2-Iodo-N-isopropyl-5-methoxybenzamide as a highly reactive and environmentally benign catalyst for alcohol oxidation

Several N-isopropyliodobenzamides were evaluated as catalysts for the oxidation of benzhydrol to benzophenone in the presence of Oxone® (2KHSO5·KHSO4·K2SO4) as a co-oxidant at room temperature. A study on the substituent effect of the benzene ring of N-isopropyl-2-iodobenzamide on the oxidation revealed that its reactivity increased in the following order of substitution: 5-NO2 < 5-CO2Me, 3-OMe < 5-OAc < 5-Cl < H, 4-OMe < 5-Me < 5-OMe. The oxidation of various benzylic and aliphatic alcohols using a catalytic amount of the most reactive 5-methoxy derivative successfully resulted in moderate to excellent yields of the corresponding carbonyl compounds. The high reactivity of the 5-methoxy derivative at room temperature is a result of the rapid generation of the pentavalent species from the trivalent species during the reaction. 5-Methoxy-2-iodobenzamide would be an efficient and environmentally benign catalyst for the oxidation of alcohols, especially benzylic alcohols.


2-Iodo-N-isopropyl-5-methoxybenzamide (17)
A solution of sodium nitrite (1.56 g, 22.5 mmol) in water (4.5 mL) was added dropwise to a solution of 2-amino-5-hydroxybenzoic acid (2.30 g, 15.0 mmol) in a mixture of water (20 mL) and concentrated sulfuric acid (2.8 mL) at 0 ºC. After stirring for 5 min, a solution of potassium iodide (3.74 g, 22.5 mmol) in water (4.5 mL) was added dropwise to the mixture. The resulting solution was heated at 100 ºC with stirring for 1 h and then allowed to cool to room temperature. After stirring for 14 h, the mixture was cooled to 0 ºC. The precipitate was collected by filtration, washed with cold water, and dried in vacuo to give crude 5-hydroxy-2-iodobenzoic acid (3.26 g) as a brown solid, which was dissolved in anhydrous DMF (65 mL).
To this solution were added potassium carbonate (12.8 g, 92.7 mmol) and iodomethane (5.8 mL, 92.7 mmol) at room temperature under a nitrogen atmosphere. After stirring for 12 h, the mixture was filtered through a pad of celite and the pad was washed with Et 2 O. The filtrate was acidified with 10% HCl and then extracted with Et 2 O. The organic layer was washed with saturated aqueous NaHCO 3 , water, and brine, dried over Na 2 SO 4 ; filtered; and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/EtOAc = 4/1) to give methyl 2-iodo-5-methoxybenzoate [2] (3.44 g, 79% in 2 steps) as a pale yellow oil: 1 H NMR (500 MHz, CDCl 3 ) δ 7.83 (1H, d, J = 8.6 Hz), 7.35 (1H, d, J = 2.9 Hz), 6.75 (1H, dd, J = 8.6, 2.9 Hz), 3.93 (3H, s), 3.82 (3H, s). To a solution of methyl 2-iodo-5-methoxybenzoate (1.21 g, 4.13 mmol) in a 3:1 mixture of MeOH and water (47 mL) was added lithium hydroxide hydrate (260 mg, 6.2 mmol) at room temperature. After stirring for 15 h, the resulting mixture was diluted with saturated aqueous NaHCO 3 and washed with CH 2 Cl 2 . The aqueous layer was acidified with 10% HCl and then extraceted with CH 2 Cl 2 . The last organic layer was washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was dissolved in thionyl chloride (5.1 mL). After heating at reflux with stirring for 2 h, the resulting solution was concentrated under reduced pressure. The remaining thionyl chloride was removed by azeotropic distillation with benzene. The residue was dissolved in anhydrous CH 2 Cl 2 (13.5 mL). To the mixture were added isopropylamine (290 mg, 4.9 mmol) and triethylamine (1.24 g, 12.2 mmol) at 0 °C under a nitrogen atmosphere.
After stirring at room temperature for 6 h, the resulting solution was diluted with EtOAc. The mixture was washed with 10% HCl, saturated aqueous NaHCO 3 , water, and brine; dried over Na 2 SO 4 ; filtered; and concentrated under reduced S3 pressure. The residue was purified by recrystallization from hexane and CHCl 3 to give 17 (991 mg, 75% in 3 steps) as
After stirring under reflux conditions for 2 h, the resulting mixture was concentrated under reduced pressure. The remaining thionyl chloride was removed by azeotropic distillation with benzene. The residue was dissolved in anhydrous CH 2 Cl 2 (3 mL). To the mixture were added isopropylamine (56 mg, 0.95 mmol) and triethylamine (240 mg, 2.37 mmol) at 0 °C under a nitrogen atmosphere. After stirring at room temperature for 13 h, the resulting solution was diluted with EtOAc. The mixture was washed with 10% HCl, saturated aqueous NaHCO 3 , water, and brine; dried over Na 2 SO 4 ; filtered; and concentrated under reduced pressure. The residue was purified by recrystallization from hexane and CHCl 3 to give 19 (138 mg, 21% in 3 steps) as colorless needles: mp 160. 5

