Hydrochloric Acid → ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate

HRID 854873Notes

Reaction equation

HRID 854873 reaction equation
[Cl:1][C:2]1[C:3]([F:11])=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=O.C([O-])([O-])=O.[K+].[K+].[F:18][C:19]([F:28])([F:27])/[CH:20]=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23].C([O-])(=O)/C=C/C.Cl>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[C:6]2[C:5](=[CH:4][C:3]=1[F:11])[O:10][CH:20]([C:19]([F:18])([F:28])[F:27])[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:7]2

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 5371261Ethyl (2E)-4,4,4-trifluoro-2-butenoateHCID 6971246CrotonateHCID 71721325-Chloro-4-fluoro-2-hydroxybenzaldehyde

Product 1

HCID 21883602ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylateYield 58.8%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
70 °C

Procedure

To the aldehyde (17.46 g, 100 mmole) from Step 1 in DMF (25 mL) was added K2CO3 (15.2 g, 110 mmole). The mixture was stirred, heated to 70° C. and treated with ethyl trifluorocrotonate (22.4 mL, 150 mmole). After 2 h, the mixture was heated to 95° C. After a total of 4 h, an additional 16 mL of crotonate was added and the mixture allowed to stir for 4 h at 95° C. and an additional 12 h at r.t. The reaction was complete by LCMS. This mixture was treated with 300 mL of 1N HCl and extracted 4× with CH2Cl2. The combined extracts were filtered through silica (4.5×6 cm) and the silica plug washed with additional CH2Cl2. The extracts were concd, the crude solid triturated with cold methanol, the solid collected and air dried to afford 19.1 g of a tan solid. The mother liquors were concd, dissolved in CH2Cl2 and filtered through a new silica plug following the same approach as above to give a second crop of 4.1 g of solid. The mother liquors were diluted with H2O and the solid collected to give a third crop of 3.16 g of solid. Total yield was 26.36 g (81.2%). The first and second crop were >95% by 1H NMR. The third crop was >90% pure: 1HNMR (CDCl3) 1.35 (t, 3H, J=7.1 Hz), 4.33 (m, 2H), 5.71 (q, 1H, J=6.7 Hz), 6.82 (d, 1H, J=9.4 Hz), 7.28 (d, 1H, 7.9 Hz), 7.63 (s, 1H). 19FNMR (CDCl3) −78.9 (d, 3F, J=6.7 Hz), −106.7 (t, 1F, J=8.7 Hz). 13CNMR (CDC13) 14.2, 61.7, 70.9 (q, C2, J=33.3 Hz), 105.5 (d, C8,J=25.5 Hz), 114.9 (d, J=18.7 Hz), 116.4, 117.1, 123.1 (q,CF3,J=287.2 Hz), 130.4 (d, J=1.5 Hz), 134.9 (d, J=1.9 Hz), 152.9 (d, J=11.4 Hz), 160.1 (d, C7, J=255.2 Hz), 163.4 (C═O)

Workup

  1. temperaturethe mixture was heated to 95° C
  2. stirringto stir for 4 h at 95° C. and an additional 12 h at r.t
  3. extractionextracted 4× with CH2Cl2
  4. filtrationThe combined extracts were filtered through silica (4.5×6 cm)
  5. washthe silica plug washed with additional CH2Cl2
  6. customthe crude solid triturated with cold methanol
  7. customthe solid collected
  8. customair dried

Sources & evidence

ORD record
ord-b7cfab9196c14f5f8fa117dd1d040c6e
Source dataset
uspto-grants-2007_08
Patent number
US07259266B2

Reaction notes

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