鋁陽離子催化對映選擇性硫-麥可加成反應用於未活化α,β-不飽和醯胺

Abstract

麥可加成因其高原子經濟性與在建立碳–碳與碳–雜原子鍵結方面的多樣性而廣受重視。然而，由於醯胺本質上具有低親電性，此類反應鮮少應用於醯胺反應物，尤其是成功應用在未活化醯胺的範例更是罕見。此研究發現，在高路易士酸性的鋁陽離子催化，芳香硫醇對未活化 α,β-不飽和醯胺進行的對映選擇性之硫-麥可加成反應。而且此鋁陽離子催化系統具有廣泛的官能基耐受性，在 0 ℃ 下最高可達 96% 分離產率與 90% 對映選擇性。值得注意的是，在加入催化量1,8-二氮雜二環[5.4.0]十一碳-7-烯後，酸性較低的脂肪硫醇也能順利反應。此外，即便是具挑戰性的反應物，如 2-巰基吡啶，在本催化系統中亦具良好相容性，突顯了鋁陽離子在不對稱催化中的潛力。

Michael additions are well-known for their high atom economy and efficiency in constructing carbon–carbon and carbon–heteroatom bonds. However, due to the inherently low electrophilicity of amides, such transformations are rarely applied to amide substrates, and successful examples involving unactivated amides remain scarce. Herein, we report the first enantioselective thia-Michael addition of aromatic thiols to unactivated α,β-unsaturated amides, enabled by a highly Lewis acidic aluminum cation catalyst. The substrate scope demonstrates the broad tolerance of the aluminum cation catalytic system, achieving up to 96% isolated yield and 90% stereoselectivity at 0 ℃. Notably, aliphatic thiols also undergo this transformation upon the addition of catalytic amount of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene). Furthermore, even the challenging substrate 2-mercaptopyridine exhibits good compatibility under the present catalytic conditions, emphasizing the potential of aluminum cations in asymmetric catalysis.