2-iodo-5-methoxyphenol

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: A solution of 2-iodo-5-methoxy-phenol (39 g, 156 mmol) in dimethylformamide (300 mL) and N,N,N′,N′-tetramethylguanidine (150 mL) is treated with copper(I) Iodide (1.89 g, 9.82 mmol) and bis(triphenylphosphine)palladium(II) chloride (1.9 g; 2.71 mmol; 1.900 g). The mixture is cooled to −78° C. Propyne (100 g; 2.50 moles) is bubbled through the mixture for 1 hour. The reaction mixture is stirred and allowed to warm to room temperature gradually over 6 hours and stirred for 2 days. The reaction mixture is quenched with water (800 mL) and extracted with EtOAc (500 mL). The organic layers are dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product is purified via flash chromatography eluting with 10% EtOAc/Hexanes. The appropriate fractions are concentrated. The material is dried in vacuo to afford the title compound (17.5 g, 69%). 1H NMR (400 MHz, CDCl3): δ 7.31-7.29 (d, 1H), 6.95 (s, 1H), 6.81-6.79 (d, 1H), 6.26 (s, 1H), 3.81 (s, 3H), 2.40 (s, 3H). to warm to room temperature gradually over 6 hours stirred for 2 days The reaction mixture is quenched with water (800 mL) extracted with EtOAc (500 mL) The organic layers are dried over Na2SO4 filtered concentrated under reduced pressure The crude product is purified via flash chromatography eluting with 10% EtOAc/Hexanes The appropriate fractions are concentrated The material is dried in vacuo

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

Procedure: A solution of 2-iodo-5-methoxy-phenol (39 g, 156 mmol) in dimethylformamide (300 mL) and N,N,N′,N′-tetramethylguanidine (150 mL) is treated with copper(I) Iodide (1.89 g, 9.82 mmol) and bis(triphenylphosphine)palladium(II) chloride (1.9 g; 2.71 mmol; 1.900 g). The mixture is cooled to −78° C. Propyne (100 g; 2.50 moles) is bubbled through the mixture for 1 hour. The reaction mixture is stirred and allowed to warm to room temperature gradually over 6 hours and stirred for 2 days. The reaction mixture is quenched with water (800 mL) and extracted with EtOAc (500 mL). The organic layers are dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product is purified via flash chromatography eluting with 10% EtOAc/Hexanes. The appropriate fractions are concentrated. The material is dried in vacuo to afford the title compound (17.5 g, 69%). 1H NMR (400 MHz, CDCl3): δ 7.31-7.29 (d, 1H), 6.95 (s, 1H), 6.81-6.79 (d, 1H), 6.26 (s, 1H), 3.81 (s, 3H), 2.40 (s, 3H). to warm to room temperature gradually over 6 hours stirred for 2 days The reaction mixture is quenched with water (800 mL) extracted with EtOAc (500 mL) The organic layers are dried over Na2SO4 filtered concentrated under reduced pressure The crude product is purified via flash chromatography eluting with 10% EtOAc/Hexanes The appropriate fractions are concentrated The material is dried in vacuo

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

Procedure: A suspension of 2-iodo-5-methoxyphenol (1.1 g, 4.41 mmol), 1-(tert-butyl-dimethylsilanyl)-3-(tert-butyl-dimethyl-silanyloxy)-propyne (1.5 g, 5.28 mmol), lithium chloride (189 mg, 4.45 mmol) and sodium carbonate (2.34 g, 22.08 mmol) in dry dimethylformamide (5 mL) at 100° C. was deoxygenated 4 times by evacuation and backfilling with nitrogen. Palladium acetate (135 mg, 0.60 mmol) was added and the reaction vessel was degassed twice with nitrogen. The reaction mixture was then stirred at this temperature for 4 hours (tlc) and the solvent was removed by distillation under vacuum. The residue was dissolved in ethyl acetate (75 mL), stirred well, filtered and treated with triethylamine (5 mL). The solution was concentrated onto silica gel (10 g) and purified by flash chromatography (silica gel, eluent=hexane/diethyl ether/triethylamine; 95:5:1%) to give the title compound as a yellow oil; (1.09 g, 87%); 1H NMR (300 MHz, CDCl3) δ 7.52 (d, 1H, J=8.57 Hz), 6.97 (d, 1H, J=2.15 Hz), 6.83 (dd, 1H, J=8.54, 2.18 Hz), 4.81 (s, 2H, CH2), 3.83 (s, 3H, OMe), 0.93 (s, 9H), 0.91 (s, 9H), 0.34 (s, 6H), 0.11 (s, 6H). was deoxygenated 4 times by evacuation and backfilling with nitrogen the reaction vessel was degassed twice with nitrogen the solvent was removed by distillation under vacuum The residue was dissolved in ethyl acetate (75 mL) stirred well filtered treated with triethylamine (5 mL) The solution was concentrated onto silica gel (10 g) purified by flash chromatography (silica gel, eluent=hexane/diethyl ether/triethylamine; 95:5:1%)

