ethyl 3-methylbut-2-enoate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of ethyl 3,3-dimethylacrylate (12.8g, 100 mmol), N-bromosuccinimide (11.8g, 66 mmol), dry benzene (50 ml) and benzoyl peroxide (20 mg) was heated under reflux for 0.5h. After cooling, filtration, concentration and distillation, ethyl 4-bromo-3-methylcrotonate was obtained. The latter (33.8 mmol) was added dropwise to triethylphosphite (47.17 mmol) at 100°. The mixture was warmed to 150o and the residue purified by distillation to give triethyl 4-phosphono-3-methylcrotonate (b.p. 120° at 0.5 mm.Hg) as a cis/trans mixture. was heated under reflux for 0.5h After cooling filtration, concentration and distillation

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3,5-Dimethylphenol (IIa) (3.2 g, 26.2 mmol), ethyl 3,3-dimethylacrylate (5 mL, 36 mmol, 1.4 eq.) and concentrated sulfuric acid (1.5 mL) were dissolved in anhydrous benzene (30 mL), and the reaction mixture was heated to reflux for 2 h. The reaction mixture was cooled to room temperature and washed successively with water (2×40 mL), 5% aqueous NaHCO3 solution (2×20 mL), brine (2×20 mL) and dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvent was removed under vacuum to obtain a dark brown gummy material. To this gummy material was added anhydrous ether (5 mL) and boiled for 2 min on a steam bath. The title compound, IIIa, (3.34 g, 16.4 mmol, Y: 62.4%) was crystallized out from the mixture upon cooling in an ice bath; mp, 95.8-96.3° C.; 1H-NMR (300 MHz, acetone-d6) δ ppm: 1.41 (6H, s, 4,4-Me2), 2.24 (3H, s, 5-Me), 2.46 (3H, s, 7-Me), 2.61 (2H, s, 3-H2), 6.68 (1H, s, Ar-H), 6.76 (1H, s, Ar-H); MS (Isobutane-DCI) m/e: 205 (M+H)+ ; IR (KBr) ν max: 1770, 1250, 1190, 870 cm-1. the reaction mixture was heated to reflux for 2 h washed successively with water (2×40 mL), 5% aqueous NaHCO3 solution (2×20 mL), brine (2×20 mL) dried over anhydrous sodium sulfate After filtering off the desiccant the solvent was removed under vacuum to obtain a dark brown gummy material The title compound, IIIa, (3.34 g, 16.4 mmol, Y: 62.4%) was crystallized out from the mixture upon cooling in an ice bath mp, 95.8-96.3° C.

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ten grams 3,3-dimethylacrylic acid was dissolved in 100 ml absolute ethanol and 0.5 ml concentrated (37% approx.) hydrochloric acid added. The reaction mix was refluxed for 24 to 48 hours with a Dean-Stark trap filled with activated molecular sieves inserted between the reaction vessel and the condenser. After cooling, the solvent was removed by rotary evaporation under reduced pressure at 50° C. to yield 6.3 g of a cloudy, yellow oil (ethyl 3-methyl-2-butenoate.) 0.5 ml concentrated (37% approx.) hydrochloric acid added The reaction mix was refluxed for 24 to 48 hours with a Dean-Stark trap filled with activated molecular sieves After cooling the solvent was removed by rotary evaporation under reduced pressure at 50° C.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 83.1 g (0.2 mol) of potassium carbonate are added, while stirring, to a solution of 28.0 g (0.2 mol) of 5-fluoro-2-hydroxy-benzaldehyde [prepared according to Y. Suzuki and H. Takahashi, Chem. Pharm. Bull. 31, 1751 (1983)] in 500 ml of N,N-dimethylformamide. 36.3 g (0.2 mol) of 3,3-dimethylacrylic acid ethyl ester are added to the resulting viscous suspension. The reaction mixture is then stirred for 16 hours at 150° and, after cooling to room temperature, concentrated by evaporation in vacuo. Water is added to the resulting solid residue and the aqueous mixture is extracted with diethyl ether. The combined ethereal phases are washed in succession with water, 2N hydrochloric acid, 2N sodium hydroxide solution and again with water, dried over sodium sulfate and concentrated by evaporation in vacuo. The resulting oily residue is chromatographed on 1000 g of silica gel (0.040-0.063 mm) with toluene as eluant, yielding 19.5 g (55% of the theoretical yield) of 2,2-dimethyl-6-fluoro-2H-chromene in the form of a light-yellow oil. concentrated by evaporation in vacuo Water is added to the resulting solid residue the aqueous mixture is extracted with diethyl ether The combined ethereal phases are washed in succession with water, 2N hydrochloric acid, 2N sodium hydroxide solution and again with water dried over sodium sulfate concentrated by evaporation in vacuo The resulting oily residue is chromatographed on 1000 g of silica gel (0.040-0.063 mm) with toluene as eluant yielding 19.5 g (55% of the

