Electrochemical Ring Expansion to Synthesize Medium-Sized Lactams Through C–C Bond Cleavage

Open AccessCCS ChemistryRESEARCH ARTICLE1 Aug 2021Electrochemical Ring Expansion to Synthesize Medium-Sized Lactams Through C–C Bond Cleavage Kun Liu†, Chunlan Song†, Xu Jiang, Xin Dong, Yuqi Deng, Wenxu Song, Yanpei Yang and Aiwen Lei Liu† College of Chemistry Molecular Sciences, Institute for Advanced Studies (IAS), Wuhan University, 430072 †K. Liu C. Song contributed equally this work.Google Scholar More articles by author , Song† Jiang Google Dong Deng *Corresponding author: E-mail Address: [email protected] State Key Laboratory Organometallic Chemistry, Shanghai Organic 230021 https://doi.org/10.31635/ccschem.020.202000469 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd favoritesTrack Citations ShareFacebookTwitterLinked InEmail Medium-sized nitrogen heterocycles are prevalent motifs in many kinds bioactive molecules natural products. Owing the unfavorable enthalpic entropic barriers during transition states, access medium-sized rings is challenging. Herein, a general practical electrochemical ring-expansion protocol has been developed from commercially available benzocyclic ketones amides. In regard, series highly functionalized eight- eleven-membered lactams could be successfully accessed high yields efficiencies. Notably, transformation features excellent tolerance toward different electronic substituents ketone aniline moieties. Furthermore, satisfactory gram-scale direct one-pot synthesis, as well esterification inert benzylic C–H bond, additional advantages. Mechanistic studies indicate that dehydrogenative ring expansion proceeds through unique remote amidyl radical migration-induced bond cleavage subsequent single-electron oxidation. Download figure PowerPoint Introduction structural found variety products medicinal compounds.1–6 states forming rings, these Conventionally, intramolecular head-to-tail cyclization strategies suffer requirements high-dilution solvents competing intermolecular reactions.7–10 Therefore, synthetic routes obtain avoiding end-to-end desirable. With such Beckmann rearrangement,11,12 retro-aldol reaction,13,14 others15–23 have proven especially useful recent years. Despite important advancements, types methodologies also show difficulties requiring multistep preparation substrates or failing serve route broad scope lactams. Recently, with readily cyclic (hetero)aryl amides substrates, coworkers22 demonstrated an elegant photocatalyzed two-step [N+3] reaction eight eleven members From proposed mechanism, oxidation hypervalent iodine reagents initiated strategy. Unfortunately, electron-rich groups electron-donating not tolerated afford very low yields. We envisage developing external oxidant-free approaches might enable broader functional group allow their efficient sustainable preparation. Electrochemical serves mild green alternative hazardous chemical oxidants oxidative cross-coupling reactions due tunable anodic potential.24–37 Via indirect electrolysis, organic can lose electrons reactive intermediates.38–59 Until now, C–H/N–H coupling afforded N-containing either electrolysis (Figure 1a).60–72,a spite advances, reports limited five- six-membered result kinetic thermodynamic control. The construction remained exclusive. we present versatile method synthesize medium-size 1b). Many biologically valuable efficiently under conditions. electron-deficient moieties transformations. On basis, achieved at Figure 1 | synthesis (a) (b) cleavage. Experimental Methods General procedure oven-dried undivided three-necked bottle (25 mL) equipped stir bar, 1a (0.2 mmol), Cp2Fe (0.02 mmol, 3.8 mg), NaOAc 16.4 nBu4NBF4 (65.8 mg, 0.2 mmol) were added. was graphite rod (φ 6 mm, about 15 mm immersion depth solution) anode platinum plate (15 × 0.3 mm) cathode charged nitrogen. Subsequently, dichloromethane (DCM)/hexafluoro-2-propanol (HFIP) (4.0/2.0 Then system stirred constant current 5 mA room temperature h. When finished, mixture washed water extracted diethyl ether (10 mL 3). layers combined, dried over Na2SO4, concentrated. pure product obtained flash column chromatography on silica gel (petroleum:ethyl acetate = 7∶1). voltammetry Cyclic performed three-electrode cell connected Schlenk line temperature. working electrode steady glassy carbon disk electrode, counter wire. reference Ag/AgCl submerged saturated aqueous KCl solution separated salt bridge. DCM/HFIP containing M poured into all experiments. scan rate 0.1 V/s, ranging 0 2.0 V. experimental details characterization Supporting Information. Results Discussion To investigate feasibility our concept, began study based 1a, which prepared dihydro-benzothiophenone acetanilide single step. Positively, when applying 10 mol % equiv NaOAc, desired nine-membered lactam 90% yield This conducted simple (Table 1, Entry 1). labile thiophenyl electrolysis. Compared