Ethyl Bromide → Methyl Benzoate

A solution of 5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-ol (5.09 g, 25.00 mmol; prepared by Friedel-Crafts alkylation/cyclization of phenol with 2,5-dichloro-2,5-dimethylhexane) and monomethyl terephthalate acid chloride (5.95 g, 29.9 mmol) in CH2Cl2 (10 mL) and hexanes (60 mL) was treated portionwise with aluminum trichloride (10.0 g, 75 mmol) over 30 minutes at ambient temperature. After the addition was complete, sulfuric acid (concentrated, 0.5 mL) was added and the orange solution was heated at reflux for 1 h. The solution was allowed to cool to ambient temperature and the reaction was quenched by slowly pouring the solution into ice/water accompanied by vigorous stirring. The mixture was stirred for an additional 30 min. The aqueous solution was extracted with EtOAc, 3×. The organic layers were combined and washed with water (2×) and brine. The organic solution was dried (NaSO4), filtered, and concentrated to give a red oil. Purification by silica gel flash chromatography (20:1=hexanes:EtOAc) gave 4-[(3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid methyl ester 3.24 g (35%) as a yellow solid: mp 155-159° C. (d); 1H NMR (400 MHz, CDCl3) δ8.18 (½ABq, J=8.3 Hz, 2H, ArH), 7.72 (½ABq, J=8.3 Hz, 2H, ArH), 7.43 (s, 1H, ArH), 7.01 (s, 1H, ArH), 3.98 (s, 3H, OCH3), 1.70 (m, 4H, 2CH2), 1.31 (s, 6H, 2CH3), 1.16(s, 6H, 2CH3). A solution of the 4-[(3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid methyl ester (433 mg, 1.18 mmol) in DMF (2mL) was treated with NaH (1.5 mmol) at 0° C. and allowed to warm to ambient temperature over 1 h. The yellow solution was cooled again to 0° C. and treated with a solution of bromoethane (83 mL, 1.30 mmol) in DMF (1 mL) and allowed to warm to ambient temperature and stirred for 10 h. The reaction was quenched with saturated aqueous NH4Cl. The aqueous solution was extracted with EtOAc, 3×. The organic layers were combined and washed with water (2×) and brine. The organic solution was dried (NaSO4), filtered, and concentrated to give a colorless oil. Purification by silica gel flash chromatography (20:1=hexanes:Et2O) gave 4-[3-ethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid methyl ester 436 mg (97%) as a white solid: 1H NMR (400 MHz, CDCl3) δ8.07 (½ABq, J=8.4 Hz, 2H, ArH), 7.82 (½ABq, J=8.4 Hz, 2H, ArH), 7.43 (s, 1H, ArH), 6.82 (s, 1H, ArH), 3.95 (s, 3H, OCH3), 3.88 (q, J=6.9 Hz, 2H, OCH2), 1.70 (m, 4H, 2CH2), 1.31 (s, 6H, 2CH3), 1.27 (s, 6H, 2CH3), 0.98 (t, J=6.9 Hz, 3H, CH3); HRMS calcd. for C25H30O4395.2222 (MH+), found 395.2219. The ethoxy keto ester was converted to the ethenyl compound by the method described in Example 2 to give, after preparative silica gel TLC (1:1:1=hexanes:EtOAc:CH2Cl2+5% MeOH), 4-[(3-ethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethenyl]benzoic acid (107) (17%) as a white solid: mp 195-200° C. (d); 1H NMR (400 MHz, CDCl3) δ8.01 (½ABq, J=8.3 Hz, 2H, ArH), 7.39 (½ABq, J=8.3 Hz, 2H, ArH), 7.19 (s, 1H, ArH), 6.74 (s, 1H, ArH), 5,67 (appp s, 1H, methylene), 5.45 (d, J=0.8 Hz, 1H, methylene), 3.78 (q, J=6.9 Hz, 2H, OCH2), 1.70 (m, 4H, 2CH2) 1.30 (s, 6H, 2CH3), 1.28 (S, 6H, 2CH3), 0.91 (t, J=6.9 Hz, 3H, CH3); HRMS calcd. for C25H30O3 378.2195 (M+), found 378.2210.

1. temperatureThe yellow solution was cooled again to 0° C.
2. temperatureto warm to ambient temperature
3. customThe reaction was quenched with saturated aqueous NH4Cl
4. extractionThe aqueous solution was extracted with EtOAc, 3×
5. washwashed with water (2×) and brine
6. dry with materialThe organic solution was dried (NaSO4)
7. filtrationfiltered
8. concentrationconcentrated
9. customto give a colorless oil
10. customPurification by silica gel flash chromatography (20:1=hexanes:Et2O)

ORD record

ord-f4450e6e49234ba4895f36081fffbb0d

Source dataset

uspto-grants-2003_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06545049B1