| 29% |
Stage #1: With diisobutylaluminium hydride In dichloromethane at -35℃; for 0.25 h;
Stage #2: With diisobutylaluminium hydride In dichloromethane at 0 - 20℃; for 4 h; |
Aldehyde preparation: To a solution of 4-chloro-3-nitrobeznoic acid (20 g, 99.2 mmol, 1.0 eq) in dimethylformamide (400 mL) was added potassium carbonate (35 g, 254 mmol, 2.55 eq). The mixture was stirred 30 min and ethyl iodide (18.6 g, 119 mmol, 1.20 eq) was added. The reaction mixture was stirred at 50 [°C] for 4h. Water (3 L) was added and the mixture was extracted with diethyl ether (2 x 500 mL). The organic extracts were combined, washed with brine (1 L), dried over anhydrous sodium sulfate and concentrated. The residue was crystallized from hexanes to provide 19.7 g (86percent) of the ester. Data [: IH] NMR (500 MHz, CDC13) [8] 8.51 (d, 1H), 8.17 (dd, 1H), 7.65 (d, 1H), 4.43 (q, 2H), 1.42 (t, 3H). Sulfur (1.60 g, 49.9 mmol, 0.58 eq) was dissolved in a solution of sodium sulfide [NONAHYDRATE] (12.0 g, 50.0 mmol, 0.58 eq) in water (60 [ML).] This solution was combined with a solution of ethyl 4-chloro-3-nitrobenzoate (19.6 g, 85.4 mmol, 1.00 eq) in ethanol (100 mL). The resulting mixture was heated at reflux for 3 h. The hot reaction mixture was poured into water (600 mL) and stirred for 15 min. The product was isolated by filtration and recrystallized from ethanol to provide 16.45 g (77percent) of the disulfide. Data: [APOS;H NMR] (500 MHz, CDC13) [5] 8.96 (d, 1H), 8.19 (dd, 1H), 7.88 (d, 1H), 4.43 (q, 2H), 1.41 (t, 3H). A mixture of diethyl 4,4'-dithiobis (3-nitrobenzoate) (11.2 g, 24.75 mmol, 1.00 eq) and zinc granules (15.0 g, 234 mmol, 9.47 eq) in formic acid (600 mL) was heated to reflux for 48 h. The mixture was cooled to room temperature and concentrated to dryness on vacuum rotary evaporator. The residue was partitioned between ethyl acetate (500 mL) and saturated aqueous sodium bicarbonate (500 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated on vacuum rotary evaporator. The residue was purified by chromatography on neutral Alumina (1/0 to 0/1 hexanes/dichloromethane) to provide 5.30 g (51percent) of the benzthiazole ester. Data: 1H NMR (500 MHz, [CDC13)] [8] [9. 08 (S, 1H),] 8.83 (d, 1H), 8.14 (dd, 1H), 8.02 (d, 1H), 4.45 (q, 2H), 1.44 (t, 3H); MS [(EI)] m/z 208 [(M++1).] Diisobutylaluminum hydride (1.0 M in dichloromethane, 6.0 mL, 6 mmol, 1.05 eq) was added over 15 min to a solution of the ester (1.18 g, 5.70 mmol) in dichloromethane (40 mL) [AT-35] [°C.] The reaction mixture was allowed to warm to rt and was maintained overnight. Analysis of the reaction progress by thin layer chromatography revealed the presence of starting material. The reaction mixture was cooled to [0 °C] and was treated with additional diisobutylaluminum hydride (6.0 mL, 6 mmol). After 4 h at rt, the reaction was quenched by the addition of water (10 mL) and the slurry was poured onto 5percent sodium hydroxide and dichloromethane (200 mL) and maintained for 30 min with vigorous stirring. The organic layer was separated, washed with brine, dried (sodium sulfate), and concentrated. The residue was dissolved in dichloromethane (100 mL) and was treated with manganese [(IV)] oxide (3.0 g) and powdered [4A] seives (3.0 g). The reaction mixture was filtered through Celite (100 mL dichloromethane rinse) after 14 h and the filtrate was extracted with 0.6 N aqueous sodium hydrogen sulite (2 x 150 mL). The combined aqueous layers were back-extracted with dichloromethane [(50] mL), were made basic (pH 11) by the addition of 50percent sodium hydroxide, and were extracted with ethyl acetate (2 x 100 mL). The ethyl acetate layers were dried (sodium sulfate) and concentrated to provide 268 mg (29percent) of the aldehyde as a tan solid. Data [: IHNMR (CDCL3) 6] 10.18 (s, 1H), 9.13 (s, [1H),] 8.61 (d, J= 1.0, 1H), 8.11 (d, J= 8.0, 1H), 8.01 (dd, J= 8.5, 1.5, 1H). Condensation: According to procedure A. Data: Yield: 86percent. 1H NMR (CD30D) 8 8.97 (s, 1H), 8.75 (s, [1H),] 8.60 (s, [1H),] 8.06 (d, [J=] 0.6, [1H),] 7. 87 (d, [J=] 8.4, [1H),] 7.82 (dt, Jd = 7.8, Jt = 1. 8, 1H), 7.30 (dd, J= 7.8, 4.8, 1H), 7.26 (dd, J= 8.4, 1.6, 1H), 6.76 (s, 1H), 3.86 (t, J= 5.5, 2H), 2.85 (m, 2H), 1.79 (m, 2H); MS [(EL)] m/z 306 [(M+ +] 1). |
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