2-(4-chlorophenyl)-1-phenylethanone

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

Procedure: To a mixture of 2-(4-chlorophenyl)-1-phenylethanone (200 mg, 0.88 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (200 mg, 0.95 mmol), and urea (156 mg, 2.65 mmol) in anhydrous EtOH (20 mL) was added concentrated HCl solution (0.1 mL), and the reaction mixture was refluxed for three days. When TLC (EtOAc:MeOH=10:1) showed that about 50% of starting materials were consumed, the reaction mixture was concentrated, and the residue was purified by column chromatography (EtOAc:MeOH=40:1) and preparative HPLC to afford Compound 27 as a yellow solid (25 mg, yield: 6.25%). 1H NMR (DMSO-d6 400 MHz TMS): δ 10.30 (s, 1H), 8.81 (s, 1H), 7.60 (s, 1H), 7.45 (s, 1H), 7.25-7.30 (m, 3H), 7.17-7.24 (m, 3H), 7.10 (d, J=8.8 Hz, 2H), 6.80 (d, J=8.4 Hz, 2H), 5.20 (d, J=2.8 Hz, 1H), 4.00-4.11 (m, 2H), 1.33 (t, J=6.8 Hz, 3H); MS (ESI): m/z 466.0 [M+1]+. the reaction mixture was refluxed for three days were consumed the reaction mixture was concentrated the residue was purified by column chromatography (EtOAc:MeOH=40:1) and preparative HPLC

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

Procedure: 69 g (0.3 mol) of phenyl 4-chlorophenylmethyl ketone, 66.3 g (0.6 mol) of 3-chloropropane-1,2-diol and 5.2 g (0.03 mol) of p-toluenesulphonic acid in 600 ml of toluene are refluxed for three days in a water separator. The reaction mixture, when it is cold, is extracted with sodium bicarbonate solution, dried over sodium sulphate and evaporated down in vacuo. 95 g (98% of theory) of 4-chloromethyl-2-(4-chlorophenylmethyl)-2-phenyl-1,3-dioxolane of melting point 65° C. are obtained. is extracted with sodium bicarbonate solution dried over sodium sulphate evaporated down in vacuo

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

Procedure: To a mixture of 2-(4-chlorophenyl)-1-phenylethanone (200 mg, 0.88 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (200 mg, 0.95 mmol), and urea (156 mg, 2.65 mmol) in anhydrous EtOH (20 mL) was added concentrated HCl solution (0.1 mL), and the reaction mixture was refluxed for three days. When TLC (EtOAc:MeOH=10:1) showed that about 50% of starting materials were consumed, the reaction mixture was concentrated, and the residue was purified by column chromatography (EtOAc:MeOH=40:1) and preparative HPLC to afford Compound 27 as a yellow solid (25 mg, yield: 6.25%). 1H NMR (DMSO-d6 400 MHz TMS): δ 10.30 (s, 1H), 8.81 (s, 1H), 7.60 (s, 1H), 7.45 (s, 1H), 7.25-7.30 (m, 3H), 7.17-7.24 (m, 3H), 7.10 (d, J=8.8 Hz, 2H), 6.80 (d, J=8.4 Hz, 2H), 5.20 (d, J=2.8 Hz, 1H), 4.00-4.11 (m, 2H), 1.33 (t, J=6.8 Hz, 3H); MS (ESI): m/z 466.0 [M+1]+. the reaction mixture was refluxed for three days were consumed the reaction mixture was concentrated the residue was purified by column chromatography (EtOAc:MeOH=40:1) and preparative HPLC

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

Procedure: To a mixture of 2-(4-chlorophenyl)-1-phenylethanone (200 mg, 0.88 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (200 mg, 0.95 mmol), and urea (156 mg, 2.65 mmol) in anhydrous EtOH (20 mL) was added concentrated HCl solution (0.1 mL), and the reaction mixture was refluxed for three days. When TLC (EtOAc:MeOH=10:1) showed that about 50% of starting materials were consumed, the reaction mixture was concentrated, and the residue was purified by column chromatography (EtOAc:MeOH=40:1) and preparative HPLC to afford Compound 27 as a yellow solid (25 mg, yield: 6.25%). 1H NMR (DMSO-d6 400 MHz TMS): δ 10.30 (s, 1H), 8.81 (s, 1H), 7.60 (s, 1H), 7.45 (s, 1H), 7.25-7.30 (m, 3H), 7.17-7.24 (m, 3H), 7.10 (d, J=8.8 Hz, 2H), 6.80 (d, J=8.4 Hz, 2H), 5.20 (d, J=2.8 Hz, 1H), 4.00-4.11 (m, 2H), 1.33 (t, J=6.8 Hz, 3H); MS (ESI): m/z 466.0 [M+1]+. the reaction mixture was refluxed for three days were consumed the reaction mixture was concentrated the residue was purified by column chromatography (EtOAc:MeOH=40:1) and preparative HPLC

