methyl 3-(2-hydroxyphenyl)-3-oxopropanoate

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

Procedure: A mixture of methyl 3-(2-hydroxyphenyl)-3-oxopropanoate (prepared according to Cushman, M. et al., J. Med. Chem. 1991, 34, 798; 500 mg, 2.56 mmol) and 3,4-dichlorobenzaldehyde (496 mg, 2.83 mmol) in isopropanol (5.0 mL) was treated with piperidine (25 μl, 257 μmol) and acetic acid (15 μl, 257 μmol) and then heated to reflux for 20 h. At the conclusion of this period, the mixture was cooled on ice, causing a gum to separate from the solution. The mixture was treated with a small amount of water and heated until homogeneous. On slow cooling to rt, a solid formed, which was collected by filtration and dried under vacuum to provide racemic methyl 2-(3,4-dichlorophenyl)-4-oxochroman-3-carboxylate as an off-white powder (496 mg, 55%). An additional sample (57 mg, 6%) was obtained by partial concentration of the filtrate. The NMR indicated predominantly the enolic form. 1H NMR (400 MHz, CDCl3) δ ppm 3.78 (s, 3 H) 6.18 (s, 1 H) 6.81 (dd, J=8.1, 1.0 Hz, 1H) 6.99 (td, J=7.4, 1.0 Hz, 1 H) 7.19 (dd, J=8.4, 1.8 Hz, 1 H) 7.31 (m, 1 H) 7.34 (d, J=8.1 Hz, 1 H) 7.43 (d, J=2.0 Hz, 1 H) 7.69 (dd, J=7.9, 1.8 Hz, 1 H) 12.28 (br. s, 1H). High resolution mass spectrum m/z found 373.0016, calcd 373.0010 (M+Na)+. heated to reflux for 20 h At the conclusion of this period, the mixture was cooled on ice to separate from the solution The mixture was treated with a small amount of water heated until homogeneous a solid formed which was collected by filtration dried under vacuum

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

Procedure: A mixture of methyl 3-(2-hydroxyphenyl)-3-oxopropanoate (prepared according to Cushman, M. et al., J. Med. Chem. 1991, 200 mg, 1.03 mmol) and 4-chloro-3-(trifluoromethyl)benzaldehyde (148 μL, 1.03 mmol) in isopropanol (4.0 mL) was treated with piperidine (10 μL, 103 μmol) and acetic acid (5.9 μL, 103 μmol) and heated to reflux for 16.5 h. After this time, water (2.0 mL) was added and the solution was slowly cooled to rt, whereupon crystals formed. After standing at rt, the mixture was cooled on ice, and the resulting crystals were collected by filtration and dried to provide methyl 2-(4-chloro-3-(trifluoromethyl)phenyl)-4-oxochroman-3-carboxylate as a white crystalline solid (204 mg, 51%). A second crop (47 mg) was obtained from the mother liquor, raising the total yield to 63%. The NMR indicated predominantly the enolic form. 1H NMR (500 MHz, CDCl3) δ ppm 3.79 (s, 3 H) 6.24 (s, 1 H) 6.82 (d, J=8.2 Hz, 1 H) 7.00 (t, J=7.7 Hz, 1 H) 7.31 (t, J=6.9 Hz, 1 H) 7.42 (m, 2 H) 7.70 (m, 2 H) 12.27 (br. s, 1 H). Mass spectrum m/z 407.19, 409.18 (M+Na)+. heated to reflux for 16.5 h formed After standing at rt the mixture was cooled on ice the resulting crystals were collected by filtration dried