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

Procedure: This compound was prepared by application of the general procedure to 2-iodo-5-methoxy-phenol, 1-benzyl-4-ethynyl-1H-pyrazole and 3,4,5-trimethoxy-iodo-benzene. The crude product was stirred with potassium carbonate (excess) in methanol to hydrolyse ester by-products and submitted to silica-gel flash chromatography (eluent=2:1 hexanes:ethyl acetate) to afford the title compound as a yellow resin that crystallised after trituration in diethyl ether (31% yield). An analytical sample was obtained by preparative thin layer chromatography (eluent=2:1 hexane:ethyl acetate). 1H-NMR (CDCl3) δ 8.10 (s, 1H), 8.03 (s, 1H), 7.36-7.21 (m, 5H), 7.13 (d, J=8.7 Hz, 1H), 7.11 (s, 2H), 7.03 (d, J=2.0 Hz, 1H), 6.79 (dd, J 8.7, 2.0 Hz, 1H), 5.29 (s, 2H), 3.92 (s, 3H), 3.85 (s, 3H), 3.75 (s, 6H). 13C-NMR (CDCl3) δ 190.3, 158.2, 154.3, 153.3, 153.0, 142.4, 139.3, 135.7, 133.7, 130.3, 128.9, 128.3, 127.8, 121.8, 120.9, 114.0, 113.1, 112.3, 107.1, 95.6, 61.1, 56.4, 56.3, 55.8.

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

Procedure: This compound was prepared by application of the general procedure to 2-iodo-5-methoxy-phenol, 1-benzyl-4-ethynyl-1H-pyrazole and 3,4,5-trimethoxy-iodo-benzene. The crude product was stirred with potassium carbonate (excess) in methanol to hydrolyse ester by-products and submitted to silica-gel flash chromatography (eluent=2:1 hexanes:ethyl acetate) to afford the title compound as a yellow resin that crystallised after trituration in diethyl ether (31% yield). An analytical sample was obtained by preparative thin layer chromatography (eluent=2:1 hexane:ethyl acetate). 1H-NMR (CDCl3) δ 8.10 (s, 1H), 8.03 (s, 1H), 7.36-7.21 (m, 5H), 7.13 (d, J=8.7 Hz, 1H), 7.11 (s, 2H), 7.03 (d, J=2.0 Hz, 1H), 6.79 (dd, J 8.7, 2.0 Hz, 1H), 5.29 (s, 2H), 3.92 (s, 3H), 3.85 (s, 3H), 3.75 (s, 6H). 13C-NMR (CDCl3) δ 190.3, 158.2, 154.3, 153.3, 153.0, 142.4, 139.3, 135.7, 133.7, 130.3, 128.9, 128.3, 127.8, 121.8, 120.9, 114.0, 113.1, 112.3, 107.1, 95.6, 61.1, 56.4, 56.3, 55.8.

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

Procedure: This compound was prepared by application of the general procedure to 2-iodo-5-methoxy-phenol, 4-ethynyl-1-(4-methoxy-benzyl)-1H-pyrazole and 3,4,5-trimethoxy-iodo-benzene. The crude product was stirred with potassium carbonate (excess) in methanol for 3 h to hydrolyse ester by-products and submitted to silica-gel flash chromatography (eluent=2:1 hexanes:ethyl acetate) to afford a mixture of the title compound and the corresponding non-carbonyl inserted derivative. This mixture was used directly in the subsequent deprotection. An analytical sample was purified by recrystallisation from dichloromethane/hexane. 1H-NMR (CDCl3) δ 8.03 (s, 1H), 8.01 (s, 1H), 7.18 (d, J=8.6 Hz, 2H), 7.14 (d, J=8.7 Hz, 1H), 7.10 (s, 2H), 7.02 (d, J=2.2 Hz, 1H), 6.86 (d, J=8.6 Hz, 2H), 6.79 (dd, J=8.7, 2.2 Hz, 1H), 5.22 (s, 2H), 3.92 (s, 3H), 3.85 (s, 3H), 3.78 (s, 3H), 3.75 (s, 6H). 13C-NMR (CDCl3) δ 190.2, 159.5, 158.1, 154.2, 153.3, 152.9, 142.3, 139.1, 133.6, 129.8, 129.3, 127.6, 121.7, 120.9, 114.2, 113.8, 112.9, 112.2, 107.0, 95.5, 60.9, 56.1, 55.8, 55.6, 55.2. to afford

