N-bromobutanimide → pyrrolidine-1,2-dicarboxylic acid 2-[2-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-2-oxo-ethyl]ester 1-tert-butyl ester

HRID 71874Notes

Reaction equation

HRID 71874 reaction equation
Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([F:17])([F:16])[C:4]=2[CH:3]=1.C([Sn](CCCC)(CCCC)[C:23]([O:25]CC)=[CH2:24])CCC.C1C(=O)N(Br)C(=O)C1.[N:44]1([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:51][CH2:50][CH2:49][C@H:45]1[C:46]([OH:48])=[O:47].CCN(C(C)C)C(C)C>O1CCOCC1.C(OCC)(=O)C.CC#N.CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].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:55]([O:54][C:52]([N:44]1[CH2:51][CH2:50][CH2:49][CH:45]1[C:46]([O:48][CH2:24][C:23]([C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([F:17])([F:16])[C:4]=2[CH:3]=1)=[O:25])=[O:47])=[O:53])([CH3:58])([CH3:57])[CH3:56]

Participants

13

Reactant 5

HCID 67184N-bromobutanimideHCID 81531DiisopropylethylamineHCID 850831,2-Pyrrolidinedicarboxylic acid, 1-(1,1-dimethylethyl) ester, (2S)-HCID 619414Stannane, tributyl(1-ethoxyethenyl)-HCID 596112352,7-Dibromo-9,9-difluorofluorene

Product 1

HCID 66620377pyrrolidine-1,2-dicarboxylic acid 2-[2-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-2-oxo-ethyl]ester 1-tert-butyl esterYield 34%

Reagents, catalysts & solvents 7

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent2×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
70 °C

Procedure

[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5%, 82 mg) and tetrakis(triphenylphosphine)palladium (5%, 115 mg) were added to the mixture of 2,7-dibromo-9,9-difluoro-9H-fluorene (720 mg, 3 mmol) and tributyl(1-ethoxyvinyl)tin (1 eq., 0.677 mL) in 12 mL dioxane. The reaction was heated to 70° C. under Argon for 4 hours. The reaction was cooled to room temperature. 3 mL water was added and followed by NBS (1 eq., 356 mg). The reaction was stirred at room temperature overnight. The reaction mixture was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer dried (MgSO4), concentrated down. The residue was dissolved in 15 mL anhydrous DMF. Boc-L-Pro-OH (4 eq., 1.72 g) was added, followed by DIEA (3.5 eq., 1.22 mL) in 5 mL MeCN and 5 mL DMF dropwise. The reaction was stirred at room temperature for 3 hours. 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, 20 to 100% ethyl acetate/hexane) to give pyrrolidine-1,2-dicarboxylic acid 2-[2-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-2-oxo-ethyl]ester 1-tert-butyl ester (363 mg, yield 34%). LCMS-ESI−: calc'd for C25H24BrF2NO5: 536.36. Found: 560.0 (M+Na+), 535.9 (M−H).

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. dissolutionThe residue was dissolved in 15 mL anhydrous DMF
  6. stirringThe reaction was stirred at room temperature for 3 hours
  7. customThe reaction crude
  8. washwashed with saturated sodium bicarbonate solution
  9. dry with materialThe organic layer dried (MgSO4)
  10. concentrationconcentrated
  11. custompurified by flash column chromatography (silica gel, 20 to 100% ethyl acetate/hexane)

Sources & evidence

ORD record
ord-f0be163942b3452eb48ab120282c638b
Source dataset
uspto-grants-2014_09
Patent number
US08822430B2

Reaction notes

Loading…