A. 6,7-Dimethoxy-1,2,3,4-tetrahydro-2-[(1-tert-butoxy-3-methyl)-2-butyliminomethyl]isoquinoline (2). In a 250-mL, round-bottomed flask 10.0 g (51.7 mmol) of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline 1 (Note 1) is combined with 11.5 g (53.7 mmol) of (S)-N,N-dimethyl-N'-(1-tert-butoxy-3-methyl)-2-butylformamidine (Note 2), 50 mL of dry toluene, and 50 mg of (+)-camphorsulfonic acid (Note 3). The mixture is heated to reflux for 24 hr and allowed to cool to room temperature. Approximately 30 mL of toluene is removed by rotary evaporation and the residual solution is heated at reflux for an additional 2 days. After the reaction mixture is cooled, it is diluted with 50 mL of dichloromethane and washed with 50 mL of 1 N sodium hydroxide and 100 mL of brine and the organic layer is dried over anhydrous potassium carbonate, filtered, and concentrated by rotary evaporation. The residue is distilled (Kugelrohr 0.1 mm, 170°C bath temp.) to give 18.0 g (96%) of 2 as a pale-yellow oil (Note 4).

B. (S)-6,7-Dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline, (−)-salsolidine (3). A 500-mL, three-necked flask, containing a magnetic stirring bar, is equipped with a three-way stopcock, a low-temperature thermometer, and a rubber septum. The flask is charged with 15.0 g (41.4 mmol) of formamidine 2, filled with argon, and kept under a pressure of ca. 100 mm against the atmosphere (Note 5). Through the septum, via a syringe, is added 300 mL of dry tetrahydrofuran (Note 6) and the solution is cooled to −75°C in a dry ice–acetone bath. A tert-butyllithium solution (21 mL of a 2.4 M solution, (Note 7)), is added dropwise within 5 min through the septum. After the deep-red solution is stirred at −75°C for 45 min, is cooled to −100°C in a liquid nitrogen–methanol bath and, after 15 min at −100°C, 3 mL of freshly distilled iodomethane (Note 8) dissolved in 10 mL of dry tetrahydrofuran is added by syringe at such a rate that the temperature of the reaction mixture does not rise above −90°C. Stirring is continued for 3 hr and the solution is poured into a 1-L separatory funnel containing 50 mL of water. This is extracted twice with 100 mL of dichloromethane and the combined organic layers are washed with 100 mL of brine, dried over potassium carbonate, and filtered. Removal of the solvent on a rotary evaporator gives a cloudy yellow oil, which is dissolved in 100 mL of 60% ethanol. To this solution is added 4.5–5.0 mL of hydrazine (Note 9) followed by 3.0 mL of glacial acetic acid (pH 8–9). The mixture is stirred overnight at ambient temperature and diluted with 50 mL of water. It is extracted twice with 100 mL of dichloromethane, and the combined organic extracts are washed with 50 mL of water, dried (potassium carbonate), filtered, and concentrated at ambient temperature under aspirator pressure. The residue, which consists of valinol tert-butyl ether and salsolidine, is distilled bulb-to-bulb under aspirator pressure at 105°C (pot temperature). This removes the valinol tert-butyl ether (Note 10), leaving crude salsolidine as the pot residue. The residue is dissolved in 100 mL of ether and washed twice with 35-mL portions of ice water–3 N hydrochloric acid (1:4). The ether layer is discarded and the acidic aqueous layer is neutralized with cold (0–5°C) aqueous 25% sodium hydroxide until it is alkaline to pH paper. The creamy mixture is immediately extracted twice with 50 mL of dichloromethane and the organic layers are drawn off, combined, and dried over anhydrous potassium carbonate. After the drying agent is removed by filtration, it is washed twice with 5 mL of dichloromethane. The filtrate and wash are concentrated by rotoevaporation, leaving a yellow oil. Distillation (Kugelrohr) at a pot temperature of 120–125°C (0.01 mm) gives 5.1–5.3 g (60–63%) of (S)-6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline (salsolidine) 3 as a pale-yellow oil, which crystallizes on standing (Note 11), mp 47–49°C, (Note 12) and (Note 13).