7-hydroxy-4-methyl-3,4-dihydrochromen-2-one

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

Procedure: Concentrated sulfuric acid (1.2 mL, 43 mmol) was added to a solution of 7-hydroxy-3,4-dihydro-4-methylcoumarin (B1) (75.8 g, 430 mmol) in methanol (1 L) at room temperature and the solution stirred for about 16 hours. At this time, TLC (8% methanol:chloroform) showed the clean formation of product at the expense of starting material. The solution was neutralized with 7% NaHCO3 solution (50 ml) and the majority of the solvent (750 ml) removed under reduced pressure. The solution was diluted with ethyl acetate (1 L), washed successively with saturated NaHCO3: saturated NaCl (1:1, 200 ml), saturated NaCl (2×200 ml), dried (Na2SO4), filtered and the solvent removed to give an orange oil. Further purification by filtering through a short pad of silica gel and eluting with 5% methanol in chloroform afforded pure product as a pale orange gel (87 g, 98%): 1H NMR (DMSO-d6) d 1.13 (d, JJ=7.0, 3H), 2.42 (dd, JJ=15.0, 8.9, 1H), 2.58 (dd, JJ=15.0, 5.8, 1H), 3.37 (m, 1H), 3.55 (s, 3H), 6.15 (dd, JJ=8.6, 2.4, 1H), 6.28 (d, JJ=2.4, 1H), 6.84 (d, JJ=8.2, 1H), 8.93 (s, 1H), 9.11 (s, 1H); 13C NMR (DMSO-d6) d 20.16, 29.09, 40.77, 51.00, 102.55, 106.02, 122.09, 127.04, 155.18, 156.27, 172.55; m/z (EI; TMS derivatized; M+) 354; IR (neat; cm−1) 3384.5, 2969.3, 1708.9, 1621.0, 1606.3, 1518.4, 1454.9, 1367.0, 1303.5, 1220.4, 1166.7, 1108.1, 976.2, 839.4, 810.1. the majority of the solvent (750 ml) removed under reduced pressure The solution was diluted with ethyl acetate (1 L) washed successively with saturated NaHCO3 saturated NaCl (1:1, 200 ml), saturated NaCl (2×200 ml), dried (Na2SO4) filtered the solvent removed to give an orange oil Further purification by filtering through a short pad of silica gel eluting with 5% methanol in chloroform afforded pure product as a pale orange gel (87 g, 98%)

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

Procedure: Concentrated sulfuric acid (1.2 mL, 43 mmol) was added to a solution of 7-hydroxy-3,4-dihydro-4-methylcoumarin (B1) (75.8 g, 430 mmol) in methanol (1 L) at room temperature and the solution stirred for about 16 hours. At this time, TLC (8% methanol:chloroform) showed the clean formation of product at the expense of starting material. The solution was neutralized with 7% NaHCO3 solution (50 ml) and the majority of the solvent (750 ml) removed under reduced pressure. The solution was diluted with ethyl acetate (1 L), washed successively with saturated NaHCO3: saturated NaCl (1:1, 200 ml), saturated NaCl (2×200 ml), dried (Na2SO4), filtered and the solvent removed to give an orange oil. Further purification by filtering through a short pad of silica gel and eluting with 5% methanol in chloroform afforded pure product as a pale orange gel (87 g, 98%): 1H NMR (DMSO-d6) d 1.13 (d, JJ=7.0, 3H), 2.42 (dd, JJ=15.0, 8.9, 1H), 2.58 (dd, JJ=15.0, 5.8, 1H), 3.37 (m, 1H), 3.55 (s, 3H), 6.15 (dd, JJ=8.6, 2.4, 1H), 6.28 (d, JJ=2.4, 1H), 6.84 (d, JJ=8.2, 1H), 8.93 (s, 1H), 9.11 (s, 1H); 13C NMR (DMSO-d6) d 20.16, 29.09, 40.77, 51.00, 102.55, 106.02, 122.09, 127.04, 155.18, 156.27, 172.55; m/z (EI; TMS derivatized; M+) 354; IR (neat; cm−1) 3384.5, 2969.3, 1708.9, 1621.0, 1606.3, 1518.4, 1454.9, 1367.0, 1303.5, 1220.4, 1166.7, 1108.1, 976.2, 839.4, 810.1. the majority of the solvent (750 ml) removed under reduced pressure The solution was diluted with ethyl acetate (1 L) washed successively with saturated NaHCO3 saturated NaCl (1:1, 200 ml), saturated NaCl (2×200 ml), dried (Na2SO4) filtered the solvent removed to give an orange oil Further purification by filtering through a short pad of silica gel eluting with 5% methanol in chloroform afforded pure product as a pale orange gel (87 g, 98%)

