Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Palladium-Catalyzed Electrochemical C−H Bromination Using NH4Br as the Brominating Reagent Qi-Liang Yang,†,‡ Xiang-Yang Wang,‡ Tong-Lin Wang,‡ Xiang Yang,‡ Dong Liu,‡ Xiaofeng Tong,† Xin-Yan Wu,*,† and Tian-Sheng Mei*,‡ †
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Key Laboratory for Advanced Materials and Institute of Fine Chemicals, School of Chemistry & Molecular Engineering, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China ‡ State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, 345 Lingling Lu, Shanghai 200032, China S Supporting Information *
ABSTRACT: The palladium-catalyzed electrochemical C−H bromination of benzamide derivatives under divided cells is developed, in which NH4Br serves as a brominating reagent and electrolyte. The protocol avoids the use of chemical oxidants and provides an alternative method for the synthesis of aryl bromides.
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Scheme 1. Catalytic Electrochemical C−H Bromination
ryl halides are not only important motifs in many natural products,1 pharmaceuticals,2 and materials3 but also ubiquitous building blocks for Grignard4 and cross-coupling5 reactions. Thus tremendous efforts have been devoted to develop useful protocols for the regioselective construction of aryl halides, including electrophilic aromatic halogenations,6 Sandmeyer-type reactions,7 and directed ortho-lithiation.8 However, these methods still have drawbacks, such as limitation to activated arenes, a narrow substrate scope, and the production of metal salts as stoichiometric byproducts. In the past decade, catalytic C−H halogenations of arenes have developed as promising tools to synthesize aryl halides.9 In this context, four types of halogenation protocols have been developed: (1) the use of halogen (X2);10 (2) the use of NXS (N-halosuccinimide);11 (3) the use of Suárez reagent IOAc,12,13 and (4) the use of halides (X−) combined with external chemical oxidants.14 For example, Yu and coworkers described catalytic C−I bond formation using I2 as the oxidant in the presence of a Pd catalyst.15 Glorius and coworkers reported catalytic C−H halogenation using NXS.16 Shi and coworkers developed Nicatalyzed C−H halogenation using lithium halides and KMnO4.17 Despite its widespread success, catalytic C−H halogenation still suffers from the use of toxic and dangerous stoichiometric chemical oxidants. Therefore, it is attractive to develop an alternative protocol to avoid the use of chemical oxidants. Recently, organic electrochemistry has received much attention, in which electric current is used an as oxidant or reductant.18−20 For instance, catalytic C−H halogenation of 2phenylpyridine using HCl, HBr, or KI as a halogenating agent under anodic oxidation conditions has been demonstrated by Kakiuchi and coworkers (Scheme 1a).21 To overcome the limitation of the pyridine directing group, the same group recently elegantly developed the catalytic electrochemical C−Cl bond formation of benzamide derivatives.22 However, the © XXXX American Chemical Society
electrochemical C−H bromination of benzamide derivatives with HBr was not successful in Kakiuchi’s protocol.22 Generally speaking, aryl bromides serve as important coupling partners in catalytic cross-coupling reactions and are less accessible than aryl chlorides, and thus the development of electrochemical C− H bromination with a broader scope is important for future synthetic application. Furthermore, the mechanistic study for the electrochemical C−H bromination is still lacking. Our group recently described catalytic electrochemical C−H functionalization, electrochemical carboxylation of allyl esters with carbon dioxide, and electrochemical thiolation of aryhalides with thiols.23 Herein we describe the Pd-catalyzed electrochemical C−H bromination of benzamides derivatives with divided cells using NH4Br as the brominating agent and electrolyte (Scheme 1b). In the beginning, this electrochemical bromination of benzamide (1a) bearing a removable PIP (2-pyridinylisopropyl) Received: February 19, 2019
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DOI: 10.1021/acs.orglett.9b00629 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Reaction Optimizationa
Scheme 3. Evaluation of Benzamide Derivativesa
entry
variation from standard conditions above
yields (%)b
1 2 3 4 5 6 7 8 9c 10 11 12 13d 14 15 16
none PdBr2 instead of Pd(OAc)2 Pd(OCOCF3)2 instead of Pd(OAc)2 DMA instead of DMF (anode) H2O instead of DMF (anode) HBr instead of NH4Br LiBr instead of NH4Br NaBr instead of NH4Br 80 °C instead of 90 °C 100 °C instead of 90 °C 2.5 mA instead of 5 mA (20 h) 10 mA instead of 5 mA (5 h) RVC anode instead of Pt anode undivided cell no Pd(OAc)2 no electric current
93 86 89 84 34