2-Iodo-N-isopropyl-4-methoxybenzamide (24)
A solution of sodium nitrite (105 mg, 1.52 mmol) in water (0.76 mL) was added dropwise to a solution of 2-amino-4-methoxybenzoic acid (127 mg, 0.76 mmol) in a mixture of water (1.9 mL), acetone (0.6 mL), and concentrated HCl (0.4 mL) at 0 ºC. After stirring for 2 h, potassium iodide (252 mg, 1.52 mmol) was added to the mixture. The resulting solution was stirred at 0 ºC for 0.5 h, heated at 90 ºC for 10 min, and then allowed to cool to room temperature. The mixture was extracted with CHCl 3 . The organic layer was washed with saturated aqueous Na 2 S 2 O 3 and water, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give crude 2-iodo-4-methoxybenzoic acid (829 mg) as a colorless solid, which was suspended in thionyl chloride (1.6 mL). The mixture was heated at reflux with stirring for 2 h. The resulting solution was concentrated under reduced pressure. The remaining thionyl chloride was removed by azeotropic distillation with benzene. The residue was dissolved in anhydrous CH 2 Cl 2 (2. was added to the mixture. The resulting solution was stirred at 0 °C for 0.5 h, heated at 90 °C for 10 min, and then allowed to cool to room temperature. The mixture was extracted with CHCl 3 . The organic layer was washed with saturated aqueous Na 2 S 2 O 3 and water, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by recrystallization from hexane and CHCl 3 to give 2-iodo-3-methoxybenzoic acid [6] (187 mg, 56%) as a colorless solid: 1  Typical experimental procedure for oxidation of secondary alcohols 14a-f [7] Secondary alcohol 14 (0.50 mmol) was added to a solution of the catalyst (0.15 mmol) and Bu 4 NHSO 4 (170 mg, 0.50 mmol) in a mixture of MeNO 2 (1.6 mL) and water (0.6 mL), followed by Oxone ® (768 mg. 1.25 mmol) at room temperature (25 ºC). After 14 was completely consumed as indicated by TLC, the resulting mixture was diluted with EtOAc and washed with water. The organic layer was then washed with saturated aqueous Na 2 S 2 O 3 and saturated aqueous NaHCO 3 , dried over MgSO 4 ; filtered; and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give pure ketone 15 and the catalyst. All ketones 15 were directly identified by comparison with the commercial samples. Typical experimental procedure for oxidation of primary alcohols 14g-k [7] Primary alcohol 14 (0.50 mmol) was added to a solution of the catalyst (0.15 mmol) and Bu 4 NHSO 4 (170 mg, 0.50 mmol) in a mixture of MeNO 2 (1.6 mL) and water (0.6 mL), followed by Oxone ® (768 mg. 1.25 mmol) at room temperature (25 °C). After 14 were completely consumed as indicated by TLC, the resulting mixture was diluted with EtOAc, water, and saturated aqueous Na 2 S 2 O 3 . The organic layer was then washed with saturated aqueous Na 2 S 2 O 3 , saturated aqueous NaHCO 3 , and brine; dried over MgSO 4 ; filtered; and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the catalyst. The combined aqueous layers were acidified with 10% HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give pure carboxylic acid 26. All carboxylic acids 26 were directly identified by comparison with the commercial samples.