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

Procedure: To a solution of 2-(4-chlorophenyl)-1-phenyl-1-ethanone (2, 1.93 g, 8.37 mmol) in 25 ml pyridine (dried over molecular sieves) under nitrogen was added at room temperature methoxylamine hydrochloride (873 mg, 10.5 mmol). The resulting slightly cloudy, pale orange mixture was stirred at room temperature overnight. The pyridine was removed in vacuo with heating. The residual solids were stirred with ether (60 ml), isolated by filtration, and discarded. The filtrate was dried over sodium sulfate, and concentrated in vacuo to give a mixture of the oxime geometrical isomers as 2.00 g of a clear, pale yellow syrup (92% yield). 1H NMR showed the isomers to be formed in a 5:3 ratio: Rf 0.64, 0.50; IR (CDCl3) 3068 (w), 2940 (m), 2819 (w), 1602 (w), 1493 (s), 1442 (m); 1H NMR (CDCl3) 7.63 (m, 2H), 7.37-7.11 (m, 11.5 H), 4.12 (s, 2H), 4.05 (s, 3H), 3.91 (s, 1.6H), 3.82 (s, 1.2H); low resolution mass spec. 259 (M+, 8), 227 (100), 192 (28), 165 (18), 134 (12), 125 (62), 119 (37). The pyridine was removed in vacuo with heating The residual solids were stirred with ether (60 ml) isolated by filtration The filtrate was dried over sodium sulfate concentrated in vacuo to give

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

Procedure: To a suspension of aluminum chloride (1.27 g, 9.52 mmol) in 30 ml dry benzene under nitrogen was added at room temperature 4-chlorophenylacetyl chloride (1.80 g, 9.52 mmol) over a period of 30 minutes as a solution in 10 ml benzene. The resulting clear, pale yellow solution was refluxed for six hours. After cooling to room temperature, the resulting grey-brown solution was poured into 100 ml ice water. The layers were separated and the aqueous portion extracted with benzene (1×20 ml). The combined organic portions were washed with water (2×30 ml), 10% NaOH (1×30 ml), water (1×30 ml), and brine (1×30 ml), and dried over magnesium sulfate. Filtration through Celite afforded, after concentration in vacuo, 2.18 g of the ketone as a white crystalline solid (99% crude yield): Rf 0.46 (benzene); 1H NMR (CDCl3) 8.03 (d, J=7.2 Hz, 2H), 7.63-7.21 (m, 7H), 4.29 (s, 2H). A portion (ca. 1 g) of the ketone was recrystallized from 75 ml boiling pet. ether/ethanol (5:1) to give a fluffy white crystalline solid: m.p. 132.5-134.0° C. (lit. m.p. 135-136° C.; Loeshorn, C. H. et al., J. Org. Chem. 48:4409 (1983)). The resulting clear, pale yellow solution was refluxed for six hours The layers were separated the aqueous portion extracted with benzene (1×20 ml) The combined organic portions were washed with water (2×30 ml), 10% NaOH (1×30 ml), water (1×30 ml), and brine (1×30 ml) dried over magnesium sulfate Filtration through Celite afforded after concentration in vacuo, 2.18 g of the ketone as a white crystalline solid (99% crude yield) A portion (ca. 1 g) of the ketone was recrystallized from 75 ml to give a fluffy white crystalline solid

