7-6.8 (m, 2H, CH═), 7.1-7.3 (m, 6H, CH═ and Ph), 7.6-7.8 (m, 5H, SO2-Ph), 8.6-8.8 (b, 2H, NH2). MS (FAB+) m/z 288 (M−Cl, 100%).

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

Procedure: Boc-Phe-VS-Ph was prepared by reaction of Boc-Phe-H with diethyl phenylsulfonylmethanephosphonate in the presence of 2 N sodium methoxide, yield 85%. 1H-NMR (CDCl3) δ 1.3-1.4 (s, 9H, Boc), 2.9 (d, 2H, CH2-Phe), 4.4-4.5 (b, 1H, α-H), 4.6-4.7 (b, 1H, NH), 6.3 (d, 1H, CH═), 6.9-7.0 (dd, 1H, CH═), 7.1-7.3 (m, 5H, Ph), 7.5-7.8 (m, 5H, SO2-Ph). MS (FAB+) m/z 388 (M+1, 15%), 288 (M−Boc+1, 100%). Boc-Phe-VS-Ph was deblocked with 6.7 N HCl in EtOAc to give Phe-VS-Ph.HCl, yield 88%. 1H-NMR (DMSO-d6) δ 2.9-3.0 (m, 1H, CH2-Phe), 3.1-3.2 (m, 1H, CH2-Phe), 4.2 (b, 1H, α-H), 6.7-6.8 (m, 2H, CH═), 7.1-7.3 (m, 6H, CH═ and Ph), 7.6-7.8 (m, 5H, SO2-Ph), 8.6-8.8 (b, 2H, NH2). MS (FAB+) m/z 288 (M−Cl, 100%).

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

Procedure: Sodium hydride (40 mg (60%), 1.09 eq) was added to a solution of diethyl phenylsulfonylmethylphosphonate (0.279 g, 1.09 eq) in dry THF (5.6 ml) at 0° C. The mixture was stirred for 20 minutes before adding, drop-wise, a solution of Boc-L-Asp(O-t-Bu)-H (0.24 g, 0.876 mmol) in 1.6 ml of THF. The mixture was stirred for 1.15 h at RT, then poured into a mix of ethyl acetate and ammonium chloride saturated solution (45/15 ml). The organic layer was dried over magnesium sulfate and the solvent was evaporated to dryness. The crude material was purified on silica gel (gradient: ethyl acetate/hexane) to make the desired compound with a high chemical yield. before adding The mixture was stirred for 1.15 h at RT poured into The organic layer was dried over magnesium sulfate the solvent was evaporated to dryness The crude material was purified on silica gel (gradient: ethyl acetate/hexane) yield

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred solution of methyl phenyl sulfone (20 g, 0.128 mol) in dry THF (200 mL) was cooled at −78° C. in an acetone/dry ice bath. Lithium bis(trimethylsilyl)amide (Li HMDS; 134 mL, 1 M solution in THF, 0.134 mol) was added dropwise over 1 h. The resulting white suspension was stirred for an additional hour at −78° C. and diethyl chlorophosphate (18.5 mL, 128 mmol) in THF (20 mL) was added. The reaction mixture was stirred at −78° C. for 0.5 h, then allowed to slowly warm to room temperature and left stirring for 4 h. The reaction mixture was next concentrated under reduced pressure, the residue was dissolved in EA (500 mL), washed with brine (100 mL),dried over anhydrous Na2CO3 and concentrated under reduced pressure. The resultant crude material was purified by flash chromatography on silica gel (EA:H, 3:1 to 1:1) to afford the desired product as white solid (17.9 g, 48%). The reaction mixture was stirred at −78° C. for 0.5 h to slowly warm to room temperature left stirring for 4 h The reaction mixture was next concentrated under reduced pressure the residue was dissolved in EA (500 mL) washed with brine (100 mL),dried over anhydrous Na2CO3 concentrated under reduced pressure The resultant crude material was purified by flash chromatography on silica gel (EA:H, 3:1 to 1:1)

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

Procedure: Combine diethyl phenylsulphonylmethylphosphonate (T. A. Blumenkopf Synth. Commun. 26, 139-147, (1986)) (117.0 g, 400 mmol) and tetrahydrofuran (500 mL). Cool in an ice-bath. Add lithium bis(trimethylsilyl)amide (480 mL, 1M in tetrahydrofuran, 480 mmol). Stir for 30 minutes after the addition of lithium bis(trimethylsilyl)amide, then add methyl benzoylformate (72.0 g, 439 mmol). Warm to ambient temperature and stir for 2 hours. Partition between water and ethyl acetate. Extract the aqueous layer with ethyl acetate. Combine the organic layers, dry over magnesium sulfate and evaporate in vacuo to give an oil. Triturate with cyclohexane to give a solid. Chromatograph the solid on silica gel eluting sequentially with 10% ethyl acetate/hexane, 15% ethyl acetate/hexane, and 33% ethyl acetate/hexane. Evaporation of the product containing fractions give a solid. Recrystallize form ethyl acetate/hexane to give 2-phenyl-3-sulfonylphenyl-propenoic acid, methyl ester as a solid. Elem. Anal calculated for C16H14O4S: C, 63.56; H, 4.67. Found: C, 63.25; H, 4.70. Cool in an ice-bath stir for 2 hours Partition between water and ethyl acetate Extract the aqueous layer with ethyl acetate dry over magnesium sulfate evaporate in vacuo to give an oil Triturate with cyclohexane to give a solid Evaporation of the product containing fractions give a solid Recrystallize form ethyl acetate/hexane

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

Procedure: Magnesium chloride (dry, 3.16 g, 33.2 mmol) was put in a flask under a nitrogen atmosphere and acetonitrile (100 mL) was added. The mixture was stirred for five minutes at room temperature. Diethyl [(phenylsulfonyl)methyl]phosphonate (10.0 g, 89% purity, 30.4 mmol) was added. After 5 minutes stirring the magnesium chloride was nearly dissolved. Triethylamine (5.01 mL, 35.9 mmol) was added and after 10 minutes at room temperature a yellow solution was obtained. Then 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanone (6.89 mg, 98% purity, 27.7 mmol) was added. After stirring for one hour additional magnesium chloride (0.1 eq.) and triethylamine (0.1 eq.) were added and the mixture was stirred for additional 30 minutes. Then, additional triethylamine (0.1 eq.) was added. Water (100 mL) and ethyl acetate (200 mL) were added and the phases were separated. After extracting the aqueous phase twice with ethyl acetate (100 mL) the combined organic phases were washed three times with water (100 mL), three times with saturated sodium bicarbonate solution (100 mL), dried over sodium sulfate, filtered and the solvents evaporated. The yellow oil was recrystallized from n-heptane. 2-(3,5-dichlorophenyl)-3,3,3-trifluoroprop-1-en-1-yl phenyl sulfone was obtained (10.5 g, 97% purity, 98% yield, E/Z (not assigned)=64/36). was nearly dissolved was obtained were added the mixture was stirred for additional 30 minutes the phases were separated After extracting the aqueous phase twice with ethyl acetate (100 mL) the combined organic phases were washed three times with water (100 mL), three times with saturated sodium bicarbonate solution (100 mL) dried over sodium sulfate filtered the solvents evaporated The yellow oil was recrystallized from n-heptane