Facile and Economical Electrochemical Dehalogenative Deuteration of (Hetero)Aryl Halides

Abstract

Open AccessCCS ChemistryCOMMUNICATION1 Nov 2021Facile and Economical Electrochemical Dehalogenative Deuteration of (Hetero)Aryl Halides Lijun Lu†, Hao Li†, Yifan Zheng, Faxiang Bu and Aiwen Lei Lijun Lu† Institute for Advanced Studies (IAS), College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072 , Hao Li† Institute for Advanced Studies (IAS), College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072 , Yifan Zheng Institute for Advanced Studies (IAS), College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072 , Faxiang Bu Institute for Advanced Studies (IAS), College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072 and Aiwen Lei *Corresponding author: E-mail Address: [email protected] Institute for Advanced Studies (IAS), College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072 National Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Jiangxi 330022 https://doi.org/10.31635/ccschem.020.202000512 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Deuterated compounds are valuable in synthetic, pharmaceutical, and analytical chemistry. The deuteration of halides is a widespread method for highly site-selective deuterium installation. However, the facile, efficient, and economical deuterium incorporation remains challenging. In this work, we introduced a practical deuteration of (hetero)aryl halides through an electrochemical reduction method. This transformation proceeded smoothly at room temperature without metal catalysts, external reductants, or toxic or dangerous reagents. Remarkably, low-cost and chemically equivalent D2O was the sole deuterium source in this reaction. Professional electrosynthesis equipment was not essential because we demonstrated common batteries and electrodes were enough for this reaction. Download figure Download PowerPoint Introduction Deuterium is an inexpensive and nonradioactive isotope of hydrogen. Moreover, the cleavage of the C–D bond is more difficult than the C–H bond. Due to the above characteristics, deuterated compounds are widely used in many fields, such as mechanistic study (kinetic isotope effect), quantitative analysis, and pharmaceutical research.1–4 In 2017, Austedo (deutetrabenazine) became the first deuterated drug to be approved by the US Food and Drug Administration.5 Deuterated drugs improve the pharmacokinetic properties and toxicity of nondeuterated analogues, which renders great potential for broad application.6 Nearly all commercially available drugs contain aromatic ring structures. Therefore, the deuteration of aromatic compounds has always attracted much attention from organic chemists. Although the direct hydrogen isotope exchange (HIE) process seems most attractive, the poor selectivity and functional group tolerance limits its application.7–11 As a kind of bulk chemical, aryl halides are still the usual choice toward the synthesis of deuterated aromatic compounds.12 Traditional metal-halogen exchange, radical halogen abstraction, and transition-metal catalysis generally suffer from hash conditions, such as low reaction temperature (−78 °C), dangerous nBuLi, toxic tin reagents, or precious metal catalysts (Scheme 1a).13–20 Recently, photoinduced deuteration of aromatic halides utilized milder conditions for this transformation (Scheme 1b).21–23 The practicability of deuterium labeling methods is key to implementing frequent deuterium incorporation. A convenient, safe, economical, and manageable deuteration strategy is urgently required. Electrochemical synthesis attracts wide interest due to its high energy efficiency and lack of transition-metal catalysts and external redox reagents.24,25 There are many reports about aryl halides being reduced at the cathode and further functionalized.26–29 Hence, electrochemical reductive deuteration of aryl halides is a promising method.30 Very recently, Zhang and colleagues31 used Cu nanowire array cathodes to achieve the deuteration of aryl halides. However, the practicability, such as common equipment and mild reaction conditions, and the compatibility, such as aryl chlorides, bromides, and iodides, are still the target for electrochemical deuteration. Additionally, the deuterium source is another important key in deuteration. Compared with expensive D2, CD3OD, and dimethyl sulfoxide (DMSO)-d6, relatively inexpensive D2O is a better choice. The amount of deuterium source is also an important factor to be considered. Herein, we reported a facile and economical deuteration of aromatic halides through electrochemical reduction (Scheme 1c). Scheme 1 | (a–c) Deuterium labeling methods of aryl halides. Download figure Download