Hydrochloric Acid → 1-Naphthol

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Reaction Steps

After 3 h, the mixture is warmed to room temperature, water is added, and 2-bromo-5,6-difluorobenzaldehyde is isolated as an oily residue by extracting the aqueous phase by shaking with diethyl ether, drying the organic phase using sodium sulfate and removing the solvent by distillation (referred to below as conventional work-up). Reaction of this compound with an equimolar amount of allylmagnesium chloride in THF at room temperature and addition of saturated aqueous ammonium chloride solution and conventional work-up gives crude 4-(2-bromo-5,6-difluorophenyl)-4-hydroxybut-1-ene. Purification by column chromatography (silica gel 60 (Merck KGaA), eluent toluene with 10 per cent by volume of isopropanol) and evaporation of the main fraction gives pure product. The intramolecular Heck coupling is carried out at 140° C. in DMF after addition of sodium acetate, benzyltriethylammonium chloride and [P(o-tolyl)3]PdCl2 as catalyst. After cooling to room temperature and dilution with water, the mixture is subjected to conventional work-up. The crude material is aromatised in a generally known manner by boiling with 2,3-dichloro-5,6-dicyanobenzoquinone in dichloromethane to give 1-naphthol, which is then converted into the benzyl ether in a suspension of an excess of potassium carbonate in acetone using benzyl bromide. The benzyl ether is dissolved in THF, lithiated in a generally known manner at −60° C. using butyllithium, and trimethyl borate is subsequently added to the dissolved organometallic compound. The boronic acid precipitating after acidification using dilute hydrochloric acid is recrystallised from n-heptane. It is subsequently dissolved in THF and, after addition of 4-propylbromobenzene and a catalytic amount of Pd[P(C6H5)4], coupled by the Suzuki method. The generally known hydrogenolysis using hydrogen in the presence of palladium (5% Pd on carbon) gives the corresponding 1-naphthol. This is dissolved in an adequate volume of ethanol at about −10° C. together with 1.1 times the molar amount of ethyl pentylformylacetate, and the solution is saturated with gaseous hydrogen chloride. The mixture is warmed to room temperature and left to stand for about 20 h. The mixture is then poured onto ice, and the 3-pentyl-8-(4-propylphenyl)benzo[h]chromen-2-one which deposits (Example 1) is recrystallised from ethanol. Hydrogenation with Pd catalysis in THF gives 3-pentyl-8-(4-propylphenyl)-3,4-dihydrobenzo[h]chromen-2-one (Example 2), which, after removal of the catalyst by filtration and removal of the solvent by distillation, is purified by recrystallisation from ethanol. This gives, in a generally known manner by reaction with LiAlH4 and boron trifluoride etherate (cf. R. Pettit et al., J. Org. Chem. 26, 4773 (1961)), 3-pentyl-8-(4-propylphenyl)-3,4-dihydrobenzo[h]chromene (Example 3). The compound of Example 2 is converted into the corresponding thione by reaction with 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (Lawesson's reagent) (cf. P. S. Pederson et al., Bull. Soc. Chim. Belg. 87, 293 (1978)), from which 2,2-difluoro-3-pentyl-8-(4-propylphenyl)-3,4-dihydrobenzo[h]chromene is formed in a generally known manner by reaction with DAST in dichloromethane (Example 4). The compounds of Examples 3 and 4 are, for purification, in each case recrystallised from ethanol after conventional work-up.

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