Acetic Acid → Racemic methyl 2-(3,4-dichlorophenyl)-4-oxochroman-3-carboxylate

HRID 409516Notes

Reaction equation

HRID 409516 reaction equation
[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:14])[CH2:9][C:10]([O:12][CH3:13])=[O:11].[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH:19]=O.N1CCCCC1.C(O)(=O)C>C(O)(C)C>[Cl:15][C:16]1[CH:17]=[C:18]([CH:19]2[CH:9]([C:10]([O:12][CH3:13])=[O:11])[C:8](=[O:14])[C:3]3[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=3)[O:1]2)[CH:21]=[CH:22][C:23]=1[Cl:24]

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 8082PiperidineHCID 227103,4-DichlorobenzaldehydeHCID 12381316Methyl 3-(2-hydroxyphenyl)-3-oxopropanoate

Product 1

HCID 67155790Racemic methyl 2-(3,4-dichlorophenyl)-4-oxochroman-3-carboxylateYield 55.2%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Procedure

A mixture of methyl 3-(2-hydroxyphenyl)-3-oxopropanoate (prepared according to Cushman, M. et al., J. Med. Chem. 1991, 34, 798; 500 mg, 2.56 mmol) and 3,4-dichlorobenzaldehyde (496 mg, 2.83 mmol) in isopropanol (5.0 mL) was treated with piperidine (25 μl, 257 μmol) and acetic acid (15 μl, 257 μmol) and then heated to reflux for 20 h. At the conclusion of this period, the mixture was cooled on ice, causing a gum to separate from the solution. The mixture was treated with a small amount of water and heated until homogeneous. On slow cooling to rt, a solid formed, which was collected by filtration and dried under vacuum to provide racemic methyl 2-(3,4-dichlorophenyl)-4-oxochroman-3-carboxylate as an off-white powder (496 mg, 55%). An additional sample (57 mg, 6%) was obtained by partial concentration of the filtrate. The NMR indicated predominantly the enolic form. 1H NMR (400 MHz, CDCl3) δ ppm 3.78 (s, 3 H) 6.18 (s, 1 H) 6.81 (dd, J=8.1, 1.0 Hz, 1H) 6.99 (td, J=7.4, 1.0 Hz, 1 H) 7.19 (dd, J=8.4, 1.8 Hz, 1 H) 7.31 (m, 1 H) 7.34 (d, J=8.1 Hz, 1 H) 7.43 (d, J=2.0 Hz, 1 H) 7.69 (dd, J=7.9, 1.8 Hz, 1 H) 12.28 (br. s, 1H). High resolution mass spectrum m/z found 373.0016, calcd 373.0010 (M+Na)+.

Workup

  1. temperatureheated
  2. temperatureto reflux for 20 h
  3. temperatureAt the conclusion of this period, the mixture was cooled on ice
  4. customto separate from the solution
  5. additionThe mixture was treated with a small amount of water
  6. temperatureheated until homogeneous
  7. customa solid formed
  8. filtrationwhich was collected by filtration
  9. customdried under vacuum

Sources & evidence

ORD record
ord-35312914542f473fa6f7bf1f7d19f488
Source dataset
uspto-grants-2014_06
Patent number
US08759390B2

Reaction notes

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