| 97% |
|
Methyl 3-(hydroxymethyl)-5-nitrobenzoate. 3-(Methoxycarbonyl)-5-nitrobenzoic acid (20.0 g, 88.9 mmol) was combined with tetrahydrofuran (150 mL) and cooled to 0 C. To this solution was added a 1 M borane tetrahydrofuran complex (178 mL, 178 mmol) cautiously over 15 min and the reaction mixture allowed to warm to room temperature overnight. The mixture was cooled to 0 C., treated with excess methanol and concentrated in vacuo to afford to afford a precipitate which was dissolved in ethyl acetate, washed with concentrated sodium bicarbonate (2×), then brine (2×), dried over sodium sulfate, and concentrated to afford 18.2 g (97%) which was used without further purification. 1H-NMR (CDCl3, 300 MHz) delta 8.70 (s, 1H), 8.39 (s, 1H), 8.30 (s, 1H), 4.84 (s, 2H), 3.95 (s, 3H). Mass spec.: 212.06 (MH)+. |
| 95% |
With dimethylsulfide borane complex; In tetrahydrofuran; at -10 - 80℃; for 0.25h; |
3-(Methoxycarbonyl)-5-nitrobenzoic acid (5.5 g, 24.4 mmol, 1 equiv) was dissolved in THF and the mixture was cooled to -10 C. At this temperature the BH3*SMe2complex, dissolved in THF (44 mL), was slowly added. The mixture was warmed upto room temperature before heating to 80 C for 15 min. Hydrolysis with acetic acidaq (50%, 3 mL) terminated the reaction. The mixture was neutralized with NaHCO3aq,THF was removed in vacuo and H2O and ethyl acetate were added to the resultingresidue. The crude product was extracted with ethyl acetate, dried with MgSO4, filtered and concentrated in vacuo. The resulting crude product (6 g) was purified by column chromatography (silica gel; CH2Cl2/MeOH = 50:1). Methyl 3-(hydroxymethyl)-5-nitrobenzoate (4.9 g, 23.2 mmol, 95%) was isolated and the crude material was used for the next step. Methyl 3-(hydroxymethyl)-5-nitrobenzoate (4.5 g, 21.3 mmol, 1 equiv) was dissolved in ethanol (150 mL) and palladium/charcoal (10%, 0.5 g, 0.4 mmol, 0.02 equiv) was added. The mixture was stirred for 8 h under hydrogen atmosphere before it was filtered over a pad of CeliteTM. The solvent was removed in vacuo. Methyl 3-amino-5-(hydroxymethyl)benzoate (3.6 g, 19.9 mmol, 86%) was isolated and directly employed in the next step. Methyl 3-amino-5-(hydroxymethyl)benzoate (10.6 g, 58.6 mmol, 1 equiv) was dissolved in ethanol (120 mL) and Boc2O (14.2 mL, 64.4 mmol, 1.1 equiv) was added. The mixtrure was stirred for 20 h at 30 C before the solvent was removed in vacuo. The crude product was purified by column chromatography (silica gel,CH2Cl2/MeOH = 10:1). Boc-protected aniline (15.5 g, 55.1 mmol, 94%) was isolatedas a colorless solid. The product was directly employed in the next step. Boc-protected aniline (15.5 g, 55.1 mmol, 1 equiv) was dissolved in CH2Cl2 (220 mL), triphenylphosphine (19.5 g, 74.4 mmol, 1.4 equiv) and imidazole (5.6 g, 82.7 mmol, 1.5 equiv) was added and the mixture was cooled to 0 C. At this temperature bromine (3.7 mL, 71.6 mmol, 1.3 equiv) was added slowly. The suspension was stirred at 0 C for 30 min and then stirred for 2 h at room temperature. The reaction was hydrolyzed with H2O (100 mL) and the product was extracted with CH2Cl2. The organic phase was extracted with Na2S2O3aq and H2O before drying with MgSO4. Filtration and concentration in vacuo yielded the crude product which was purified by column chromatography (silica gel, CH2Cl2/MeOH = 50:1 20:1). The resulting benzyl bromide (17.1 g, 49.6 mmol, 90%) was directly employed in the next step. Trimethylsilylacetylene (4 mL, 28.4 mmol) was dissolved in THF (15 mL) under an argon atmosphere and cooled to -78 C. At this temperature a n-butyllithium solution (2.5 M, hexane) was slowly added. In a second flask, indium(III) chloride (2.3 g, 10.2 mmol) was flame dried in vacuo and afterwards cooled to room temperature before suspending the salt in THF (15 mL). The suspension was cooled to -78 C and the solution of the lithium acetylide was added dropwise to the indium suspension. The resulting reaction mixture was stirred for 30 min at -78 C, warmed up to room temperature and stirred for additional 30 min. The benzyl bromide (5 g, 14.6 mmol, 1 equiv) was dissolved in THF (60 mL) in a third flask and Pd(dppf)Cl2 x CH2Cl2 (0.22 g, 0.29 mmol; 0.02 equiv) was added. The mixture was warmed up to 65 C and at this temperature the previously prepared indium tri(trimethylsilylacetylene) solution (10.2 mmol, 0.7 equiv) was added slowly. The mixture was stirred for 20 h at 65 C before it was hydrolyzed by the addition of methanol. The crude product was directly adsorbed on silica gel and purified by column chromatography (silica gel; petroleum ether/ethyl acetate = 10:1 5:1). Methyl 3-[(tert-butoxycarbonyl)amino]-5-(3-(trimethylsilyl)prop-2-yn-1-yl)benzoate (4.4 g, 12.1 mmol, 83%) was isolated as a colorless oil. Methyl 3-[(tert-butoxycarbonyl)-amino]-5-(3-(trimethylsilyl)prop-2-yn-1-yl)benzoate (4.4 g, 12.1 mmol, 1 equiv) was dissolved in CH2Cl2 (100 mL) and then cooled to -55 C. At this temperature diisobutylaluminium hydride solution (1 M, hexane, 36.3 mL, 3 equiv) was added and the mixture stirred for 30 min at -55 C before stirring for another 20 h at room temperature. The reaction was controlled by TLC and revealed a bit of starting material. Therefore, additional diisobutylaluminium hydride solution (1 M, hexane, 8 mL) was added. After 2 h the conversion was completed and the mixture was poured into an ice cold aqueous sodium-potassium tartrate solution, diluted with CH2Cl2 (100 mL) and vigorously stirred for 2 h. After separation of the phases the crude product was extracted with CH2Cl2, the organic phase was dried with MgSO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 2:1). The resulting tert-butyl {3-(hydroxymethyl)-5-[3-(trimethylsilyl)prop-2-yn-1-yl]phenyl}carbamate (2.9 g, 8.6 mmol, 71%) was directly employed for the next step. tert-But... |
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