Toluene → 6-Bromoquinoline-3-carbaldehyde

Participants

Reaction Conditions

Reaction Steps

5-Bromo-2-nitrobenzaldehyde 1 (6.03 g, 26.2 mmol) was dissolved in MeOH (200 mL) and treated with 5N HCl (10 mL). The mixture was heated to 70° C. and iron powder (7.32 g, 131 mmol) was added in five portions every 5 min. Upon completion (by TLC) the reaction was cooled and DCM (200 mL) was added before filtering through a pad of celite. The filtrate was concentrated under reduced pressure to 150 mL. To this material, a solution of 1,1,3,3-tetramethoxypropane (9.52 ml, 57.7 mmol) in 5N HCl (10 mL) pre-mixed for 45 min was added. The reaction mixture was stirred at 80° C. for 60 min. Toluene (100 mL) and acetic acid (40 mL) were added and the solution was heated to 110° C. for 3 h, then cooled and evaporated to dryness under reduced pressure. The crude material was purified using silica chromatography (20-60% ethyl acetate in hexane gradient) to give 6-bromoquinoline-3-carbaldehyde 2. Step 2 6-Bromoquinoline-3-carbaldehyde 2 (2.8 g, 12.0 mmol) and methyl(triphenylphosphoranylidene)acetate (4.0 g, 12.0 mmol) were dissolved in dry THF (50 mL) and heated to 50° C. After 40 min the solution was evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to 60% ethyl acetate in hexane gradient) gave methyl 3-(6-bromoquinolin-3-yl)acrylate 3 as a mixture of E and Z isomers. Step 3 Methyl 3-(6-bromoquinolin-3-yl)acrylate 3 (0.91 g, 3.1 mmol), 2-methylphenyl boronic acid (R1 substituted ring A in 4 above; 0.61 g), potassium acetate (1.0 g) and bis(4-(di-tert-butylphosphino)-N,N-dimethylbenzenamine)dichloropalladium (II) (0.19 g) were suspended in ethanol (70 mL) and water (5 mL) and heated to reflux for 90 min. LC/MS showed the bromoquinoline had been consumed the reaction was evaporated to dryness under reduced pressure. The crude was partitioned between ethyl acetate and water. The organic layer was separated and dried with magnesium sulfate, evaporated to dryness under reduced pressure and purified using silica chromatography (hexane to ethyl acetate gradient) to give methyl 3-(6-o-tolylquinolin-3-yl)acrylate 4 (representative compound 4 wherein ring A is ortho-toluene).

Provenance & Evidence