本文发展了一种一锅法且无金属催化、室温条件下进行的三组分反应,用于合成含氟异吲哚啉-1-酮衍生物。该方法以易得的2-甲酰基苯甲酸、伯胺和氟代丙二酸二烷基酯为原料,在温和的室温、乙醇体系中顺利进行,避免了金属残留对产物的影响。该转化通过连续的缩合/Michael加成/原位内酰胺化过程,在高效构建异吲哚啉酮母核的同时,一步精准引入氟原子,提升目标产物的类药性价值,同时引入丙二酸酯官能团,为分子的进一步结构多样化提供了便利。该反应具有优异的官能团兼容性,可兼容多种芳胺和脂肪胺,其中富电子芳胺和苄胺衍生物能以中等到优异的产率（最高达90%）生成相应的3-(氟代丙二酸酯)取代的异吲哚啉-1-酮产物。这种无金属、温和条件的多组分策略,为构建基于异吲哚啉-1-酮优势骨架、结构多样的含氟类活性化合物库提供了一种直接且通用的新途径。
A one-pot, metal-free three-component reaction has been developed for the synthesis of fluorinated isoindolin-1-one derivatives under room temperature conditions. This method employs readily available 2-formylbenzoic acid, primary amines, and fluorinated dialkyl malonates, which takes place smoothly in a mild system of ethanol at room temperature and avoids the impact of metal contamination on the products. The transformation proceeds via a sequential condensation/Michael addition/in situ lactamization process, efficiently constructing the isoindolin-1-one core while precisely introducing a fluorine atom in one step to enhance the drug-likeness of the target products. Meanwhile, a malonate ester functionality is introduced, providing convenience for further structural diversification of the molecules. The reaction exhibits good functional group compatibility with a variety of aromatic and aliphatic amines, and electron-rich aromatic amines as well as benzylamine derivatives afford the corresponding 3-(fluoromalonate)-substituted isoindolin-1-ones in moderate to excellent yields (up to 90%). This metal-free, mild-condition multicomponent strategy might provide a direct and versatile new approach for constructing structurally diverse fluorinated bioactive compound libraries based on the privileged isoindolin-1-one scaffold.
[1] (a) Dong C.; Tan G.-H.; Jin, Y.-X. Chin. J. Org. Chem.2014, 34, 578.(in Chinese)
(董超, 谭广慧, 金英学. 有机化学. 2014, 34, 578.).
(b) Yang, K.; Liu, M.-J.; Zhang, Y.-N.; Zhan, J.-Q.; Deng, L.-X.; Zheng, X.-J.; Zhou, Y.-J.; Wang, Z.-Y.Chin. J. Org. Chem. 2021, 41, 2175.(in Chinese)
(杨凯, 刘美娟, 张毓娜, 占佳琦, 邓璐璇, 郑雪洁, 周永军, 汪朝阳. 有机化学. 2021, 41, 2175).
[2] Madaan K.; Singh R. ChemMedChem2025, 20, e202500420.
[3] Upadhyay S. P.; Thapa P.; Sharma R.; Sharma M. Fitoterapia2020, 146, 104722.
[4] Samandram R.; Krishnamoorthy R.; Jayaraj P.; Dhanasekaran S.; Anaikutti P. ChemistrySelect2025, 10, e01272.
[5] (a) Ordoñez M.; Tibhe G. D.; Zamudio-Medina A.; Viveros-Ceballos J. V. Synthesis2012, 44, 569.
(b) Jiang C.; Yan S.-H.; Zhang Y.; Zhang Q.; Ma X.-M.; Zhang, W. J. Org. Chem.2024, 89, 9125.
(c) Zou Z.-R.; Cai G.-N.; Chen W.-H.; Zou C.-L.; Li Y.-M.; Wu H.-T.; Chen L.; Hu J.-H.; Li Y.-B.; Huang, Y.-B. J. Org. Chem.2021, 86, 15777.
(d) Wang Y.; Chen M. -T.; Zhang K. Y.; Wu H.-M.; Wang J.-L.; Cheng Y.-R.; Liu Y.-X.; Wei Z.-J. ACS Catal.2023, 13, 12601.
(e) Shi L.-Y.; Hu L.; Wang J.-Q.; Cao X.-Q.; Gu H.-W. Org. Lett.2012, 14, 1876.
(f) Taylor S. R.; Roberts M. P.; Wyatt N. A.; Pham T. Q.; Stark D.; Bourdier T.; Roselt P.; Katsifis A.; Greguric, I. Aust. J. Chem.2013, 66, 491.
