Mechanistic Insights on Orthogonal Selectivity in Heterocycle Synthesis

Recently,
we have developed a method for catalytic regioselective
synthesis of 2-substituted and 3-substituted benzofurans starting
from phenols. The choice of reacting partner, olefin versus α,β-unsaturated
acid, is critical to dictate the isomeric product formation. Instances
are known where these olefinic partners did not complement each other
and yield a similar outcome. In the current work, we have addressed
this paradox with emphasis on (a) the origin of orthogonal selectivity
and (b) the key requirements to expect complementary behavior. Experimental
and computational studies provided important mechanistic insights.
Electrostatic compatibility during migratory insertion and the positioning
of the carboxylic acid moiety in catalytic steps are found to exert
a paramount impact in determining the regioselectivity. The study
offers a predictable single component tuning tool to control the regioselectivity.

近期，我们开发了一种以苯酚（phenols）为起始原料，催化区域选择性合成2-取代及3-取代苯并呋喃（benzofurans）的方法。反应底物的选择——烯烃（olefin）与α,β-不饱和酸（α,β-unsaturated acid）——对决定异构产物的生成至关重要。已有研究案例显示，这类烯烃类底物有时无法表现出互补性，最终得到相似的产物结果。在本研究中，我们针对这一矛盾现象展开了探究，重点关注（a）正交选择性（orthogonal selectivity）的起源，以及（b）实现互补行为的关键条件。实验与计算研究为该反应提供了重要的机理认知。研究发现，迁移插入（migratory insertion）过程中的静电相容性，以及催化步骤中羧酸基团（carboxylic acid moiety）的空间排布，对区域选择性的判定起到了决定性作用。本研究提供了一种可预测的单组分调控手段，用于精准控制区域选择性。