Benzo[b]thiophene-2-methanol

White to yellow solid

REFERENCE EXAMPLE 5 General procedure: To a suspension of LiAlH4 (4.60 g, 121.2 mmol) in dry THF (150 mL) at 0 oC, methylbenzo[b]thiophene-2-carboxylate 14 (10 g, 48.5 mmol) indry THF (30 mL) was slowly added via syringe. After the addition of the compound, the reaction mixture was stirred at 0 °C for 30 min. Then, it was quenched with methanol (5 drops), followed by 5 percent NaOH (6 mL). The insoluble residue was filtered off and dried (Na2SO4). The removal of the solvent in vacuo afforded crude alcohol. The solution of crude benzo[b]thiophene-2-methanol (6.5 g, 39.5 mmol) in dry DCM (80 mL) at 0 oC, PBr3 (7.5 mL, 79.1 mmol) was added slowly through syringe and the reaction mixture was then stirred at room temperature for 30 min under N2 atmosphere. After the reaction was completed (monitored by TLC), it wasdiluted with ice water and the organic layer was extracted with DCM (2 x 50 mL) and dried (Na2SO4).Removal of solvent in vacuo afforded bromomethyl benzo[b]thiophene as a colorless solid. The bromo compound (9.0 g, 32.4 mmol) was reacted with triethyl phosphite (16.5 mL, 97.2 mmol) at reflux under N2 for2 h. After consumption of the bromo compound (monitored by TLC), the reaction mass was poured over crushed ice (100 g) containing Conc. HCl (2 mL) and extracted with DCM (3x50 mL). The organic layer was washed with brine (2 x 50 mL) and dried (Na2SO4). The solvent was removed under vacuo to give crudephosphonate ester 15 as a thick brown liquid. The crude product was used as such for next step without anyfurther purification. Yield: 10.1 g (67percent) over 3 steps.b) benzo[b]thiophene-2-carbaldehyde To a solution of (benzo[b]thiophen-2-yl)methanol (4.94 g) obtained in Example 23 a) in dimethyl sulfoxide (35 ml) was added triethylamine (29 ml), and a solution of sulfur trioxide-pyridine complex (14.78 g) in dimethyl sulfoxide (40 ml) was added dropwise. The mixture was stirred for 1 hr. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with distilled water, 1N hydrochloric acid, aqueous sodium hypochlorite solution, saturated aqueous ammonium chloride solution and saturated brine, dried over magnesium sulfate, concentrated and purified by silica gel column chromatography to give the title compound (4.41 g).Dimethyl sulfoxide (3.2 ml, 44.8 mmol) was added dropwise to a solution of oxayl chloride (11.2 ml, 22.4 mmol) in DCM (150 ml) at -78 C. After string for 30 minutes, a solution of crude 2 (1.8 g) in DCM (50 ml) was added and stirred for 1 hour at -78 C. To the resulting mixture, triethylamine (12.4 ml, 89.6 mmole) was added and the mixture was allowed to warmed to room temperature. After 1 hour, the mixture was poured into saturated aqueous NaHCO3 and extracted with DCM (×3). The combined organics were washed with brine, dried (NaSO4), concentrated in vacuo and purified by flash column chromatography (100% DCM) to give 1.8 g of pure 103.General procedure: 1 mmol benzyl alcohol, 1.375 g catalyst, 20 ml water, and15 ml ether were mixed in a flask (50 ml). A balloon wasused to introduce O2 at ambient pressure, keeping the temperatureat 30 C for a given time. At the end of the reaction, a few drops of diluted HCl solution (1 mol/L) wereadded to the reaction system, and the pH of water wasadjusted to 3-4. After stirring, the catalyst was transferredinto the water and the upper organic layer was isolated forGC analysis.To Compound 2b (2.52 g, 16.8 mmol) was added 10 mL of thionyl chloride and refluxed for 1.5 h. The reaction was concentrated under reduced pressure at rt, and the residue was treated with hexanes. After concentration, the residue was treated with excess triethylphosphite Compound 1 b and refluxed for 1.5 h. The reaction was concentrated under reduced pressure at 90° C. and purified by flash column chromatography (silica, 0 to 40percent EtOAc/Hexane) to yield Compound 2c (2.5 g) as an oil: HPLC: 3.32 min; MS (ES) m/z 285 (MH+).A solid of 2-(hydroxymethyl)benzo[b]thiophene (4.6 g, 28.0 mmol) was suspended in a cold conc. hydrochloric acid (140 mL). The resulting suspension was stirred at room temperature for 2 hours. TLC established completion of the reaction. The suspension was poured into a cold diethyl ether (500 mL) and the mixture was separated. The aqueous layer was extracted with diethyl ether (2 x 200 mL). The ether layers were combined, washed with brine (4 x 75 mL), dried over Na2SO4 and evaporated to afford 2-chloromethylbenzothiophene (9) (4.94 g, 97percent) as a pale yellow powder. It was used in the next step without further purification.Benzothiophene [(5.] [0G, ] [37.] 3 mmol) in anhydrous THF (100 ml) stirring at-20 C was treated with n-butyllithium (34 ml, 1.6 M, 55. [8MMOL)] and stirred for 1 hour. The mixture was cooled to-78 C and treated with [PARAFORMALDEHYDE] (7.8g, 261 mmol) in four portions. The mixture was allowed to slowly warm to room temperature with stirring overnight. The mixture was treated with 2N [HC1] (100 ml) and extracted with diethyl ether (2X 100 ml). The organic phases were combined, dried over [NAS04, ] filtered, and the filtrate concentrated under reduced pressure. The residue was crystallized from [DCM/HEXANES] to provide the title [COMPOUND. IH] NMR (300 MHz, CDC13) [6] 4.94 (s, 2H) 7.23 (s, 1H) 7.33 (m, 3H) [7.] 74 [(M, ] [1H)] ; (ESI) [M/Z] 165 (M+H) [+.]

Molecular Weight:164.23
XLogP3:2.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:164.02958605
Monoisotopic Mass:164.02958605
Topological Polar Surface Area:48.5
Heavy Atom Count:11
Complexity:138
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes