Tetrahydrofuran → methyl 3-[2'-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-6-methoxy-4'-(trifluoromethyl)biphenyl-3-yl]propanoate

HRID 529729Notes

Reaction equation

HRID 529729 reaction equation
[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]3[C@H:19]([C:22]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=4Br)[CH2:20][CH2:21][C@@H:14]23)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1COCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:48][O:49][C:50]1[CH:55]=[CH:54][C:53]([CH2:56][CH2:57][C:58]([O:60][CH3:61])=[O:59])=[CH:52][C:51]=1B1OC(C)(C)C(C)(C)O1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].O>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]3[C@H:19]([C:22]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=4[C:55]4[C:50]([O:49][CH3:48])=[CH:51][CH:52]=[C:53]([CH2:56][CH2:57][C:58]([O:60][CH3:61])=[O:59])[CH:54]=4)[CH2:20][CH2:21][C@@H:14]23)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1

Participants

8

Reactant 4

HCID 8028TetrahydrofuranHCID 62657Potassium Phosphate, TribasicHCID 67036621Methyl 3-(4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate2×HCID 86682295(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[2-bromo-5-(trifluoromethyl)phenyl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one

Product 1

HCID 71526552methyl 3-[2'-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-6-methoxy-4'-(trifluoromethyl)biphenyl-3-yl]propanoateYield 90.9%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 12976736Bis(ditert-butyl(cyclopenta-2,4-dien-1-yl)phosphane);iron(2+)CatalystHCID 962WaterSolvent

Conditions

Temperature
62 °C

Procedure

To Intermediate B2 (30 mg, 0.044 mmol) was added THF (2 mL), water (0.1 mL), tribasic potassium phosphate (45.3 mg, 0.213 mmol), methyl 3-[4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (51.3 mg, 0.16 mmol) (Intermediate H), palladium(II) acetate (1.2 mg, 5.34 mmol), and 1,1′-bis(di-tert-butylphosphino)ferrocene (2.53 mg, 5.34 μmol). The system was flushed with nitrogen gas and was heated at 62° C. overnight. The reaction was diluted with ethyl acetate:hexanes (1:2, 10 mL) and was partitioned with water (10 mL). The organic was dried over sodium sulfate, filtered and concentrated. The crude product was purified by reverse phase HPLC to yield methyl 3-[2′-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-6-methoxy-4′-(trifluoromethyl)biphenyl-3-yl]propanoate (27 mg, 0.04 mmol). 1H NMR indicated that this compound exists as a pair of rotamers at 1.2:1 ratio. 1H NMR (500 MHz, CDCl3) δ7.87 (s, 1H), 7.81 (s, 2H), 7.75 (s, 1H, major rotamer), 7.73 (s, 1H, minor rotamer) 7.6 (m, 1H) 6.8-7.3 (m, 4H), 6.06 (d, J=7.9 Hz, 1H, major rotamer), 6.06 (d, J=7.9 Hz, 1H, major rotamer), 6.01 (d, 1H, minor rotamer), 5.12 (m, 1H, major rotamer), 4.98 (m, 1H, minor rotamer), 4.1 (m, 1H), 3.84 (s, 3H, major rotamer), 3.68 (s, 3H), 3.67 (s, 3H) 3.62 (s, 3H, minor rotamer), 2.9 (m, 2H), 2.6 (m, 2H), 0.9-1.7 (m, 4H). MS ESI calc'd. for C32H27F9NO5 [M+H]+ 676.2, found 676.4. RTA (95% HS): 296 nM

Workup

  1. customThe system was flushed with nitrogen gas
  2. additionThe reaction was diluted with ethyl acetate:hexanes (1:2, 10 mL)
  3. customwas partitioned with water (10 mL)
  4. dry with materialThe organic was dried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe crude product was purified by reverse phase HPLC

Sources & evidence

ORD record
ord-5033a65e38414d709efa5cb683a1e2dd
Source dataset
uspto-grants-2016_05
Patent number
US09346825B2

Reaction notes

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