1-(Bromomethyl)-3-chlorobenzene → 4-(3-Chlorobenzyl)-4-(2-methylpropane-2-sulphinylamino)-piperidine-1-carboxylic acid tert-butyl ester

HRID 2405997Notes

Reaction equation

HRID 2405997 reaction equation
[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:15]([S:19]([NH2:21])=[O:20])([CH3:18])([CH3:17])[CH3:16].[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[CH2:26][Mg]Br.ClC1C=C(C=CC=1)CBr.[Mg]>C1COCC1.[Cl-].[Na+].O.C(OCC)(=O)C.C(OCC)C.[Cl-].[NH4+].[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:26][C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([Cl:22])[CH:24]=2)([NH:21][S:19]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:20])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]

Participants

12

Reactant 5

HCID 698381-(Bromomethyl)-3-chlorobenzeneHCID 3382465Tert-ButanesulfinamideHCID 5462224MagnesiumHCID 7577838tert-Butyl 2-oxopiperidine-1-carboxylateHCID 178478084HCID 178478084, compound

Product 1

HCID 668730384-(3-Chlorobenzyl)-4-(2-methylpropane-2-sulphinylamino)-piperidine-1-carboxylic acid tert-butyl esterYield 31.5%

Reagents, catalysts & solvents 6

HCID 76524Titanium tetraethoxideCatalystHCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolventHCID 25517Ammonium ChlorideSolventHCID 57417360Sodium chloride; waterSolvent

Procedure

A solution of N—BOC-piperidone (0.205 g, 1.03 mmol), t-butylsulphinamide (0.13 g, 1.07 mmol) and titanium tetraethoxide (0.42 ml, 2.0 mmol) in dry THF (5 ml) was refluxed under nitrogen for 5 h. The cooled solution was diluted with brine (10 ml) and ethyl acetate (10 ml). The suspension was shaken, the filtered through Celite, washing with ethyl acetate (10 ml). The two-phase filtrate was separated and the organic layer was dried (Na2SO4) filtered and concentrated to give the crude sulphinimine (0.293 g). The crude sulphinimine (0.293 g) was suspended in dry THF (2 ml) and stirred at room temperature under nitrogen. A solution of 3-chlorobenzyl magnesium bromide (ca. 4 mmol) (freshly prepared as a solution in diethyl ether from 3-chlorobenzylbromide and magnesium turnings) was added to give an orange solution. After 3 hours, the mixture was diluted with saturated aqueous ammonium chloride (20 ml) and extracted with ethyl acetate (20 ml). The extract was washed with water (20 ml), brine (10 ml), dried (Na2SO4), filtered and concentrated. Flash column chromatography, eluting with 50% ethyl acetate-hexanes, gave 4-(3-chlorobenzyl)-4-(2-methylpropane-2-sulphinylamino)-piperidine-1-carboxylic acid tert-butyl ester as a straw-coloured foam (0.139 g, 0.324 mmol, 31%). LC-MS (LCT) m/z 451, 453 [M+Na+], Rt 8.22 min.

Workup

  1. filtrationthe filtered through Celite
  2. washwashing with ethyl acetate (10 ml)
  3. customThe two-phase filtrate was separated
  4. dry with materialthe organic layer was dried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customto give the crude sulphinimine (0.293 g)
  8. stirringstirred at room temperature under nitrogen
  9. additionwas added
  10. customto give an orange solution
  11. extractionextracted with ethyl acetate (20 ml)
  12. washThe extract was washed with water (20 ml), brine (10 ml)
  13. dry with materialdried (Na2SO4)
  14. filtrationfiltered
  15. concentrationconcentrated
  16. washFlash column chromatography, eluting with 50% ethyl acetate-hexanes

Sources & evidence

ORD record
ord-f38da22c15124c7d81a607b23ab02860
Source dataset
uspto-grants-2014_08
Patent number
US08809336B2

Reaction notes

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