A solution of isochroman 25.30g (188.5 mmol) in acetic acid 100mL was cooled on ice-water bath. 33% HBr in acetic acid 3.0mL was added followed by a “tip of spatula” amount of solid AIBN, followed by neat bromine 10.0 mL over 10 min (carefully!). The mixture was stirred on ambient water bath for 1 day. 33% HBr in acetic acid 50mL was then added and the mix was refluxed on a 90C oil bath for 30 min. Acetic acid and HBr was then removed carefully by vacuum distillation first at 50 Torr from 90C bath, and then at 15 Torr/90C. The obtained residue was then distilled at 0.6 Torr from 90 -140C oil bath. The main fraction distilled at 105C/0.6 Torr. Y=34.35g (85.5% th) of a pale blue oily liquid that is somewhat impure (about 15% impurity) and it is best used immediately for the next step.
A mixture of methanol 100mL and 25% wt methanolic sodium methoxide solution 1.0mL (Aldrich) was cooled on ice bath and nitromethane 9.0mL was added, followed by neat crude 2-(2′-bromoethyl)-benzaldehyde 25.89g (121.5 mmol) from the previous step. (The flask containing the aldehyde was washed with a portion of the reaction mixture and the washings were added back to the reaction mixture). The reaction mix was stirred on ice for 10 min, then additional 25% wt sodium methoxide in methanol 33mL (=30g) was added over 10 min and the stirring on ice was continued for 90 min. Meanwhile 600mL of 6M HCl (conc. HCl + water 1:1 by volume) in a large beaker was chilled on ice bath. The reaction mix was poured into cold stirred 6M HCl in a thin stream and the resulting sludge was stirred on ice for 30 min. The solids were collected by filtration using a large glass Buchner funnel, washed thoroughly with ice-cold water, then rinsed with a small volume of cold hexane (about 20mL) on the Buchner funnel, dried by suction and on highvac. The crude product was re-dissolved in hot benzene 30mL and the solution was gradually diluted with cyclohexane 250mL at reflux and the solution was then allowed to crystallize overnight. The crystalline precipitate was collected by filtration, washed with hexane and dried on highvac. This provided 13.88g of pure nitrostyrene product. Additional 5.673g of pure product was obtained by concentrating the supernatants and purifying the residue on a column of silica (100g) in 3:1 hexane-ethyl acetate. (The zone of the purified product on silica has a tendency to crystallize on he column so it is advisable to avoid using Combiflash and work reasonably fast. ) Combined Y= 19.553g (63% th)
Anhydrous FeCl3 30g was suspended in anhydrous dichloromethane 450mL under Ar and cooled to -18C on ice/salt slush. Acetyl chloride 9.0mL was added dropwise and the mixture was stirred for 15 min. The nitrostyrene from the previous step, 15.77g (61.57 mmol) dissolved in anh. dichloromethane 50mL was then slowly added through a canula over 20 min at -18C. After additional 45 min at -18C the mix was placed on ice bath and stirred at 0C for 4 hours 30 min. The reaction mix was then poured onto crushed ice 300g in a large beaker and the mix was stirred for 45 min. The obtained biphasic mix was filtered through a 150mL glass medium-porosity Buchner funnel, the obtained precipitate was thoroughly washed with water and then with small volume of chilled dichloromethane (2x10mL) to provide 4.498g of pure product as a off-white powder. The combined filtrates were separated, the organic phases were washed with half-saturated NaCl aq. solution. The aqueous phases were re-extracted with dichloromethane (3x300mL). The combined organic extracts were dried (MgSO4) and concentrated down to about 100mL volume, then placed to a fridge (0C) overnight. The precipitated second crop was collected by filtration, washed with a small volume of chilled dichloromethane and dried. This provided 4.139g of pure product. A third crop 1.250g was obtained by applying the supernatants on a column of silica (80g) and eluting with EtOAc gradient in DCM, 0 to 20% EtOAc, UV detection @261 nm. The combined Y=9.887g (56.5% th)
1H(d6-DMSO, 400MHz): 10.787(s, 1H), 7.275(t, 7.8Hz, 1H), 6.968(d, 7.8Hz, 1H), 6.778(d, 7.7Hz, 1H), 5.708(s, 1H), 3.755(m, 2H), 3.217(m, 2H)