An annulation reaction for the synthesis of morpholines, thiomorpholines, and piperazines from beta-heteroatom amino compounds and vinyl sulfonium salts.
An annulation reaction for the synthesis of morpholines, thiomorpholines, and piperazines from beta-heteroatom amino compounds and vinyl sulfonium salts.
复制标题
DOI：
10.1002/anie.200800373
复制
发表时间：
2008-05
影响因子：
--
通讯作者：
M. Yar;E. McGarrigle;V. Aggarwal
中科院分区：
文献类型：
--
作者：
M. Yar;E. McGarrigle;V. Aggarwal
The nitrogen-containing heterocycles comprising morpholines, thiomorpholines, and piperazines are some of the most important pharmacophores in medicinal chemistry. However, the direct synthesis of such compounds by alkylation of b-amino alcohols/thiols/amines with 1,2-dihalo derivatives is often fraught with low yields and side reactions. 1,2Dihalogen derivatives are generally poor electrophiles and reactions are often accompanied by competing elimination processes. A solution to this problem is to carry out a threestep sequence employing an a-halogen acid halide as the electrophile. Following amide formation and intramolecular alkylation, reduction finally furnishes the required heterocycles. Herein, we describe the application of a novel concept to prepare these pharmacologically important heterocycles from b-amino alcohols/thiols/amines in one step and high yield. We reasoned that soft electrophiles operating under less basic conditions would minimize competing elimination pathways and therefore considered the possibility of employing Michael acceptors. This led us to vinyl onium salts (e.g., 1). We expected that, following conjugate addition of one of the heteroatoms, an ylide 4 would be generated that could undergo proton transfer with the other heteroatom (Scheme 1). The heteroatom anion generated, 5, would then attack the onium ion electrophile to effect ring-closure and produce the required heterocycle. Although vinyl onium salts have been employed in three-component coupling reactions with nucleophiles and electrophiles, their potential to react according to the pathway shown in Scheme 1 has not previously been recognized. Of the readily available vinyl onium salts, it was thought that sulfonium and phosphonium would be better at promoting the conjugate addition step than ammonium since the ylide intermediate is better stabilized. However, to promote cyclization leaving group ability of the onium is critical and this falls in the order S>N @ P. These considerations led us to examine vinyl sulfonium salts, and in particular diphenyl vinyl sulfonium salt 1. This salt was easily prepared through a modified procedure as shown in Scheme 2. In this
