tert-Butyl 4-iodobenzoate

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of tert-butyl 4-iodobenzoate (0.304 g, 1.0 mmol) in 10 mL THF at −40° C. was added a solution of isopropylmagnesium bromide (1.05 ml, 1.05 mmol, 1M in THF) dropwise under argon. After stirring for 1 hour at −40° C., ethyl benzoylformate (0.175 ml, 1.1 mmol) was added dropwise and the cold bath allowed to warm to room temperature over a 40 min. period. The reaction was quenched by the addition of an aqueous solution of 20% ammonium chloride. The reaction mixture was extracted twice with ether, the combined organic layers washed with brine, dried over Na2SO4 and was evaporated to give an oil that was chromatographed on 10 g silica gel using a gradient elution from 0-40% EtOAc in Hexanes. Product containing fractions were combined and concentrated to give (0.078 g, 22%) ethyl (4-tert-butyloxycarbonylphenyl)(hydroxy)phenylacetate as a colorless oil. NMR, 400 MHz (CDCl3) 7.95 ppm (d, J=8.55 Hz, 2H), 7.52 ppm (d, J=8.55 Hz, 2H), 7.30-7.40 ppm (m, 5H), 4.33 ppm (q, J=7.08 Hz, 2H), 4.29 ppm (s, OH, 1H), 1.59 ppm (s, 9H), 1.28 ppm (t, J=7.08 Hz, 3H). to warm to room temperature over a 40 min. period The reaction was quenched by the addition of an aqueous solution of 20% ammonium chloride The reaction mixture was extracted twice with ether the combined organic layers washed with brine dried over Na2SO4 was evaporated to give an oil that was chromatographed on 10 g silica gel using a gradient elution from 0-40% EtOAc in Hexanes Product containing fractions concentrated

Conditions: temp:-25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: All glassware was dried prior to use. THF was dried over molecular sieves. LiCl was dried at 150° C. for 1 h, then stored in a closed bottle. All reaction solutions were made under nitrogen, and the solutions were transferred via syringe. 4-Iodobenzoic acid tert-butyl ester (3 g, 9.9 mmol) was dissolved in THF (7.5 ml), and cooled to −20 to −30° C. Isopropyl magnesium chloride (10.9 mmol, 2M in THF) was added over 5 min, and the solution was stirred for 30 min. A solution of CuCN (0.97 g, 10.9 mmol) and LiCl (0.92 g, 21.7 mmol) in 7.5 ml THF was added. The reaction was removed from the cold bath and allowed to warm to rt. After 15 min, trimethylphosphite (0.62 ml) was added. After stirring for 5 min—iodododecanoic acid methyl ester (2.69 g, 7.89 mmol) was added in a solution of THF (5 ml). After stirring for 16 h, the reaction was quenched with sat. NH4Cl (6 ml). Water (100 ml) was added and the solution was extracted with AcOEt (3×100 ml). The organic extracts were pooled ant washed with water (100 ml) (some sat. NaCl and MeOH was added to aid phase separation) and sat. NaCl (100 ml), dried over MgSO4 and concentrated under vacuum to yield a two-phased residue (5.85 g). The residue was dissolved in AcOEt and added drop wise to a bed of silica in a glass filter (7.5 cm dia×3 cm). 200 ml of AcOEt was washed through the silica, and the filtrate was concentrated to yield a residue. This was dissolved in DCM (10 ml) and purified by flash chromatography (15 cm×40 mm, eluant 9:1 heptane/AcOEt). The relevant fractions were pooled and concentrated under vacuum. This was dissolved in 9:1 heptane/AcOEt (7 ml) and purified again by flash chromatography (15 cm×40 mm, eluant 9:1 heptane/AcOEt) to yield a colorless oil (185 mg). All glassware was dried THF was dried over molecular sieves LiCl was dried at 150° C. for 1 h the solutions were transferred via syringe The reaction was removed from the cold bath to warm to rt After 15 min trimethylphosphite (0.62 ml) was added After stirring for 16 h the reaction was quenched with sat. NH4Cl (6 ml) Water (100 ml) was added the solution was extracted with AcOEt (3×100 ml) The organic extracts were pooled ant washed with water (100 ml) (some sat. NaCl and MeOH was added phase separation) and sat. NaCl (100 ml) dried over MgSO4 concentrated under vacuum

