通过伯脲与醛反应合成脲

在有些情况下，我们也会通过伯脲与醛进行还原胺化合成需要的脲。

实例一：通过伯脲与醛反应合成脲

To a suspension of benzamide (722 mg,5.91 mmol) in toluene (8 mL) was added benzaldehyde (200 mL, 1.97 mmol)followed by triethylsilane (950 mL, 5.91 mmol) and trifluoroacetic acid (450 mL,5.79 mmol). The resulting reaction mixture was stirred at reflux for 18 hours and the solvent was removed in vacuo. The residue was purified by flash chromatography to afford N-benzyl-benzamide (381 mg, 91% yield) as a white solid. ^[1]

通过钯催化或铜催化氧化合成脲

我们也可以利用钯催化氧化作用下，两种胺在DME中通一氧化碳加热加压来氧化合成脲。

实例：钯催化氧化合成脲

A 250 mL stainless steel autoclave was charged in the presence of air with a solution of the aniline (350.0 mg, 3.76 mmol), and then PdI₂ (4.9 mg, 0.0136 mmol), KI (22.1 mg, 0.13 mmol), and a solution of morpholine (352.0 mg, 4.04 mmol) in DME (8.0 mL) were added. While stirring, the autoclave was pressurized with CO (16 atm) and air (up to 20 atm) and then heated at 100 °C for 5 h. After cooling, the autoclave was degassed, solvent was evaporated, and products were purified by column chromatography(SiO₂, hexane-acetone from 6:4 to 4:6) to give the desired compound (660mg, 85% yield). ^[2]

通过烷基化或芳基化合成复杂的多取代脲

我们有时也会通过烷基化或芳基化的方法合成一些多取代的脲。

实例一：通过芳基化合成多取代脲

1-(4-methoxy-phenyl)-3- methyl-1-((Z)-1-phenyl-propenyl)-urea (0.250 g,0.84 mmol), 3-bromobenzonitrile (0.307 g, 1.68 mmol), Xantphos (0.049 g, 0.084mmol), Pd₂(dba)₃ (0.039 g, 0.042 mmol) and NaOtBu (0.243g, 2.52 mmol) were dissolved in toluene(10 mL) and sparged under nitrogen for 1hour. The resulting mixture was heated to 110 ^oC for 48 hours. After cooling to room temperature saturated aqueous NH₄Cl was added and the mixture was extracted twice (EtOAc). The organic phases were combined, dried (MgSO₄) and the solvent removed under reduced pressure. The crude product was purified by flash column chromatography to yield the desired N-aryl urea (0.146 g, 44% yield). ^[3]

脲的合成方法小结：

经验交流

对于异氰酸酯合成脲的经验小结如下：

1. 对于碱性强的胺，用三光气做异氰酸酯时易生成胺的自身偶合我们可以采取如下条件：

A）换成合适的碱，如饱和碳酸氢钠水溶液。

B) 溶剂可用DCM, THF.

C) 低温反应(0度)。

D）反应液要稀，50 mL/g.

2. 对于碱性较弱的胺（如多个N的杂环），可以采用下面条件：

A) 换成强碱，如NaH  等。

B) 溶剂可用THF.

C) 室温或加热。

D) 反应液浓度，20 mL/g.

【参考文献】

[1] Daniel DubS etcTetrahedron Letters,40(12), 2295-2298; 1999

[2] Bartolo Gabriele etc Journal ofOrganic Chemistry, 69(14), 4741-4750; 2004

[3] Daniel J. Tetlow, UlrichHennecke etc Organic Letters, 12(23), 5442-5445; 2010