2023 Volume 91 Issue 11 Pages 112006
Herein, we report that the 2,7-dimethoxynaphthyl (2,7-DMN) group is a novel electroauxiliary that is readily installed at the N-α position of a carbamate through Friedel–Crafts-type arylation. The resulting N-α C–C bond is easily cleaved through low-potential electrochemical oxidation to give the corresponding iminium cation.
Electrochemical methodologies have enabled a variety of highly chemoselective electron-promoted molecular transformations in approaches that depend on the redox potential of the substrate.1–3 The ionization energy of the highest occupied molecular orbital (HOMO) is reflected in the oxidation potential (Eox) of the substrate during anodic oxidation; consequently, constant potential manipulation frequently gives good results. However, this Eox-dependent reaction system is sometimes incompetent. For instance, intermolecular reactions between high Eox substrates and low Eox nucleophiles are difficult owing to the inevitable primary oxidation of the nucleophile. Yoshida and co-workers established “electroauxiliary” as a key concept to overcome this problem and to achieve regioselective redox reactions under mild potential conditions (Fig. 1a).4–6 Sulfur-based electroauxiliaries are frequently employed to activate a heteroatomic α-position through spontaneous oxidative cleavage of a C–S bond via a radical-cation intermediate, and the utility of this methodology has been demonstrated by the syntheses of carbohydrates and peptides.7–10 However, sulfur-based substituents at N-α positions are fragile owing of the instability of the hemiaminal moiety; consequently, the late-stage diversification of a nitrogen-containing substrate, such as an amino-acid derivative, is difficult using traditional electroauxiliary-based strategies.
Electroauxiliary-assisted substitution reaction at N-α positions.
With this background in mind, we previously reported that the 2,4,6-trimethoxyphenyl (TMP) group is a chemically stable electroauxiliary11 and that robust C–C bonds at N-α-positions are maintained during harsh acidic treatments to afford the corresponding deprotected free amines, which enabled proline derivatives to be N-diversified at an early-stage (Fig. 1b). The TMP group is easily cleaved by electrochemical oxidation at a low anode potential, and the resulting iminium cation equivalent can be reacted with a nucleophile to afford the corresponding coupling product. We hypothesized that more-electron-rich aryls enabled the use of nucleophile with lower Eox value than that of the TMP group (Fig. 1c). Herein, we report that the 2,7-dimethoxynaphthyl (2,7-DMN) group is a novel aryl-type electroauxiliary. The synthetic utility of the 2,7-DMN group was explored and the mechanism associated with the electrochemical C–C bond cleavage reaction was investigated using density functional theory (DFT) calculations.
1H and 13C NMR spectra were acquired in CDCl3 and CD3OD on a JEOL ECA-600 spectrometer (1H, 600 MHz; 13C, 151 MHz), a JEOL ECA-400 spectrometer (1H, 400 MHz; 13C, 100 MHz), and a Bruker DRX500 spectrometer (1H, 500 MHz; 13C, 126 MHz). Tetramethylsilane (1H, 0.00 ppm), CHCl3 (1H, 7.26 ppm, 13C, 77.16 ppm) and CD3OD (1H, 3.31 ppm) were used as internal standards. Mass spectra were recorded on JEOL JMS-T100GCV mass spectrometer. Gas chromatography-mass spectrometry (GC-MS) was performed on a Shimadzu GC-2010 and GCMS-QP2010 using Agilent DB-5 ms column (30 m × 0.25 mm). Melting points were measured on an Sansho SMP-500 melting point measuring instrument.
2.2 MaterialsAll materials were obtained from TCI Fine Chemicals, Wako Pure Chemical Industries, Kanto Chemical, or Sigma–Aldrich, and used without purification. Merck precoated silica gel F254 plates (thickness: 0.25 mm) were used for thin-layer chromatography (TLC). Silica gel column chromatography was performed by using Kanto Chemical Silica Gel 60N (spherical, neutral, 63–210 µm).
2.3 Cyclic voltammetryCyclic voltammetry (CV) was performed using Biologic VSP-3A potentiostat. All CV experiments were carried out in a three-electrode system fitted with a glassy carbon (GC) disk anode (φ = 3.0 mm), a Pt disk cathode (φ = 3.0 mm), and a Ag/AgCl reference electrode. 1 M (= mol L−1) LiClO4-MeNO2 solution was used as the electrolyte.
