Iodine → HCID 51354962, compound

HRID 625864Notes

Reaction equation

HRID 625864 reaction equation
II.[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH2:16]I)[C:12]([O:14][CH3:15])=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].C1(P(C2CCCCC2)[C:25]2[CH:30]=[CH:29][CH:28]=[C:27](OC)[C:26]=2[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2OC)CCCCC1.Br[C:48]1[CH:53]=[CH:52][C:51]([F:54])=[C:50]([Cl:55])[CH:49]=1>CCOC(C)=O.[Zn].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].CN(C=O)C>[CH:35]1[C:34]2[CH:6]([CH2:3][O:7][C:8]([NH:10][C@@H:11]([CH2:16][C:48]3[CH:53]=[CH:52][C:51]([F:54])=[C:50]([Cl:55])[CH:49]=3)[C:12]([OH:14])=[O:13])=[O:9])[C:25]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:33]=2[CH:38]=[CH:37][CH:36]=1.[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH2:16][C:48]1[CH:53]=[CH:52][C:51]([F:54])=[C:50]([Cl:55])[CH:49]=1)[C:12]([O:14][CH3:15])=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4]

Participants

10

Reactant 4

HCID 807Iodine2×HCID 35430654-Bromo-2-chloro-1-fluorobenzeneHCID 10903591methyl (2R)-2-(((tert-butoxy)carbonyl)amino)-3-iodopropanoateHCID 53417025HCID 53417025, compound

Product 2

HCID 51354962HCID 51354962, compoundYield 345%HCID 904567581629658-17-8

Reagents, catalysts & solvents 4

HCID 23994ZincCatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
50 °C

Procedure

To an oven dried 8 mL vial with teflon cap purged with N2 was added Zinc dust (298 mg, 4.56 mmol), DMF (1.5 mL), and iodine (57.8 mg, 0.228 mmol). To this mixture was added (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (500 mg, 1.519 mmol), immediately followed by iodine (57.8 mg, 0.228 mmol). Pd2(dba)3 (69.6 mg, 0.076 mmol), 2-dicyclohexylphosphino-2′6-dimethoxybiphenyl (62.4 mg, 0.152 mmol) and 4-bromo-2-chloro-1-fluorobenzene (477 mg, 2.279 mmol) were then added and the reaction mixture was allowed to stir at 50° C. for 3 hours. The crude mixture was diluted in 30 mL of EtOAc and DMF was removed with 4 aqueous washes. The organic phase was dried over anhydrous sodium sulfate. The solution was filtered and concentrated, and the crude product was purified by silica gel chromatography using 100% hexanes to 30% EtOAc/Hexanes. The desired product was obtained as a pale yellow oil, (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(3-chloro-4-fluorophenyl)propanoate (0.174 g, 35%). 1H NMR (400 MHz, chloroform-d) δ 7.27 (s, 1H), 7.17 (dd, J=6.9, 1.4 Hz, 1H), 7.11-6.93 (m, 1H), 5.03 (d, J=6.8 Hz, 1H), 4.55 (d, J=6.4 Hz, 1H), 3.73 (s, 3H), 3.19-3.04 (m, 1H), 2.98 (dd, J=13.9, 5.9 Hz, 1H), 1.49-1.37 (m, 10H).

Workup

  1. dry with materialTo an oven dried 8 mL vial with teflon
  2. customcap
  3. custompurged with N2
  4. customDMF was removed with 4 aqueous washes
  5. dry with materialThe organic phase was dried over anhydrous sodium sulfate
  6. filtrationThe solution was filtered
  7. concentrationconcentrated
  8. customthe crude product was purified by silica gel chromatography

Sources & evidence

ORD record
ord-0106b00d393c4f86928650be13495c55
Source dataset
uspto-grants-2016_04
Patent number
US09308236B2

Reaction notes

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