Isopropylamine → HCID 66684643, compound

HRID 513039Notes

Reaction equation

HRID 513039 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][C:12]([F:15])([F:14])[CH2:11][N:10]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C1C[O:26][CH2:25]C1.N12CCCN=C1CCCCC2.[CH:39]([NH2:42])([CH3:41])[CH3:40]>CCOC(C)=O.[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo]>[F:14][C:12]1([F:15])[CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[C:25](=[O:26])[NH:42][CH:39]([CH3:41])[CH3:40])[CH2:13]1

Participants

7

Reactant 4

HCID 6363IsopropylamineHCID 8028TetrahydrofuranHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 66684645HCID 66684645, compound

Product 1

HCID 66684643HCID 66684643, compound

Reagents, catalysts & solvents 2

HCID 98885Molybdenum carbonyl (Mo(CO)6)CatalystHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
150 °C

Procedure

To a nitrogen-flushed microwave vial was added (R)-tert-butyl 2-(2-bromo-5-fluorophenyl)-4,4-difluoro-pyrrolidine-1-carboxylate (I-49) (304 mg, 0.80 mmol), molybdenum hexacarbonyl (211 mg, 0.80 mmol), trans-di-μ-acetatobis[2-di-o-tolylphosphino)benzyl]-dipalladium(II) (Palladacycle) (30 mg, 4 mol %), THF (1.6 mL), 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU) (239 μL, 1.6 mmol) and isopropylamine (171 μL, 2.0 mmol). The vial was capped and then heated at 150° C. for 30 minutes in a Biotage microwave reactor. The cooled reaction mixture was diluted with EtOAc and filtered through Celite. The combined filtrates were washed successively with saturated aqueous NH4Cl, water, 2% citric acid and brine, then dried over sodium sulfate and concentrated. The residue was purified by silica chromatography with EtOAc/Hex (5-30%) as eluent, to yield (R)-tert-butyl 4,4-difluoro-2-(5-fluoro-2-(isopropylcarbamoyl)phenyl)pyrrolidine-1-carboxylate (I-50) as an off-white foam. 1H NMR (400 MHz, CDCl3) δ 7.44 (bs, 1 H), 7.11 (bs, 1 H), 7.00 (td, J=2.5, 8.2 Hz, 1 H), 5.31 (t, J=7.7 Hz, 1 H), 4.23 (bs, 1 H), 4.09-3.87 (m, 2 H), 2.91 (bs, 1 H), 2.41 (bs, 1 H), 1.45 (bs, 6 H), 1.26 (d, J=6.5 Hz, 6 H), 1.19 (bs, 3 H). MS m/z 331.1 (M−55)+.

Workup

  1. customTo a nitrogen-flushed microwave vial
  2. customThe vial was capped
  3. customThe cooled reaction mixture
  4. filtrationfiltered through Celite
  5. washThe combined filtrates were washed successively with saturated aqueous NH4Cl, water, 2% citric acid and brine
  6. dry with materialdried over sodium sulfate
  7. concentrationconcentrated
  8. customThe residue was purified by silica chromatography with EtOAc/Hex (5-30%) as eluent

Sources & evidence

ORD record
ord-083a97a2cab14ab594c7b473a69720f9
Source dataset
uspto-grants-2015_08
Patent number
US09102671B2

Reaction notes

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