Communications
Cathodic N–O Bond Cleavage of N-Alkoxy Amide
2023 Volume 91 Issue 11 Pages 112005
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2023 Volume 91 Issue 11 Pages 112005
Cathodic reduction efficiently cleaved N–O bonds. The simple cathodic reduction of Weinreb amides in a divided cell afforded the corresponding amide in good yields. Cyclic voltammetry experiments and density functional theory calculations suggested that the direct reduction of the N-methoxy amide generates the methoxy radical and amide anion. The release of methanol derived from methoxy radical would be the driving force of the N–O bond cleavage.
N-alkoxy amides are ubiquitous compounds in organic chemistry. For instance, N-methoxy-N-methyl amides, also known as Weinreb amides, are widely used in ketone synthesis.1–3 In addition, several synthetic applications of N-alkoxy amides have been reported. For instance, the N–O moieties can be used as a directing group for C–H functionalization reactions.4–6 In contrast, N–O should often be cleaved after C–H functionalization reactions from the perspective of organic synthesis. Strategies for N–O bond cleavage can be categorized into three reaction types: strong basic conditions,7,8 single-electron reduction conditions,9–13 or the use of transition metal catalyst14,15 (Scheme 1). The first strategy requires strong basic reagents such as lithium diisopropyl amide.7 Inter- or intramolecular proton abstraction proceeds via N–O cleavage along with the elimination of the aldehyde (Fig. 1). A similar N–O cleavage was achieved with the combination of tert-butyldimethylsilyl triflate (TBSOTf) and triethylamine (Et3N) (Scheme 1A).8 To avoid the strong basic conditions, the single electron reductants were also used to cleave the N–O bond (Scheme 1B). Several single-electron donor reagents, such as samarium (II) diiodide (SmI2),9,10 sodium metal,11 and lithium reagents,12 allow the reductive cleavage of the N–O bond. Most recently, Gilmour reported that photoinduced electron transfer (PET) conditions using anthracene or 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN) under photoirradiation can cleave the N–O bond of Weinreb amides.13 Palladium14 or ruthenium15 catalysts have also been used to achieve the reductive cleavage of the N–O bond through metal insertion into the labile N–O bond (Scheme 1C). Although these strategies achieve N–O bond cleavage in good yields, they require harsh conditions, sensitive reagents, and expensive catalysts.
N–O bond cleavage of N-alkoxy amides.
Base-promoted N–O bond cleavage.
Electrochemistry, in contrast, provides a simple oxidation or reduction methodology, and electrochemical organic synthesis has been applied for various transformations in recent years.16–19 The cyclic voltammetry of N-alkoxy amides has been performed,13 and the cathodic peak of the voltammograms suggests the possibility of the cathodic cleavage of the N–O bond. However, the bulk electrolysis of N-alkoxy amides has not yet been reported. Herein, we demonstrated the bulk electrolysis of N-alkoxy amides to achieve N–O bond cleavage (Scheme 1D).
First, we performed the cathodic reduction of N-methoxy-N-methyl benzamide (1a) in a divided cell (Table 1). Cathodic reduction using tetrabutylammonium tetrafluoroborate (Bu4NBF4) as the supporting electrolyte proceeded with N–O bond cleavage in 98 % yield, and the corresponding amide 2a was obtained (entry 1). No significant electrolyte effect was observed during this reaction. Each tetrabutylammonium salt of perchlorate, hexafluorophosphate, and triflate afforded similar results, and the desired amide 2a was obtained in 96–98 % yields (entries 2–4). Although decreasing the amount of electricity reduced the yield, the current efficiency increased significantly (entries 5–7). When 0.2 F mol−1 of electricity was applied to the reaction mixture, the amide was obtained in 43 % yield, and a current efficiency of 215 % was achieved. These results suggest that cathodic N–O bond cleavage involves an electron-catalyzed reaction mechanism20,21 though this catalytic pathway is yet to be elucidated. Moreover, the use of DMF (entry 8) or CH2Cl2 (entry 9) as a solvent reduced the yield of 2a, and carbon felt cathode decreased the efficiency of the cathodic cleavage of the N-methoxy amide (entry 10).
Cathodic N–O bond cleavage of various N-methoxy amides was thereafter performed (Scheme 2). N–O bond cleavage proceeded with electron-donating or electron-withdrawing groups on the phenyl ring of the benzamide, and high-to-moderate yields were obtained (2b–2i). Interestingly, the position of functional groups on the aromatic ring affected the yield of N–O bond cleavage. The steric hindrance of a methyl group on the ortho position (2d) of Weinreb amide would reduce the planarity, which is important to delocalize and stabilize the radical anion of the Weinreb amides. In addition, the electron-donating effects of methyl or methoxy groups would also make the radical anions unstable. The instability of the radical anion of Weinreb amides would cause side reactions and decrease the yield of the cleaved compounds. Other aromatic rings, such as naphthalene, pyridine, or furan, were acceptable for cathodic cleavage, and N-methyl-2-naphthamide (2j), N-methylpicolinamide (2k), N-methyl-1-furamide (2l), and N-methyl-2-furamide (2m) were obtained in 21 %, 34 %, 69 %, and 21 % yields, respectively. In contrast, chloro or bromo groups on the phenyl ring were reduced by cathodic reduction and dehalogenation,22–24 which resulted in the unavoidable generation of benzamide 2a. Thus, the yields of 4-chloro- and 4-bromobenzamide (2n, 16 %, 2o, 12 %) were lower than those of the other compounds. Although N-methoxy-N-methylheptaneamide (1p) was reduced, the reduction of cinnamamide 1p and dehydrocinnamamide 1q did not afford the corresponding amides. It has been reported that side reactions of 1p, such as the rearrangement or over-reduction illustrated in Fig. 2, cannot be ignored under strong reduction conditions.11
Substrate scopes.
