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

Abstract

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