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

Procedure: To a suspension of aluminum chloride (1.27 g, 9.52 mmol) in 30 ml dry benzene under nitrogen was added at room temperature 4-chlorophenylacetyl chloride (1.80 g, 9.52 mmol) over a period of 30 minutes as a solution in 10 ml benzene. The resulting clear, pale yellow solution was refluxed for six hours. After cooling to room temperature, the resulting grey-brown solution was poured into 100 ml ice water. The layers were separated and the aqueous portion extracted with benzene (1×20 ml). The combined organic portions were washed with water (2×30 ml), 10% NaOH (1×30 ml), water (1×30 ml), and brine (1×30 ml), and dried over magnesium sulfate. Filtration through Celite afforded, after concentration in vacuo, 2.18 g of the ketone as a white crystalline solid (99% crude yield): Rf 0.46 (benzene); 1H NMR (CDCl3) 8.03 (d, J=7.2 Hz, 2H), 7.63-7.21 (m, 7H), 4.29 (s, 2H). A portion (ca. 1 g) of the ketone was recrystallized from 75 ml boiling pet. ether/ethanol (5:1) to give a fluffy white crystalline solid: m.p. 132.5-134.0° C. (lit. m.p. 135-136° C.; Loeshorn, C. H. et al., J. Org. Chem. 48:4409 (1983)). The resulting clear, pale yellow solution was refluxed for six hours The layers were separated the aqueous portion extracted with benzene (1×20 ml) The combined organic portions were washed with water (2×30 ml), 10% NaOH (1×30 ml), water (1×30 ml), and brine (1×30 ml) dried over magnesium sulfate Filtration through Celite afforded after concentration in vacuo, 2.18 g of the ketone as a white crystalline solid (99% crude yield) A portion (ca. 1 g) of the ketone was recrystallized from 75 ml to give a fluffy white crystalline solid

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

Procedure: A benzene solution containing 51.2 g 4-chlorophenylacetic acid and 39.3 g thionyl chloride is refluxed for 6 hours and the solvent removed. The crude reaction product is added dropwise to a slurry of 40 g aluminum chloride in 200 ml benzene maintaining the temperature below 50° C. After addition the reaction is refluxed for 1.5 hours. After cooling, the mixture is poured into ice and the resulting white solid is separated yielding 61.3 g of crude product. The product is taken up in methylene chloride and washed with 5% sodium hydroxide solution followed by water, dried over sodium sulfate and stripped yielding 49.3 g (71%) of >95% pure 4'-chlorodeoxybenzoin. 15 g of 4-chlorodeoxybenzoin is dissolved in 105 ml pyridine. An aqueous solution containing 15 g potassium permanganate is added and the reaction stirred for 6 hours at room temperature using dry ice to buffer the pH near 7. The mixture is extracted with methylene chloride, the extract washed with water, dried over Na2SO4 and stripped. The residue is recrystallized from ethanol yielding 6.1 g of white plate-like crystals which is identified as starting material. Concentration of the mother liquor yields 4 g of 4-chlorobenzil. is refluxed for 6 hours the solvent removed The crude reaction product After addition the reaction is refluxed for 1.5 hours After cooling the mixture is poured into ice the resulting white solid is separated yielding 61.3 g of crude product washed with 5% sodium hydroxide solution dried over sodium sulfate

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

Procedure: To a mixture of 2-(4-chlorophenyl)-1-phenylethanone (200 mg, 0.88 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (200 mg, 0.95 mmol), and urea (156 mg, 2.65 mmol) in anhydrous EtOH (20 mL) was added concentrated HCl solution (0.1 mL), and the reaction mixture was refluxed for three days. When TLC (EtOAc:MeOH=10:1) showed that about 50% of starting materials were consumed, the reaction mixture was concentrated, and the residue was purified by column chromatography (EtOAc:MeOH=40:1) and preparative HPLC to afford Compound 27 as a yellow solid (25 mg, yield: 6.25%). 1H NMR (DMSO-d6 400 MHz TMS): δ 10.30 (s, 1H), 8.81 (s, 1H), 7.60 (s, 1H), 7.45 (s, 1H), 7.25-7.30 (m, 3H), 7.17-7.24 (m, 3H), 7.10 (d, J=8.8 Hz, 2H), 6.80 (d, J=8.4 Hz, 2H), 5.20 (d, J=2.8 Hz, 1H), 4.00-4.11 (m, 2H), 1.33 (t, J=6.8 Hz, 3H); MS (ESI): m/z 466.0 [M+1]+. the reaction mixture was refluxed for three days were consumed the reaction mixture was concentrated the residue was purified by column chromatography (EtOAc:MeOH=40:1) and preparative HPLC