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

Procedure: A mixture of methyl 3-(2-hydroxyphenyl)-3-oxopropanoate (prepared according to Cushman, M. et al., J. Med. Chem. 1991, 34, 798; 250 mg, 1.29 mmol) and 3-chlorobenzaldehyde (146 μL, 1.29 mmol) in isopropanol (5.0 mL) was treated with piperidine (13 μL, 129 μmol) and acetic acid (7.4 μL, 129 μmol) and heated to reflux for 17 h. After this time, the mixture was cooled to rt. The cooled solution was concentrated under vacuum and the resulting residue was purified by rotary TLC, eluting with 9:1 hexane-ethyl acetate, to provide a colorless gum. The colorless gum was crystallized from a hot isopropanol/water solution to provide methyl 2-(3-chlorophenyl)-4-oxochroman-3-carboxylate as an off-white solid (173 mg, 42%). The NMR indicated predominantly the enolic form. 1H NMR (400 MHz, CDCl3) δ ppm 3.78 (s, 3 H) 6.21 (s, 1 H) 6.82 (d, J=8.1 Hz, 1 H) 6.97 (t, J=7.9 Hz, 1 H) 7.18-7.32 (m, 4 H) 7.34 (m, 1 H) 7.69 (dd, J=7.9, 1.8 Hz, 1 H) 12.28 (br. s, 1 H). High resolution mass spec (M+H)+ calc. 317.0581, found 317.0597. heated to reflux for 17 h The cooled solution was concentrated under vacuum the resulting residue was purified by rotary TLC eluting with 9:1 hexane-ethyl acetate to provide a colorless gum The colorless gum was crystallized from a hot isopropanol/water solution

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

Procedure: A mixture of methyl 3-(2-hydroxyphenyl)-3-oxopropanoate (prepared according to Cushman, M. et al., J. Med. Chem. 1991, 34, 798; 500 mg, 2.56 mmol) and 3,4-dichlorobenzaldehyde (496 mg, 2.83 mmol) in isopropanol (5.0 mL) was treated with piperidine (25 μl, 257 μmol) and acetic acid (15 μl, 257 μmol) and then heated to reflux for 20 h. At the conclusion of this period, the mixture was cooled on ice, causing a gum to separate from the solution. The mixture was treated with a small amount of water and heated until homogeneous. On slow cooling to rt, a solid formed, which was collected by filtration and dried under vacuum to provide racemic methyl 2-(3,4-dichlorophenyl)-4-oxochroman-3-carboxylate as an off-white powder (496 mg, 55%). An additional sample (57 mg, 6%) was obtained by partial concentration of the filtrate. The NMR indicated predominantly the enolic form. 1H NMR (400 MHz, CDCl3) δ ppm 3.78 (s, 3 H) 6.18 (s, 1 H) 6.81 (dd, J=8.1, 1.0 Hz, 1H) 6.99 (td, J=7.4, 1.0 Hz, 1 H) 7.19 (dd, J=8.4, 1.8 Hz, 1 H) 7.31 (m, 1 H) 7.34 (d, J=8.1 Hz, 1 H) 7.43 (d, J=2.0 Hz, 1 H) 7.69 (dd, J=7.9, 1.8 Hz, 1 H) 12.28 (br. s, 1H). High resolution mass spectrum m/z found 373.0016, calcd 373.0010 (M+Na)+. heated to reflux for 20 h At the conclusion of this period, the mixture was cooled on ice to separate from the solution The mixture was treated with a small amount of water heated until homogeneous a solid formed which was collected by filtration dried under vacuum

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

Procedure: A mixture of methyl 3-(2-hydroxyphenyl)-3-oxopropanoate (prepared according to Cushman, M. et al., J. Med. Chem. 1991, 200 mg, 1.03 mmol) and 4-chloro-3-(trifluoromethyl)benzaldehyde (148 μL, 1.03 mmol) in isopropanol (4.0 mL) was treated with piperidine (10 μL, 103 μmol) and acetic acid (5.9 μL, 103 μmol) and heated to reflux for 16.5 h. After this time, water (2.0 mL) was added and the solution was slowly cooled to rt, whereupon crystals formed. After standing at rt, the mixture was cooled on ice, and the resulting crystals were collected by filtration and dried to provide methyl 2-(4-chloro-3-(trifluoromethyl)phenyl)-4-oxochroman-3-carboxylate as a white crystalline solid (204 mg, 51%). A second crop (47 mg) was obtained from the mother liquor, raising the total yield to 63%. The NMR indicated predominantly the enolic form. 1H NMR (500 MHz, CDCl3) δ ppm 3.79 (s, 3 H) 6.24 (s, 1 H) 6.82 (d, J=8.2 Hz, 1 H) 7.00 (t, J=7.7 Hz, 1 H) 7.31 (t, J=6.9 Hz, 1 H) 7.42 (m, 2 H) 7.70 (m, 2 H) 12.27 (br. s, 1 H). Mass spectrum m/z 407.19, 409.18 (M+Na)+. heated to reflux for 16.5 h formed After standing at rt the mixture was cooled on ice the resulting crystals were collected by filtration dried