PowerPoint Results and Discussion Initially, we chose 2-bromonaphthalene ( 1a) and deuterium oxide (D2O) as model substrates (Table 1, see details in Supporting Information Section S1). With platinum plate as both anode and cathode, CH3CN as solvent, and 0.25 mmol nBu4NBF4 as electrolyte, no desired product was obtained under 15 mA constant current in an undivided cell (entry 1). Changing the solvent had a large influence on this reaction, and dimethylformamide (DMF) was better than DMSO (entries 2 and 3). A graphite rod with Pt plate as anode (entry 4) had a similar effect. However, the conversion matched well with the yield by using Fe plate rather than Pt plate as cathode (entry 5). Other deuterium sources such as DMSO-d6 or CD3OD gave worse deuterium labeling (entries 6 and 7). The conversion of 1a was challenging for this transformation, so we added sacrificial reagents to improve the reaction yield. Both NEt3 and PPh3 were helpful for increasing the yields, but the addition of NEt3 worsened the deuterium incorporation due to its active alkyl group (entries 8 and 9). Using a Pb plate instead of the Fe plate as cathode further increased the deuterium incorporation (entry 10). Approximately, 99% yield of the desired product with 95% deuterium incorporation was obtained by using NPh3 as the additive (entries 10 and 11). Table 1 | Investigation of the Reaction Conditionsa Entry Electrodes Solvent D Source Additive Yield (%)b D Incorporation (%)c 1 Pt(+)|Pt(−) CH3CN D2O — n.d. — 2 Pt(+)|Pt(−) DMSO D2O — 28 26 3 Pt(+)|Pt(−) DMF D2O — 43 88 4 C(+)|Pt(−) DMF D2O — 40 89 5 Pt(+)|Fe(−) DMF D2O — 31 90 6 Pt(+)|Fe(−) DMF CD3OD — 44 32 7 Pt(+)|Fe(−) DMF DMSO-d6 — 35 55 8 Pt(+)|Fe(−) DMF D2O NEt3 75 17 9 Pt(+)|Fe(−) DMF D2O PPh3 70 88 10 Pt(+)|Pb(−) DMF D2O PPh3 53 90 11 Pt(+)|Pb(−) DMF D2O NPh3 96 88 12d Pt(+)|Pb(−) DMF D2O NPh3 > 99(99) 95 aStandard conditions: 1a (0.5 mmol), D2O (5.0 mmol), platinum plate anode, lead plate cathode (15 mm × 15 mm × 0.3 mm), constant current = 15 mA, nBu4NBF4 (0.25 mmol), DMF (6.0 mL), additive (1.0 mmol), undivided cell, N2, 4 h, room temperature. bYields were determined by GC analysis, calibrated using 9-fluorenone as the internal standard (isolated yield in parentheses). cDeuterium incorporations were determined by 1H NMR or GC-MS. dNPh3 (0.3 mmol), 3 h. With the optimized reaction conditions determined, we began investigating the substrate scope. A series of aromatic bromides were tested (Scheme 2). Like 1a, both 1-bromonaphthalene ( 1b) and 9-bromophenanthrene ( 1c) afforded the corresponding products in high yields and deuterium incorporation ( 2b and 2c). 2-Bromo-6-methoxynaphthalene, 4-bromo-1,1′-biphenyl, and 3-bromo-1,1′-biphenyl also gave high yields (91–99%) with slightly reduced deuterium incorporation (87–91%) ( 2d– 2f). Electron-donating phenoxy, methoxy, and ether groups decreased the yields due to the higher reduction potentials ( 2g– 2i). p-Butyl, p-TMS, and o-di-Cl benzene gave good deuterium incorporation ( 2j– 2l), and o-, m-, and p-CN group all proceeded smoothly in this transformation ( 2m– 2o). The electron-withdrawing ester group was compatible under the standard conditions ( 2p and 2q). Heteroaromatic thiophene was also tolerated ( 2r and 2s). Scheme 2 | Substrate scope of (hetero)aryl bromides. Standard conditions: 1 (0.5 mmol), D2O (5.0 mmol), platinum plate anode, lead plate cathode (15 mm × 15 mm × 0.3 mm), constant current = 15 mA, nBu4NBF4 (0.25 mmol), DMF (6.0 mL), NPh3 (0.3 mmol), undivided cell, N2, 3 h. Isolated or gas chromatography (GC) yields are displayed. Deuterium incorporation is determined by proton nuclear magnetic resonance (1H NMR) or gas chromatography–mass spectrometry (GC-MS). aReaction time: 4 h. b1r (0.25 mmol). Download figure Download PowerPoint Then, we focused our attention on other aromatic halides (Scheme 3). 2-Iodonaphthalene and 4-iodo-1,1′-biphenyl nearly achieved equivalent conversion with 98% and 95% deuterium incorporation, respectively ( 4a and 4b). To our delight, 4,4′-diiodo-1,1′-biphenyl with two reactive sites also gave the desired disubstituted product ( 4c). When substrates contained different halogens, the deuteration selectively occurred at C–I bond, which had a lower reduction potential ( 4d and 4e). The o-, m-, and p-CN group were all compatible ( 4f– 4h). Electron-withdrawing ethyl 4-iodobenzoate afforded 69% yield and 92% deuterium incorporation ( 4i). Indole and carbazole also worked well in this reaction ( 4j and 4k). The deuterium incorporation was relatively lower for chlorides because of the higher reduction potentials ( 6a– 6d). Scheme 3 | Substrate scope of (hetero)aryl halides. Standard conditions: 3 or 5 (0.5 mmol), D2O (10.0 mmol), platinum