Acetic Acid → Methyl 2-(3-chlorophenyl)-4-oxochroman-3-carboxylate

HRID 409507Notes

Reaction equation

HRID 409507 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][CH:23]=1)[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][CH:23]=1

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 8082PiperidineHCID 114773-ChlorobenzaldehydeHCID 12381316Methyl 3-(2-hydroxyphenyl)-3-oxopropanoate

Product 1

HCID 67155819Methyl 2-(3-chlorophenyl)-4-oxochroman-3-carboxylateYield 42.3%

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; 250 mg, 1.29 mmol) and 3-chlorobenzaldehyde (146 μL, 1.29 mmol) in isopropanol (5.0 mL) was treated with piperidine (13 μL, 129 μmol) and acetic acid (7.4 μL, 129 μmol) and heated to reflux for 17 h. After this time, the mixture was cooled to rt. The cooled solution was concentrated under vacuum and the resulting residue was purified by rotary TLC, eluting with 9:1 hexane-ethyl acetate, to provide a colorless gum. The colorless gum was crystallized from a hot isopropanol/water solution to provide methyl 2-(3-chlorophenyl)-4-oxochroman-3-carboxylate as an off-white solid (173 mg, 42%). The NMR indicated predominantly the enolic form. 1H NMR (400 MHz, CDCl3) δ ppm 3.78 (s, 3 H) 6.21 (s, 1 H) 6.82 (d, J=8.1 Hz, 1 H) 6.97 (t, J=7.9 Hz, 1 H) 7.18-7.32 (m, 4 H) 7.34 (m, 1 H) 7.69 (dd, J=7.9, 1.8 Hz, 1 H) 12.28 (br. s, 1 H). High resolution mass spec (M+H)+ calc. 317.0581, found 317.0597.

Workup

  1. temperatureheated
  2. temperatureto reflux for 17 h
  3. concentrationThe cooled solution was concentrated under vacuum
  4. customthe resulting residue was purified by rotary TLC
  5. washeluting with 9:1 hexane-ethyl acetate
  6. customto provide a colorless gum
  7. customThe colorless gum was crystallized from a hot isopropanol/water solution

Sources & evidence

ORD record
ord-1c4385163a12453db589a5f2a66f6129
Source dataset
uspto-grants-2014_06
Patent number
US08759390B2

Reaction notes

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