(1S)-3-chloro-1-phenylpropan-1-ol

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

Procedure: Commercially available (S)-3-chloro-1-phenyl-1-propanol (6 g) was heated with excess sodium iodide (4 equiv., 18 g) and a few drops of triethylamine in 30 mL of methyl ethyl ketone at 100° C. for 20 h. A sample was taken and monitored by NMR to determine the extent of conversion. The solvent was removed in vacuo and the residue was taken up in dichloromethane and filtered to remove the salts and the iodoalcohol was purified by flash chromatography to yield 6.9 g of product. The solvent was removed in vacuo filtered to remove the salts the iodoalcohol was purified by flash chromatography

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Following a similar procedure for the chiral synthesis of fluoxetine [Srebnik, M. et al., J. Org. Chem. 53(13), 2916-20 (1938), hereby incorporated by reference herein], a solution of (S)-(−)3-chloro-1-phenyl-1-propanol (4.00 g, 23.4 mmol), 3-fluorophenol (2-63 g, 23.4 mmol), and diethyl azodicarboxylate (4.00 g, 23.4 mmol) were dissolved in THF (200 mL). The mixture was cooled to 0° C. and triphenylphosphine (6.77 g, 25.8 mmol, 1.1 equiv) was added slowly over 10 min. The reaction mixture was then stirred at room temperature for 18 h. The THF was subsequently evaporated under vacuum to afford a gel which was washed with pentane (3×50 mL). The pentane washings were filtered and the filtrate was evaporated under vacuum to give a clear oil. This oil was dissolved in diethyl ether (150 mL) and washed with 1% HCl-satd. NaCl (25 mL), 0.1N NaOH-satd. NaCl (2×25 mL), and finally H2O (2×25 mL). The organic layer was then dried (anh. Na2SO4), filtered, and evaporated to dryness under vacuum to give an orange oil. The crude product was chromatographed on silica gel (25×180 mm, gravity column), elution with 40:1 hexane-EtOAc, to provide 971 mg (15.7%) of product as a colorless oil. The THF was subsequently evaporated under vacuum to afford a gel which was washed with pentane (3×50 mL) The pentane washings were filtered the filtrate was evaporated under vacuum to give a clear oil washed with 1% HCl-satd The organic layer was then dried (anh. Na2SO4) filtered evaporated to dryness under vacuum to give an orange oil The crude product was chromatographed on silica gel (25×180 mm, gravity column), elution with 40:1 hexane-EtOAc

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Following a similar procedure for the chiral synthesis of fluoxetine [Srebnik, M. et al., J. Org. Chem. 53(13), 2916-20 (1988), hereby incorporated by reference herein], a solution of (S)-(−)3-chloro-1-phenyl-1-propanol (4.00 g, 23.4 mmol), 3-fluorophenol (2.63 g, 23.4 mmol), and diethyl azodicarboxylate (4.00 g, 23.4 mmol) were dissolved in THF (200 mL). The mixture was cooled to 0° C. and triphenylphosphine (6.77 g, 25.8 mmol, 1.1 equiv) was added slowly over 10 min. The reaction mixture was then stirred at room temperature for 18 h. The THF was subsequently evaporated under vacuum to afford a gel which was washed with pentane (3×50 mL). The pentane washings were filtered and the filtrate was evaporated under vacuum to give a clear oil. This oil was dissolved in diethyl ether (150 mL) and washed with 1% HCl-satd. NaCl (25 mL), 0.1N NaOH-satd. NaCl (2×25 mL), and finally H2O (2×25 mL). The organic layer was then dried (anh. Na2SO4), filtered, and evaporated to dryness under vacuum to give an orange oil. The crude product was chromatographed on silica gel (25×180 mm, gravity column), elution with 40:1 hexane-EtOAc, to provide 971 mg (15.7%) of product as a colorless oil. The THF was subsequently evaporated under vacuum to afford a gel which was washed with pentane (3×50 mL) The pentane washings were filtered the filtrate was evaporated under vacuum to give a clear oil washed with 1% HCl-satd The organic layer was then dried (anh. Na2SO4) filtered evaporated to dryness under vacuum to give an orange oil The crude product was chromatographed on silica gel (25×180 mm, gravity column), elution with 40:1 hexane-EtOAc

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

Procedure: Commerically available (S)-3-chloro-1-phenyl-1-propanol (6 g) was heated with excess sodium iodide (4 equiv., 18 g) and a few drops of triethylamine in 30 mL of methyl ethyl ketone at 100° C. for 20 hours. A sample was taken and monitored by NMR to determine the extent of conversion. The solvent was removed in vacuo and the residue was taken up in dichloromethane and filtered to remove the salts and the iodoalcohol was purified by flash chromatography to yield 6.9 g of product. The solvent was removed in vacuo filtered to remove the salts the iodoalcohol was purified by flash chromatography

