Ammonium Hydroxide → 5-(imino-morpholin-4-yl-methyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester

HRID 8731Notes

Reaction equation

HRID 8731 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2Br)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[N:24]1([C:30]#[N:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.[Cl-].[NH4+].[OH-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[C:30](=[NH:31])[N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

7

Reactant 5

HCID 14923Ammonium HydroxideHCID 25517Ammonium ChlorideHCID 737384-MorpholinecarbonitrileHCID 18315369tert-Butyl 5-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylateHCID 178418339Butyllithium

Product 1

HCID 695955285-(imino-morpholin-4-yl-methyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl esterYield 54.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A solution of 5-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester 26a (0.4 g, 1.28 mmol) in tetrahydrofuran (10 mL) under argon, was cooled to −78° C. A solution of 2.5 M n-butyllithium in hexanes (0.61 mL, 1.53 mmol) was added dropwise over 5 min. After the addition, stirring was continued for 15 min at −78° C. 4-Morpholinecarbonitrile (0.172 g, 1.53 mmol) was added all at once and reaction continued for 90 min at that temperature. A saturated ammonium chloride solution was added at −78° C. After warming to room temperature the mixture was made basic (pH 9) with concentrated ammonium hydroxide and the product was extracted with dichloromethane. The combined organics were dried with magnesium sulfate, the solvent was evaporated and the residue purified by flash chromatography eluting with 6% methanol in dichloromethane containing 0.6% of ammonium hydroxide, to yield 0.24 g of 5-(imino-morpholin-4-yl-methyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester 27a.

Workup

  1. additionAfter the addition
  2. customreaction
  3. waitcontinued for 90 min at that temperature
  4. extractionthe product was extracted with dichloromethane
  5. dry with materialThe combined organics were dried with magnesium sulfate
  6. customthe solvent was evaporated
  7. customthe residue purified by flash chromatography
  8. washeluting with 6% methanol in dichloromethane containing 0.6% of ammonium hydroxide

Sources & evidence

ORD record
ord-f8a4a9cfb4e24026804bd3e8127fe6d1
Source dataset
uspto-grants-2006_08
Patent number
US07091200B2

Reaction notes

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