【Nature Chemistry】無金屬催化的硼酸和對甲苯磺酰腙的C-C鍵形成的偶聯反應

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碳-碳鍵的形成是有機合成中非常重要的反應。 盡管現在有很多可行的方法，但在反應選擇性、底物的可獲得性、操作的簡單性、官能團的耐受性、環境可持續性和經濟方面的優勢方法也是化學家不斷追求目標。 在此背景下，利用廉價無毒金屬作為催化劑的新型交叉偶聯反應的研究越來越受到人們的關注。 同樣，不需要金屬催化劑的高效工藝也非常有意義。2009年，Carlos Valde ′s和Jose Barluenga團隊在化學類頂刊發文報道了無金屬參與腙與硼酸高效構建碳碳鍵的反應，他們利用碳酸鉀作堿，二氧六環作為溶劑，110度下進行反應，可高效構建一系列的烷烴衍生物，此反應具有非常高的官能團耐受度(Nature Chemistry, 2009 , 1, 494–499；DOI: 10.1038/NCHEM.328)。由于所需的酰腙很容易從羰基化合物中生成，因此可以看作是羰基的還原偶聯，此前要實現此轉變，使用其他方法需要幾個步驟，而此方法則直接合成，實用性極高。

酯基，氨(胺)基，醛酮在此反應條件下都不受影響。

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.

由于制備腙的反應極易進行，醛酮也可以直接制備腙不用分離，直接加入硼酸進行此反應，反應效果也很好。

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.

反應機理

腙鹽II加熱分解得到重氮化合物III，反應可能通過兩種不同的反應歷程進行：一種是重氮化合物III先和芳基硼酸反應通過中間體IV重排消除氮氣得到烷基硼酸VII；另一種是先消除氮氣得到卡賓，再和芳基硼酸反應，重排后得到烷基硼酸VII。最后堿性條件下脫硼得到最終產物。