Speculated side reaction.
We measured the cyclic voltammograms of N-methoxy-N-methyl benzamide (1a) and N-methyl benzamide (2a) to gain further insight into the reductive N–O bond cleavage. The onset of the reduction peak of 1a started at approximately −1.8 V (vs. Fc/Fc+) (Fig. 3), and it is revealed that 1a could be easily reduced with more positive potential than 2a. Density functional theory (DFT) calculation (Fig. 4) suggests the instability of the radical anion A and low transition energy barrier (ΔG = 2.6 kcal mol−1) of the N–O bond cleavage. Thus, the spontaneous cleavage would result the irreversible redox behavior of the reduced radical anion, and it was difficult to detect the radical anion species. The cyclic voltammograms, illustrated in the Supporting Information (Fig. S3), suggest that the other Weinreb amides could also be reduced at a similar potential as 1a. Although the relationships between the reduction potentials and the yields of the N–O cleavage reaction were not observed, the cathodic reduction generates corresponding radical anions followed by the N–O cleavage gave N-methyl amides.
Cyclic voltammograms of 1a and 2a. The cyclic voltammetry was performed under the following conditions; solvent: CH3CN, supporting electrolyte: Bu4NBF4 (0.1 mol L−1), substrate concentration: 50 mM, working electrode: Pt, counter electrode: Pt coil, reference electrode: Ag/Ag+ (CH3CN), standard: Fc/Fc+, scan rate: 100 mV s−1.
The DFT calculations and the mechanism of the cathodic N–O bond cleavage.
Based on the cyclic voltammograms and DFT calculations of which detail is described in the Supporting Information (Fig. S4), we speculated the following N–O cleavage mechanism (Fig. 4). First, the cathodic reduction generates radical anion A of the starting material. The labile N–O bond of A should be cleaved to obtain the methoxy radical25,26 and amide anion D. In this step, the DFT calculations suggested that the methoxy radical and amide anion D pair are more stable than the pair of the methoxide and amidyl radical (see the Supporting Information, Fig. S4). Hydrogen atom transfer from acetonitrile to the methoxy radical forms methanol, as detected by direct NMR analysis of the reaction mixture (see the Supporting Information, Fig. S2). Our DFT calculations and a previous report on the cathodic behavior of N-oxyphthalimides25 suggest that the reductive decomposition of N–O compounds generates O-centered radicals and nitrogen anions. Acetonitrile, which is used as the reaction solvent, can protonate the amide anion D, or protonation through a work-up procedure can afford the desired amide 2a. The proposed mechanism requires a stoichiometric amount of electricity to consume the N-alkoxy amide, and the other pathway, which enables more than 100 % of current efficiency (Table 1, entries 5–7), is not clear yet.
In conclusion, we achieved N–O bond cleavage of N-methoxy amides by the cathodic reduction. This simple electrolysis setup allows for the reductive N–O bond cleavage without any reductant or other reagents. Moreover, the current efficiency suggests the possibility of a semi-catalytic pathway for N–O cleavage, although the catalytic mechanism remains under investigation.
This work was supported in part by JSPS KAKENHI grant numbers JP23K13748 (E. S.), JP22H02122 (K. M.), JP22K05115 (S. S.), and JP21H05214 (Digi-TOS) (S. S.).
The data that support the findings of this study are openly available under the terms of the designated Creative Commons License in J-STAGE Data at https://doi.org/10.50892/data.electrochemistry.24069996.
Eisuke Sato: Data curation (Supporting), Funding acquisition (Equal), Investigation (Equal), Writing – original draft (Lead)
Sayaka Ogita: Data curation (Lead), Investigation (Lead), Writing – review & editing (Supporting)
Koichi Mitsudo: Funding acquisition (Equal), Writing – review & editing (Equal)
Seiji Suga: Funding acquisition (Equal), Supervision (Lead), Writing – review & editing (Equal)
The authors declare no conflict of interest in the manuscript.
Japan Society for the Promotion of Science: JP23K13748
Japan Society for the Promotion of Science: JP22H02122
Japan Society for the Promotion of Science: JP22K05115
Japan Society for the Promotion of Science: JP21H05214
E. Sato, K. Mitsudo, and S. Suga: ECSJ Active Members