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

Procedure: Concentrated sulfuric acid (1.2 mL, 43 mmol) was added to a solution of 7-hydroxy-3,4-dihydro-4-methylcoumarin (B1) (75.8 g, 430 mmol) in methanol (1 L) at room temperature and the solution stirred for about 16 hours. At this time, TLC (8% methanol:chloroform) showed the clean formation of product at the expense of starting material. The solution was neutralized with 7% NaHCO3 solution (50 ml) and the majority of the solvent (750 ml) removed under reduced pressure. The solution was diluted with ethyl acetate (1 L), washed successively with saturated NaHCO3: saturated NaCl (1:1, 200 ml), saturated NaCl (2×200 ml), dried (Na2SO4), filtered and the solvent removed to give an orange oil. Further purification by filtering through a short pad of silica gel and eluting with 5% methanol in chloroform afforded pure product as a pale orange gel (87 g, 98%): 1H NMR (DMSO-d6) d 1.13 (d, JJ=7.0, 3H), 2.42 (dd, JJ=15.0, 8.9, 1H), 2.58 (dd, JJ=15.0, 5.8, 1H), 3.37 (m, 1H), 3.55 (s, 3H), 6.15 (dd, JJ=8.6, 2.4, 1H), 6.28 (d, JJ=2.4, 1H), 6.84 (d, JJ=8.2, 1H), 8.93 (s, 1H), 9.11 (s, 1H); 13C NMR (DMSO-d6) d 20.16, 29.09, 40.77, 51.00, 102.55, 106.02, 122.09, 127.04, 155.18, 156.27, 172.55; m/z (EI; TMS derivatized; M+) 354; IR (neat; cm−1) 3384.5, 2969.3, 1708.9, 1621.0, 1606.3, 1518.4, 1454.9, 1367.0, 1303.5, 1220.4, 1166.7, 1108.1, 976.2, 839.4, 810.1. the majority of the solvent (750 ml) removed under reduced pressure The solution was diluted with ethyl acetate (1 L) washed successively with saturated NaHCO3 saturated NaCl (1:1, 200 ml), saturated NaCl (2×200 ml), dried (Na2SO4) filtered the solvent removed to give an orange oil Further purification by filtering through a short pad of silica gel eluting with 5% methanol in chloroform afforded pure product as a pale orange gel (87 g, 98%)

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

Procedure: Sodium hydroxide (5.0 M, 27 ml, 135 mmol) was added to a suspension of 7-hydroxy-3,4-dihydro-4-methylcoumarin (Compound of formula B1) (8.0 g, 45 mmol) in water (40 ml) at room temperature and the resulting solution stirred for 20 min. At this time, TLC (4% methanol:chloroform) showed the clean formation of product at the expense of starting material. The solution was cooled to 5° C. and carefully acidified with concentrated HCl to pH less than about 1, keeping the temperature at less than about 15° C. throughout the addition. The solution was extracted with ethyl ether (4×100 ml), the organic layers washed with saturated NaCl (4×50 ml), combined, dried (Na2SO4), filtered and the solvent removed to give a pale orange oil. Further purification by filtering through a short pad of silica gel and eluting with ethyl acetate afforded pure product as a white solid (8.3 g, 94%): m.p. 92-94° C.; 1H NMR (DMSO-d6) d 1.13 (d, JJ=7.0, 3H), 2.33 (dd, JJ=15.0, 8.9, 1H), 2.52 (dd, JJ=15.5, 7.3, 1H), 3.32 (m, 1H), 6.16 (dd, JJ=8.2, 2.4, 1H), 6.28 (d, JJ=2.4, 1H), 6.84 (d, JJ=8.2, 1H), 9.08 (s, 1H), 9.59 (s, 1H), 11.87 (s, 1H); 13C NMR (DMSO-d6) d 20.39, 28.97, 41.0, 102.58, 106.01, 122.55, 127.27, 155.19, 156.18, 173.74; m/z (EI; TMS derivatized; M+) 412; IR (neat; cm1) 3360.1, 2974.1, 2935.1, 2876.4, 1748.0, 1713.8, 1625.9, 1606.3, 1518.4, 1459.8, 1381.6, 1347.4, 1283.9, 1254.6, 1239.9, 1156.9, 1117.8, 1025.0, 981.0, 937.1, 849.1, 810.1. at less than about 15° C. throughout the addition The solution was extracted with ethyl ether (4×100 ml) the organic layers washed with saturated NaCl (4×50 ml) dried (Na2SO4) filtered the solvent removed to give a pale orange oil Further purification by filtering through a short pad of silica gel eluting with ethyl acetate afforded pure product as a white solid (8.3 g, 94%)

