Реакция #69683

Уравнение реакции

2-(2,4-dimethoxybenzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid methyl ester

lithium hydroxide monohydrate

2-(2,4-dimethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid lithium salt

morpholine

EDAC

HOBt

→

[2-(2,4-dimethoxybenzyl)-2,3-dihydro-1H-isoindol-5-yl]-morpholin-4-yl-methanone

Растворители

THF MeOH—H2O

DMF

Условия реакции

Обработка

1. 1
   workup.STIRRINGstirring
2. 2
   workup.WAITcontinued for 7 hours
3. 3
   ДругоеThe reaction was evaporated
4. 4
   Другоеthen re-evaporated with MeOH/toluene (×2)
5. 5
   workup.STIRRINGwas stirred at room temperature overnight
6. 6
   Другоеthen evaporated in vacuo
7. 7
   ДругоеThe residue was partitioned between EtOAc and saturated NaHCO3
8. 8
   Другоеthe EtOAc layer was separated
9. 9
   Промывкаwashed with brine
10. 10
    Сушкаdried (MgSO4)
11. 11
    Другоеevaporated
12. 12
    ДругоеPurification by flash column chromatography (2%

Методика

A mixture of 2-(2,4-dimethoxybenzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid methyl ester (4.65 g; 14.2 mmol) and lithium hydroxide monohydrate (660 mg; 1.1 equiv.) in 4:1:1 THF-MeOH—H2O (60 ml) was stirred at room temperature overnight. A further 170 mg of base were added and stirring continued for 7 hours. The reaction was evaporated then re-evaporated with MeOH/toluene (×2). A mixture of the crude 2-(2,4-dimethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid lithium salt (1.5 g; 4.7 mmol), morpholine (820 μl; 2 equiv.), EDAC (1.1 g; 1.2 equiv.) and HOBt (760 mg; 1.2 equiv.) in DMF (25 ml) was stirred at room temperature overnight then evaporated in vacuo. The residue was partitioned between EtOAc and saturated NaHCO3, the EtOAc layer was separated, washed with brine, dried (MgSO4) and evaporated. Purification by flash column chromatography (2% then 5% MeOH/DCM as eluant) gave 1.1 g of [2-(2,4-dimethoxybenzyl)-2,3-dihydro-1H-isoindol-5-yl]-morpholin-4-yl-methanone as a red/brown gum. 1H NMR (DMSO-d6) 7.30-7.18 (4H, m), 6.56 (1H, d), 6.52 (1H, dd), 3.85 (4H, s), 3.78 (5H, m), 3.73 (3H, s).

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