Conditions: temp:-25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: All glassware was dried prior to use. THF was dried over molecular sieves. LiCl was dried at 150° C. for 1 h, then stored in a closed bottle. All reaction solutions were made under nitrogen, and the solutions were transferred via syringe. 4-Iodobenzoic acid tert-butyl ester (3 g, 9.9 mmol) was dissolved in THF (7.5 ml), and cooled to −20 to −30° C. Isopropyl magnesium chloride (10.9 mmol, 2M in THF) was added over 5 min, and the solution was stirred for 30 min. A solution of CuCN (0.97 g, 10.9 mmol) and LiCl (0.92 g, 21.7 mmol) in 7.5 ml THF was added. The reaction was removed from the cold bath and allowed to warm to rt. After 15 min, trimethylphosphite (0.62 ml) was added. After stirring for 5 min—iodododecanoic acid methyl ester (2.69 g, 7.89 mmol) was added in a solution of THF (5 ml). After stirring for 16 h, the reaction was quenched with sat. NH4Cl (6 ml). Water (100 ml) was added and the solution was extracted with AcOEt (3×100 ml). The organic extracts were pooled ant washed with water (100 ml) (some sat. NaCl and MeOH was added to aid phase separation) and sat. NaCl (100 ml), dried over MgSO4 and concentrated under vacuum to yield a two-phased residue (5.85 g). The residue was dissolved in AcOEt and added drop wise to a bed of silica in a glass filter (7.5 cm dia×3 cm). 200 ml of AcOEt was washed through the silica, and the filtrate was concentrated to yield a residue. This was dissolved in DCM (10 ml) and purified by flash chromatography (15 cm×40 mm, eluant 9:1 heptane/AcOEt). The relevant fractions were pooled and concentrated under vacuum. This was dissolved in 9:1 heptane/AcOEt (7 ml) and purified again by flash chromatography (15 cm×40 mm, eluant 9:1 heptane/AcOEt) to yield a colorless oil (185 mg). All glassware was dried THF was dried over molecular sieves LiCl was dried at 150° C. for 1 h the solutions were transferred via syringe The reaction was removed from the cold bath to warm to rt After 15 min trimethylphosphite (0.62 ml) was added After stirring for 16 h the reaction was quenched with sat. NH4Cl (6 ml) Water (100 ml) was added the solution was extracted with AcOEt (3×100 ml) The organic extracts were pooled ant washed with water (100 ml) (some sat. NaCl and MeOH was added phase separation) and sat. NaCl (100 ml) dried over MgSO4 concentrated under vacuum

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Iodobenzoic acid (10 g, 40.3 mmol) was dissolved in dry toluene (100 ml, dried over mol. sieves). The solution was heated to 70° C. under a flow of nitrogen. A solution of N,N′-dimethylformamide di-tert-butyl acetal (24.6 g, 121 mmol) in toluene (25 ml) was added over ca. 30 min. The reaction was mixed for 16 h. At some point the heating unit failed, So the reaction cooled from 70° C. to rt. The solution was heated to 70° C. for and mixed for 5 h. The sample was concentrated under vacuum, and AcOEt (400 ml) was added. The solution was then washed with 1:1 sat. NaHCO3/water (150 ml), and sat. NaHCO3, water and sat. NaCl (75 ml each). The organic phase was dried (MgSO4) and concentrated under vacuum to yield a light brown oil. The reaction was mixed for 16 h cooled from 70° C. to rt The solution was heated to 70° C. for and mixed for 5 h The sample was concentrated under vacuum, and AcOEt (400 ml) was added The solution was then washed with 1:1 sat. NaHCO3/water (150 ml), and sat. NaHCO3, water and sat. NaCl (75 ml each) The organic phase was dried (MgSO4) concentrated under vacuum to yield a light brown oil

