(3-tert-butylphenyl)Methanol synthesis

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Yield:51503-09-4 100%

Reaction Conditions:

with lithium aluminium tetrahydride in tetrahydrofuran at 20; for 2 h;Inert atmosphere;

Steps:

4.1.2.5. 3-tert-Butylbenzyl bromide (7d)

3-t-Butylphenol (1.00 g, 6.66 mmol) was dissolved in anhydrous CH₂Cl₂ (130 mL) and cooled to 0 °C in an ice bath. 2,6-Lutidine (1.7 mL, 14.64 mmol) and triflic anhydride (2.2 mL, 13.31 mmol) were added successively. The mixture was stirred overnight at room temperature, quenched with water and extracted with CH₂Cl₂. The organic phase was washed successively with aqueous saturated NaHCO₃ solution and brine, dried with MgSO₄, filtered and evaporated to yield 1.109 g (59%) of 7a. ¹H NMR δ (CDCl₃) 1.33 (s, 9H, t-butyl), 7.09 (ddd, 1H, J₁ = 1.4 Hz, J₂ = 2.2 Hz, J₃ = 7.8 Hz 4-CH), 7.25 (t, 1H, J₁ = 2.0 Hz, 2-CH), 7.40 (m, 2H, 5-CH and 6-CH). The triflic ester 7a (1.11 g, 3.93 mmol) was dissolved in anhydrous DMF (150 mL) and anhydrous MeOH (50 mL). Et₃N (1.6 mL, 11.76 mmol), Pd(OAc)₂ (265 mg, 1.18 mmol) and 1,3-bis(diphenylphosphino) propane (486 mg, 1.18 mmol) were added. Gaseous CO was bubbled for 1 h through the mixture while it was heated to 90 °C. The reaction mixture was then stirred overnight at room temperature under a CO atmosphere, after which it was poured into brine and extracted with Et₂O. The organic phase was washed with water, brine, dried over MgSO₄, filtered and evaporated. The crude product was purified by flash chromatography on silica gel using hexanes/EtOAc (95/5) to yield 554 mg (73%) of 7b. ¹H NMR δ (CDCl₃) 1.35 (s, 9H, t-butyl), 3.92 (s, 3H, COOCH₃), 7.37 (t, 1H, J = 7.8 Hz, 5-CH), 7.60 (dq, 1H, J₁ = 1.2 Hz, J₂ = 7.9 Hz, 4-CH), 7.86 (dt, 1H, J₁ = 1.3 Hz, J₂ = 7.7 Hz, 6-CH), 8.08 (t, 1H, J = 1.8 Hz, 2-CH). The ester 7b (554 mg, 2.88 mmol) was dissolved in anhydrous THF (30 mL) and cooled to 0 °C. Lithium aluminum hydride (219 mg, 5.76 mmol) was added in small portions and the mixture stirred 2 h under argon at room temperature. Water was then added, concentrated HCl added to acidify the solution and the mixture was extracted with Et₂O, dried over MgSO₄, filtered and concentrated to achieve quantitatively 7c. ¹H NMR δ (CDCl₃) 1.34 (s, 9H, t-butyl), 4.70 (s, 2H, PhCH₂OH), 7.19 (d, 1H, J₁ = 6.9 Hz, 6-CH), 7.33 (m, 2H, 4-CH and 5-CH), 7.40 (s, 1H, 2-CH).

References:

Fournier, Diane;Poirier, Donald [European Journal of Medicinal Chemistry,2011,vol. 46,# 9,p. 4227 - 4237] Location in patent:experimental part

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6-Oxatricyclo[3.2.1.02,7]octan-8-ol, 8-(1,1-dimethylethyl)-, (1α,2β,5α,7β,8R*)- (9CI)

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51503-09-4
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