N-bromobutanimide → 2-Aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 3-(2-{7-[2-(1-tert-butoxycarbonyl-pyrrolidine-2-carbonyloxy)-acetyl]-dibenzothiophen-3-yl]-2-oxo-ethyl) ester 2-tert-butyl ester

HRID 71868Notes

Reaction equation

HRID 71868 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([O:15][CH2:16][C:17]([C:19]1[CH:20]=[CH:21][C:22]2[C:26]3[CH:27]=[CH:28][C:29](Br)=[CH:30][C:25]=3[S:24][C:23]=2[CH:32]=1)=[O:18])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:38]([O:40]CC)=[CH2:39])CCC.C1C(=O)N(Br)C(=O)C1.[C:59]([O:63][C:64]([N:66]1[CH:71]([C:72]([OH:74])=[O:73])[CH:70]2[CH2:75][CH:67]1[CH2:68][CH2:69]2)=[O:65])([CH3:62])([CH3:61])[CH3:60]>O1CCOCC1.C(OCC)(=O)C.CN(C=O)C.CC#N.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.O>[C:59]([O:63][C:64]([N:66]1[CH:71]([C:72]([O:74][CH2:39][C:38]([C:29]2[CH:28]=[CH:27][C:26]3[C:22]4[CH:21]=[CH:20][C:19]([C:17](=[O:18])[CH2:16][O:15][C:13]([CH:9]5[CH2:10][CH2:11][CH2:12][N:8]5[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:14])=[CH:32][C:23]=4[S:24][C:25]=3[CH:30]=2)=[O:40])=[O:73])[CH:70]2[CH2:75][CH:67]1[CH2:68][CH2:69]2)=[O:65])([CH3:62])([CH3:60])[CH3:61]

Participants

11

Reactant 4

HCID 67184N-bromobutanimideHCID 619414Stannane, tributyl(1-ethoxyethenyl)-HCID 150563882-(tert-Butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acidHCID 66620445Pyrrolidine-1,2-dicarboxylic acid 2-[2-(7-bromo-dibenzothiophen-3-yl)-2-oxo-ethyl]ester 1-tert-butyl ester

Product 1

HCID 679716832-Aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 3-(2-{7-[2-(1-tert-butoxycarbonyl-pyrrolidine-2-carbonyloxy)-acetyl]-dibenzothiophen-3-yl]-2-oxo-ethyl) ester 2-tert-butyl ester

Reagents, catalysts & solvents 6

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 6228DimethylformamideSolvent2×HCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent2×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

[1,1′-Bis(triphenylphosphine)dichloropalladium(II) (3%, 14 mg, 0.02 mmol) and tetrakis(triphenylphosphine)palladium (3%, 23 mg, 0.02 mmol) were added to the mixture of Pyrrolidine-1,2-dicarboxylic acid 2-[2-(7-bromo-dibenzothiophen-3-yl)-2-oxo-ethyl]ester 1-tert-butyl ester (345 mg, 0.665 mmol) and tributyl(1-ethoxyvinyl)tin (1.2 eq., 0.269 mL) in 5 mL dioxane. The reaction was heated to 80° C. under Are for 4 hours. The reaction was cooled to room temperature. 1.5 mL water was added and followed by NBS (1 eq., 142 mg). The reaction was stirred at room for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer dried (MgSO4), concentrated down and dried on vacuum to give residue which was used in next step. The residue was dissolved in 4 mL anhydrous DMF. 2-Aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester (2 eq., 321 mg, 1.33 mmol g) was added, followed by TEA (2.2 eq., 204 mg) in 4 mL MeCN and 3 mL DMF dropwise. The reaction was stirred at room temperature overnight. The reaction crude was diluted with EtOAc and washed with saturated sodium bicarbonate solution. The organic layer dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 0 to 50% ethyl acetate/hexane) to give 2-Aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 3-(2-{7-[2-(1-tert-butoxycarbonyl-pyrrolidine-2-carbonyloxy)-acetyl]-dibenzothiophen-3-yl]-2-oxo-ethyl) ester 2-tert-butyl ester as a yellow residue (92.5 mg, yield 19%). LCMS-ESI−: calc'd for C38H44N2O10S: 720.83. Found: 743.2 (M+Na+).

Workup

  1. temperatureThe reaction was cooled to room temperature
  2. washwashed with saturated sodium bicarbonate solution
  3. dry with materialThe organic layer dried (MgSO4)
  4. concentrationconcentrated down
  5. customdried on vacuum
  6. customto give residue which
  7. stirringThe reaction was stirred at room temperature overnight
  8. customThe reaction crude
  9. washwashed with saturated sodium bicarbonate solution
  10. dry with materialThe organic layer dried (MgSO4)
  11. concentrationconcentrated
  12. custompurified by flash column chromatography (silica gel, 0 to 50% ethyl acetate/hexane)

Sources & evidence

ORD record
ord-43cd971a09fe477f94dbc32ab4600550
Source dataset
uspto-grants-2014_09
Patent number
US08822430B2

Reaction notes

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