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

Procedure: Commerically available (S)-3-chloro-1-phenyl-1-propanol (6 g) was heated with excess sodium iodide (4 equiv., 18 g) and a few drops of triethylamine in 30 mL of methyl ethyl ketone at 100° C. for 20 hours. A sample was taken and monitored by NMR to determine the extent of conversion. The solvent was removed in vacuo and the residue was taken up in dichloromethane and filtered to remove the salts and the iodoalcohol was purified by flash chromatography to yield 6.9 g of product. The solvent was removed in vacuo filtered to remove the salts the iodoalcohol was purified by flash chromatography

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

Procedure: The compound [R]-(+)-1-chloro-3-phenyl-3-(4-iodo-2-methylphenoxy)propane (Compound 5) was prepared in the same manner as for the preparation of Compound 2 in Example 1, but using [S]-3-chloro-1-phenylpropanol (1.0 g, 5.88 mmol), 4-iodo-2-methylphenol (1.38 g, 5.88 mmol), triphenylphosphine (1.54 g, 5.88 mmol), and ethyl azodicarboxylate (0.93 mL, 1.04 g, 5.88 mmol) in THF (15 mL) at room temperature for 15 hours. Workup and purification gave 1.60 g (70%) of Compound 5 as a thick pale yellow liquid: [απ25D +14.02 (c 7.7, CHCL3); 1H NMR (CDCl3, 250 MHz) δ 7.41-7.20 (m, 7H), 6.39 (d, J=8.8 Hz, 1H), 5.34 (dd, J=4.4, 8.8 Hz, 1H), 3.81-3 72 (m, 1H), 3.63-3.55 (m, 1H), 2.55-2.41 (m, 1H), 2.31-2.16 (m, 1H), 2.7 (s, 3H); FTIR (neat) 3080, 3020, 2970, 2915, 1585, 1485(s), 1450, 1390, 1360, 1290, 1245(s), 1180, 1130 cm-1. Anal. C17H20INO: C,H. at room temperature for 15 hours Workup and purification

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

Procedure: The compound [R]-(+)-1-chloro-3-phenyl-3-(4-iodo-2-methylphenoxy)propane (Compound 5) was prepared in the same manner as for the preparation of Compound 2 in Example 1, but using [S]-3-chloro-1-phenylpropanol (1.0 g, 5.88 mmol), 4-iodo-2-methylphenol (1.38 g, 5.88 mmol), triphenylphosphine (1.54 g, 5.88 mmol), and ethyl azodicarboxylate (0.93 mL, 1.04 g, 5.88 mmol) in THF (15 mL) at room temperature for 15 hours. Workup and purification gave 1.60 g (70%) of Compound 5 as a thick pale yellow liquid: [απ25D +14.02 (c 7.7, CHCL3); 1H NMR (CDCl3, 250 MHz) δ 7.41-7.20 (m, 7H), 6.39 (d, J=8.8 Hz, 1H), 5.34 (dd, J=4.4, 8.8 Hz, 1H), 3.81-3 72 (m, 1H), 3.63-3.55 (m, 1H), 2.55-2.41 (m, 1H), 2.31-2.16 (m, 1H), 2.7 (s, 3H); FTIR (neat) 3080, 3020, 2970, 2915, 1585, 1485(s), 1450, 1390, 1360, 1290, 1245(s), 1180, 1130 cm-1. Anal. C17H20INO: C,H. at room temperature for 15 hours Workup and purification

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

Procedure: A solution of 3-chloropropiophenone (8.93 g, 50 mmol in 25 ml THF) was added to (-) diisopinocampheylchloroborane (Ipc2BCl, 18.0 g, 56 mmole, in 25 ml THF at -24° C.). The reaction was complete within 7 hours after which all volatiles were removed under reduced pressure. The residue was dissolved in ether, and diethanolamine (2 equivalents) was added. The resulting suspension was stirred for two hours and filtered. The solid residue was washed with ether and the combined wasings and filtrate were concentrated. Distillation furnished [S]-(-)-3-chloro-1-phenyl-1-propanol. Yield: 6.1 g, 72%; mp 56°-57° C.; [α]D23 25.25, c=7.05, CHCl3 ; 97% ee. after which all volatiles were removed under reduced pressure The residue was dissolved in ether filtered The solid residue was washed with ether the combined wasings and filtrate were concentrated Distillation

