Trifluoroacetic acid → 2-[4-(2-Diisopropylamino-ethoxy)-3-methoxy-phenyl]-2,3-dihydro-isoindol-1-one

HRID 1353064Notes

Reaction equation

HRID 1353064 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[N:6]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])=[C:14]([O:28][CH3:29])[CH:13]=1)[C:5]2=[O:30].[BH4-].[Na+].C(N(C(C)C)CCOC1C=CC(N2C(O)C3C(=CC=CC=3)C2=O)=CC=1OC)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C1COCC1.C(O)(=O)C.ClCCl.C(O)(C)C>[CH:25]([N:21]([CH:22]([CH3:24])[CH3:23])[CH2:20][CH2:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([N:6]2[CH2:7][C:8]3[C:4](=[CH:3][CH:2]=[CH:10][CH:9]=3)[C:5]2=[O:30])=[CH:13][C:14]=1[O:28][CH3:29])([CH3:26])[CH3:27]

Participants

10

Reactant 5

HCID 6422Trifluoroacetic acidHCID 12052TriethylsilaneHCID 4311764Sodium borohydrideHCID 179893652-[4-(2-Diisopropylamino-ethoxy)-3-methoxy-phenyl]-3-hydroxy-2,3-dihydro-isoindol-1-oneHCID 17989375HCID 17989375, compound

Product 1

HCID 179893332-[4-(2-Diisopropylamino-ethoxy)-3-methoxy-phenyl]-2,3-dihydro-isoindol-1-one

Reagents, catalysts & solvents 4

HCID 176Acetic AcidCatalystHCID 3776IsopropanolSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

A solution of 5-bromo-2-[4-(2-diisopropylamino-ethoxy)-3-methoxy-phenyl]-isoindole-1,3-dione [Example A1] (66 mg, 0.14 mmol) was dissolved in THF (ml) and treated with sodium borohydride (5.2 mg, 0.14 mmol). After stirring for 2 hours, the mixture was treated with isopropanol, stirred for a further 1 h then treated with acetic acid (2 drops) and stirred for 16 h at RT. The solvent was removed and the residue purified by flash chromatography to give an approximately 1:1 mixture of the 5- and 6-bromo substituted isomers of 2-[4-(2-diisopropylamino-ethoxy)-3-methoxy-phenyl]-3-hydroxy-2,3-dihydro-isoindol-1-one (37 mg). This material was dissolved in dichloromethane (2 ml) and treated with triethylsilane (1 ml) and trifluoroacetic acid (0.5 ml). The mixture was stirred at RT for 16 hours, the solvents were removed in vacuo and the residue purified by flash chromatography on silica gel (eluting with methanol-dichloromethane-aq. ammonia) to obtain 2-[4-(2-diisopropylamino-ethoxy)-3-methoxy-phenyl]-2,3-dihydro-isoindol-1-one as an approximately 1:1 mixture of 5- and 6-bromo isomers (33 mg). A solution of this material in benzene (5 ml) was treated with aqueous sodium carbonate (2M, 1 ml), ethanol (1 ml), phenylboronic acid (9 mg, 0.07 mmol) and tetrakis(triphenylphosphine)palladium[0] (10 mg) and the mixture heated to reflux for 16 h. The less dense phase was decanted, filtered through filter-aid (washing with dichloromethane), the filtrate evaporated and purified by flash chromatography on silica gel (eluting with dichloromethane-methanol-aq. ammonia) and reverse phase preparative chromatography (aq. MeCN, TFA) to give the title compounds as an approximately 1:1 mixture of isomers as their TFA salts;

Workup

  1. stirringstirred for a further 1 h
  2. stirringstirred for 16 h at RT
  3. customThe solvent was removed
  4. customthe residue purified by flash chromatography
  5. customto give
  6. stirringThe mixture was stirred at RT for 16 hours
  7. customthe solvents were removed in vacuo
  8. customthe residue purified by flash chromatography on silica gel (eluting with methanol-dichloromethane-aq. ammonia)

Sources & evidence

ORD record
ord-ff0b98be29de41549ab7f2356b6d6f51
Source dataset
uspto-grants-2007_05
Patent number
US07220777B2

Reaction notes

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