Methyl Acrylate → 6'-(3-Fluoropropoxy)spiro[cyclohexane-1,2'-indene]-1',4(3'H)-dione

HRID 1770912Notes

Reaction equation

[F:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][CH2:11][C:12]2=[O:15])=[CH:8][CH:7]=1.[C:16]([O:20]C)(=O)[CH:17]=[CH2:18].[CH3:22][C:23](C)([O-])C.[K+].[OH-].[K+]>[Cl-].[Na+].O.O>[F:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][C:11]3([CH2:18][CH2:17][C:16](=[O:20])[CH2:23][CH2:22]3)[C:12]2=[O:15])=[CH:8][CH:7]=1

Participants

Conditions

Temperature: 0 °C

Procedure

A mixture of 6-(3-fluoropropoxy)-2,3-dihydro-1H-inden-1-one (Intermediate 62, 3.42 g, 16.4 mmol) and methyl acrylate (3.26 mL, 36.1 mmol) in 2-Me THF (15 mL) was cooled to 0° C. Potassium tert-butoxide (2.21 g, 19.71 mmol) was added in portions. After stirring for 1 h at r.t., water (22.5 mL) and KOH (0.921 g, 16.4 mmol) were added and the mixture was heated at reflux for 4.5 h. The mixture was allowed to cool to r.t. and brine was added. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to yield 3.14 g (66% yield) of the title compound which was used in the next step without further purification: 1H NMR (400 MHz, CDCl3) δ 1.82-1.91 (m, 2H), 2.13-2.27 (m, 4H), 2.41-2.52 (m, 2H), 2.70 (dt, 2H), 3.16 (s, 2H), 4.11-4.17 (m, 2H), 4.60 (t, 1H), 4.72 (t, 1H), 7.21-7.27 (m, 2H), 7.39 (dd, 1H); MS (ES+) m/z 291 [M+H]+.

Workup

temperaturethe mixture was heated
temperatureat reflux for 4.5 h
temperatureto cool to r.t.
customThe layers were separated
extractionthe aqueous layer was extracted with EtOAc
dry with materialThe combined organic layers were dried over Na2SO4
filtrationfiltered
concentrationconcentrated in vacuo

Sources & evidence

ORD record: ord-43add99f0e46449789853bac3400e491
Source dataset: uspto-grants-2016_02
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09248129B2

Reaction notes

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