为避免使用有毒性的光气或三光气，研究人员也有通过碳酸酯或硫代碳酸酯来制备脲。通常这种方法条件比较温和，收率比较高，对环境无毒或低毒。例如用胺与Boc₂O在DMAP催化下合称脲或者通过氨基碳酸酯合成脲。另外，也有不少文献报道由硅试剂或金属试剂催化碳酸酯或N-烷基碳酸酯与胺反应合成脲，收率非常高。

通过DMAP催化与Boc₂O合成脲

To a solution of (Boc)₂O (683 mg, 3.13 mmol) in DCM (10 mL) was added successively a solution of DMAP (36 mg, 0.30 mmol) in DCM (3 mL) and a solution of 1,1,3,3-tetramethylbutylamine (385 mg, 2.98 mmol) in DCM (5 mL).  After stirring for 20 min at room temperature, p-anisidine (385 mg, 3.13 mmol) in DCM was added.  The mixture was heated for 14 hours at 40 ^oC. The mixture was concentrated in vacuo and the residue was purified by flash chromatography on silica gel to afford further product (825 mg, 99% yield). ^[1]

碳酸二甲酯与胺反应合成脲

Into a flame-dried 10 mL CEM microwave reaction vessel was added 2-hydroxypyridine (HYP) (9.5 mg, 0.10 mmol), 4- phenoxyaniline (102 mg, 1.10mmol), and dimethylcarbonate (126 L, 3.00 mmol). To this mixture was added Zr(Ot-Bu)₄(20 mL, 0.10 mmol) and the reaction was stirred at 80 °C for 12 h. The volatiles were evaporated in vacuo and 4-methyl-2-hydroxyquinoline (MeHYQ) (32 mg, 0.20 mmol), N-methylpentylamine(68.6 L, 1.00 mmol), chlorobenzene (0.25 mL, 2.0 M) and Zr(Ot-Bu)₄(20 L, 0.10 mmol) were added successively. The reaction was incubated in CEM single mode microwave reactor (Explorer/Discover model) with the dynamic cooling system(PowerMax®) on at 120 ^oC for 15 min (maximum ramp time: 10 min, maximumpower: 300 W).  The reaction was quenched by addition of MeOH (2 mL) and CH₂Cl₂ (2 mL).The mixture was concentrated in vacuo and purified by flash chromatography on silica gel(hexane:EtOAc= 3: 1) to afford urea as a pale yellow solid (149 mg, 95% yield). ^[2]

由氨基碳酸酯合成脲示例二

The solution of 1(7.7 g, 24.2 mmol) in anhydrous THF (50 mL) was added dropwise to a suspension of NaH (60% dispersion in mineral oil, 0.7 g, 48.4 mmol) in THF (50 mL) at 0 ^oC.The reaction mixture was heated at reflux for 3 h. Upon cooling to room temperature, the mixture was poured into ice H₂O (50 mL), and extracted with ethyl acetate.The extracts were washed with H₂O and brine, dried, filtered, and concentrated to give the desired product (5.3 g, 90% yield), mp 212-213 ^oC.^[3]

另外通过硫代碳酸甲酯合成脲也是一种非常好的方法。 DMDTC作为一种光气的替代品，所有生成脲的两步反应都可以在水溶液中进行，对环境友好且低毒。对称的脲直接加两当量的胺与一当量的DMDTC在60度条件下得到，当然反应最好是用氮气保护。如果是不对称的脲，可以在室温条件下先选择性N-烷基硫代碳酸甲酯中间体，然后在下一步再同伯胺或仲胺加热完成。此方法收率和纯度都非常高。是一种非常好的制备脲的方法。不过该方法的缺点是会生成两当量的甲硫醇，味道较大。

由硫代碳酸甲酯合成脲

Hexylamine (2.02 g, 20mmol) was added dropwise over a period of 10 min to a suspension of S,S-dimethyl dithiocarbonate (1;1.22 g, 10 mmol) in H₂O (5 mL), under vigorous stirring. The reaction was mildly exothermic, and during the addition the temperature of the mixture was maintained at 20–25 °C with an ice-water bath. The progress of the reaction was monitored by GC and GC-MS analyses. During the reaction an emulsion was formed. Stirring at r.t. (20–25 °C) was maintained until disappearance of 1 (2 h). The mixture was then treated with cold CH₂Cl₂/aq5% HCl (2:1, 100 mL). The aqueous solution was separated and extracted with CH₂Cl₂ (30 mL). The combined organic extracts were washed with H₂O (30 mL), dried (Na₂SO₄), and evaporated under reduced pressure to give crude compound 2; (1.75 g, ca. 100%); 99.9% purity (GC analysis); mp 56.5–57.5 °C(pentane).

A suspension of crude S-methyl N-hexylthiocarbamate (2; 1.75 g, 10 mmol), obtained in the first step as described above, in H₂O (5 mL) was heated to 60 °C in an oil-bath, under vigorous stirring. Anaq 40% soln of benzylamine (1.07 g, 10 mmol) in H₂O (2.7 mL) was added dropwise and then N₂ was flushed through the mixture.  At once 5d became oil that emulsified in the reaction medium. Progress of the reaction was monitored by GC and GC-MS analyses.  After 1 h, a colorless solid separated out from the mixture. To make the stirring easier, another portion of H₂O (5 mL) was added. The reaction was complete after 2 h when 5d disappeared and 10e was the only product. The mixture was extracted with CH₂Cl₂(2 × 80 mL); the organic layers were collected and washed with aq. 5% HCl(50 mL) and then with H₂O (50 mL), dried (Na₂SO₄), and evaporated under reduced pressure. The crude residue was the title compound 3; overall yield of the two steps, based on the starting DMDTC (1): (2.32 g, 99%yield); 99.5% purity (GC analysis); mp 77.2– 78.7 °C; mp 79.2–79.6 °C(recrystallized from CHCl₃–pentane) (Lit. mp 77–78 °C). ^[4]

【参考文献】

[1] Hans-Joachim Knolker etc Synlett, (6), 502-504; 1996

[2]Chong Han and John A. Porco, JrOrganic Letters, 2007, 9(8), 1517-1520

[3]Yanyun Zhu etc European Journal of Medicinal Chemistry, 2010, 4953-4962

[4]Emma Artuso etc Synthesis 2007, No. 22, 3497–3506