Acetic Acid → Methyl 2-(chroman-6-ylmethylene)-3-oxobutanoate

HRID 1912540Notes

Reaction equation

HRID 1912540 reaction equation
[O:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[O:13]=[C:14]([CH3:20])[CH2:15][C:16]([O:18][CH3:19])=[O:17].N1CCCCC1.CC(O)=O>C1C=CC=CC=1>[O:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[C:15]([C:14](=[O:13])[CH3:20])[C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 7757Methyl acetoacetateHCID 8082PiperidineHCID 6504215Chroman-6-carbaldehyde

Product 1

HCID 78036909Methyl 2-(chroman-6-ylmethylene)-3-oxobutanoateYield 60.47%

Reagents, catalysts & solvents 1

HCID 241BenzeneSolvent

Procedure

A solution of 6-iodochroman (13.8 g, 53.1 mmol) in tetrahydrofuran (THF) (143 mL) was cooled to −78° C. in a dry ice/acetone bath and then treated with n-BuLi, 2.5M solution in hexanes (23.35 mL, 58.4 mmol). The mixture was stirred for 10 minutes before being treated with N,N-dimethylformamide (6.16 mL, 80 mmol) and the resultant was warmed to ambient temperature and stirred for 10 minutes. The mixture was quenched with saturated NH4Cl and extracted with ethyl acetate. The extracts were washed with brine, dried over Na2SO4, filtered and concentrated to afford the crude chroman-6-carbaldehyde as a yellow solid which was used without further purification. LC/MS (m/z) ES+=163.22 (M+1). A solution of the crude chroman-6-carbaldehyde, methyl 3-oxobutanoate, piperidine (0.263 mL, 2.66 mmol) and AcOH (0.152 mL, 2.66 mmol) in Benzene (113 mL) was refluxed (DS-trap) overnight. The mixture was concentrated and diluted with ethyl acetate. The dilution was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel (0-30% hexanes/ethyl acetate) the afford methyl 2-(chroman-6-ylmethylene)-3-oxobutanoate (mixture of E and Z isomers, 8.352 g, 32.08 mmol, 60.47% yield) as a thick yellow oil. 1H NMR (400 MHz, CHLOROFORM-d, major isomer) δ ppm 7.48 (s, 1 H), 7.22-7.12 (m, 2 H), 6.78 (d, J=8.6 Hz, 1 H), 4.27-4.18 (m, 2 H), 3.92-3.81 (m, 3 H), 2.77 (t, J=6.3 Hz, 2 H), 2.39 (s, 3 H), 2.06-1.99 (m, 2 H); 1H NMR (400 MHz, CHLOROFORM-d, minor isomer) δ ppm 7.58 (s, 1 H), 7.16-7.08 (m, 2 H), 6.79-6.71 (m, 1 H), 4.23-4.18 (m, 2 H), 3.84-3.78 (m, 3 H), 2.76 (t, J=6.4 Hz, 2 H), 2.38 (s, 3 H), 2.03-1.96 (m, 2 H); LC/MS (m/z) ES+=261.2 (M+1).

Workup

  1. customwas used without further purification
  2. concentrationThe mixture was concentrated
  3. additiondiluted with ethyl acetate
  4. washThe dilution was washed with brine
  5. dry with materialdried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated

Sources & evidence

ORD record
ord-b98ade996d4f4af59701cdc4ebf22703
Source dataset
uspto-grants-2013_12
Patent number
US08609653B2

Reaction notes

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