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

Procedure: A mixture of methyl 3-(2-hydroxyphenyl)-3-oxopropanoate (prepared according to Cushman, M. et al., J. Med. Chem. 1991, 34, 798; 250 mg, 1.29 mmol) and 3-chlorobenzaldehyde (146 μL, 1.29 mmol) in isopropanol (5.0 mL) was treated with piperidine (13 μL, 129 μmol) and acetic acid (7.4 μL, 129 μmol) and heated to reflux for 17 h. After this time, the mixture was cooled to rt. The cooled solution was concentrated under vacuum and the resulting residue was purified by rotary TLC, eluting with 9:1 hexane-ethyl acetate, to provide a colorless gum. The colorless gum was crystallized from a hot isopropanol/water solution to provide methyl 2-(3-chlorophenyl)-4-oxochroman-3-carboxylate as an off-white solid (173 mg, 42%). The NMR indicated predominantly the enolic form. 1H NMR (400 MHz, CDCl3) δ ppm 3.78 (s, 3 H) 6.21 (s, 1 H) 6.82 (d, J=8.1 Hz, 1 H) 6.97 (t, J=7.9 Hz, 1 H) 7.18-7.32 (m, 4 H) 7.34 (m, 1 H) 7.69 (dd, J=7.9, 1.8 Hz, 1 H) 12.28 (br. s, 1 H). High resolution mass spec (M+H)+ calc. 317.0581, found 317.0597. heated to reflux for 17 h The cooled solution was concentrated under vacuum the resulting residue was purified by rotary TLC eluting with 9:1 hexane-ethyl acetate to provide a colorless gum The colorless gum was crystallized from a hot isopropanol/water solution

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

Procedure: A mixture of methyl 3-(2-hydroxyphenyl)-3-oxopropanoate (prepared according to Cushman, M. et al., J. Med. Chem. 1991, 34, 798; 250 mg, 1.29 mmol) and 3-chlorobenzaldehyde (146 μL, 1.29 mmol) in isopropanol (5.0 mL) was treated with piperidine (13 μL, 129 μmol) and acetic acid (7.4 μL, 129 μmol) and heated to reflux for 17 h. After this time, the mixture was cooled to rt. The cooled solution was concentrated under vacuum and the resulting residue was purified by rotary TLC, eluting with 9:1 hexane-ethyl acetate, to provide a colorless gum. The colorless gum was crystallized from a hot isopropanol/water solution to provide methyl 2-(3-chlorophenyl)-4-oxochroman-3-carboxylate as an off-white solid (173 mg, 42%). The NMR indicated predominantly the enolic form. 1H NMR (400 MHz, CDCl3) δ ppm 3.78 (s, 3 H) 6.21 (s, 1 H) 6.82 (d, J=8.1 Hz, 1 H) 6.97 (t, J=7.9 Hz, 1 H) 7.18-7.32 (m, 4 H) 7.34 (m, 1 H) 7.69 (dd, J=7.9, 1.8 Hz, 1 H) 12.28 (br. s, 1 H). High resolution mass spec (M+H)+ calc. 317.0581, found 317.0597. heated to reflux for 17 h The cooled solution was concentrated under vacuum the resulting residue was purified by rotary TLC eluting with 9:1 hexane-ethyl acetate to provide a colorless gum The colorless gum was crystallized from a hot isopropanol/water solution

