Dave Nichols, et. al. Journal of Medicinal Chemistry, Vol 44, No 6, 1003-1010 (2001)[ Back to the Chemistry Archive ]1,4-Bis(2-chloroethoxy)benzene[1]Pyridine (29.4ml, 364mmol) was added to a mechanically stirred solution of 1,4-bis(hydroxyethoxy)benzene (30g, 152mmol) in DCM (300ml) at 0 deg C. Next thionyl chloride (25.4ml, 348mmol) was added dropwise such that the internal temperature did not exceed 5 deg C. This mixture was allowed to gradually warm to room temperature and was stirred overnight. Aqueous 2N HCl (500ml) was added slowly and the layers were separated. The aqueous layer was extracted with DCM (3x75ml) and the organic extracts were combined. The pooled organic extracts were then washed with aqueous 2N HCl (2x200ml), water (200ml), 1N NaOH (100ml) and brine (100ml). The organic extracts were then dried(MgSO4) and evaporated to leave an tan solid that was recrysatallized from ethanol to afford white crystals 31.4g (88%), mp. 90-91 deg C. 1,4-Bis(2-chloroethoxy)2,5-dibromobenzene[2]Zinc chloride (38.2g, 280mmol) was added to a solution of [1] (27.5g, 117mmol) in acetic acid (280ml). After enclosing the apparatus in aluminum foil to exclude light, bromine (39.3g, 246mmol) dissolved in acetic acid was added dropwise to the suspension over 1.5 hours. The reaction was allowed to stir overnight, during which time a precipitate had formed. The reaction was diluted with aqueous saturated sodium thiosulphate (500ml) and extracted with DCM (5x200ml). The organic layers were combined and washed with aqueous 1N NaOH (200ml), brine (100ml), dried (MgSO4), filtered and evaporated to leave an off-white solid. Recrystallization from EtOH afforded a crystalline white product 50.0g (91%), mp. 120 deg C. 2,3,6,7-Tetrahydrobenzo[1,2-b;4,5-b’]difuran[3]To a suspension of Mg powder (50 mesh, 3.7g, 152mmol) in anhydrous THF (50ml) was slowly added EtMgBr (3.4ml, 10mmol, 3M solution in Et2O). An anhydrous solution of [2] (20g, 51mmol) in THF (125ml) was then added dropwise such that the internal reaction temperature did not exceed 35 deg C. Upon completion of the addition, the reaction was heated at reflux for 3 hours. The reaction was then cooled to room temperature and carefully poured into cold 1N HCl (200ml). Upon cessation of gas evolution, the mixture was extracted with Et2O (3x300ml). The organic layers were combined and washed with aqueous 1N NaOH (4x75ml), brine (50ml), dried (MgSO4), filtered and concentrated by rotary evaporation to afford a tan solid. This was recrystallized from EtOH to afford off-white, platelike crystals 6.5g (79%), mp. 155 deg C. (R)-N-Trifluoroacetylalanine[4]Triethylamine (3.1ml, 22mmol) was added to a solution of D-alanine (2g, 22mmol) in MeOH (11ml). After 5 minutes, ethyl trifluoroacetate (3.3ml, 28mmol) was added and the reaction was allowed to stir for 24 hours. The solvent was removed by rotary evaporation and the residue that remained was dissolved in water (35ml) and acidified with concentrated HCl (4ml). After stirring for 15 minutes, the mixture was extracted with EtOAc (4x30ml). The combined extracts were washed with brine (25ml), dried (MgSO4) and concentrated by rotary evaporation to leave a clear oil. After being subjected to vacuum for 24 hours, the clear oil solidified into a fluffy hydroscopic solid 2.7g (86%) mp. 69 deg C. (R)-(+)-N-Trifluoroacetyl-2,3,6,7-tetrahydro-4-alanylbenzo[1,2-b;4,5-b’]difuran[5]Trifluoroacetamide-protected D-alanine[4] (4.09g, 22mmol) was added to a pretared flask and placed under high-vacuum for 24 hours to remove any moisture. The flask was then reweighed to record the accurate weight of the starting material. Next, DCM (100ml) was added to the flask followed by pyridine (2 drops) and