2.4 General anodic-oxidation procedureAll equipment (syringe, test tube) and LiClO4 were dried in a vacuum oven at 150 °C. MeNO2 was dried over 4 Å molecular sieves. The substrate (0.1 mmol), LiClO4 (1.59 g, 15 mmol), MeNO2 (15 mL), AcOH (43 µL, 0.75 mmol), and the nucleophile (0.5 mmol) were added to a test tube after which it was subjected to a constant electrical current of 0.25 mA/cm2 (1.5 F/mol, 14.5 C) through the GC anode (2 × 2 cm) and the Pt cathode (2 × 2 cm). The reaction mixture was partitioned between saturated aqueous NaHCO3 (50 mL) and CHCl3 (20 mL) following electrolysis. The aqueous layer was extracted with CHCl3 (3 × 10 mL) and the combined organic layer was dried over anhydrous Na2SO4. The filtrate was concentrated in vacuo and the resulting residue was subjected to 1H NMR spectroscopy or column chromatography.
A divided cell experiment was performed using an H-type cell (4G glass filter). The substrate (0.1 mmol), nucleophile (0.5 mmol), MeNO2 (15 mL), and LiClO4 (1.59 g, 15 mmol) were added to the anode chamber, and AcOH (43 µL, 0.75 mmol), MeNO2 (15 mL), and LiClO4 (1.59 g, 15 mmol) were added to the cathode chamber. The anolyte was transferred into a separating funnel following constant-current electrolysis (0.25 mA/cm2, 1.5 F/mol, 14.5 C) and partitioned between saturated aqueous NaHCO3 (50 mL) and CHCl3 (20 mL). The aqueous layer was extracted with CHCl3 (3 × 10 mL) and the combined organic layer was dried over anhydrous Na2SO4. The filtrate was concentrated in vacuo and the resulting residue was subjected to 1H NMR spectroscopy.
2.5 ComputationsAll calculations were performed using Gaussian 16 software. Geometries were optimized at the B3LYP/6-31G(d) level of theory, with frequencies calculated at the same level.
We used 2,7-dimethoxynaphthyl derivative 3b, along with TMP derivative 3a, as 2-pyrrolidone derivatives bearing electron-rich aryl functionalities (Scheme 1). Accordingly, N-Boc protection and hydride reduction with diisobutylaluminum hydride (DIBAL) afforded hemiaminal 2, with subsequent Lewis-acid-mediated Friedel–Crafts type arylation yielding 3a–b.
Synthesis of 3a–b. [a] Abbreviations: Boc, tert-butoxycarbonyl; DMAP, 4-dimethylaminopyridine; DIBAL, diisobutylaluminum hydride; THF, tetrahydrofuran.
Anodic oxidation was carried out in MeNO2-LiClO4 (1 M) in the presence of AcOH and allyltrimethylsilane. The reactivity of the TMP group was re-evaluated as a benchmark, with allylated product 4 obtained in good yield (Table 1, entry 1). No reaction was observed using CH2Cl2-Bu4NPF6 as the electrolyte, with the substrate remaining mostly intact (Table 1, entry 2). Our previous study revealed that concentrated MeNO2-LiClO4 functions as a weakly donating electrolyte system because the aggregation of lithium cation and perchlorate anion decreases the Lewis basicity of perchlorate anion;12,13 hence, preventing the anionic species from electrostatically interacting with the radical cation intermediate appears to be crucial for promoting the substitution reaction at the N-α position. The reaction was less efficient in a divided cell (Table 1, entry 3). AcOH plays the expected role of proton source that prevents the undesired cathodic reduction of the anodically generated cationic species. However, our previous study revealed that the cathodically generated acetate anion determines the stability of the iminium cation intermediate through ionic or covalent interactions in the MeNO2-LiClO4 system.14 The current divided-cell experiment also suggested that the acetate anion crucially stabilizes the iminium cation intermediate. The 2,7-dimethoxynaphthyl (2,7-DMN) group also act as electroauxiliary (Table 1, entry 4); however, as was observed for the TMP group, lower reaction efficiencies were also observed in the divided-cell experiment (Table 1, entry 5). Therefore, we conclude that both the TMP and 2,7-DMN groups act as electroauxiliaries through same mechanism.
