Cesium carbonate → tert-butyl (2-chloro-5-cyano-3-(1,1-dioxidotetrahydro-2H-isothiazolo[2,3-a]pyrazin-5(3H)-yl)phenyl)carbamate

HRID 921950Notes

Reaction equation

HRID 921950 reaction equation
Br[C:2]1[C:3]([Cl:18])=[C:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[S:19]1(=[O:29])(=[O:28])[N:23]2[CH2:24][CH2:25][NH:26][CH2:27][CH:22]2[CH2:21][CH2:20]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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]>[Cl:18][C:3]1[C:2]([N:26]2[CH2:25][CH2:24][N:23]3[S:19](=[O:29])(=[O:28])[CH2:20][CH2:21][CH:22]3[CH2:27]2)=[CH:7][C:6]([C:8]#[N:9])=[CH:5][C:4]=1[NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 59215775Hexahydro-2H-isothiazolo[2,3-a]pyrazine 1,1-dioxideHCID 86708481Tert-butyl (3-bromo-2-chloro-5-cyanophenyl)carbamate

Product 1

HCID 131734958tert-butyl (2-chloro-5-cyano-3-(1,1-dioxidotetrahydro-2H-isothiazolo[2,3-a]pyrazin-5(3H)-yl)phenyl)carbamateYield 37.4%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
105 °C

Procedure

A mixture of tert-butyl (3-bromo-2-chloro-5-cyanophenyl)carbamate (160 mg, 0.482 mmol), hexahydro-2H-isothiazolo[2,3-a]pyrazine 1,1-dioxide (85 mg, 0.482 mmol), Pd2dba3 (44.2 mg, 0.048 mmol), BINAP (90 mg, 0.145 mmol), and Cs2CO3 (471 mg, 1.447 mmol) in Dioxane (5 mL) was evacuated and filled with nitrogen 3× and heated at 105° C. overnight. The reaction mixture was filtered through a plug of celite and the filtrate was concentrated. The crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g column, eluting with 1-10% Methanol in DCM) to give tert-butyl (2-chloro-5-cyano-3-(1,1-dioxidotetrahydro-2H-isothiazolo[2,3-a]pyrazin-5(3H)-yl)phenyl)carbamate (77 mg)

Workup

  1. customwas evacuated
  2. additionfilled with nitrogen 3×
  3. filtrationThe reaction mixture was filtered through a plug of celite
  4. concentrationthe filtrate was concentrated
  5. customThe crude product was purified by flash chromatography on silica gel using
  6. washan automated ISCO system (40 g column, eluting with 1-10% Methanol in DCM)

Sources & evidence

ORD record
ord-0eb0ce9342ca45beaf4ad61008737ce9
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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