Thionyl Chloride → 5-(2-chloroethyl)-1-(4'-fluorobiphenyl-2-ylmethyl)-1H-imidazole

HRID 1877948Notes

Reaction equation

HRID 1877948 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]2[C:19]([CH2:20][CH2:21]O)=[CH:18][N:17]=[CH:16]2)=[CH:4][CH:3]=1.S(Cl)([Cl:25])=O>C(Cl)Cl>[Cl:25][CH2:21][CH2:20][C:19]1[N:15]([CH2:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:16]=[N:17][CH:18]=1

Participants

4

Reactant 2

HCID 24386Thionyl ChlorideHCID 668864042-[3-(4'-fluorobiphenyl-2-ylmethyl)-3H-imidazol-4-yl]ethanol

Product 1

HCID 668862185-(2-chloroethyl)-1-(4'-fluorobiphenyl-2-ylmethyl)-1H-imidazole

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of 2-[3-(4′-fluorobiphenyl-2-ylmethyl)-3H-imidazol-4-yl]ethanol (0.341 g, 1.15 mmol) in CH2Cl2 (10 mL) is added, thionyl chloride (0.11 mL, 1.50 mmol) at 0° C. The mixture is then heated to reflux for 3 h before the solvent is removed and the residue dried under reduced pressure to give 5-(2-chloroethyl)-1-(4′-fluorobiphenyl-2-ylmethyl)-1H-imidazole. The residue is taken up in THF (60 mL). TMEDA (0.71 ml, 4.72 mmol) is added, followed by a hexane/THF solution of LDA (2.62 mL, 1.8 M) at −78° C. The resulting mixture is stirred at −78° C. for 5 h. The excess LDA is then quenched by the addition of saturated NH4Cl. The mixture is then diluted with CH2Cl2 and water. The organic layer is separated and washed with water, brine and dried over Na2SO4. After concentration, the residue is purified by flash chromatography (CH2Cl2/MeOH) to give 5-(4′-fluorobiphenyl-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole. MS (ESI) m/z 279.1 (M+H). Resolution of the (R) and (S) enantiomers of the title compound is achieved by chiral HPLC using ChiralPak AD column and 13% IPA:hexane to give enantiomer A (tr=9.6 min) and enantiomer B (tr=12.6 min). For enantiomer B: 1H NMR (400 MHz, CDCl3) (HCl salt) δ ppm 2.68-2.79 (m, 1 H), 2.95-3.06 (m, 2 H), 3.13-3.22 (m, 1 H), 5.55 (app t, J=7.6 Hz, 1 H), 6.96 (dd, J=7.6, 1.5 Hz, 1 H), 7.13 (s, 1 H), 7.18 (app t, J=8.6 Hz, 2 H), 7.27-7.32 (m, 2 H), 7.33-7.38 (m, 1 H), 7.40-7.49 (m, 2 H), 8.01 (s, 1 H).

Workup

  1. customat 0° C
  2. temperatureThe mixture is then heated
  3. temperatureto reflux for 3 h before the solvent
  4. customis removed
  5. customthe residue dried under reduced pressure

Sources & evidence

ORD record
ord-33907eb1150e4cf3938db646dbffbfa7
Source dataset
uspto-grants-2012_11
Patent number
US08314097B2

Reaction notes

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