Isopropanol → HCID 86709878, compound

HRID 2206977Notes

Reaction equation

HRID 2206977 reaction equation
ClC1C(Cl)=C(C2C=CC(Cl)=CC=2)N=C(C(Cl)=O)C=1.[F-].[K+].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:33]=[C:32]([C:34](F)=[O:35])[CH:31]=[C:30]([F:37])[C:29]=2[F:38])=[CH:24][CH:23]=1.C(N(CC)CC)C.[CH:46]([OH:49])([CH3:48])[CH3:47]>S1(CCCC1)(=O)=O.O>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:33]=[C:32]([C:34]([O:49][CH:46]([CH3:48])[CH3:47])=[O:35])[CH:31]=[C:30]([F:37])[C:29]=2[F:38])=[CH:24][CH:23]=1

Participants

8

Reactant 5

HCID 3776IsopropanolHCID 8471TriethylamineHCID 522689Potassium FluorideHCID 86709874HCID 86709874, compoundHCID 86709879HCID 86709879, compound

Product 1

HCID 86709878HCID 86709878, compoundYield 48%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 31347SulfolaneSolvent

Conditions

Temperature
130 °C

Procedure

To a solution of 4,5-dichloro-6-(4-chlorophenyl)picolinoyl chloride (2.0 g, 6.23 mmol) in sulfolane (40 mL, dried over 4 Å molecular sieves, 100 ppm H2O) was added potassium fluoride (2.2 g, 37.4 mmol). The reaction mixture was heated at 130° C. for 24 h. Reaction mixture was analyzed by GC-MS and 19F NMR. (Data for 6-(4-chlorophenyl)-4,5-difluoropicolinoyl fluoride, GC-MS: m/z=271, 223; 19F NMR (376 MHz, Toluene-d8) δ 17.05 (s), −123.81 (d, J=19.1 Hz), −140.17 (d, J=19.1 Hz). Reaction was allowed to cool to room temperature and triethylamine (1.1 mL, 7.8 mmol) and isopropanol (0.7 mL, 9.4 mmol) were added. After stirring for 1.5 h, the reaction mixture was diluted with water (100 mL) and transferred to a separatory funnel. The reaction mixture was extracted with methyl tert-butyl ether (MTBE, 2×50 mL). The combined organic extracts were washed with water (3×50 mL) and saturated aqueous NaCl solution (50 mL) and concentrated under reduced pressure to provide a brown oil. The crude product oil was purified by silica gel flash chromatography (hexane/ethyl acetate gradient, 100% hexane→20% hexane/ethyl acetate) to provide 0.93 g (48% yield) of isopropyl 6-(4-chlorophenyl)-4,5-difluoropicolinate as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.04-7.98 (m, 2H), 7.90 (dd, J=9.4, 5.3 Hz, 1H), 7.51-7.45 (m, 2H), 5.31 (hept, J=6.3 Hz, 1H), 1.43 (d, J=6.3 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 162.72 (d, J=3.5 Hz), 158.12 (d, J=12.6 Hz), 155.49 (d, J=12.4 Hz), 149.41 (d, J=11.0 Hz), 147.16 (dd, J=7.9, 1.0 Hz), 146.73 (d, J=10.9 Hz), 136.51 (d, J=0.9 Hz), 130.34 (d, J=6.6 Hz) 128.93 (s), 113.80 (d, J=16.1 Hz), 70.25 (s), 21.85 (s). 19F NMR (376 MHz, CDCl3) δ −124.73 (dd, J=17.7, 9.5 Hz), −144.38 (dd, J=17.7, 5.4 Hz). LRMS. Calcd. C16H15F2NO3: 307.10. Found: m/z=307 (M+), 221, 206. MP. 73-74° C.

Workup

  1. customReaction mixture
  2. customReaction
  3. temperatureto cool to room temperature
  4. customtransferred to a separatory funnel
  5. extractionThe reaction mixture was extracted with methyl tert-butyl ether (MTBE, 2×50 mL)
  6. washThe combined organic extracts were washed with water (3×50 mL) and saturated aqueous NaCl solution (50 mL)
  7. concentrationconcentrated under reduced pressure
  8. customto provide a brown oil
  9. customThe crude product oil was purified by silica gel flash chromatography (hexane/ethyl acetate gradient, 100% hexane→20% hexane/ethyl acetate)

Sources & evidence

ORD record
ord-2177d12a97624e45810a0c734a85d631
Source dataset
uspto-grants-2016_06
Patent number
US09376388B2

Reaction notes

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