无金属催化的硼酸和对甲苯磺酰腙的C-C键形成的偶联反应

碳-碳键的形成是有机合成中非常重要的反应。 尽管现在有很多可行的方法，但在反应选择性、底物的可获得性、操作的简单性、官能团的耐受性、环境可持续性和经济方面的优势方法也是化学家不断追求目标。 在此背景下，利用廉价无毒金属作为催化剂的新型交叉偶联反应的研究越来越受到人们的关注。 同样，不需要金属催化剂的高效工艺也非常有意义。2009年，Carlos Valde ´s和Jose Barluenga团队在化学类顶刊发文报道了无金属参与腙与硼酸高效构建碳碳键的反应，他们利用碳酸钾作碱，二氧六环作为溶剂，110度下进行反应，可高效构建一系列的烷烃衍生物，此反应具有非常高的官能团耐受度(Nature Chemistry, 2009, 1, 494–499；DOI: 10.1038/NCHEM.328)。由于所需的酰腙很容易从羰基化合物中生成，因此可以看作是羰基的还原偶联，此前要实现此转变，使用其他方法需要几个步骤，而此方法则直接合成，实用性极高。酯基，氨(胺)基，醛酮在此反应条件下都不受影响。

General procedure for the reductive coupling of tosylhydrazones 1 with boronic acids 2.

A reaction tube was charged with potassium carbonate (207.3 mg, 1.5 mmol), the boronic acid 2 (1.5 mmol), the tosylhydrazone 1 (1.0 mmol) and dioxane (4.3 mL). The system was heated at 110 ºC with stirring and reflux. The reaction was monitored by GCMS. When the reaction was completed, the crude reaction mixture was allowed to reach room temperature, the solvent was eliminated and a saturated solution of NaHCO3 and dichloromethane were added and the layers were separated. The aqueous phase was extracted three times with dichloromethane. The combined organic layers were washed with two portions of a saturated solution of NaHCO3, brine and then dried over MgSO4 and filtered. Solvent was removed under reduced pressure. If necessary, products were purified by chromatography on silica gel or alumina.

General procedure for the one pot reductive coupling of carbonyl compounds 4 with boronic acids 2.

A solution of the carbonyl compound 4 and tosylhydrazine in 4 mL of dioxane was stirred at 80 ºC for 90 min in a reaction tube provided with a reflux condenser. Then, potassium carbonate (207.3 mg, 1.5 mmol) and the boronic acid 2 (1.5 mmol) were added to the reaction mixture. The system was heated at 110ºC with stirring and reflux. The reaction was monitored by GCMS. When the reaction was completed, the crude reaction mixture was allowed to reach room temperature, the solvent was eliminated and a saturated solution of NaHCO3 and dichloromethane were added and the layers were separated. The aqueous phase was extracted three times with dichloromethane. The combined organic layers were washed with two portions of a saturated solution of NaHCO3, brine and then dried over MgSO4 and filtered. Solvent was removed under reduced pressure. If necessary, products were purified by chromatography on silica gel or alumina.

反应机理

腙盐II加热分解得到重氮化合物III，反应可能通过两种不同的反应历程进行：一种是重氮化合物III先和芳基硼酸反应通过中间体IV重排消除氮气得到烷基硼酸VII；另一种是先消除氮气得到卡宾，再和芳基硼酸反应，重排后得到烷基硼酸VII。最后碱性条件下脱硼得到最终产物。