We next examined thiophenol as nucleophile. Pleasingly, the 2,7-DMN-containing substrate 3b afforded a higher yield of the thiophenylated product 5 than TMP derivative 3a (Fig. 2a). CV revealed that the 2,7-DMN group exhibits a peak oxidation potential of around +1.08 V (vs. Ag/AgCl), which is lower than those of thiophenol (+1.16 V) and the TMP group (+1.2 V) (Fig. 2c). These results suggest that the electron-rich nature of the 2,7-DMN group suppresses the competitive oxidation of thiophenol. We questioned why 3b gave lower yield than 3a in allylation reaction (Table 1). CV analysis indicated 2,7-dimethoxynaphthalene, which can be generated by oxidative C–C bond cleavage of 3b, has same oxidation potential with 3b, but three times higher current was observed (Fig. 2c, orange and yellow line). This result indicated that competitive oxidation of eliminated 2,7-dimethoxynaphthalene decreases current efficiency of allylation reaction.
(a) Substitution reactions involving thiophenol (isolated yield is noted in parenthesis). (b) Visualizing the spin density of 3a–b•+. Hydrogen atom was not displayed. ISO value = 0.001. (c) Cyclic voltammograms for compounds 3a–b and thiophenol in MeNO2-LiClO4 (1.0 M). Scan rate: 100 mV/s; sample concentration: 6.7 mM (0.1 mmol/15 mL). (d) CV for 1,3,5-trimethoxybenzene and 2,7-dimethoxynaphthalene. (e) Plausible mechanism.
DFT calculations revealed that the spin density of 3a•+ and 3b•+ were delocalized on their nitrogen and aryl moiety (Fig. 2b), which suggests that the existence of two equilibrium states, namely aryl radical cation and aminium radical cation (Fig. 2d). Both resonance structures can be converted to each other through reversible intramolecular electron transfer as Moeller et al. described,15 and homolytic C–C bond cleavage at the N-α position can proceed from aminium radical cation.16,17 Therefore, we considered aminium radical cation is a key intermediate in our reaction.
A plausible mechanism for the overall transformation is shown in Fig. 2e. Anodic oxidation of 3b affords radical cation A, with homolytic cleavage at N-α position yielding iminium cation B, which is stabilized by the cathodically generated acetate anion. Subsequent reaction with a nucleophile proceeds in an SN1 manner to afford C. Spontaneous cleavage gives aryl radical D, which dimerizes through radical recombination; this dimer E was observed by GC-MS in both allylation and thiophenylation reaction (see Figs. S1–S2 in Supporting Information). On the other hands, 2,7-dimethoxynaphthalene F was also observed in GC-MS, thus hydrogen atom abstraction (HAT) pathway also can be considered.
In this study, we discovered that the 2,7-dimethoxynaphthyl (2,7-DMN) group is a novel aryl-type electroauxiliary; it is introduced at the N-α position of a carbamate using Friedel–Crafts-type arylation, and the resulting N-α C–C bond is readily oxidatively cleaved using low-potential electrochemistry to give the corresponding iminium cation. Our results are expected to expand the versatility of the electroauxiliary concept in the synthetic chemistry field.
This work was supported by JSPS KAKENHI (22J00431 to K.O., 22H02118 and 23H04916 to N.S., 20H03072 to Y.K., 20H02513, 21H05215 and 22K18915 to M.A., 19H00930 and 19K22272 to K.C.) and JST CREST (JPMJCR18R1 to M.A., JPMJCR19R2 to K.C.).
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.24124875.
Kazuhiro Okamoto: Conceptualization (Lead), Data curation (Lead), Formal analysis (Lead), Investigation (Lead), Methodology (Lead), Software (Lead), Visualization (Lead), Writing – original draft (Lead)
Yasushi Imada: Conceptualization (Lead)
Naoki Shida: Formal analysis (Equal), Funding acquisition (Equal), Writing – review & editing (Equal)
Yoshikazu Kitano: Funding acquisition (Equal), Writing – review & editing (Equal)
Mahito Atobe: Funding acquisition (Equal), Writing – review & editing (Equal)
Kazuhiro Chiba: Conceptualization (Lead), Funding acquisition (Lead), Supervision (Lead), Writing – review & editing (Lead)
The authors declare no conflict of interest in the manuscript.
Japan Society for the Promotion of Science: 22J00431
Japan Society for the Promotion of Science: 22H02118
Japan Society for the Promotion of Science: 23H04916
Japan Society for the Promotion of Science: 20H03072
Japan Society for the Promotion of Science: 22K18915
Japan Society for the Promotion of Science: 20H02513
Japan Society for the Promotion of Science: 21H05215
Japan Society for the Promotion of Science: 19K22272
Japan Society for the Promotion of Science: 19H00930
Core Research for Evolutional Science and Technology: JPMJCR18R1
Core Research for Evolutional Science and Technology: JPMJCR19R2
K. Okamoto, N. Shida, M. Atobe, and K. Chiba: ECSJ Active Members
