5-IODO-2-METHOXYBENZALDEHYDE

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

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

Procedure: A solution of 1.0 grams (3.82 mmol) of the above aldehyde, 0.85 mL of ethylene glycol, 20 mg of p-toluenesulfonic acid and 42 mL of toluene was refluxed under nitrogen for 18 hours, cooled and concentrated in vacuo. The residue was redissolved in 50 mL of CH2Cl2, washed with saturated aqueous NaHCO3, dried over MgSO4 and concentrated to an oil. Chromatography on silica gel (10% ethyl acetate (EtOAc): 90% hexane) gave 2-(5-iodo-2-methoxyphenyl)-1,3-dioxolane as a clear oil, 0.68 grams (58%). cooled concentrated in vacuo The residue was redissolved in 50 mL of CH2Cl2 washed with saturated aqueous NaHCO3 dried over MgSO4 concentrated to an oil

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

Procedure: A solution of 1.0 grams (3.82 mmol) of the above aldehyde, 0.85 mL of ethylene glycol, 20 mg of p-toluenesulfonic acid and 42 mL of toluene was refluxed under nitrogen for 18 hours, cooled and concentrated in vacuo. The residue was redissolved in 50 mL of CH2Cl2, washed with saturated aqueous NaHCO3, dried over MgSO4 and concentrated to an oil. Chromatography on silica gel (10% ethyl acetate (EtOAc): 90% hexane) gave 2-(5-iodo-2-methoxyphenyl)-1,3-dioxolane as a clear oil, 0.68 grams (58%). cooled concentrated in vacuo The residue was redissolved in 50 mL of CH2Cl2 washed with saturated aqueous NaHCO3 dried over MgSO4 concentrated to an oil

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2.04 grams (8.72 mmol) of 4-iodoanisole in 36 mL of CH2Cl2, cooled to 0° C., was added dropwise 2.0 mL (18.7 mmol) of titanium tetrachloride. After stirring for 30 min., 0.93 mL (10.3 mmol) of α, α-dichloromethyl methyl ether was added and the reaction maintained at 0° C. for another 2 hours. The reaction mixture was then poured with stirring into a mixture of 50 mL of CH2Cl2 and 50 mL of saturated aqueous sodium bicarbonate (NaHCO3). After 30 min., this was filtered through diatomaceous earth, the organic layer was separated, the aqueous layer was twice extracted with CH2Cl2, and all of the organic layers were combined, dried with MgSO4 and concentrated in vacuo. The crude residue was recrystallized from ethanol (EtOH) to give 5-iodo-2-methoxybenzaldehyde as pale yellow needles, 1.37 grams (60%). The reaction mixture was then poured After 30 min. this was filtered through diatomaceous earth the organic layer was separated the aqueous layer was twice extracted with CH2Cl2 dried with MgSO4 concentrated in vacuo The crude residue was recrystallized from ethanol (EtOH)

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

Conditions: temp:67.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Methoxy-5-iodobenzaldehyde (1.0 g, 3.82 mmol) is dissolved in 25 ml of acetonitrile and oxygen is removed by bubbling nitrogen through the solution. Triethylamine (3.71 ml, 26.7 mmol) and methyl acrylate (0.686, ml, 7.63 mmol) are added dropwise with stirring to the solution, followed by four portions of 0.0214 g of tri-o-tolylphosphine (0.095 mmol) and 0.008 g of palladium (II) acetate (0.047 mmol) at 1 hour intervals. The mixture is then heated at 65-70° C. for 4 hours, volatiles are removed by distillation and the residue is dissolved in dichloromethane. The resulting solution is percolated through silica gel eluting with a mixture of hexane-ethyl acetate (6:4). The percolate is evaporated to dryness, re-dissolved in 20 ml of methanol and 10 ml of 20% aqueous potassium carbonate solution added. The mixture is stirred for 6 hours at room temperature and concentrated under reduced pressure to a third of its volume. The solution is taken to a pH value of 1 with concentrated hydrochloride acid and the precipitate is filtered and recrystallized from isopropanol, to give 0.472 g of 3-formyl-4-methoxycinnamic acid (2.29 mmol) as a crystalline white solid. A second harvest obtained by concentration of the mother liquor gave an additional 0.105 g. oxygen is removed by bubbling nitrogen through the solution volatiles are removed by distillation the residue is dissolved in dichloromethane The resulting solution is percolated through silica gel eluting with a mixture of hexane-ethyl acetate (6:4) The percolate is evaporated to dryness re-dissolved in 20 ml of methanol 10 ml of 20% aqueous potassium carbonate solution added The mixture is stirred for 6 hours at room temperature concentrated under reduced pressure to a third of its volume the precipitate is filtered recrystallized from isopropanol

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

Procedure: In order to implement this procedure, 2-methoxy-5-iodobenzaldehyde (V) was used as starting material, which, through a Heck-type reaction with methyl acrylate followed by in situ hydrolysis of the ester gave 3-formyl-4-methoxycinnamic acid (VI). Alternatively, the coupling reaction may be carried out with acrylic acid, therefore avoiding the hydrolysis step. The 3-formyl-4-methoxycinnamic acid (VI) was reacted with 3 equivalents of Deoxo-Fluor® solution in toluene or tetrahydrofuran, preferably Deoxo-Fluor® 50% in toluene. Dichloromethane the is the preferred reaction solvent between 0° and a reflux temperature, preferably 250. Upon completion of the reaction (determined by thin-layer chromatography) the mixture is diluted with dichloromethane and percolated through a silica gel bed under an inert atmosphere to remove the by-products from the fluorination reaction, giving a solution of 3-difluoromethyl-4-methoxy cinnamyl fluoride (VII).

