Hydrochloric Acid → Methyl 3-cyano-2-(4-fluorophenyl)propanoate

HRID 1667227Notes

Reaction equation

HRID 1667227 reaction equation
C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=1.Br[CH2:24][C:25]#[N:26].Cl>O1CCCC1.C(OCC)(=O)C>[C:25]([CH2:24][CH:18]([C:15]1[CH:14]=[CH:13][C:12]([F:11])=[CH:17][CH:16]=1)[C:19]([O:21][CH3:22])=[O:20])#[N:26]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 11534BromoacetonitrileHCID 2733233Methyl 2-(4-fluorophenyl)acetateHCID 2733832Lithium Hexamethyldisilazide

Product 1

HCID 67358817Methyl 3-cyano-2-(4-fluorophenyl)propanoate

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

To lithium bis(trimethylsilyl)amide (1.0 Min tetrahydrofuran) (18.73 mL, 18.73 mmol) at −78° C. was added methyl 2-(4-fluorophenyl)acetate (3.00 g, 17.84 mmol) as a solution in tetrahydrofuran (5 mL) dropwise. During the addition, a white solid precipitated. After the addition, the reaction was placed in an ice bath and stirred for 1 hour. 2-Bromoacetonitrile (2.354 g, 19.62 mmol) was added as a solution in tetrahydrofuran (2 mL) and the reaction was allowed to stir for an additional 1 hour. The reaction was poured into a mixture of 1 N HCl (50 mL) and ethyl acetate (50 mL). The organic layer was separated, washed with brine (50 mL), dried over magnesium sulfate and concentrate. The resulting reside was chromatographed over silica gel (SF40-115, Analogix®) eluting with a gradient of 5% to 50% ethyl acetate/hexanes (Flow=85 mL/minute) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 7.31-7.19 (m, 2H), 7.13-7.01 (m, 2H), 3.93 (t, J=7.6, 1H), 3.73 (s, 3H), 3.02 (dd, J=7.2, 16.8, 1H), 2.81 (dd, J=8.0, 16.9, 1H).

Workup

  1. additionDuring the addition
  2. customa white solid precipitated
  3. additionAfter the addition
  4. customthe reaction was placed in an ice bath
  5. stirringto stir for an additional 1 hour
  6. customThe organic layer was separated
  7. washwashed with brine (50 mL)
  8. dry with materialdried over magnesium sulfate
  9. concentrationconcentrate
  10. customThe resulting reside was chromatographed over silica gel (SF40-115, Analogix®)
  11. washeluting with a gradient of 5% to 50% ethyl acetate/hexanes (Flow=85 mL/minute)

Sources & evidence

ORD record
ord-2eb5c286025b40bbb4bbb0b4c837d5f1
Source dataset
uspto-grants-2011_10
Patent number
US08044069B2

Reaction notes

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