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

Procedure: This compound was prepared by application of the general procedure to 2-iodo-5-methoxy-phenol, 4-ethynyl-1-(4-methoxy-benzyl)-1H-pyrazole and 3,4,5-trimethoxy-iodo-benzene. The crude product was stirred with potassium carbonate (excess) in methanol for 3 h to hydrolyse ester by-products and submitted to silica-gel flash chromatography (eluent=2:1 hexanes:ethyl acetate) to afford a mixture of the title compound and the corresponding non-carbonyl inserted derivative. This mixture was used directly in the subsequent deprotection. An analytical sample was purified by recrystallisation from dichloromethane/hexane. 1H-NMR (CDCl3) δ 8.03 (s, 1H), 8.01 (s, 1H), 7.18 (d, J=8.6 Hz, 2H), 7.14 (d, J=8.7 Hz, 1H), 7.10 (s, 2H), 7.02 (d, J=2.2 Hz, 1H), 6.86 (d, J=8.6 Hz, 2H), 6.79 (dd, J=8.7, 2.2 Hz, 1H), 5.22 (s, 2H), 3.92 (s, 3H), 3.85 (s, 3H), 3.78 (s, 3H), 3.75 (s, 6H). 13C-NMR (CDCl3) δ 190.2, 159.5, 158.1, 154.2, 153.3, 152.9, 142.3, 139.1, 133.6, 129.8, 129.3, 127.6, 121.7, 120.9, 114.2, 113.8, 112.9, 112.2, 107.0, 95.5, 60.9, 56.1, 55.8, 55.6, 55.2. to afford

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

Procedure: A suspension of 2-iodo-5-methoxyphenol (1.1 g, 4.41 mmol), 1-(tert-butyldimethylsilyl)-3-(tert-butyldimethylsilyloxy)propyne (1.5 g, 5.28 mmol), lithium chloride (189 mg, 4.45 mmol) and sodium carbonate (2.34 g, 22.08 mmol) in dry dimethylformamide (5 mL) at 100° C. was deoxygenated 4 times by evacuation and backfilling with nitrogen. Palladium acetate (135 mg, 0.60 mmol) was added and the reaction vessel was degassed twice with nitrogen. The reaction mixture was then stirred at this temperature for 4 hours (monitored by tlc) and the solvent was removed by distillation under vacuum. The residue was dissolved in ethyl acetate (75 mL), stirred well, filtered and treated with triethylamine (5 mL). The solution was concentrated onto silica gel (10 g) and purified by flash chromatography (silica gel, eluent=hexane/diethyl ether/triethylamine; 95:5:1%) to give the title compound as a yellow oil (1.09 g, 87%); 1H NMR (300 MHz, CDCl3) δ 7.52 (d, 1H, J=8.57 Hz), 6.97 (d, 1H, J=2.15 Hz), 6.83 (dd, 1H, J=8.54, 2.18 Hz), 4.81 (s, 2H, CH2), 3.83 (s, 3H, OMe), 0.93 (s, 9H), 0.91 (s, 9H), 0.34 (s, 6H), 0.11 (s, 6H). was deoxygenated 4 times by evacuation and backfilling with nitrogen the reaction vessel was degassed twice with nitrogen the solvent was removed by distillation under vacuum The residue was dissolved in ethyl acetate (75 mL) stirred well filtered treated with triethylamine (5 mL) The solution was concentrated onto silica gel (10 g) purified by flash chromatography (silica gel, eluent=hexane/diethyl ether/triethylamine; 95:5:1%)

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

Procedure: Example 15(a) was prepared from 2-iodo-5-methoxyphenol (896 mg, 3.6 mmole) and 3-methyl-1-butyne in a manner as previously described for example 12a to give 265 mg (38%) of an amber oil. 1H NMR (CDCl3) δ7.33 (1H, d, J=8.6 Hz), 6.97 (1H, d, J=2.2 Hz), 6.80 (1H, dd, J=2.2, 8.6 Hz), 6.26 (1H, s), 3.83 (3H, s), 3.07-3.01 (1H, m), 1.31 (6H, d, J=7.1 Hz).