Li Jianyu, Gong Sheng, Gao Shaolun, Chen Jianfeng, Chen Wen-Wen, Zhao Baoguo
The Education Ministry Key Lab of Resource Chemistry, Shanghai Frontiers Science Center of Biomimetic Catalysis and Shanghai Normal University, Shanghai, 200234, China.
Nat Commun. 2024 Jan 31;15(1):939. doi: 10.1038/s41467-024-45131-3.
Primary alkyl amines are highly reactive in N-nucleophilic reactions with electrophiles. However, their α-C-H bonds are unreactive towards electrophiles due to their extremely low acidity (pK ~57). Nonetheless, 1,8-diazafluoren-9-one (DFO) can activate primary alkyl amines by increasing the acidity of the α-amino C-H bonds by up to 10 times. This makes the α-amino C-H bonds acidic enough to be deprotonated under mild conditions. By combining DFO with an iridium catalyst, direct asymmetric α-C-H alkylation of NH-unprotected primary alkyl amines with allylic carbonates has been achieved. This reaction produces a wide range of chiral homoallylic amines with high enantiopurities. The approach has successfully switched the reactivity between primary alkyl amines and allylic carbonates from intrinsic allylic amination to the α-C-H alkylation, enabling the construction of pharmaceutically significant chiral homoallylic amines from readily available primary alkyl amines in a single step.
伯烷基胺在与亲电试剂的N-亲核反应中具有高度反应性。然而，由于其极低的酸度（pK ~57），它们的α-C-H键对亲电试剂无反应性。尽管如此，1,8-二氮杂芴-9-酮（DFO）可以通过将α-氨基C-H键的酸度提高多达10倍来活化伯烷基胺。这使得α-氨基C-H键酸性足够强，能够在温和条件下被去质子化。通过将DFO与铱催化剂相结合，实现了NH-未保护的伯烷基胺与烯丙基碳酸酯的直接不对称α-C-H烷基化反应。该反应产生了一系列具有高对映体纯度的手性高烯丙基胺。该方法成功地将伯烷基胺与烯丙基碳酸酯之间的反应性从固有的烯丙基胺化转变为α-C-H烷基化，从而能够从容易获得的伯烷基胺一步构建具有药学意义的手性高烯丙基胺。
