铜催化N-脱甲基反应.pdf

摘要 C-N 键是自然界中最常见的化学键之一，广泛存在于有机大分子和 生物分子当中。如何绿色、高效地断裂C-N 键一直是化学学科的热点 问题。N-脱甲基反应是C-N 键断裂的一种形式，高效的N-脱甲基反应 对化学合成、生物碱衍生、药物合成等具有重要意义。酰胺是一种常 见的化合物，在医药、染料、农药、化工方面都占有重要地位，目前 酰胺类药物大约占已注册药物的25% 。酰胺相较于胺，更难以发生氧 化反应和亲核取代反应，所以酰胺的N-脱甲基反应一直是有机合成的 难题。 本文建立了一种新的酰胺N-脱甲基反应的方法。反应利用N-氟代 双苯磺酰胺(NFSI)作为氧化剂，乙酰丙酮铜作为催化剂，通过连续的单 电子转移-氢原子转移-水解过程，将N- 甲基酰胺转化为对应的甲醇基 胺，再由甲醇基胺分解得到N-脱甲基产物。本文通过一系列的优化实 验，得到了最佳的反应条件。利用最佳的反应条件，对30 余种不同的 N- 甲基酰胺进行N-脱甲基反应实验。通过循环伏安法、仪器分析、同 位素标记法等方法，对反应的机理进行了推测及证明。反应具有反应 条件温和、底物适用性广的特点。这一方法解决了酰胺难以发生N-脱 甲基反应的难题。 关键词：N-脱甲基反应；酰胺；NFSI；铜催化 1 Abstract The C-N bond is one of the most common chemical bonds in nature, and it is widely found in organic macromolecules and biomolecules. How to break the C-N bond greenly and efficiently has always been a hot issue in the discipline of chemistry. The N-demethylation reaction is a form of C-N bond breaking, and the efficient N-demethylation reaction is of great significance for chemical synthesis, alkaloid derivation, and drug synthesis. Amide is a common compound that occupies an important position in medicine, dyes, pesticides, and chemicals. At present, amide drugs account for about 25% of registered drugs. Compared with amines, amides are more difficult to undergo oxidation and nucleophilic substitution reactions, so the N- demethylation of amides has always been a problem in organic synthesis. In this paper, a new method for N-demethylation of amides is established. The reaction uses N-fluorobisbenzenesulfonamide (NFSI) as the oxidant and copper acetylacetonate as the catalyst to convert N- methylamides to the corresponding carbonolamines through a successive single electron transfer-hydrogen atom transfer-hydrolysis process, and carbonolamines decompose to N-demethylated amides. In this paper, through a series of optimization experiments, the best reaction cond