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Iodobenzoic acid (10 g, 40.3 mmol) was dissolved in dry toluene (100 ml, dried over mol. sieves). The solution was heated to 70° C. under a flow of nitrogen. A solution of N,N′-dimethylformamide di-tert-butyl acetal (24.6 g, 121 mmol) in toluene (25 ml) was added over ca. 30 min. The reaction was mixed for 16 h. At some point the heating unit failed, So the reaction cooled from 70° C. to rt. The solution was heated to 70° C. for and mixed for 5 h. The sample was concentrated under vacuum, and AcOEt (400 ml) was added. The solution was then washed with 1:1 sat. NaHCO3/water (150 ml), and sat. NaHCO3, water and sat. NaCl (75 ml each). The organic phase was dried (MgSO4) and concentrated under vacuum to yield a light brown oil. The reaction was mixed for 16 h cooled from 70° C. to rt The solution was heated to 70° C. for and mixed for 5 h The sample was concentrated under vacuum, and AcOEt (400 ml) was added The solution was then washed with 1:1 sat. NaHCO3/water (150 ml), and sat. NaHCO3, water and sat. NaCl (75 ml each) The organic phase was dried (MgSO4) concentrated under vacuum to yield a light brown oil

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

Procedure: 4-Iodobenzoic Acid (25 g, 0.10M) was suspended in 200 ml of anhydrous dioxane containing 14 ml of concentrated sulfuric acid. Isobutylene (200 ml) was condensed and added to the suspension. The reaction vessel was sealed and stirred at room temperature for 3 days, during which time most of the material dissolved. The reaction mixture was cautiously poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried with anhydrous sodium carbonate, filtered and evaporated to a colorless oil (18 g, (60%). 1H NMR (CDCl3) δ 1.59 (s, 9H), 7.68 (d, J=8 Hz, 2H), 7.75 (d, J=8 Hz, 2H). condensed added to the suspension The reaction vessel was sealed dissolved extracted with ethyl acetate The organic layer was dried with anhydrous sodium carbonate filtered evaporated to a colorless oil (18 g, (60%)

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

Procedure: 4-Iodobenzoic Acid (25 g, 0.10M) was suspended in 200 ml of anhydrous dioxane containing 14 ml of concentrated sulfuric acid. Isobutylene (200 ml) was condensed and added to the suspension. The reaction vessel was sealed and stirred at room temperature for 3 days, during which time most of the material dissolved. The reaction mixture was cautiously poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried with anhydrous sodium carbonate, filtered and evaporated to a colorless oil (18 g, (60%). 1H NMR (CDCl3) δ 1.59 (s, 9H), 7.68 (d, J=8 Hz, 2H), 7.75 (d, J=8 Hz, 2H). condensed added to the suspension The reaction vessel was sealed dissolved extracted with ethyl acetate The organic layer was dried with anhydrous sodium carbonate filtered evaporated to a colorless oil (18 g, (60%)

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

Procedure: A mixture of 1,1-dimethylethyl 4-iodobenzoate (1.1 g, 3.62 mmol, e.g. which can be preparable e.g. according to E. C. Taylor, J. Org. Chem., 1995, 60(24), 7947), 3-butyn-1-ol (0.36 ml, 4.70 mmol, 1.3 equivalents), bis(triphenylphosphine)palladium(II)dichloride [(PPh3)2PdCl2] (0.13 g, 018 mmol, 5 mol %) and copper(I)iodide (0.014 g, 0.07 mmol, 2 mol %) in triethylamine (5 ml) was stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane (50 ml) and washed with water (50 ml). The organic phase was collected by passing through a hydrophobic frit and evaporated to give a dark brown oil (1.3 g). This was purified by flash chromatography on silica gel (100 g silica cartridge, FlashMaster II), eluting with a gradient of 0 to 100% ethyl acetate in cyclohexane over 20 minutes. Fractions containing product (obtained from 4:1 cyclohexane:ethyl acetate eluant) were pooled and evaporated to dryness to give the title compound as a brown gummy oil (0.9 g). 1H NMR (400 MHz, chloroform-d) δ (delta) ppm 1.60 (9H, s), 1.85 (1H, t, J=6.27 Hz), 2.73 (2H, t, J=6.27 Hz), 3.85 (2H, q, J=6.27 Hz), 7.45 (2H, d, J=8.53 Hz), 7.92 (2H, d, J=8.53 Hz). washed with water (50 ml) The organic phase was collected evaporated

