How Do Analogous α-Chloroenamides and α-Iodoenamides Give Different Product Distributions in 5-<i>Endo</i> Radical Cyclizations?

5-Endo cyclizations of N-alkenyl carbamoylmethyl radicals provide γ-lactam radicals, which in turn evolve to reduced or non-reduced (alkene) products depending on reagents and reaction conditions. Several groups have made surprising observations that chlorides are better radical precursors than iodides in such cyclizations. Here is described a detailed study of tin and silicon hydride-mediated radical cyclizations of N-benzyl-2-halo-N-cyclohex-1-enylacetamides. The ratios of directly reduced, cyclized/reduced, and cyclized/non-reduced products depend not only on the reaction conditions and reducing reagent but also on the precursor. Prior explanations for the precursor-dependent product ratios based on amide rotamer effects are ruled out. The precursor-dependent behavior is further dissected into two different effects: (1) the ratio of cyclized/reduced products to cyclized/non-reduced products depends on the ability of the radical precursor to react with the product γ-lactam radical in competition with tin hydride (iodides can compete, chlorides cannot), and (2) the occurrence of large amounts of directly reduced (noncyclized) products in the case of iodides is attributed to a competing ionic chain reaction by which the precursor is reductively deiodinated with HI. This side reaction is not available to chlorides, thereby explaining why the chlorides are better precursors in such reactions. The ability of the iodides to provide cyclized products can be largely restored by adding base. The chlorides and iodides then become complementary precursors, with chlorides giving largely cyclized/reduced products and iodides giving largely cyclized/non-reduced products.N-烯基氨基甲酰甲基自由基（N-alkenyl carbamoylmethyl radicals）的5-内环化（5-Endo cyclization）可生成γ-内酰胺自由基（γ-lactam radicals），后者可根据所使用的试剂与反应条件，进一步转化为还原产物或非还原（烯烃）产物。已有多个研究团队观测到一项反直觉的现象：在这类环化反应中，氯化物作为自由基前体的效果优于碘化物。本文详细研究了氢化锡与氢化硅介导的N-苄基-2-卤代-N-环己-1-烯基乙酰胺（N-benzyl-2-halo-N-cyclohex-1-enylacetamides）自由基环化反应。直接还原产物、环化/还原产物与环化/非还原产物的生成比例，不仅受反应条件与还原剂的影响，还与前体底物密切相关。此前基于酰胺旋转异构体效应对前体依赖性产物比例提出的解释已被排除。我们将前体依赖的反应行为进一步拆解为两种不同效应：(1) 环化/还原产物与环化/非还原产物的比例，取决于自由基前体与产物γ-内酰胺自由基发生竞争反应的能力（该竞争反应与氢化锡的反应相竞争）——碘化物可参与该竞争反应，而氯化物则无法参与；(2) 碘化物体系中大量生成直接还原（非环化）产物的原因，是存在竞争性离子链反应：在此反应中前体通过碘化氢（HI）发生还原脱碘。氯化物无法发生该副反应，这也解释了为何氯化物在这类反应中是更优异的前体。向体系中添加碱可在很大程度上恢复碘化物生成环化产物的能力。此时氯化物与碘化物成为互补的前体：氯化物主要生成环化/还原产物，而碘化物则主要生成环化/非还原产物。