Conditions: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A Parr hydrogenator (1 L) was charged with 7-hydroxy-4-methylcoumarin, i.e., Compound of formula A1, (60 g, 0.34 mol) and acetic acid (350 ml). A suspension of 10% Pd/C (6.0 g) in acetic acid (150 ml) was added and the reactor sealed, evacuated and purged with nitrogen (4×). The reactor was pressurized to 320 psi with hydrogen and stirred at 30° C. for 16 hr, at which point no hydrogen was consumed and TLC (4% methanol:chloroform) showed the clean formation of product at the expense of starting material. The reactor was evacuated, purged with nitrogen and the mixture filtered through celite. The solvent was removed to give a white solid (60.5 g, 100%). Recrystallization from ethyl acetate:hexane afforded pure product as a white solid: m.p. 109-110° C.; 1H NMR (DMSO-d6) d 1.19 (d, JJ=6.7, 3H), 2.52 (dd, JJ=15.9, 7.3, 1H), 2.84 (dd, JJ=15.9, 5.5, 1H), 3.08 (m, 1H), 6.46 (d, JJ=2.4, 1H), 6.58 (dd, JJ=8.2, 2.4, 1H), 7.10 (d, JJ=8.2, 1H), 9.66 (s, 1H); 13C (DMSO-d6) d 19.84, 27.87, 36.45, 103.17, 111.38, 118.29, 127.17, 151.45, 157.17, 168.11; m/z (EI; TMS derivatized; M+) 250; IR (neat; cm−1) 3379.6, 2969.2, 2930.2, 2871.5, 1748.0, 1630.7, 1601.4, 1518.4, 1454.89, 1352.3, 1283.9, 1249.7, 1239.9, 1152.0, 1117.8, 1078.7, 1020.1, 995.7, 942.0, 854.0, 814.9. was added the reactor sealed evacuated purged with nitrogen (4×) was consumed The reactor was evacuated purged with nitrogen the mixture filtered through celite The solvent was removed

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

Procedure: Concentrated sulfuric acid (1.2 mL, 43 mmol) was added to a solution of 7-hydroxy-3,4-dihydro-4-methylcoumarin (B1) (75.8 g, 430 mmol) in methanol (1 L) at room temperature and the solution stirred for about 16 hours. At this time, TLC (8% methanol:chloroform) showed the clean formation of product at the expense of starting material. The solution was neutralized with 7% NaHCO3 solution (50 ml) and the majority of the solvent (750 ml) removed under reduced pressure. The solution was diluted with ethyl acetate (1 L), washed successively with saturated NaHCO3: saturated NaCl (1:1, 200 ml), saturated NaCl (2×200 ml), dried (Na2SO4), filtered and the solvent removed to give an orange oil. Further purification by filtering through a short pad of silica gel and eluting with 5% methanol in chloroform afforded pure product as a pale orange gel (87 g, 98%): 1H NMR (DMSO-d6) d 1.13 (d, JJ=7.0, 3H), 2.42 (dd, JJ=15.0, 8.9, 1H), 2.58 (dd, JJ=15.0, 5.8, 1H), 3.37 (m, 1H), 3.55 (s, 3H), 6.15 (dd, JJ=8.6, 2.4, 1H), 6.28 (d, JJ=2.4, 1H), 6.84 (d, JJ=8.2, 1H), 8.93 (s, 1H), 9.11 (s, 1H); 13C NMR (DMSO-d6) d 20.16, 29.09, 40.77, 51.00, 102.55, 106.02, 122.09, 127.04, 155.18, 156.27, 172.55; m/z (EI; TMS derivatized; M+) 354; IR (neat; cm−1) 3384.5, 2969.3, 1708.9, 1621.0, 1606.3, 1518.4, 1454.9, 1367.0, 1303.5, 1220.4, 1166.7, 1108.1, 976.2, 839.4, 810.1. the majority of the solvent (750 ml) removed under reduced pressure The solution was diluted with ethyl acetate (1 L) washed successively with saturated NaHCO3 saturated NaCl (1:1, 200 ml), saturated NaCl (2×200 ml), dried (Na2SO4) filtered the solvent removed to give an orange oil Further purification by filtering through a short pad of silica gel eluting with 5% methanol in chloroform afforded pure product as a pale orange gel (87 g, 98%)