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

Procedure: To a mixture of 2-(4-chlorophenyl)-1-phenylethanone (200 mg, 0.88 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (200 mg, 0.95 mmol), and urea (156 mg, 2.65 mmol) in anhydrous EtOH (20 mL) was added concentrated HCl solution (0.1 mL), and the reaction mixture was refluxed for three days. When TLC (EtOAc:MeOH=10:1) showed that about 50% of starting materials were consumed, the reaction mixture was concentrated, and the residue was purified by column chromatography (EtOAc:MeOH=40:1) and preparative HPLC to afford Compound 27 as a yellow solid (25 mg, yield: 6.25%). 1H NMR (DMSO-d6 400 MHz TMS): δ 10.30 (s, 1H), 8.81 (s, 1H), 7.60 (s, 1H), 7.45 (s, 1H), 7.25-7.30 (m, 3H), 7.17-7.24 (m, 3H), 7.10 (d, J=8.8 Hz, 2H), 6.80 (d, J=8.4 Hz, 2H), 5.20 (d, J=2.8 Hz, 1H), 4.00-4.11 (m, 2H), 1.33 (t, J=6.8 Hz, 3H); MS (ESI): m/z 466.0 [M+1]+. the reaction mixture was refluxed for three days were consumed the reaction mixture was concentrated the residue was purified by column chromatography (EtOAc:MeOH=40:1) and preparative HPLC

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

Procedure: To a solution of 2-(4-chlorophenyl)-1-phenyl-1-ethanone (2, 1.93 g, 8.37 mmol) in 25 ml pyridine (dried over molecular sieves) under nitrogen was added at room temperature methoxylamine hydrochloride (873 mg, 10.5 mmol). The resulting slightly cloudy, pale orange mixture was stirred at room temperature overnight. The pyridine was removed in vacuo with heating. The residual solids were stirred with ether (60 ml), isolated by filtration, and discarded. The filtrate was dried over sodium sulfate, and concentrated in vacuo to give a mixture of the oxime geometrical isomers as 2.00 g of a clear, pale yellow syrup (92% yield). 1H NMR showed the isomers to be formed in a 5:3 ratio: Rf 0.64, 0.50; IR (CDCl3) 3068 (w), 2940 (m), 2819 (w), 1602 (w), 1493 (s), 1442 (m); 1H NMR (CDCl3) 7.63 (m, 2H), 7.37-7.11 (m, 11.5 H), 4.12 (s, 2H), 4.05 (s, 3H), 3.91 (s, 1.6H), 3.82 (s, 1.2H); low resolution mass spec. 259 (M+, 8), 227 (100), 192 (28), 165 (18), 134 (12), 125 (62), 119 (37). The pyridine was removed in vacuo with heating The residual solids were stirred with ether (60 ml) isolated by filtration The filtrate was dried over sodium sulfate concentrated in vacuo to give

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

Procedure: To a suspension of aluminum chloride (1.27 g, 9.52 mmol) in 30 ml dry benzene under nitrogen was added at room temperature 4-chlorophenylacetyl chloride 0.80 g, 9.52 mmol) over a period of 30 minutes as a solution in 10 ml benzene. The resulting clear, pale yellow solution was refluxed for six hours. After cooling to room temperature, the resulting grey-brown solution was poured into 100 ml ice water. The layers were separated and the aqueous portion extracted with benzene (1×20 ml). The combined organic portions were washed with water (2×30 ml), 10% NaOH (1×30 ml), water (1×30 ml), and brine (1×30 ml), and dried over magnesium sulfate. Filtration through Celite afforded, after concentration in vacuo, 2.18 g of the ketone as a white crystalline solid (99% crude yield): Rf 0.46 (benzene); 1H NMR (CDCl3) 8.03 (d, J=7.2 Hz, 2H), 7.63-7.21 (m, 7H), 4.29 (s, 2H). A portion (ca. 1 g) of the ketone was recrystallized from 75 mi boiling pet. ether/ethanol (5:1) to give a fluffy white crystalline solid: m.p. 132.5°-134.0° C. (lit. m.p. 135°-136° C.; Loeshorn, C. H. et al., J. Org. Chem. 48:4409 (1983)). The resulting clear, pale yellow solution was refluxed for six hours The layers were separated the aqueous portion extracted with benzene (1×20 ml) The combined organic portions were washed with water (2×30 ml), 10% NaOH (1×30 ml), water (1×30 ml), and brine (1×30 ml) dried over magnesium sulfate Filtration through Celite afforded after concentration in vacuo, 2.18 g of the ketone as a white crystalline solid (99% crude yield) A portion (ca. 1 g) of the ketone was recrystallized from 75 mi to give a fluffy white crystalline solid