the solution was cooled to 0 deg C. Oxalyl chloride (4.3ml, 49mmol) was then added via syringe and the reaction was allowed to gradually warm to room temperature and stir for 3.5 hours. The solvent and excess oxalyl chloride was removed by rotary evaporation at 35 deg C to afford the acid chloride which was not characterized. The heterocycle [3] (1.1g, 6.6mmol) was dissolved in DCM (35ml) and this solution was slowly added via dropping funnel to a suspension of AlCl3 (2.4g, 18.3mmol) in DCM (50ml). This was followed by slow addition of the acid chloride [13] dissolved in DCM (45ml). The mixture was allowed to stir for 16 hours at which time TLC showed only one yellow spot. The reaction mixture was poured slowly onto ice to quench the reaction and the phases where then separated. The aqueous layer was extracted with DCM (4x75ml) and the organic layers were combined and washed with cold aqueous 1N HCl (75ml), water (50ml) and then saturated NaHCO3 (2x50ml). The organic solution was dried (MgSO4), filtered and concentrated to leave a yellow solid that was recrystallized from MeOH to afford fluffy yellow crystals 1.88g (86%), mp 209-210 deg C (R)-(+)-N-Trifluoroacetyl-1-(2,3,6,7-tetrahydrobenzo-[1,2-b;4,5-b’]difuran-4-yl)-2-aminopropane[6]The ketone [5] (0.94g, 2.9mmol) was dissolved in trifluoroacetic acid (9.4ml) and then triethylsilane (2.3ml, 14.5mmol) was added. The mixture was heated at reflux for 6 hours, at which time TLC showed no starting material. The reaction was cooled to room temperature followed by very slow addition of saturated aq. NaHCO3 until evolution of gas had ceased and the solution remained alkaline. The mixture was then extracted with Et2O (4x75ml), the organic layers combined and dried (MgSO4), filtered and evaporated to leave a tan solid. The product was titurated with hexanes and the resulting suspension was then vacuum filtered to leave a white solid 0.84g, (92%), mp. 139-140 deg C. (R)-(-)-1-(2,3,6,7-Tetrahydrobenzo[1,2-b;4,5-b’]difuran-4-yl)-2-aminopropane Hydrochloride[7]The protected amine [6] (0.1g, 0.3mmol) was dissolved in MeOH (20ml) and cooled to 0 deg C. Aqueous 5N NaOH (5ml) was added to this solution and the mixture was allowed to stir overnight and was then diluted with Et2O (50ml). The phases were separated and the aqueous layer was extracted with Et2O (3x15ml). The organic layers were combined, dried (MgSO4), filtered and the solvent evaporated to leave a tan oil. This oil was taken up in dry Et2O (15ml) and filtered through glass wool. A slight excess of 1N HCl in EtOH was added dropwise to the solution with vigorous stirring. The flask was then placed in a freezer overnight and the precipitate was collected by vacuum filtration. The resulting solid was recrystallized from IPA to afford white flyffy crystals 0.073g (86%), mp275-276 deg C. Representative aromatization of substituted 2,3,6,7-tetrahydrobenzo[1,2-b;4,5-b’]difurans to benzo[1,2-b;4,5-b’]difurans: (R)-(+)-N-Trifluoroacetyl-1-(benzo[1,2-b;4,5-b’]difuran-4-yl)-2-aminopropane[8]A solution of DDQ (0.42g, 1.85mmol) in 1,4-dioxane (8ml) was slowly added to a solution of protected amine (0.2g, 0.63mmol) in 1,4-dioxane (10ml). The solution was heated at reflux for 24 hours at which time TLC indicated reaction completion. The reaction was then cooled to room temperature and the precipitate formed was removed by vacuum filtration. The filter cake was washed thoroughly with DCM and then the solvents removed by rotary evaporation. The brown oil that remained was subjected to column chromatography (4:1 hexanes-EtOAc as eluent) to afford a white solid product 0.134g, (64%), mp. 150-151 deg C. References [1]
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