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

Procedure: Sodium hydroxide (5.0 M, 27 ml, 135 mmol) was added to a suspension of 7-hydroxy-3,4-dihydro-4-methylcoumarin (Compound of formula B1) (8.0 g, 45 mmol) in water (40 ml) at room temperature and the resulting solution stirred for 20 min. At this time, TLC (4% methanol:chloroform) showed the clean formation of product at the expense of starting material. The solution was cooled to 5° C. and carefully acidified with concentrated HCl to pH less than about 1, keeping the temperature at less than about 15° C. throughout the addition. The solution was extracted with ethyl ether (4×100 ml), the organic layers washed with saturated NaCl (4×50 ml), combined, dried (Na2SO4), filtered and the solvent removed to give a pale orange oil. Further purification by filtering through a short pad of silica gel and eluting with ethyl acetate afforded pure product as a white solid (8.3 g, 94%): m.p. 92-94° C.; 1H NMR (DMSO-d6) d 1.13 (d, JJ=7.0, 3H), 2.33 (dd, JJ=15.0, 8.9, 1H), 2.52 (dd, JJ=15.5, 7.3, 1H), 3.32 (m, 1H), 6.16 (dd, JJ=8.2, 2.4, 1H), 6.28 (d, JJ=2.4, 1H), 6.84 (d, JJ=8.2, 1H), 9.08 (s, 1H), 9.59 (s, 1H), 11.87 (s, 1H); 13C NMR (DMSO-d6) d 20.39, 28.97, 41.0, 102.58, 106.01, 122.55, 127.27, 155.19, 156.18, 173.74; m/z (EI; TMS derivatized; M+) 412; IR (neat; cm−1) 3360.1, 2974.1, 2935.1, 2876.4, 1748.0, 1713.8, 1625.9, 1606.3, 1518.4, 1459.8, 1381.6, 1347.4, 1283.9, 1254.6, 1239.9, 1156.9, 1117.8, 1025.0, 981.0, 937.1, 849.1, 810.1. at less than about 15° C. throughout the addition The solution was extracted with ethyl ether (4×100 ml) the organic layers washed with saturated NaCl (4×50 ml) dried (Na2SO4) filtered the solvent removed to give a pale orange oil Further purification by filtering through a short pad of silica gel eluting with ethyl acetate afforded pure product as a white solid (8.3 g, 94%)

Conditions: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A Parr hydrogenator (1 L) was charged with 7-hydroxy-4-methylcoumarin, i.e., Compound of formula A1, (60 g, 0.34 mol) and acetic acid (350 ml). A suspension of 10% Pd/C (6.0 g) in acetic acid (150 ml) was added and the reactor sealed, evacuated and purged with nitrogen (4×). The reactor was pressurized to 320 psi with hydrogen and stirred at 30° C. for 16 hr, at which point no hydrogen was consumed and TLC (4% methanol:chloroform) showed the clean formation of product at the expense of starting material. The reactor was evacuated, purged with nitrogen and the mixture filtered through celite. The solvent was removed to give a white solid (60.5 g, 100%). Recrystallization from ethyl acetate:hexane afforded pure product as a white solid: m.p. 109-110° C.; 1H NMR (DMSO-d6) d 1.19 (d, JJ=6.7, 3H), 2.52 (dd, JJ=15.9, 7.3, 1H), 2.84 (dd, JJ=15.9, 5.5, 1H), 3.08 (m, 1H), 6.46 (d, JJ=2.4, 1H), 6.58 (dd, JJ=8.2, 2.4, 1H), 7.10 (d, JJ=8.2, 1H), 9.66 (s, 1H); 13C (DMSO-d6) d 19.84, 27.87, 36.45, 103.17, 111.38, 118.29, 127.17, 151.45, 157.17, 168.11; m/z (EI; TMS derivatized; M+) 250; IR (neat; cm−1) 3379.6, 2969.2, 2930.2, 2871.5, 1748.0, 1630.7, 1601.4, 1518.4, 1454.89, 1352.3, 1283.9, 1249.7, 1239.9, 1152.0, 1117.8, 1078.7, 1020.1, 995.7, 942.0, 854.0, 814.9. was added the reactor sealed evacuated purged with nitrogen (4×) was consumed The reactor was evacuated purged with nitrogen the mixture filtered through celite The solvent was removed