以重水为氘源的钴催化脱卤氘代反应

doi:10.1016/S1872-2067(23)64624-8

催化学报 ›› 2024, Vol. 59: 250-259.DOI: 10.1016/S1872-2067(23)64624-8

以重水为氘源的钴催化脱卤氘代反应

陈炳志^a^,^b, 季定纬^a^,^*(), 周博超^a^,^b, 王小雨^a^,^b, 刘恒^a^,^b, 万伯顺^a, 胡向平^a^,^b^,^*(), 陈庆安^a^,^b^,^*()

^a中国科学院大连化学物理研究所, 辽宁大连 116023
^b中国科学院大学, 北京 100049

收稿日期:2023-12-14 接受日期:2024-02-07 出版日期:2024-04-18 发布日期:2024-04-15
通讯作者: *电子邮箱: dingweiji@dicp.ac.cn (季定纬), xiangping@dicp.ac.cn (胡向平), qachen@dicp.ac.cn (陈庆安).
基金资助:
国家自然科学基金(22271277);国家自然科学基金(21971234)

Cobalt-catalyzed dehalogenative deuterations with D₂O

Bing-Zhi Chen^a^,^b, Ding-Wei Ji^a^,^*(), Bo-Chao Zhou^a^,^b, Xiao-Yu Wang^a^,^b, Heng Liu^a^,^b, Boshun Wan^a, Xiang-Ping Hu^a^,^b^,^*(), Qing-An Chen^a^,^b^,^*()

^aDalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, Liaoning, China
^bUniversity of Chinese Academy of Sciences, Beijing 100049, China

Received:2023-12-14 Accepted:2024-02-07 Online:2024-04-18 Published:2024-04-15
Contact: *E-mail: dingweiji@dicp.ac.cn (D.-W. Ji), xiangping@dicp.ac.cn (X.-P. Hu), qachen@dicp.ac.cn (Q.-A. Chen).
Supported by:
The National Natural Science Foundation of China(22271277);The National Natural Science Foundation of China(21971234)

摘要/Abstract

摘要：

自2017年氘代丁苯那嗪获得美国食品药品监督管理局批准以来, 氘代化合物在药物开发领域的潜力受到越来越多的重视. 开发高效实用的有机分子选择性氘化方法成为有机和药物化学家的研究热点. 有机卤化物是性质稳定且来源广泛的化学品, 其脱卤氘代反应已经发展成为构建氘代化合物的有效策略. 然而, 已报道的制备方法普遍存在氘代试剂昂贵、底物适用范围较窄或需要使用特殊的反应设备(光催化或电化学)等诸多问题. 因此, 开发简单普适的廉价金属催化体系, 实现以廉价重水为氘源的脱卤氘代反应, 具有重要的研究意义.

相较于钯、铑等贵金属, 储量丰富且毒性较低的钴金属催化剂对水分敏感度较低, 且对C(sp²)-X和C(sp³)-X键活化都表现出较好的反应活性. 基于此, 本文开发了制备简单、普适性较好的钴催化体系, 实现了位点选择性氘代化合物的构建. 反应以锰金属为还原剂, 重水为氘源, 对各种类有机卤化物或类卤化合物, 如芳基、烯基、苄基、烯丙基或烷基卤化物, 均获得较好的收率和氘代率. 值得注意的是, 对于炔丙基乙酸酯类化合物, 该催化体系也展现出较好的适用性, 可以专一的选择性得到氘代联烯类化合物. 在此基础上, 成功将该方法应用于一系列药物类似物的选择性脱卤氘代. 利用简单的C-O偶联和脱溴氘代反应, 即可实现氘代的N-甲基度洛西汀的合成. 鉴于药物分子直接进行氢-氘同位素交换时位点选择性控制的挑战, 本文发展了卤代-氘代的两步策略. 该策略成功应用于生育酚、萘普生、黄毒素、萘丁美酮等多个药物分子的位点选择性氢-氘同位素交换, 充分展现出该催化合成方法在药物开发领域的应用潜力. 为了验证反应机理, 开展了一系列对照实验. 结果表明, 反应可能是由一价钴物种催化启动的. 此外, 自由捕获和抑制实验结果表明, 反应并非通过自由基反应过程进行. 基于以上实验结果提出了一个反应机理, 它涉及Co(I)到Co(III)再回到Co(I)的催化循环. 具体来说, 首先, 一价钴络合物与底物发生氧化加成生成三价钴络合物; 随后, 三价钴物种与重水络合, 并通过还原消除的方式生成氘代化合物和一价钴物种. 最后, 为了验证这一机理, 还利用密度泛函理论进行了计算, 结果进一步证明了该机理的合理性.

综上, 本文利用钴催化体系, 以廉价重水为氘源, 实现芳基、烯基、苄基、烯丙基或烷基等卤化物, 以及炔丙基乙酸酯类类卤化合物的选择性氘代反应. 该反应表现出较好的底物适用性, 为相关氘代有机化合物的制备提供了新思路.