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 83.1 g (0.2 mol) of potassium carbonate are added, while stirring, to a solution of 28.0 g (0.2 mol) of 5-fluoro-2-hydroxy-benzaldehyde [prepared according to Y. Suzuki and H. Takahashi, Chem. Pharm. Bull. 31, 1751 (1983)] in 500 ml of N,N-dimethylformamide. 36.3 g (0.2 mol) of 3,3-dimethylacrylic acid ethyl ester are added to the resulting viscous suspension. The reaction mixture is then stirred for 16 hours at 150° and, after cooling to room temperature, concentrated by evaporation in vacuo. Water is added to the resulting solid residue and the aqueous mixture is extracted with diethyl ether. The combined ethereal phases are washed in succession with water, 2N hydrochloric acid, 2N sodium hydroxide solution and again with water, dried over sodium sulfate and concentrated by evaporation in vacuo. The resulting oily residue is chromatographed on 1000 g of silica gel (0.040-0.063 mm) with toluene as eluant, yielding 19.5 g (55% of the theoretical yield) of 2,2-dimethyl-6-fluoro-2H-chromene in the form of a light-yellow oil. concentrated by evaporation in vacuo Water is added to the resulting solid residue the aqueous mixture is extracted with diethyl ether The combined ethereal phases are washed in succession with water, 2N hydrochloric acid, 2N sodium hydroxide solution and again with water dried over sodium sulfate concentrated by evaporation in vacuo The resulting oily residue is chromatographed on 1000 g of silica gel (0.040-0.063 mm) with toluene as eluant yielding 19.5 g (55% of the

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The olefins 66 can also be prepared by reacting the corresponding substituted phenols with ethyl 4-bromo-3-methyl-2-butenate in the presence of potassium carbonate and small amount of 18-crown-ether in methylene chloride. The starting material ethyl 4-bromo-3-methylbutenate has been obtained from the reaction of ethyl 3,3-dimethylacrylate with N-bromosuccinimide (NBS) as follows: to 20 g of ethyl 3,3-dimethylacrylate in 250 ml of carbon tetrachloride, 30 g of N-bromosuccinimide (NBS) and 0.01 g of azobisisobutyronitrile were added. The mixture was refluxed for 3 hours. Succinimide was removed by filtration and the filtrate was washed with chloroform. The combined organic layers were washed sequentially with saturated sodium sulfite, saturated sodium chloride and then dried over anhydrous magnesium sulfate. Evaporation of the solvent afforded 34.4 g ethyl 4-bromo-3-methyl-2-butenate (Safaryn, J. E.; Chiarello, J.; Chen, K. M.; Joullie, M. M.; Tetrahedron, 1986, 42, 2635). The product can be further purified by silica gel flash column chromatography using ether/hexane (e.g. 1:50) as eluent, and hydrolyzed to the corresponding carboxylic acid with aqueous methanolic NaOH. ##STR12## wherein R1 =H, CF3, R or OR; The mixture was refluxed for 3 hours Succinimide was removed by filtration the filtrate was washed with chloroform The combined organic layers were washed sequentially with saturated sodium sulfite, saturated sodium chloride dried over anhydrous magnesium sulfate Evaporation of the solvent