Introduction

Both within academic and industrial organic synthesis, chlorinated compounds are being extensively used as building blocks for the synthesis of different value-added products, such as bioactive compounds, fine chemicals, materials, natural products, and pharmaceuticals (Figure 1).¹ Furthermore, strategic incorporations of chlorine atoms have been shown to significantly alter or even enhance the biological properties of small molecules intended for therapeutic applications.^{1d, 1f, 2} In addition, chlorinated heteroarenes constitute valuable precursors for organometallic reagents³ and substrates for nucleophilic aromatic substitution⁴ and cross-coupling reactions.⁵ Given the ever-increasing applications of chloroarenes in organic synthesis and medicinal chemistry research, there has emerged a rapidly growing demand from synthetic chemists for novel and broadly applicable chlorination methodologies. Although, there exists a rich variety of classical reagents that allow for aromatic chlorination today, such as Cl₂, SO₂Cl₂, t-BuOCl, N-chlorosuccinimide, chlorobis(methoxycarbonyl)guanidine, 1,3-dichloro-5,5-dimethyl-2,4-imidazolidinedione, or trichloroisocyanuric acid, the vast majority of these reagents require harsh reaction conditions and suffer from poor chemo- and regioselectivity, which in turn translates into poor product yields and significant amounts of chemical waste.^{6, 7} More recently, C−H chlorination of heteroarenes by electrophilic Cl⁺ species, obtained via the oxidation of chloride anions using stoichiometric amounts of chemical oxidants such as K₂S₂O₈, PhI(OAc)₂, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or metal salts as oxidants, has been explored as an alternative synthetic strategy to conventional reagents.⁸ Unfortunately, many of these more modern methods suffer from complicated purification processes, pertaining primarily to the separation of excess oxidants and byproducts formed from undesired side reactions.

In contrast to traditional stoichiometric reagent-dependent redox chemistry, electrochemical synthesis has emerged as a more efficient and selective option, as it enables electrons to be used as green and highly modular redox reagents instead, which can simplify both the experimental setup and the subsequent purification process.⁹ In this context, the merger of C−H activation and electrooxidation was recently recognized as a particularly powerful prospect in molecular catalysis for converting renewable energy into fascinating chemical products, while circumventing the need for stoichiometric amounts of chemical oxidants.¹⁰ However, due to the relative difficulty of oxidizing Cl⁻ by anodic oxidation, the development of new electrochemical C−H chlorination¹¹ methodologies has progressed slower than those of the corresponding C−H bromination and iodination reactions. In this regard, the pioneering work of Kakiuchi and coworkers in 2009 represents an important milestone within the area electrocatalytic C−H chlorination,¹² as they were the first to demonstrate the successful ortho-chlorination of heteroaromatic scaffolds. Unfortunately, this method required the use of a large excess of HCl as the chlorinating agent as well as a divided cell set-up that limited its practicality, and moreover, the method was restricted to only 2-arylpyridine and 2-arylpyrimidine derivatives. With the aim of developing a more general and practical C−H chlorination strategy, our group recently launched a research campaign pursuing the design of a broadly applicable and operationally simple C−H chlorination protocol that could be strategically tuned to give either the mono- or bis-chlorinated products, and which could be carried out in high efficiency using an inexpensive chloride source in an undivided cell setup. The successful outcome of this work is presented herein, which describes a novel and highly practical palladaelectro-catalyzed protocol for heteroarene C−H chlorination that allows for both mono- and bis-chlorinated products to be obtained in high selectivity and yield through the precise tuning of the electric current and the loading of catalyst and chlorine source (Scheme 1).

中文翻译：

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区域选择性 Palladada 电催化的芳烃在未分割细胞中的氯化反应

 介绍

在学术和工业有机合成中，氯化化合物被广泛用作合成不同增值产品的基础模块，例如生物活性化合物、精细化学品、材料、天然产物和药物（图 1）。¹ 此外，氯原子的战略性掺入已被证明可以显着改变甚至增强用于治疗应用的小分子的生物学特性。^1D、1F、2此外，氯化杂芳烃构成了有机金属试剂³ 的有价值的前体和亲核芳香族取代⁴ 和交叉偶联反应的底物。⁵ 鉴于氯芳烃在有机合成和药物化学研究中的应用不断增加，合成化学家对新颖且广泛适用的氯化方法的需求迅速增长。尽管今天存在多种允许芳香族氯化的经典试剂，例如 Cl₂、SO₂、Cl₂、t-BuOCl、N-氯琥珀酰亚胺、氯双（甲氧基羰基）胍、1,3-二氯-5,5-二甲基-2,4-咪唑烷二酮或三氯异氰尿酸，但这些试剂中的绝大多数需要苛刻的反应条件，并且化学选择性和区域选择性差， 这反过来又会导致产品产量低下和大量化学废物。^6、7最近，通过使用化学计量量的化学氧化剂（如 K₂S₂O₈、PhI（OAc）₂、2,3-二氯-5,6-二氰基-1,4-苯醌 （DDQ） 或金属盐作为氧化剂，通过氯化阴离子氧化获得亲电 Cl⁺ 物种对杂芳烃进行 C-H 氯化，已被探索作为常规试剂的替代合成策略。⁸ 不幸的是，许多这些更现代的方法都受到复杂的纯化过程的影响，主要与分离过量的氧化剂和由不需要的副反应形成的副产物有关。

与传统的化学计量试剂依赖性氧化还原化学相比，电化学合成已成为一种更高效、更具选择性的选择，因为它使电子能够用作绿色和高度模块化的氧化还原试剂，从而简化实验设置和后续纯化过程。⁹ 在此背景下，C-H 活化和电氧化的合并最近被认为是分子催化中一个特别强大的前景，可以将可再生能源转化为迷人的化学产品，同时规避对化学氧化剂化学计量量的需求。¹⁰ 然而，由于阳极氧化氧化 Cl⁻ 的相对困难，新的电化学 C-H 氯化¹¹ 方法的开发进展慢于相应的 C-H 溴化和碘化反应。在这方面，Kakiuchi 及其同事在 2009 年的开创性工作代表了电催化 C-H 氯化领域的一个重要里程碑，¹² 因为他们是第一个成功证明杂芳烃支架邻位氯化的人。不幸的是，这种方法需要使用大量过量的 HCl 作为氯化剂以及分流池设置，这限制了其实用性，此外，该方法仅限于 2-芳基吡啶和 2-芳基嘧啶衍生物。 为了开发更通用和实用的 C-H 氯化策略，我们小组最近发起了一项研究活动，旨在设计一种广泛适用且操作简单的 C-H 氯化方案，该方案可以进行战略调整以提供单氯化或双氯化产物，并且可以在未分割的单元设置中使用廉价的氯化物源高效进行。本文介绍了这项工作的成功结果，它描述了一种新颖且高度实用的杂芳烃 C-H 氯化法电催化方案，该方案允许通过精确调节电流和催化剂和氯源的负载（方案 1）以高选择性和产率获得单氯化和双氯化产物（方案 1）。