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

Procedure: A mixture of methyl 3-(2-hydroxyphenyl)-3-oxopropanoate (prepared according to Cushman, M. et al., J. Med. Chem. 1991, 34, 798; 500 mg, 2.56 mmol) and 3,4-dichlorobenzaldehyde (496 mg, 2.83 mmol) in isopropanol (5.0 mL) was treated with piperidine (25 μl, 257 μmol) and acetic acid (15 μl, 257 μmol) and then heated to reflux for 20 h. At the conclusion of this period, the mixture was cooled on ice, causing a gum to separate from the solution. The mixture was treated with a small amount of water and heated until homogeneous. On slow cooling to rt, a solid formed, which was collected by filtration and dried under vacuum to provide racemic methyl 2-(3,4-dichlorophenyl)-4-oxochroman-3-carboxylate as an off-white powder (496 mg, 55%). An additional sample (57 mg, 6%) was obtained by partial concentration of the filtrate. The NMR indicated predominantly the enolic form. 1H NMR (400 MHz, CDCl3) δ ppm 3.78 (s, 3 H) 6.18 (s, 1 H) 6.81 (dd, J=8.1, 1.0 Hz, 1H) 6.99 (td, J=7.4, 1.0 Hz, 1 H) 7.19 (dd, J=8.4, 1.8 Hz, 1 H) 7.31 (m, 1 H) 7.34 (d, J=8.1 Hz, 1 H) 7.43 (d, J=2.0 Hz, 1 H) 7.69 (dd, J=7.9, 1.8 Hz, 1 H) 12.28 (br. s, 1H). High resolution mass spectrum m/z found 373.0016, calcd 373.0010 (M+Na)+. heated to reflux for 20 h At the conclusion of this period, the mixture was cooled on ice to separate from the solution The mixture was treated with a small amount of water heated until homogeneous a solid formed which was collected by filtration dried under vacuum

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

Procedure: A mixture of methyl 3-(2-hydroxyphenyl)-3-oxopropanoate (prepared according to Cushman, M. et al., J. Med. Chem. 1991, 200 mg, 1.03 mmol) and 4-chloro-3-(trifluoromethyl)benzaldehyde (148 μL, 1.03 mmol) in isopropanol (4.0 mL) was treated with piperidine (10 μL, 103 μmol) and acetic acid (5.9 μL, 103 μmol) and heated to reflux for 16.5 h. After this time, water (2.0 mL) was added and the solution was slowly cooled to rt, whereupon crystals formed. After standing at rt, the mixture was cooled on ice, and the resulting crystals were collected by filtration and dried to provide methyl 2-(4-chloro-3-(trifluoromethyl)phenyl)-4-oxochroman-3-carboxylate as a white crystalline solid (204 mg, 51%). A second crop (47 mg) was obtained from the mother liquor, raising the total yield to 63%. The NMR indicated predominantly the enolic form. 1H NMR (500 MHz, CDCl3) δ ppm 3.79 (s, 3 H) 6.24 (s, 1 H) 6.82 (d, J=8.2 Hz, 1 H) 7.00 (t, J=7.7 Hz, 1 H) 7.31 (t, J=6.9 Hz, 1 H) 7.42 (m, 2 H) 7.70 (m, 2 H) 12.27 (br. s, 1 H). Mass spectrum m/z 407.19, 409.18 (M+Na)+. heated to reflux for 16.5 h formed After standing at rt the mixture was cooled on ice the resulting crystals were collected by filtration dried

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

Procedure: A mixture of methyl 3-(2-hydroxyphenyl)-3-oxopropanoate (prepared according to Cushman, M. et al., J. Med. Chem. 1991, 34, 798; 250 mg, 1.29 mmol) and 3-chlorobenzaldehyde (146 μL, 1.29 mmol) in isopropanol (5.0 mL) was treated with piperidine (13 μL, 129 μmol) and acetic acid (7.4 μL, 129 μmol) and heated to reflux for 17 h. After this time, the mixture was cooled to rt. The cooled solution was concentrated under vacuum and the resulting residue was purified by rotary TLC, eluting with 9:1 hexane-ethyl acetate, to provide a colorless gum. The colorless gum was crystallized from a hot isopropanol/water solution to provide methyl 2-(3-chlorophenyl)-4-oxochroman-3-carboxylate as an off-white solid (173 mg, 42%). The NMR indicated predominantly the enolic form. 1H NMR (400 MHz, CDCl3) δ ppm 3.78 (s, 3 H) 6.21 (s, 1 H) 6.82 (d, J=8.1 Hz, 1 H) 6.97 (t, J=7.9 Hz, 1 H) 7.18-7.32 (m, 4 H) 7.34 (m, 1 H) 7.69 (dd, J=7.9, 1.8 Hz, 1 H) 12.28 (br. s, 1 H). High resolution mass spec (M+H)+ calc. 317.0581, found 317.0597. heated to reflux for 17 h The cooled solution was concentrated under vacuum the resulting residue was purified by rotary TLC eluting with 9:1 hexane-ethyl acetate to provide a colorless gum The colorless gum was crystallized from a hot isopropanol/water solution