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

Procedure: A solution of 1.0 grams (3.82 mmol) of the above aldehyde, 0.85 mL of ethylene glycol, 20 mg of p-toluenesulfonic acid and 42 mL of toluene was refluxed under nitrogen for 18 hours, cooled and concentrated in vacuo. The residue was redissolved in 50 mL of CH2Cl2, washed with saturated aqueous NaHCO3, dried over MgSO4 and concentrated to an oil. Chromatography on silica gel (10% ethyl acetate (EtOAc): 90% hexane) gave 2-(5-iodo-2-methoxyphenyl)-1,3-dioxolane as a clear oil, 0.68 grams (58%). cooled concentrated in vacuo The residue was redissolved in 50 mL of CH2Cl2 washed with saturated aqueous NaHCO3 dried over MgSO4 concentrated to an oil

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2.04 grams (8.72 mmol) of 4-iodoanisole in 36 mL of CH2Cl2, cooled to 0° C., was added dropwise 2.0 mL (18.7 mmol) of titanium tetrachloride. After stirring for 30 min., 0.93 mL (10.3 mmol) of α,α-dichloromethyl methyl ether was added and the reaction maintained at 0° C. for another 2 hours. The reaction mixture was then poured with stirring into a mixture of 50 mL of CH2 Cl2 and 50 mL of saturated aqueous sodium bicarbonate (NaHCO3). After 30 min., this was filtered through diatomaceous earth, the organic layer was separated, the aqueous layer was twice extracted with CH2 Cl2, and all of the organic layers were combined, dried with MgSO4 and concentrated in vacuo. The crude residue was recrystallized from ethanol (EtOH) to give 5-iodo-2-methoxybenzaldehyde as pale yellow needles, 1.37 grams (60%). The reaction mixture was then poured After 30 min. this was filtered through diatomaceous earth the organic layer was separated the aqueous layer was twice extracted with CH2 Cl2 dried with MgSO4 concentrated in vacuo The crude residue was recrystallized from ethanol (EtOH)

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

Procedure: To a stirred solution of 67 (500 mg, 1.9 mmol) and ammonium acetate (1.5 g, 19.4 mmol) in dry methanol (6 mL) NaCNBH3 (170 mg, 2.66 mmol) was added in one portion. The resulting mixture was stirred at room temperature for 48 h. Concentrated HCl was added until pH<2. The methanol was evaporated and the resulting white residue was dissolved in water (10 mL) and washed with Et2O (2×10 mL). The aqueous phase was then basified with aqueous KOH (45%), saturated with NaCl and extracted with CH2Cl2 (10 mL×4). The combined organic phases were dried over Na2SO4, filtered and concentrated to give 68 as a yellow oil (200 mg, 40%). 1H NMR (CDCl3, 300 MHz) δ 7.55-7.45 (m, 2H), 6.46-6.58 (m, 1H), 3.82-3.72 (m, 5H), 1.63 (br s, 2H). MS (m/e) (positive FAB) 264.1 (M+H)+, m.p. 95-97° C. The methanol was evaporated the resulting white residue was dissolved in water (10 mL) washed with Et2O (2×10 mL) extracted with CH2Cl2 (10 mL×4) The combined organic phases were dried over Na2SO4 filtered concentrated

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

Procedure: 5-Iodo-salicylaldehyde (1.0 g, 4.0 mmol) was dissolved in DMF (10 mL) and to the stirred solution K2CO3 (0.828 g, 6.0 mmol) and CH3I (1.14 g, 8.0 mmol) were added. The mixture was stirred at room temperature overnight. The suspension was concentrated in vacuo, and the residue was partitioned between water (30 mL) and Et2O (30 mL). The aqueous phase was separated and extracted with ether (20 mL×2). The combined organic phases were dried over Na2SO4, filtered and concentrated to give 67 (1.02 g, 98%). 1H NMR (CDCl3, 300 MHz) δ 10.34(s, 1H), 7.82-7.78 (m, 1H), 7.26 (s, 1H), 6.78 (d, J=8.7 Hz, 1H), 3.91 (s, 3H). MS (m/e) (positive FAB) 262.1 (M+H)+, m.p. 140-142° C. were added The suspension was concentrated in vacuo the residue was partitioned between water (30 mL) and Et2O (30 mL) The aqueous phase was separated extracted with ether (20 mL×2) The combined organic phases were dried over Na2SO4 filtered concentrated

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

Procedure: A solution of 1.0 grams (3.82 mmol) of the above aldehyde, 0.85 mL of ethylene glycol, 20 mg of p-toluenesulfonic acid and 42 mL of toluene was refluxed under nitrogen for 18 hours, cooled and concentrated in vacuo. The residue was redissolved in 50 mL of CH2Cl2, washed with saturated aqueous NaHCO3, dried over MgSO4 and concentrated to an oil. Chromatography on silica gel (10% ethyl acetate (EtOAc): 90% hexane) gave 2-(5-iodo-2-methoxyphenyl)-1,3-dioxolane as a clear oil, 0.68 grams (58%). cooled concentrated in vacuo The residue was redissolved in 50 mL of CH2Cl2 washed with saturated aqueous NaHCO3 dried over MgSO4 concentrated to an oil