Hydrochloric Acid → (2-Amino-3-cyclopropoxyphenyl)(3-fluorophenyl)methanone

HRID 2276869Notes

Reaction equation

HRID 2276869 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[Li]CCCC.[NH2:14][C:15]1[C:26]([O:27][CH:28]2[CH2:30][CH2:29]2)=[CH:25][CH:24]=[CH:23][C:16]=1[C:17](N(OC)C)=[O:18].Cl>O1CCCC1>[NH2:14][C:15]1[C:26]([O:27][CH:28]2[CH2:29][CH2:30]2)=[CH:25][CH:24]=[CH:23][C:16]=1[C:17]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)=[O:18]

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 707251-Fluoro-3-iodobenzeneHCID 900798402-amino-3-cyclopropoxy-N-methoxy-N-methylbenzamideHCID 178418339Butyllithium

Product 1

HCID 90079930(2-Amino-3-cyclopropoxyphenyl)(3-fluorophenyl)methanoneYield 69.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of 1-fluoro-3-iodobenzene (1.009 mL, 8.59 mmol) in tetrahydrofuran (100 mL) was cooled to −78° C. in a dry ice/acetone bath under nitrogen. Then a solution of n-BuLi (1.8 M in hexanes, 5.37 mL, 8.59 mmol) was added via syringe over 15 minutes and stirred for 60 minutes to give gave a dark-yellow suspension. Then a solution of 2-amino-3-cyclopropoxy-N-methoxy-N-methylbenzamide (0.58 g, 2.455 mmol) in 10 mL of THF was added via syringe and the reaction mixture was stirred for 40 minutes at −78° C. After 40 minutes the mixture was poured into a mixture of ice and 1N HCl and extracted into ethyl acetate to give a light-yellow solution. The organic layer was washed with water and brine and concentrated to give a dark-yellow oil residue. The crude product mixture was purified via ISCO (0%-100% of EtOAC/heptane in 15 minutes, 40 g column) to give (2-amino-3-cyclopropoxyphenyl)(3-fluorophenyl)methanone (0.46 g, 1.696 mmol, 69.1% yield). HPLC: RT=3.481 min (H2O/MeOH with TFA, SunFire C18 3.5 μm, 2.1×30 mm, gradient=4 min, wavelength=220 nm); MS(ES):m/z=272.16 [M+H]+; 1H NMR (400 MHz, chloroform-d) δ 7.48-7.40 (m, 2H), 7.36 (ddd, J=9.3, 1.9, 1.1 Hz, 1H), 7.27-7.18 (m, 2H), 7.08 (dd, J=8.3, 1.2 Hz, 1H), 6.58 (t, J=8.0 Hz, 1H), 6.39 (br. s., 2H), 3.83 (t, J=4.5 Hz, 1H), 0.86 (d, J=4.4 Hz, 4H).

Workup

  1. customto give
  2. customgave a dark-yellow suspension
  3. stirringthe reaction mixture was stirred for 40 minutes at −78° C
  4. extractionextracted into ethyl acetate
  5. customto give a light-yellow solution
  6. washThe organic layer was washed with water and brine
  7. concentrationconcentrated
  8. customto give a dark-yellow oil residue
  9. customThe crude product mixture was purified via ISCO (0%-100% of EtOAC/heptane in 15 minutes, 40 g column)

Sources & evidence

ORD record
ord-f967cbefa4564146909c8722cc1b1d49
Source dataset
uspto-grants-2015_09
Patent number
US09133139B2

Reaction notes

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