Tris(furan-2-yl)phosphane → HCID 86695478, compound

HRID 1487528Notes

Reaction equation

HRID 1487528 reaction equation
Br[C:2]1[S:6][C:5]([CH:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=1.[Cl:19][CH:20]([Cl:39])[C:21]([NH:23][C@H:24]([CH2:37][F:38])[C@H:25]([OH:36])[C:26]1[CH:31]=[CH:30][C:29]([Sn](C)(C)C)=[CH:28][CH:27]=1)=[O:22].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>CN1CCCC1=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]>[Cl:19][CH:20]([Cl:39])[C:21]([NH:23][C@H:24]([CH2:37][F:38])[C@@H:25]([C:26]1[CH:27]=[CH:28][C:29]([C:2]2[S:6][C:5]([CH:7]3[CH2:11][CH2:10][CH2:9][N:8]3[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=2)=[CH:30][CH:31]=1)[OH:36])=[O:22]

Participants

6

Reactant 3

HCID 521585Tris(furan-2-yl)phosphaneHCID 866953832,2-Dichloro-N-[(1S,2R)-1-fluoromethyl-2-hydroxy-2-(4-trimethylstannanyl-phenyl)-ethyl]-acetamideHCID 86695477HCID 86695477, compound

Product 1

HCID 86695478HCID 86695478, compoundYield 46.5%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
80 °C

Procedure

To a stirred solution of tert-butyl 2-(5-bromothiophen-2-yl)pyrrolidine-1-carboxylate (0.750 g, 2.26 mmol), 2,2-dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(trimethylstannyl)phenyl)propan-2-yl)acetamide (1.0 g, 2.26 mmol), and tri(furan-2-yl)phosphine (105 mg, 0.452 mmol) in N-Methyl-2-pyrrolidone (10 mL) degassed with nitrogen is added Pd2(dba)3 (207 mg, 0.226 mmol). The reaction mixture is heated to 80° C. for 5 hours then left at ambient 70 hours. Reaction mixture partitioned between ethyl acetate (100 mL) and water (100 mL). Organic phase is isolated and concentrated in vacuo to give the crude material, which is purified by column chromatography on silica gel eluting in 0-100% ethyl acetate in heptane to give the title compound (559 mg): 1H-NMR (400 MHz, CDCl3) δ 1.32-1.52 (m, 9H), 1.89-2.15 (m, 3H), 2.21-2.37 (m, 1H), 2.59-2.78 (m, 1H), 3.40-3.66 (m, 2H), 4.25-4.38 (m, 1H), 4.43-4.49 (m, 0.5H), 4.54-4.62 (m, 1H), 4.66-4.73 (m, 0.5H), 5.01-5.25 (m, 2H), 5.89 (s, 1H), 6.83 (bs, 1H), 7.06 (d, J=8.6 Hz, 1H), 7.14 (d, J=3.5 Hz, 1H), 7.38 (d, J=8.1 Hz, 2H), 7.56 (d, J=8.1 Hz, 2H). m/z (CI) M-boc+H 431.0.

Workup

  1. customReaction mixture
  2. custompartitioned between ethyl acetate (100 mL) and water (100 mL)
  3. customOrganic phase is isolated
  4. concentrationconcentrated in vacuo
  5. customto give the crude material, which
  6. customis purified by column chromatography on silica gel eluting in 0-100% ethyl acetate in heptane

Sources & evidence

ORD record
ord-708c5538119c4e96b18de9acf2e4159f
Source dataset
uspto-grants-2016_08
Patent number
US09428528B2

Reaction notes

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