A. 2-(3-Iodopropyl)-1H-isoindole-1,3(2H)-dione 2. A dry, one-necked, 500-mL, round-bottomed flask equipped with a magnetic stirring bar and a reflux condenser with a gas inlet at the top, is charged with 13.4 g (50 mmol) of 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione 1 (Note 1), 17.95 g (120 mmol) of sodium iodide (Note 2), and 100 mL of acetone. The reaction mixture is stirred at reflux under nitrogen for 21 hr (Note 3). The solvent is removed on a rotary evaporator and the resulting solid is dissolved in 300 mL of dichloromethane and 200 mL of water. The two layers are separated in a separatory funnel and the aqueous layer is extracted with two 100-mL portions of dichloromethane. The combined organic extracts are washed successively with 100 mL of an aqueous 10% solution of sodium thiosulfate, three 100-mL portions of water and 150 mL of brine. The organic layer is dried over anhydrous magnesium sulfate. After filtration, the solvent is removed on a rotary evaporator. The crude white solid is dried for several hours at room temperature under reduced pressure to remove traces of solvent [15.0–15.5 g (47.6–49.2 mmol) 95–98% yield]. This material can be used directly in the next step (Note 4).

B. Formation of the copper-zinc organometallic 3 from 2-(3-iodopropyl)-1H-isoindole-1,3(2H)-dione. A dry, 100-mL, three-necked, round-bottomed flask is equipped with a magnetic stirring bar, 50-mL pressure-equalizing addition funnel bearing a rubber septum, three-way stopcock, and a thermometer. The air in the flask is replaced by dry argon and the flask is charged with 4.71 g (72 mmol) of cut zinc (ca. 1.5 × 1.5 mm; (Note 5)). The flask is again flushed three times with argon. 1,2-Dibromoethane (Note 6), (0.2 mL, 2.3 mmol) and 3 mL of tetrahydrofuran (THF) (Note 7) are successively injected into the flask which is then heated gently with a heat gun until ebullition of solvent is observed; the zinc suspension is stirred a few minutes and heated again. The process is repeated three times; 0.15 mL (1.2 mmol) of chlorotrimethylsilane^{2 3 4} is then injected into the addition funnel. The cut zinc foil turns grey. After 15 min the reaction mixture is heated to 30°C with an oil bath and 18.9 g (60 mmol) of iodide 2 dissolved in 30 mL of THF is added dropwise over 40 min. After addition, the reaction mixture is stirred for 4 hr at 43°C to give a dark brown-yellow solution of the zinc reagent (Note 8). A second, dry, 250-mL, three-necked, round-bottomed flask is equipped with a magnetic stirring bar, three-way stopcock connected to vacuum and an argon source, and two glass stoppers. The flask is charged with 4.59 g (108 mmol) of lithium chloride (Note 9). The flask is heated with an oil bath at 130°C (oil bath temperature) under vacuum (0.1 mm) for 2 hr to dry the lithium chloride. The reaction flask is then cooled to 25°C and flushed with argon. The two glass stoppers are replaced by a low temperature thermometer and a rubber septum and 4.84 g (54 mmol) of copper cyanide (Note 10) is added. The flask is flushed three times with argon and 40 mL of freshly-distilled THF (Note 7) is added to give, after 15 min, a clear yellow-green solution of the complex CuCN·2LiCl (Note 11). This solution is cooled to ca. −40°C and the two flasks are connected via a stainless steel cannula. The solution of the zinc reagent is transferred to the THF solution of copper cyanide and lithium chloride (Note 12). The resulting dark green solution is warmed to 0°C within 5 min and is ready to use in the next step after 5 min of stirring at this temperature.

C. (E)-2-(4-Hydroxy-6-phenyl-5-hexenyl)-1H-isoindole-1,3(2H)-dione 4. The THF solution of the copper-zinc reagent is cooled to −78°C and 19.9 mL (162 mmol) of boron trifluoride etherate (Note 13) is added dropwise. The reaction mixture is warmed to −30°C and stirred for 30 min, then cooled to −60°C. (E)-Cinnamaldehyde (5.71 g, 43.2 mmol) is added slowly via a syringe. The reaction mixture is allowed to stir at −30°C for 14 hr (Note 14) and for 30 min at 0°C. After this time, conversion is complete as indicated by GLC analysis and the reaction mixture is poured into an Erlenmeyer flask containing 500 mL of ethyl acetate, 100 mL of a saturated aqueous solution of ammonium chloride and 5 mL of ammonium hydroxide. The mixture is filtered by suction through 10 g of Celite on a sintered glass funnel, the contents of the funnel are washed twice with 50 mL of ethyl acetate and the filtrate is separated into two layers. The organic layer is washed successively with 100 mL of aqueous 10% sodium thiosulfate, and twice with 100 mL of a saturated aqueous solution of ammonium chloride. The combined aqueous phases are extracted with 100 mL of ethyl acetate and the combined organic phases are washed with 100 mL of a saturated aqueous sodium chloride solution, then dried over magnesium sulfate. After filtration, the solvent is removed on a rotary evaporator (ca. 10 mm) to afford 19.85 g of a crude yellowish oil. Flash chromatography separation⁵ of the oil using silica gel (230-400 mesh, 570 g) and ethyl acetate/hexane (1:2) gives 6.92 g (50% yield) of the 1,2-addition product 4 as a pale yellow solid, mp 87–88°C, after removal of the solvents (Note 15).