1,1,4,4-Tetramethyl-1,2,3,4-tetrahydronaphthalene

Uses

1,1,4,4-Tetramethyl-1,2,3,4-tetrahydronaphthalene can be used as an intermediate to participate in a variety of chemical reactions and is used in the synthesis of a variety of compounds and drugs. For example, 6-lodo-1,1,4,4-tetramethyl-l,2,3,4-tetrahydronaphthalene, 6-bromo-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene and 1,1,4,4-tetramethyl-6-nitro-1,2,3,4- tetrahydronaphthalene and others.

Preparation

2,5-dichloro-2,5- dimethylhexane (300 mg, 1.64 mmol, 1 eq) was dissolved in dry benzene (25 mL). Then added AlCl₃ (22.0 mg, 0.164 mmol, 0.1 eq) to the solution, which was stirred at reflux for 16 hours. The reaction was stopped with 3M HCl (5 mL) and extracted with hexanes (10 mL x 3). The combined organic layer was washed with brine, dried with Na2S04, filtered, and concentrated in vacuo. Finally, the crude was purified by flash chromatography (100% hexanes) to obtained the colourless oil (1,1,4,4-Tetramethyl-1,2,3,4-tetrahydronaphthalene).Yield=91%

Synthesis

General procedure for the synthesis of 1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene from 2,5-dichloro-2,5-dimethylhexane and benzene: 2,5-dichloro-2,5-dimethylhexane (300 mg, 1.64 mmol, 1 eq.) was dissolved in dry benzene (25 mL). To this solution was added anhydrous aluminum trichloride (AlCl3, 22.0 mg, 0.164 mmol, 0.1 eq.) and the reaction mixture was stirred under reflux conditions for 16 hours. Upon completion of the reaction, the reaction was quenched with 3M hydrochloric acid (5 mL) and extracted with hexane (10 mL × 3). The organic layers were combined, washed with saturated saline, dried over anhydrous sodium sulfate (Na2SO4), filtered and concentrated in vacuum. The crude product was purified by fast column chromatography (100% hexane as eluent) to afford 1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (309 mg, 91% yield) as a colorless oil. The product was characterized as follows: 1H NMR (500 MHz, CDCl3) δ 1.33 (s, 12H), 1.74 (s, 4H), 7.16-7.19 (m, 2H), 7.34-7.36 (m, 2H, J = 2 Hz and 8.4 Hz); 13C NMR (500 MHz, CDCl3) δ 31.9, 34.2, 35.1, 125.5, 13C NMR (500 MHz, CDCl3) δ 31.9, 34.2 35.1, 125.5, 126.5, 144.8.

References

[1] Patent: WO2015/188015, 2015, A1. Location in patent: Page/Page column 31
[2] Patent: WO2018/107289, 2018, A1. Location in patent: Page/Page column 17
[3] Journal of the Brazilian Chemical Society, 2018, vol. 29, # 1, p. 109 - 124
[4] Journal of Medicinal Chemistry, 1988, vol. 31, # 11, p. 2182 - 2192
[5] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 6, p. 1948 - 1959