Rhodium-Catalyzed Annulation of N-Methoxy-amides: Synthesis of Isoquinolones
Rhodium-Catalyzed Annulation of N-Methoxy-amides: Synthesis of Isoquinolones
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DOI：
10.1055/s-0037-1609316
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发表时间：
2018-03
期刊：
影响因子：
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通讯作者：
V. Snieckus;M. J. Jalil Miah
中科院分区：
文献类型：
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作者：
V. Snieckus;M. J. Jalil Miah
重要性：报道了N-甲氧基酰胺1与α-氯乙醛2在钯催化下的环化反应，合成了2-甲氧基异喹啉-1（2 H）-酮3和3-羟基-2-甲氧基-3，4-二氢异喹啉-1（2 H）-酮4。具有对位取代的EDG和EWG的化合物1耐受性良好，得到产物3或4（方法A）。间溴取代的苯甲酰胺仅得到相应的产物3，产率为56%。具有间甲氧基的底物得到异构异喹诺酮3a和3b的混合物。N-甲氧基呋喃-2-甲酰胺和噻吩-2-甲酰胺不能进行任何反应。氯醛2（R2 = Oct、Pent、Bu、Pr、Et）以45-65%产率提供异喹诺酮3。2-氯-3-环己基丙醛以55%的产率得到N-甲氧基异喹诺酮3，以10%的产率得到3，4-二氢异喹诺酮4。2-芳基-2-氯醛只得到产物4（方法B）。化合物1（R1 = 2-NO2，2-卤代）通过方法B反应仅得到3，4-二氢异喹啉4，而化合物1（R1 = 2-OMe，2-Me）主要得到4a，沿着少量的3c。吲哚-2-甲酰胺1a与2a（R2 = Bn）反应得到产物4 b。评论：异喹诺酮是许多生物碱和药物的核心结构，是合成中有用的中间体（参见，例如：R。G. Chary等人，Chem.Commun. 2014，50，6797）。已知许多合成它们的方法（参见下面的综述）。本方法涉及一种简单的区域选择性路线，用于从容易获得的起始材料合成所需产物3和4，产率≤84%。反应的区域选择性取决于底物1和2以及添加剂的空间效应。2a和1b（R1 = t-Bu）与1g（R1 = I）之间的分子间竞争反应表明，具有缺电子取代基的芳环增强C-H键活化。此外，醛上的α-氢原子是反应发生所必需的。该方法的应用是通过将所得产物转化为许多其他杂环，如异喹啉（3d）或内酯来证明的。基于动力学同位素效应的研究提出了一种机制。
Significance: Reported is the synthesis of 2methoxyisoquinolin-1(2H)-ones 3 and 3-hydroxy2-methoxy-3,4-dihydroisoquinolin-1(2H)-ones 4 by palladium-catalyzed annulation of N-methoxyamides 1 with α-chloroacetaldehydes 2. Compounds 1 with para-substituted EDGs and EWGs were well tolerated and afforded products 3 or 4 (method A). A meta-bromo-substituted benzamide afforded exclusively the corresponding product 3 in 56% yield. Substrates with a metamethoxy group gave a mixture of isomeric isoquinolones, 3a and 3b. N-Methoxyfuran-2-carboxamides and thiophene-2-carboxamides failed to give any reaction. Chloroaldehydes 2 (R2 = Oct, Pent, Bu, Pr, Et) afforded the isoquinolones 3 in 45–65% yield. 2-Chloro-3-cyclohexylpropanal gave N-methoxyisoquinolone 3 in 55% yield and 3,4-dihydroisoquinolone 4 in 10% yield. 2-Aryl-2chloroaldehydes afforded products 4 exclusively (method B). Compounds 1 (R1 = 2-NO2, 2-halo) reacted by method B gave the 3,4-dihydroisoquinolines 4 exclusively, whereas 1 (R1 = 2-OMe, 2-Me) gave 4a predominantly, along with a minor amount of 3c. The reaction of indole-2-carboxamide 1a with 2a (R2 = Bn) gave product 4b. Comment: Isoquinolones are core structures of many alkaloids and pharmaceuticals, and are useful intermediates in synthesis (see, for example: R. G. Chary et al. Chem. Commun. 2014, 50, 6797). Many methods for their synthesis are known (see Review below). The present method involves a simple regioselective route for the synthesis of the desired products 3 and 4 from readily available starting materials, with ≤84% yield. The reaction regioselectivity is determined by the steric effects of substrates 1 and 2 and the additive. An intermolecular competitive reaction between 2a and 1b (R1 = t-Bu) and 1g (R1 = I) indicated that an aryl ring with an electron-deficient substituent enhances C–H bond activation. In addition, an α-hydrogen atom at the aldehyde is necessary for the reaction to occur. The application of the method is demonstrated by the transformation of the resulting products into many other heterocycles, such as isoquinolines (3d) or lactones. A mechanism is proposed based on kinetic isotope effect studies.