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: tert-Butyl 4-iodobenzoate (25.9 g, 85.2 mmol) and 2,2,6,6-tetramethyl-3,5-heptanedione (7.01 mL, 34.1 mmol) were diluted with NMP (70 mL) and bubbled with Argon for 20 minutes. Copper (I) chloride (16.9 g, 170 mmol), ethyl 6-chloro-7-hydroxychroman-4-carboxylate (24.0 g, 93.7 mmol) and cesium carbonate (55.5 g, 170 mmol) were combined and added to the reaction using a small funnel which was rinsed with NMP (30 mL). The reaction was purged for an additional 10 minutes and then heated to 100° C. and stirred for 5 hours under Argon. The reaction was cooled and loaded directly onto a silica plug (2 kg) and eluted with 10% ethyl acetate/hexanes to yield 10 g of crude product. The crude material was purified by silica gel column chromatography, eluting with 5% ethyl acetate/hexanes to 50% ethyl acetate/hexanes to provide the desired product (14 g, 32.3 mmol, 38.0% yield) as a viscous oil. bubbled with Argon for 20 minutes added to the reaction was rinsed with NMP (30 mL) The reaction was purged for an additional 10 minutes The reaction was cooled eluted with 10% ethyl acetate/hexanes to yield 10 g of crude product The crude material was purified by silica gel column chromatography eluting with 5% ethyl acetate/hexanes to 50% ethyl acetate/hexanes

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Iodobenzoic acid (10 g, 40.3 mmol) was dissolved in dry toluene (100 ml, dried over mol. sieves). The solution was heated to 70° C. under a flow of nitrogen. A solution of N,N′-dimethylformamide di-tert-butyl acetal (24.6 g, 121 mmol) in toluene (25 mL) was added over ca. 30 min. The reaction was mixed for 16 h. At some point the heating unit failed, so the reaction cooled from 70° C. to rt. The solution was heated to 70° C. for and mixed for 5 h. The sample was concentrated under vacuum, and AcOEt (400 ml) was added. The solution was then washed with 1:1 sat. NaHCO3/water (150 ml), and sat. NaHCO3, water and sat. NaCl (75 mL each). The organic phase was dried (MgSO4) and concentrated under vacuum to yield light brown oil. The reaction was mixed for 16 h cooled from 70° C. to rt The solution was heated to 70° C. for and mixed for 5 h The sample was concentrated under vacuum, and AcOEt (400 ml) was added The solution was then washed with 1:1 sat. NaHCO3/water (150 ml), and sat. NaHCO3, water and sat. NaCl (75 mL each) The organic phase was dried (MgSO4) concentrated under vacuum to yield light brown oil

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of tert-butyl 4-iodobenzoate (0.304 g, 1.0 mmol) in 10 mL THF at −40° C. was added a solution of isopropylmagnesium bromide (1.05 ml, 1.05 mmol, 1M in THF) dropwise under argon. After stirring for 1 hour at −40° C., ethyl benzoylformate (0.175 ml, 1.1 mmol) was added dropwise and the cold bath allowed to warm to room temperature over a 40 min. period. The reaction was quenched by the addition of an aqueous solution of 20% ammonium chloride. The reaction mixture was extracted twice with ether, the combined organic layers washed with brine, dried over Na2SO4 and was evaporated to give an oil that was chromatographed on 10 g silica gel using a gradient elution from 0-40% EtOAc in Hexanes. Product containing fractions were combined and concentrated to give (0.078 g, 22%) ethyl (4-tert-butyloxycarbonylphenyl)(hydroxy)phenylacetate as a colorless oil. NMR, 400 MHz (CDCl3) 7.95 ppm (d, J=8.55 Hz, 2H), 7.52 ppm (d, J=8.55 Hz, 2H), 7.30-7.40 ppm (m, 5H), 4.33 ppm (q, J=7.08 Hz, 2H), 4.29 ppm (s, OH, 1H), 1.59 ppm (s, 9H), 1.28 ppm (t, J=7.08 Hz, 3H). to warm to room temperature over a 40 min. period The reaction was quenched by the addition of an aqueous solution of 20% ammonium chloride The reaction mixture was extracted twice with ether the combined organic layers washed with brine dried over Na2SO4 was evaporated to give an oil that was chromatographed on 10 g silica gel using a gradient elution from 0-40% EtOAc in Hexanes Product containing fractions concentrated