N-Boc-pyrrolidine → Tert-butyl 2-(6-(benzylthio)isoquinolin-1-yl)pyrrolidine-1-carboxylate

HRID 1473397Notes

Reaction equation

HRID 1473397 reaction equation
[N:1]1([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])(CC)C.[CH2:18]([S:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[C:32](Cl)=[N:31][CH:30]=[CH:29]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.C1COCC1>[CH2:18]([S:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[C:32]([CH:2]1[CH2:3][CH2:4][CH2:5][N:1]1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[N:31][CH:30]=[CH:29]2)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1

Participants

8

Reactant 3

HCID 643455N-Boc-pyrrolidineHCID 866874176-(Benzylthio)-1-chloroisoquinolineHCID 178418400CID 53628100

Product 1

HCID 86687441Tert-butyl 2-(6-(benzylthio)isoquinolin-1-yl)pyrrolidine-1-carboxylate

Reagents, catalysts & solvents 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 3007855ZincchlorideCatalystHCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-30 °C

Procedure

A 100-mL round-bottom flask was charged with tert-butyl 1-pyrrolidinecarboxylate (1.625 ml, 9.27 mmol) and THF (23.33 ml) to give a clear solution. The flask was flushed with Ar (g), then cooled in a −30° C. dry ice-acetone bath for 10 min. Sec-butyllithium (1.4 M in cyclohexane) (8.75 ml, 12.25 mmol) was added drop wise over 5 min. The resulting mixture was stirred for 10 minutes at −30° C., then zinc chloride (1.0 M in diethyl ether) (7.00 ml, 7.00 mmol) was added drop wise. The reaction was stirred for 5 minutes, then the cooling bath was removed. After 25 min, a solid mixture of 6-(benzylthio)-1-chloroisoquinoline (from Intermediate LLL, step 1; 1.0 g, 3.50 mmol), Pd(Ph3P)4 (0.809 g, 0.700 mmol), and copper(i) iodide (0.333 g, 1.750 mmol) was added in one portion. The reaction was capped and stirred at 60° C. for one hour. The reaction was filtered through a pad of diatomaceous earth, washing thoroughly with ethyl acetate. The filtrate was concentrated and purified via column chromatography (80 g silica gel column, gradient elution 0 to 100% EtOAc:Heptane followed by a 20% MeOH/EtOAc flush) to afford tert-butyl 2-(6-(benzylthio)isoquinolin-1-yl)pyrrolidine-1-carboxylate as a yellow solid. (ESI) 421.3 (M+H)+.

Workup

  1. customto give a clear solution
  2. customThe flask was flushed with Ar (g)
  3. stirringThe reaction was stirred for 5 minutes
  4. customthe cooling bath was removed
  5. waitAfter 25 min
  6. additionwas added in one portion
  7. customThe reaction was capped
  8. stirringstirred at 60° C. for one hour
  9. filtrationThe reaction was filtered through a pad of diatomaceous earth
  10. washwashing thoroughly with ethyl acetate
  11. concentrationThe filtrate was concentrated
  12. custompurified via column chromatography (
  13. wash80 g silica gel column, gradient elution 0 to 100% EtOAc
  14. customflush)

Sources & evidence

ORD record
ord-a557d6ee4f1c4342aa906a043753a3b4
Source dataset
uspto-grants-2015_04
Patent number
US09012443B2

Reaction notes

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