[6] (a) Ghosh, U.; Bhattacharyya, R.; Keche, A.Tetrahedron 2010, 66, 2148.
(b) Mamidyala S. K.; Cooper, M. A. Chem. Commun.2013, 49, 8407.
(c) Zhang W.-S.; Li Y.; Cui H.-Y.; Su X.-L.; Xu, S.-P. Chin. J. Org. Chem.2022, 42, 2456 (in Chinese).
(张文生, 李焱, 崔海燕, 苏小莉, 徐素鹏, 有机化学, 2022, 42, 2456.)
[7] (a) Muddala N. P.; Nammalwar B.; Bunce, R. A. RSC Adv.2015, 5, 28389.
(b) Adib M.; Sheikhi E.; Yazzaf R.; Bijanzadeh H. R.; Mirzaei P. Tetrahedron Lett.2016, 57, 841.
(c) Jelali H.; Al Nasr I. S.; Koko W. S.; Khan T. A.; Deniau E.; Sauthier M.; Alresheedi F.; Hamdi, N. J. Heterocycl. Chem.2022, 59, 493.
[8] (a) Chen T.-T.; Cai C. Catal. Commun.2016, 74, 119.
(b) Baum J. S.; Staveski, M. M. Synth. Commun.1989, 19, 2283.
(c) Nammalwar B.; Muddala N. P.; Murie M.; Bunce, R. A. Green Chem.2015, 17, 2495.
(d) Hu L.-J.; Zhan Z.-J.; Lei M.; Hu L.-H. Arkivoc2013, iii, 189.
(e) Dhanasekaran S.; Suneja A.; Bisai V.; Singh, V. K. Org. Lett.2016, 18, 634.
[9] Shen S. C.; Sun X. W.; Lin, G. Q. Green Chem.2013, 15, 896.
[10] Natte K.; Chen J.; Li H.; Neumann H.; Beller M.; Wu, X. F. Chem. Eur. J.2014, 20, 14184.
[11] (a) Bisai V.; Dhanasekaran S.; Suneja A.; Unhale R. A.; Singh, V. K. Org. Lett.2014, 16, 6068.
(b) Dhanasekaran S.; Kayet A.; Suneja A.; Bisai V.; Singh, V. K. Org. Lett.2015, 17, 2780.
[12] Yuan D.; Duan Z.; Rao Y.; Ding M. W. Tetrahedron2016, 72, 338.
[13] Ramazani A.; Rezaei A.; Ahankar H.; Ganjeie B.; Joo, S. W. Phosphorus, Sulfur Silicon Relat. Elem.2016, 191, 952.
[14] Sun M.; Zeng C.-Y.; Zhang E.-S.; Zhang Q.; Chen K.; Xu Y.-G.; Fan M.-X.; He M.-R.; Shi J.-H.; Ding, M.-W. Asian J. Org. Chem.2024, 13, e202400036.
[15] Mukherjee S.; Rani U.; Chandra G.; Pal, S. Org. Biomol. Chem.2025, 23, 7821.
[16] Bhattarai P.; Trombley T. A.; Altman R. A.J. Med. Chem. 2026, 69, 1916.
[17] Liu S.; Zhou J.; Yu L.; Liu Y.; Huang Y.; Ouyang Y.; Liu G.-K.; Xu X.-H.; Shibata N. Chem. Rev.2025, 125, 4603.
[18] Ding C.-L.; Xu Q.; Wu S.; Zhong Y.; He X.; Lin Y.; Li Y.; Ye K.-Y. Org. Lett.2024, 26, 1645.
[19] (a) Gao G.; Wang P.; Liu P.; Zhang W.-H.; Mo L.-P.; Zhang, Z.-H. Chin. J. Org. Chem.2018, 38, 846 (in Chinese).
(高歌, 王萍, 刘鹏, 张卫红, 默丽萍, 张占辉, 有机化学, 2018, 38, 846.)
(b) Gui Q.-W.; Wang B.-B.; Zhu S.; Li F.-L.; Zhu M.-X.; Yi M.; Yu J.-L.; Wu Z.-L.; He W.-M. Green Chem.2021, 23, 4430.
(c) Yi R.-N.; He, W.-M. Chin. Chem. Lett.2024, 35, 110115.
(d) Guan Y.; Ying Y.-L.; Wang B.; Mo L.-P.; Zhang Z.-H. J. Catal.2025, 443, 115938.
