Toluene → 2-(4-(2-((Benzyloxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol

HRID 1972404Notes

Reaction equation

HRID 1972404 reaction equation
[CH2:1]([O:8][CH2:9][CH:10]1[NH:15][CH2:14][CH2:13][N:12]([S:16]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)(=[O:18])=[O:17])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:25]1[CH:30]=[CH:29][C:28]([C:31]([OH:37])([CH3:36])[C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:11][N:12]([S:16]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:18])[CH2:13][CH2:14][N:15]1[C:25]1[CH:30]=[CH:29][C:28]([C:31]([OH:37])([CH3:36])[C:32]([F:34])([F:35])[F:33])=[CH:27][CH:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

8

Reactant 4

HCID 1140TolueneHCID 23676156Sodium t-butoxideHCID 583472902-(4-Bromophenyl)-1,1,1-trifluoropropan-2-olHCID 665827403-(Benzyloxymethyl)-1-(thiophen-2-ylsulfonyl)piperazine

Product 1

HCID 665825752-(4-(2-((Benzyloxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanolYield 87.3%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 162179852-Dicyclohexylphosphino-2',6'-diisopropoxybiphenylCatalystHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 3-(benzyloxymethyl)-1-(thiophen-2-ylsulfonyl)piperazine (2.95 g, 8.37 mmol), 2-(4-bromophenyl)-1,1,1-trifluoropropan-2-ol (2.70 g, 10.04 mmol, Example 27, step 1), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (0.156 g, 0.335 mmol, Strem Chemicals, Newburyport, Mass.), tris(dibenzylideneacetone)dipalladium (0) (0.153 g, 0.167 mmol, Strem Chemicals, Newburyport, Mass.), sodium tert-butoxide (2.011 g, 20.92 mmol) and toluene (50 mL) was added to a high-pressure reaction vessel. The vessel was sealed and heated at 100° C. for 16 h. The solution was then diluted with EtOAc (200 mL). The organic solution was washed with water (100 mL) and brine (100 mL) then dried (MgSO4), filtered and concentrated. The crude material was subjected to flash chromatography on silica gel (120 g, 5-80% (10% MeOH-EtOAc) in hexanes) to give 2-(4-(2-((benzyloxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (3.95 g) as a mixture of four isomers.

Workup

  1. additionwas added to a high-pressure reaction vessel
  2. customThe vessel was sealed
  3. washThe organic solution was washed with water (100 mL) and brine (100 mL)
  4. dry with materialthen dried (MgSO4)
  5. filtrationfiltered
  6. concentrationconcentrated

Sources & evidence

ORD record
ord-55f97bf3aa1043258d831a55b934e78c
Source dataset
uspto-grants-2013_04
Patent number
US08431563B2

Reaction notes

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