Liu’s method,22 where 20% same substrate, approach higher efficiency greener Control experiments showed poor given without Cp2Fe, most starting material decomposed 2). Changing other mediators potassium iodide (KI), tetramethylpiperidine N-oxyl (TEMPO), (4-BrC6H4)3N resulted decreased Entries 3–5). hand, no detected addition large amount substrate 6). Replacing stronger bases like Na2CO3 KOtBu led lower 7 8). regard solvent effect, DCM essential good 9), 43% absence HFIP 10). changing MeCN, only 12% corresponding furnished 11). addition, performing MeOH gave 12). effect electrodes then investigated. still nickel cathode, albeit 13–15). Moreover, conducting standard atmospheric conditions furnish 16), happened electricity 17). Table Investigation Reaction Conditionsa Variation Standard Conditions Conversion (%) Yield None 99 90 2 No 86 3 KI instead 75 n.d. 4 TEMPO 82 29 89 51 33 95 58 8 97 9 Without 41 63 43 11 MeCN/HFIP 20 12 DCM/MeOH 96 13 92 53 14 Ni 98 83 Pt 64 16 Conducted air 81 17 electric n.r. aReaction conditions: mm), (Janode ≈ 5.6 mA/cm2), (0.20 mmol). mL), N2, r.t., h (4.6 F). Isolated shown. detected. reaction. After obtaining optimized conditions, first evaluated moiety Anilines bearing fluoride, chloride, substituent para-position reactivity ( 2–4). amides, failed previously,22 now suitable Strong methoxy methyl sulfide did affect reaction, affording 88% 85% yield, respectively. electron-withdrawing trifluoromethoxy trifluoromethyl incorporated para- meta-positions anilines, 7–9). naphthalene carbazole Besides thiophene migrating groups, benzothiophene anisole survived 56–92% after Halogen F Cl, provide extra opportunities further transformations 12–16). It particularly noteworthy effectively transformed pyridyl-fused 89% Similarly, 2-quinolyl-fused reacted nine- 86–92% 18– 20). These results highlight pretty both Substrate Next, explored substituted Unsubstituted tetrahydronaphthalene satisfied 21 22). bromide substitution moiety, 86% afforded, highlighted potential 23). 3,4-dichlorophenyl 24). Gratifyingly, utility successful fused arenes within backbones expanding ten-membered 25–28). ketones. streamline lactams, wondered if it would possible merge step process. Fortunately, some effort, succeeded integrating nucleophilic attack transformation, thus enabling derivatives As shown 4, proceeded heteroarenes thiophene, benzothiophene, naphthalene, carbazole, pyridine, quinolone. Various trifluoromethyl, thiomethyl, chloro, tolerated. should noted electrolyte base required synthesis. One-pot purification. amide (0.55 (0.5 nBuLi mL, 2.4 THF), THF (3 –78 °C; (0.05 (7/4 Interestingly, 1u applied atom react anion 5a 5a). equal amounts phenylpropionic acid 4,4-difluorocyclohexane-1-carboxylic sodium hydroxide, 5b 5c 55% 48% respectively (Figures 5c). explore utilities scaled up gram scale 6a). applications. presence give 83% 6b). phenyl undergo Suzuki arylboronic 5d 91% 6c). (a–c) coupled bond. 13.4 (0.6 (or 0.6 mmol NaOH), Gram-scale exploration, made efforts understand mechanism First, carried out. 7a, 0.31 V (vs Ag/AgCl), obvious peak observed 1.4 Ag/AgCl). However, added change spotted Cp2Fe. meantime, N-(p-toly)acetamide measured. onset 1.3 Ag/AgCl) 7b. By adding one equivalent new appeared 1.0 V, caused hydrogen bonding-assisted deprotonation generate radical. 2-methylthiophene oxidized voltage combination NaOAc. controlled 7c 7d). controlling oxidized, initial 1.42 gradually 1.35 remained. While increasing anode, 3.67 mA. Electrolysis full conversion 82% isolated 2.28 measured ranged 1.63 1.85 mechanistic indicated Fc Fc+ able oxidize but responsible its generation. Meanwhile, formation oxyamination 5f 5e scavenger 35% 8a), involvement supported competitions between anilines 8b 8c). High selectivities more electro-rich voltammograms s−1 Black line, Cp2Fe; red 1a; blue N-(p-tolyl)acetamide; N-(p-tolyl)acetamide+NaOAc; 2-methylthiophene; background. (c) Controlled (d) Radical trapping competition Based above results, 9. lost electron I assisted base. delocalized II, followed selective hydroxyl ortho-carbon III. oxidation-generated 1. extent, prevent overoxidation aromatics. adjacent alkyl-substituted thiophenes N-phenylacetamide cationic pathway, fast cation quenching anilides β-scission ketyl Plausible mechanism. Conclusion benzo-cyclic breakthroughs protocol. radicalmigration-induced Footnote During manuscript, annulated reported Ruan co-workers.72 Information available. Conflicts Interest authors declare financial interests. Dedicated P.H. Dixneuf his outstanding contribution organometallic chemistry catalysis. Acknowledgments thank National Natural Science Foundation China (no. 21520102003), Hubei Province 2017CFA010), Program Introducing Talents Discipline Universities (111 Program) generous support. References Abraham D. J.; Rosenstein R. D.; Lyon L.; Fong H. 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