关键词: 钴催化, 脱卤氘代, 位点选择性氘代, 有机卤代物, 氘代药物

Abstract:

The regioselective incorporation of deuterium to organic skeletons has gained ever-growing attention among scientific community. Herein, we present a robust and general protocol for site-specific deuteration through the cobalt catalyzed dehalogenative process. Using D₂O as the economical deuterium reagent, we achieved excellent substrate compatibility across a wide collection of organohalides or pseudo-halides, such as aryl, alkenyl, benzyl, allyl, or alkyl halides and propargyl acetates. Preliminary experimental evidences and related DFT calculation are also presented to support a mechanistic scenario involving a Co(I)-C(III)-Co(I) cycle. The generality and potential utilization of this moisture-insensitive catalysis have also been demonstrated by the selective deuterodehalogenation of drug-like candidates, concise synthesis of D-labeled pharmaceutical molecule, as well as the stepwise hydrogen isotope exchange of bioactive compounds.

Key words: Cobalt catalysis, Deuterodehalogenation, Site-specific deuteration, Organohalides, D-labeled pharmaceutical

陈炳志, 季定纬, 周博超, 王小雨, 刘恒, 万伯顺, 胡向平, 陈庆安. 以重水为氘源的钴催化脱卤氘代反应[J]. 催化学报, 2024, 59: 250-259.

Bing-Zhi Chen, Ding-Wei Ji, Bo-Chao Zhou, Xiao-Yu Wang, Heng Liu, Boshun Wan, Xiang-Ping Hu, Qing-An Chen. Cobalt-catalyzed dehalogenative deuterations with D₂O[J]. Chinese Journal of Catalysis, 2024, 59: 250-259.

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链接本文: https://www.cjcatal.com/CN/10.1016/S1872-2067(23)64624-8

https://www.cjcatal.com/CN/Y2024/V59/I4/250

图/表 7

Fig. 1. Transition-metal-catalyzed deuterodehalogenation reactions. (A) Hydrogen's isotope deuterium and its applications. (B) Metal-promoted or -catalyzed dehalogenative deuterations. (C) This work: Co-catalyzed dehalogenative deuterations with D2O.

Fig. 2. Optimization of reaction conditions. Reaction conditions: substrate (0.10 mmol), MLn (dimer 2.5 mol% or monomer 5 mol%), PPh3 (10 mol%) or ligand (5 mol%), Mn (0.15 mmol), ZnI2 (0.15 mmol), CH3CN (1.0 mL), 80 °C, 30 min. Yield and deuterium incorporation were determined by 1H NMR spectroscopy analysis with 1,3,5-trimethoxybenzene as the internal standard. aCH3CN (0.5 mL).

Fig. 3. Co-catalyzed deuterodehalogenation reactions with D2O. Reaction conditions: Substrate (0.20 mmol), CoBr2 (5 mol%), Ligand (5 mol%), Mn (0.30 mmol), ZnI2 (0.30 mmol), D2O (2.0 mmol), CH3CN (2.0 mL), 80 °C, 30 min. Dppf was used as a ligand for aryl halides 1, bipyridine was used as a ligand for substrates 3, 5 and 7. Deuterium incorporation was determined by 1H NMR spectroscopy analysis and isolated yields were reported for all cases. a DMF (1.0 mL) and bipyridine were used instead of CH3CN and dppf. b CH3CN (1.0 mL) was used as solvent for the synthesis of 6. c Extend the reaction time to 12 h.

Fig. 4. Substrate scope of propargyl acetates. Reaction conditions: Substrate (0.20 mmol), CoBr2 (5 mol%), dppf (5 mol%), Mn (0.30 mmol), ZnI2 (0.30 mmol), D2O (2.0 mmol), CH3CN (2.0 mL), 80 °C, 30 min. Deuterium incorporation was determined by 1H NMR spectroscopy analysis and isolated yields were reported for all cases. See the Supporting Information for full experimental details. a BINAP was used instead of dppf. b10 mmol scale, 2 h.

Fig. 5. Selective deuteration of drug-like molecules. Deuterium incorporation was determined by 1H NMR spectroscopy analysis and isolated yields were reported for all cases. See the Supporting Information for full experimental details.

Fig. 6. Stepwise hydrogen isotope exchange for drug molecules. Deuterium incorporation was determined by 1H NMR spectroscopy analysis and isolated yields are reported for all cases. See the Supporting Information for full experimental details.

Fig. 7. Mechanistic studies and proposed mechanism. a DFT calculations were performed at the M06-L/6-311++G(2df,2p)-SDD(Co)/SMD(Acetonitrile)//M06-L/6-31G(d)-SDD(Co) level of theory.

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以重水为氘源的钴催化脱卤氘代反应

Cobalt-catalyzed dehalogenative deuterations with D₂O

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以重水为氘源的钴催化脱卤氘代反应

Cobalt-catalyzed dehalogenative deuterations with D2O

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Cobalt-catalyzed dehalogenative deuterations with D₂O