### Progress in Heterocyclic Synthesis Methodology Based on Acrylamides at Xiamen University's College of Chemistry and Chemical Engineering A significant breakthrough has been reported by Professor Longwu Ye's research team at Xiamen University's College of Chemistry and Chemical Engineering in the field of heterocyclic synthesis methodology based on acrylamides. The findings, titled "Rapid and practical access to diverse quindolines by catalyst-free and regioselectivity-reversed Povarov reaction," were published online in *Cell Reports Physical Science* on June 3, 2021, with the DOI: https://doi.org/10.1016/j.xcrp.2021.100448. Quindolines, a class of nitrogen-containing heterocycles, exhibit a wide range of biological activities, including antimalarial, anticancer, antibacterial, and antiviral properties. However, traditional organic synthesis methods have struggled to construct these highly conjugated indoloquinoline frameworks, particularly in creating a diverse and highly functionalized quindoline skeleton. This limitation has significantly hindered the biological activity studies of these compounds. The Povarov reaction is a well-known method for the form [4 + 2] cycloaddition between N-aryl imines and electron-rich olefins, which efficiently constructs tetrahydroquinoline compounds. Typically, this reaction requires the catalytic action of Lewis acids or proton acids and is generally believed to proceed via a stepwise mechanism. Despite its rapid development over the past few decades, several challenges remain unresolved. These include the difficulty in achieving 3-position heteroatom substitution in quinoline skeletons due to the stepwise mechanism, the limited substrate scope to heteroatom-substituted olefins, and the strong dependence on acid catalysts, which can be incompatible with various acid-sensitive functional groups. Professor Ye's team has been dedicated to developing methodologies for heterocyclic synthesis using acrylamides and other heteroatom-substituted alkynes. Over the years, they have achieved notable success in both transition-metal-catalyzed and metal-free catalytic reactions involving acrylamides. These methodologies have been successfully applied to the efficient and concise synthesis of over thirty natural products, bioactive molecules, and drugs. Recently, the team synthesized a series of aryl aldehyde-substituted acrylamides and conducted a novel Povarov reaction with more than thirty commercially available aniline derivatives. This reaction, which occurs without the addition of any catalysts or additives, involves a cascade of anti-polar Povarov cyclization, isomerization, and oxidation, leading to the one-step construction of complex quindoline derivatives and similar structures in over fifty examples. This significantly expands the variety of quindoline natural products. Key features of this reaction include: 1. **First Implementation of Povarov Reaction with Acrylamides and Electron-Rich Alkynes**: The team successfully performed the Povarov reaction using acrylamides and other electron-rich alkynes, a first in the field. 2. **Development of the First Catalyst-Free Anti-Polar Povarov Reaction**: This reaction does not require any catalysts, making it highly practical and versatile. 3. **Efficient Construction of Valuable Quindoline Natural Product Skeletons**: The reaction constructs a series of valuable quindoline frameworks, including those of seven natural products or bioactive molecules, through a form [1 + 2 + 3] cycloaddition mechanism. 4. **High Efficiency and Excellent Substrate Scope**: The reaction demonstrates high efficiency and broad substrate compatibility. The study was primarily conducted by Zhang Yingqi, a 2020 PhD student in Professor Ye's group, with assistance from other graduate and undergraduate students. Engineer Zanbin Wei contributed to the single-crystal testing. The research was supported by various funding sources, including the National Natural Science Foundation of China (Grants 21772161 and 21622204), the Fujian Provincial Natural Science Foundation (Grant 2019J02001), the Xiamen University President's Fund (Grant 20720180036), and the National Fund for Fostering Talents of Basic Science (Grant J1310024). ### Summary Professor Longwu Ye's research team at Xiamen University's College of Chemistry and Chemical Engineering has developed a novel, catalyst-free, and regioselectivity-reversed Povarov reaction for the rapid and practical synthesis of diverse quindoline derivatives. This breakthrough addresses several longstanding challenges in the field, such as the difficulty in achieving 3-position heteroatom substitution in quinoline skeletons and the limited substrate scope of traditional Povarov reactions. The reaction involves a cascade of anti-polar Povarov cyclization, isomerization, and oxidation, leading to the one-step construction of complex quindoline structures, including those of seven natural products or bioactive molecules. The methodology is highly efficient and compatible with a broad range of substrates, making it a valuable tool for the synthesis of natural products and bioactive molecules. The research, primarily conducted by PhD student Zhang Yingqi, was supported by multiple national and provincial funding agencies.