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

HRID 1470279
Notes
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Reaction equation

HRID 1470279 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]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

12

Reactant 5

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

Product 1

HCID 66873038
4-(3-Chlorobenzyl)-4-(2-methylpropane-2-sulphinylamino)-piperidine-1-carboxylic acid tert-butyl ester
Yield 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-083c1327c02c4bd78d682f3a5fa53f28
Source dataset
uspto-grants-2015_04
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09006430B2

Reaction notes

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