Methanol → (R)-2-(5-Nitro-1-oxoisoquinolin-2(1H)-yl)propyl acetate

Participants

Reaction Conditions

Reaction Steps

A mixture of 5-nitro-isochromen-1-one (6.81 g, 0.0320 mol), (2R)-2-Aminopropan-1-ol (5.0 mL, 0.064 mol) and methanol (210 mL, 5.1 mol) was heated at reflux for 1 hour. 10 ml of Triethylamine was added and the reaction temperature was lowered to 60° C. and stirred at this temperature for 3 hours. LC-MS analysis showed the starting material was consumed. The reaction mixture was reduced in vacuo and the reaction flask was placed under high vacuum for 1 hour. The black residue was taken up in a mixture of methylene chloride (200 mL, 2 mol) and N,N-dimethylformamide (7.6 mL, 0.098 mol). Acetyl chloride (9.1 mL, 0.13 mol) and N,N-diisopropylethylamine (14 mL, 0.078 mol) were added and the reaction was allowed to stir at 40° C. for 5 hours. LC-MS analysis showed that the reaction did not go to completion. Two equivalents of acetyl chloride and 1 equivalent of N,N-Diisopropylamine were added and the reaction was left to stir overnight at room temperature. After analysis showed that less than 50% of the starting material was consumed, 4 more equivalents of acetyl chloride and 2 equivalents of N,N-diisopropylethylamine were added and the reaction temperature raised to 40° C. The reaction was allowed to stir for 4 more hours. LC-MS analysis showed the presence of approximately 5% of unreacted material. The flask was cooled to room temperature and reduced in vacuo. The dark yellow residue was taken up in 300 ml ethyl acetate and washed 3 times with 50 ml water. Saturated sodium chloride solution was added to remove any emulsion formed between the layers. Most of the desired product stayed in the organic layer although a minimal amount was in the aqueous layer. The organic layer was dried with sodium sulfate and reduced in vacuo to produce a brownish-yellow oil which was purified via flash chromatography using a 120 g normal phase silica column and an Ethyl acetate:Hexane gradient (0-60%). The pure fractions were collected and volatiles were removed under reduced pressure to give a yellow oil. M+1=291.0 1H-NMR (400 MHz, DMSO-d6) δ 8.63 (dq, 1H), 8.48 (dd, 1H), 7.83 (d, 1H, J=8.02 Hz), 7.69 (t, 1H, J=8.02 Hz), 7.09 (dd, 1H, J=8.02 Hz), 5.32-5.22 (m, 1H), 4.33 (d, 2H, J=6.26 Hz), 1.93 (s, 3H), 1.40 (d, 3H, J=7.11 Hz).

Provenance & Evidence