以甲醇为碳源和氢源，钯碳催化硝基化合物的N-甲基化反应

chem有机方法2023-07-225.9K+

文献(DOI:10.1021/acs.joc.9b02141)报道了一种以甲醇为C源和H₂源，硝基(胺基)化合物在Pd/C催化下，实现N-甲基化。作者选择性合成了30种不同结构的N-甲基化合物，分离产率高达95%；通过该方法也实现了非甾体抗炎药尼美舒利(nimesulide)的选择性N-甲基化和氘化。

以甲醇为碳源和氢源，钯碳催化硝基化合物的N-甲基化反应第1张

该反应体系以甲醇为C源和H₂源，在Pd/C和^tBuOK作用下实现了硝基化合物的N-(单)甲基化、N`N-(双)甲基化及胺基的甲基化，可能机理如下:

以甲醇为碳源和氢源，钯碳催化硝基化合物的N-甲基化反应第2张

普适性考察

硝基化合物的N-甲基化及尼美舒利(nimesulide)的选择性N-甲基化和氘化

以甲醇为碳源和氢源，钯碳催化硝基化合物的N-甲基化反应第3张

^aReaction conditions: 0.5 mmol of nitroarene, 10% Pd/C(4.7 mol% Pd, 25 mg), 2 ml of MeOH as a reagent and solvent, t-BuOK (2mmol, 4 equiv.), 20 h, 130 °C, isolated yields. ^b Pd/C (50 mg), 48h, 150 °C. ^c Pd/C (80 mg), t-BuOK (280 mg), 150 °C, 72 h. ^d2 ml of CD₃OD as a reagent and solvent, t-BuOK (2 mmol,4 equiv.), 20 h, 130 °C, isolated yield.

操作:An oven dried 15 mL pressure tube, equipped witha stirring bar, was charged with 10% Pd/C (4.7 mol% Pd, 25 mg), t-BuOK (2 mmol, 4equiv) and nitroarene (0.5 mmol), and then MeOH (2 mL, 9.37 mmol) was slowly added to the mixture. The pressure tube was flushed with nitrogen and sealed with a suitably strong screw cap and heated to 130 °C (oil bath) for 20-48 h. After the completion of reaction, the pressure tube was cooled to RT,and the pressure build-up in the tube has been released slowly by losing the screw cap with caution in a fume hood. The catalyst was separated from themixture by filtration through a filter paper and the solid catalyst was washedwith EA. After evaporating the solvent, the obtained crude product was purified by column chromatography (Hexane: EA) to achieve the pure productwhich was further submitted for analysis.

硝基化合物的N`N-二甲基化

以甲醇为碳源和氢源，钯碳催化硝基化合物的N-甲基化反应第4张

^aReaction conditions: 0.5 mmol of nitroarene, 10% Pd/C(4.7 mol% Pd, 25 mg), 2 ml of MeOH as a reagent and solvent, t-BuOK (2 mmol,4 equiv.), 36 h, 150 °C, isolated yields. ^b 48 h. ^c 30 h.^d 60 h. ^e Pd/C (60 mg), t-BuOK (2 mmol, 224 mg),150 °C, 72 h.

操作:An oven dried 15 mL pressure tube, equipped witha stirring bar, was charged with 10% Pd/C (4.7 mol% w/w, 25 mg), t-BuOK (2 mmol, 4equiv) and nitroarene (0.5 mmol), and then MeOH (2 mL, 9.37 mmol) was slowly added to the mixture. The pressue tube was flushed with nitrogen and sealed with a suitably strong screw cap and heated to 150 °C (oil bath) for 36 h.After the completion of reaction, the pressure tube was cooled to RT, and thepressure build-up in the tube has been released slowly by losing the screw cap with caution in a fume hood. The catalyst was separated from the mixture by filtration through a filter paper and the solid catalyst was washed with EA. After evaporating the solvent, the obtained crude product was purified by column chromatography (Hexane:EA) to achieve the pure product which was further submitted for analysis.

通过以上两个表格对比可知，N-甲基化较N`N-二甲基化容易，通过控制反应时间和反应温度可以得到相应的产物。

胺基化合物的N`N-二甲基化

以甲醇为碳源和氢源，钯碳催化硝基化合物的N-甲基化反应第5张

其中化合物21是合成Bromhexine的重要原料；同时Hordinine也获得中等收率，大麦芽碱结构。

^aReaction conditions: 0.5 mmolof amine, 10% Pd/C (4.7 mol% Pd, 25 mg), 2 ml of MeOH as a reagent and solvent,t-BuOK (1 mmol, 2 equiv.), 12 h, 130 °C, isolated yields. ^b14 h. ^c16 h. ^d30 h. ^e GC yields.

操作:An oven dried 15 mL pressure tube, equipped with a stirring bar,was charged with 10% Pd/C (4.7 mol%, 25 mg), t-BuOK (2 mmol, 4 equiv) and amine (0.5mmol), and then MeOH (2 mL) was slowly added to the mixture. The pressure tube was flushed with nitrogen and sealed with a suitably strong screw cap and heated to 130 °C (oil bath) for 12 h. After the completion of reaction, the pressure tube was cooled to RT, and the pressure build-up in the tube has been released slowly by losing the screw cap with caution in a fume hood. The catalyst was separated from the mixture by filtration through a filter paper and the solidcatalyst was washed with EA. After evaporating the solvent, the obtained crude product was purified by column chromatography (Hexane: EA) to achieve the pure productwhich was further submitted for analysis.

同时作者也比较了芳香胺与脂肪胺的选择性

从反应结果可以看出:与脂肪伯胺相比，芳香伯胺的N-甲基化具有很高的选择性；且酰胺不会被甲基化。

同时作者通过该方法实现了苯并咪唑的合成

操作:An oven dried 15 mL pressure tube, equipped with a stirring bar, was charged with 10% Pd/C (4.9, 25 mg), t-BuOK (2 mmol, 4 equiv)and o-phenylenediamine (0.5 mmol), and then MeOH (2 mL, 9.37 mmol) was slowly added to the reaction mixture in the presence of an ice bath. The pressure tube was flushed with nitrogen and sealed with a suitably strong screw cap and heated to 130 °C for 12 h. After the completion of reaction, the pressure tube was cooled to RT, and the pressure build-up in the tube has beenreleased slowly by losing the screw cap with caution in a fume hood. The catalyst was separated from the mixture by filtration through a filter paper and thesolid catalyst was washed with EA. After evaporating the solvent, the obtained crude product was purified by column chromatography (Hexane: EA) to achieve thepure product which was further submitted for analysis.

克级放大反应

Pd/C的回收操作

The solid Pd/C catalyst obtained after the reaction similar to thegeneral procedure for N-methylation of nitroarenes was washed with water, ethanol and dichloromethane sequentially in each run and the washed catalyst was dried in vacuum oven at 80°C for overnight and reused for next cycle

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参考文献: DOI:10.1021/acs.joc.9b02141

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