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Following a similar procedure for the chiral synthesis of fluoxetine [Srebnik, M. et al., J. Org. Chem. 25 53(13), 2916-20 (1988), hereby incorporated by reference herein], a solution of (S)-(−)3-chloro-1-phenyl-1-propanol (4.00 g, 23.4 mmol), 3-fluorophenol (2.63 g, 23.4 mmol), and diethyl azodicarboxylate (4.00 g, 23.4 mmol) were dissolved in THF (200 mL). The mixture was cooled to 0° C. and triphenylphosphine (6.77 g, 25.8 mmol, 1.1 equiv) was added slowly over 10 min. The reaction mixture was then stirred at room temperature for 18 h. The THF was subsequently evaporated under vacuum to afford a gel which was washed with pentane (3×50 mL). The pentane washings were filtered and the filtrate was evaporated under vacuum to give a clear oil. This oil was dissolved in diethyl ether (150 mL) and washed with 1% HCl-satd. NaCl (25 mL), 0.1N NaOH-satd. NaCl (2×25 mL), and finally H2O (2×25 mL). The organic layer was then dried (anh. Na2SO4), filtered, and evaporated to dryness under vacuum to give an orange oil. The crude product was chromatographed on silica gel (25×180 mm, gravity column), elution with 40:1 hexane-EtOAc, to provide 971 mg (15.7%) of product as a colorless oil. The THF was subsequently evaporated under vacuum to afford a gel which was washed with pentane (3×50 mL) The pentane washings were filtered the filtrate was evaporated under vacuum to give a clear oil washed with 1% HCl-satd The organic layer was then dried (anh. Na2SO4) filtered evaporated to dryness under vacuum to give an orange oil The crude product was chromatographed on silica gel (25×180 mm, gravity column), elution with 40:1 hexane-EtOAc

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 8 ml of DMF and 0.44 g of 60% sodium hydride in mineral oil at 5° C. in an ice bath was added dropwise a solution of 1.44 g of 1-naphthol in 8 ml of DMF. The reaction mixture was stirred at 5° C. for two hours and a solution of 1.71 g of (S)-(-)-3-chloro-1-phenyl-1-propanol in 5 ml of DMF was added. After stirring overnight at room temperature, the reaction mixture was poured into 150 ml of water and extracted with ethyl acetate (3×50 ml). The combined extracts were combined and washed with water and 1N sodium hydroxide solution and dried over sodium sulfate. Yield: 2.56 g (92%). The crude product can be recrystallized from 95:5 hexane/ethyl acetate to give 1.5 g (54%) of purified (S)-(+)-3-(1-naphthalenyloxy)-1-phenyl-1-propanol, mp 76°-78° C. After stirring overnight at room temperature extracted with ethyl acetate (3×50 ml) washed with water and 1N sodium hydroxide solution dried over sodium sulfate The crude product can be recrystallized from 95:5 hexane/ethyl acetate

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 8 ml of DMF and 0.44 g of 60% sodium hydride in mineral oil at 5° C. in an ice bath was added dropwise a solution of 1.44 g of 1-naphthol in 8 ml of DMF. The reaction mixture was stirred at 5° C. for two hours and a solution of 1.71 g of (S)-(-)-3-chloro-1-phenyl-1-propanol in 5 ml of DMF was added. After stirring overnight at room temperature, the reaction mixture was poured into 150 ml of water and extracted with ethyl acetate (3×50 ml). The combined extracts were combined and washed with water and 1N sodium hydroxide solution and dried over sodium sulfate. Yield: 2.56 g (92%). The crude product can be recrystallized from 95:5 hexane/ethyl acetate to give 1.5 g (54%) of purified (S)-(+)-3-(1-naphthalenyloxy)-1-phenyl-1-propanol, mp 76°-78° C. After stirring overnight at room temperature extracted with ethyl acetate (3×50 ml) washed with water and 1N sodium hydroxide solution dried over sodium sulfate The crude product can be recrystallized from 95:5 hexane/ethyl acetate

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

Procedure: Commercially available (S)-3-chloro-1-phenyl-1-propanol (6 g) was heated with excess sodium iodide (4 equiv., 18 g) and a few drops of triethylamine in 30 mL of methyl ethyl ketone at 100° C. for 20 h. A sample was taken and monitored by NMR to determine the extent of conversion. The solvent was removed in vacuo and the residue was taken up in dichloromethane and filtered to remove the salts and the iodoalcohol was purified by flash chromatography to yield 6.9 g of product. The solvent was removed in vacuo filtered to remove the salts the iodoalcohol was purified by flash chromatography