plate anode, lead plate cathode (15 mm × 15 mm × 0.3 mm), constant current = 15 mA, nBu4NBF4 (0.25 mmol), DMF (6.0 mL), PPh3 (1.0 mmol), undivided cell, N2, 4 h. Isolated or GC yields are displayed. Deuterium incorporation is determined by 1H NMR or GC-MS. a3c (0.25 mmol). b3k (0.3 mmol). cD2O (5.0 mmol), additive: OPh2 (0.3 mmol), reaction time: 3 h. Download figure Download PowerPoint To gain more insight into the mechanism of the reaction, relevant experiments were conducted under the standard reaction conditions. First, we performed radical trapping experiments. When 1,1-diphenylethene was applied, bromine radical was trapped, which indicates that a radical process was probably involved in this transformation (see details in Supporting Information Section S2). To further confirm the presence of a radical species, electron paramagnetic resonance (EPR) tests are essential (see details in Supporting Information Section S4). A radical trapping reagent, dimethyl-1-pyrroline N-oxide (DMPO), was added into the reaction system. As shown in Figure 1a, characteristic EPR peaks of DMPO−C adduct (g = 2.0064, AN = 14.10 G, AH1 = 18.6 G, AH2 = 2.00 G, marked by #) are observed. Characteristic EPR peaks of DMPO−H adduct (g = 2.0062, AN = 14.8 G, AH1 = 19.4 G, AH2 = 19.4 G, marked by *) are also observed because water can be a hydrogen radical source (Figure 1b). Then, we used cyclic voltammetry (CV) experiments to study the redox process of this reaction (see details in Supporting Information Sections S2 and S3). Reduction of 1a started at approximately −1.75 V, and no obvious reduction peak of D2O was observed (Figure 1c). Bromine anion had an oxidation peak at ca. 0.87 V, and NPh3 oxidation began at approximately 1.00 V (Figure 1d). Figure 1 | Mechanistic studies. (a) EPR spectrum of DMPO-C. (b) EPR spectrum of DMPO-H. (c and d) Cyclic voltammograms of related compounds (5 mM) in corresponding solvent containing 25 mM nBu4NBF4. Pb plate or Pt plate working electrode, Ag/AgCl reference electrode, platinum wire counter electrode. Scan rate: 0.1 Vs−1. Download figure Download PowerPoint Based on our results, we propose a plausible reaction mechanism (Figure 2a) where, first, 1a was reduced at the cathode to produce naphthyl radical and bromine anion. Concurrently, D2O was reduced to afford deuterium radical. The desired product was formed by radical–radical cross-coupling. Bromine anion was oxidized at the anode to give bromine radical, which would further react with NPh3. Figure 2 | (a) Proposed mechanism. (b and c) Experimental setup with three AA batteries as the power source. Download figure Download PowerPoint To further explore the practicability of this electrochemical deuteration, we used a cheap and readily available instrument to conduct this reaction. With three AA size batteries as the power source, graphite rod as the anode, lead plate as the cathode, and a test tube as reaction vessel, 80% yield and 90% deuterium incorporation of 2a were obtained (Figures 2b and 2c, see details in Supporting Information Section S1). General labs could easily perform this procedure to get the desired deuterated products. Conclusion We have succeeded in developing a practical electrochemical deuteration of aromatic halides. The operation is simple and safe, which improves upon traditional methods. A probable radical cross-coupling process is proposed. We think this strategy has the potential for use in many fields. Supporting Information Supporting Information is available, including the general information, experimental methods, detail descriptions, and copies of NMR and GC-MS spectra for products. Conflict of Interest There is no conflict of interest to report. Funding Information This work was supported by the National Natural Science Foundation of China (no. 21520102003) and the Hubei Province Natural Science Foundation of China (no. 2017CFA010). The Program of Introducing Talents of Discipline to Universities of China (111 Program) is also appreciated. Acknowledgments This work is dedicated to P.H. Dixneuf for his outstanding (and meaningful) contribution to organometallic chemistry and catalysis. References 1. Simmons E. M.; Hartwig J. 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Google Scholar Previous articleNext article FiguresReferencesRelatedDetails Issue AssignmentVolume 3Issue 11Page: 2669-2675Supporting Information Copyright & Permissions© 2020 Chinese Chemical SocietyKeywordselectrochemical synthesisdeuterium oxidedehalogenationdeuterationaryl halidesAcknowledgmentsThis work is dedicated to P.H. Dixneuf for his outstanding (and meaningful) contribution to organometallic chemistry and catalysis. Downloaded 3,133 times PDF DownloadLoading ...