Gold‐Catalyzed Oxyarylation/Hydroxylation of N‐Alkoxypropiolamides for Chemoselective Synthesis of 4‐Aryl‐3‐(2H)‐isoxazolones
Gold‐Catalyzed Oxyarylation/Hydroxylation of N‐Alkoxypropiolamides for Chemoselective Synthesis of 4‐Aryl‐3‐(2H)‐isoxazolones
复制标题
金催化 N-烷氧基丙酰胺的氧化芳基化/羟基化用于化学选择性合成 4-芳基-3-(2H)-异恶唑酮
DOI：
10.1002/adsc.202200860
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Ueda Masafumi
中科院分区：
文献类型：
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作者：
Yasui Motohiro;Tahara Naoko;Matsubara Hiroshi;Takeda Norihiko;Ueda Masafumi
3‐（2H）‐异恶唑酮是医药和农业化学中重要的骨架结构。但其合成方法的底物范围有限，需要非常规的底物合成。同时，由于不良的质子化副反应，金催化的分子内氧化交叉偶联尚未报道，该偶联涉及具有炔基结构的底物的5/6内端双环化。因此，我们假设环n‐烷氧基丙酰胺的反应性会抑制质子化并允许双官能化。结果，金催化的n -烷氧基丙酰胺的5 -内环双环化、氧化交叉偶联和羟基化反应被开发出来，合成了4 -芳基- 3 - (2H) -异恶唑酮。在优化研究中，二甲基甲酰胺（DMF）和水是连续反应的有效溶剂。该方法使3‐（2H）‐异恶唑酮骨架在一次合成过程中引入了芳基和羟基。此外，还观察到对活性官能团（如酮羰基）的耐受性。对合成的4 -芳基- 3 - (2H) -异恶唑酮进行了一些化学转化，以证明官能团相互转换、C - C键形成和附加杂环合成的可行性。值得注意的是，通过分子内氧化交叉偶联得到了一个荧光四环杂环。对照实验表明烷氧酰胺部分抑制了质子化反应活性。从而提高了氧化芳基化的化学选择性。最后，通过密度泛函理论（DFT）计算来估计反应途径，结果表明，涉及溶剂（H2O或DMF）的开环对这些顺序反应很重要。
3‐(2H)‐isoxazolone is an important skeletal structure in medicinal and agricultural chemistry. However, its synthetic methodology has limited substrate scope and requires unconventional substrate synthesis. Meanwhile, gold‐catalyzed intramolecular oxidative cross‐coupling involving the5/6‐endo‐digcyclization of substrates bearing an ynone structure has not been reported because of an undesirable protonation as a side‐reaction. Thus, we hypothesized that the reactivity of cyclicN‐alkoxypropiolamides would suppress protonation and allow dual functionalization. As a result, sequential gold‐catalyzed 5‐endo‐digcyclization, oxidative cross‐coupling, and hydroxylation ofN‐alkoxypropiolamides was developed to synthesize 4‐aryl‐3‐(2H)‐isoxazolones with a hydroxy group. In an optimization study, dimethylformamide (DMF) and H2O were effective solvents for the sequential reaction. This method enabled 3‐(2H)‐isoxazolone backbone synthesis with the introduction of an aryl and hydroxy group in a single procedure. Moreover, a tolerance toward reactive functional groups, such as ketocarbonyl groups, was observed. Some chemical transformations of the synthesized 4‐aryl‐3‐(2H)‐isoxazolone were conducted to demonstrate the feasibility of functional group interconversion, C−C bond formation, and additional heterocycle synthesis. Notably, a fluorescent tetracyclic heterocycle was obtained by intramolecular oxidative cross‐coupling. Control experiments indicated that the reactivity for protonation was suppressed by an alkoxyamide moiety. Therefore, the chemoselectivity of oxyarylation was improved. Finally, density functional theory (DFT) calculations were performed to estimate the reaction pathway, which suggested that ring‐opening involving solvents (H2O or DMF) is important for these sequential reactions.