Electrochemically Induced Synthesis of Imidazoles from Vinyl Azides and Benzyl Amines

An electrochemically induced synthesis of imidazoles from vinyl azides and benzyl amines was developed. A wide range of imidazoles were obtained, with yields of 30 to 64%. The discovered transformation is a multistep process whose main steps include the generation of electrophilic iodine species, 2H-azirine formation from the vinyl azide, followed by its reactions with benzyl amine and with imine generated from benzyl amine. The cyclization and aromatization of the obtained intermediate lead to the target imidazole. The synthesis proceeds under constant current conditions in an undivided cell. Despite possible cathodic reduction of various unsaturated intermediates with C=N bonds, the efficient electrochemically induced synthesis of imidazoles was carried out.

The electrolysis can be performed in an undivided or divided cell under controlled potential (CPE) or constant current conditions (CCE). Constant current (CCE) conditions benefit from the high current density, shorter process time, and technically convenient reaction setup. Using an undivided cell is more practical, but at the same time, undesirable processes connected to the counter-electrode action at reaction intermediates must be avoided.
As far as we know, the electrochemical method for the synthesis of substituted imidazoles using vinyl azides has not been disclosed yet. Inspired by the synthetic application of vinyl azides and our experience in the organic electrosynthesis [44], herein, we report an electrochemical approach to imidazoles from vinyl azides and benzyl amines (Scheme 1c).

Results and Discussion
We began testing our hypotheses using (1-azidovinyl)benzene 1a and benzyl amine 2a as the model substrates in N,N-dimethylformamide (DMF) with tetrabutylammonium iodide (TBAI) as the electrolyte under electrolysis at 30 mA (j = 10 mA/cm 2 ) with 4.0 F/mol electricity passed, as shown in Table 1. To our delight, the expected 1-benzyl-2,4-diphenyl-1H-imidazole (3a) was isolated, with a yield of 24% from the crude mixture (entry 1, Table 1). We then investigated other reaction parameters. The detailed optimization of the imidazole electrosynthesis is presented in SI (Table S1).
Screening of electrolytes indicated that KI (37%, entry 2) was superior to TBAI and LiClO 4 , which gave lower yields (entries 1 and 3, 24% and 22%, respectively). The yield of 3a has not risen with an increase in benzyl amine amount to 4.0 eq. (entry 4). The addition of p-TsOH·H 2 O improved the 3a yield up to 48% (entry 5). The product (3a) was isolated, with a yield of 39% with the applied current density 20 mA/cm 2 (entry 6). The yield increased as the amount of electricity passed achieved 6.0 F/mol (entry 7). When the electric current was absent, traces of the product formed (entry 8). Several acids were later screened. When H 2 SO 4 or CH 3 SO 3 H were employed, the expected product (3a) was not detected (entries 9, 10); the replacement of p-TsOH·H 2 O with Amberlyst-15 dramatically lowered the yield (entry 11). To compare the influence of the cathode materials, the reaction was carried out with glassy carbon, stainless steel, and nickel cathodes (entries [12][13][14]. Nickel cathode was almost as effective as platinum (48%, entries 7 and 14), the others were less. Product 3a was obtained with a yield of 36% when a graphite plate was employed as anode (entry 15), and even lower yield was observed with platinum plate as anode (entry 16). Similar efficiency was obtained when dimethyl sulfoxide (DMSO) (34%, entry 17) was used as a solvent. However, the yield of product 3a decreased to 18% when the reaction was performed in PhCl (entry 18). The reduction in the temperature to 70 • C led to the best 3a yield (61%, entry 19). A further reduction in the temperature to 50 • C significantly drops the yield of the cyclization product, suggesting that the temperature also plays a crucial role in the electrochemical cyclization (entry 20). Under optimal conditions (yield 3a 61%, entry 19), a complete conversion of 1a was observed, with no evidence of byproducts that could be isolated.   With the best conditions in hand (Table 1, entry 19), we next turned our attention to the scope of various vinyl azides 1 as depicted in Scheme 2. Substituted (1-azidovinyl)benzenes 1 were subjected to transformation under the reaction conditions. All (1-azidovinyl)benzenes 1 containing electron-donating (e.g., CH 3 , t-Bu, and OCH 3 ) as well as electron-withdrawing groups (e.g., F, Br, and Cl) worked well, affording the desired products 3a-3i with yields of 34-64%. (1-Azidovinyl)benzene 1j with the other azido-group gave the desired product 3j with a yield of 30%. The aliphatic vinyl azide 1k did not provide the cyclization product, and the possible reason is insufficient stabilization of the imine-enamine intermediates due to the lack of a conjugated bond system. Subsequently, representative amines 2 with electron-donating and electron-withdrawing groups were evaluated (Scheme 3). The various benzyl amines 2 were suitable for this transformation, giving the desired products 3l-p, with yields of 35-55%. 2-(Aminomethyl)furan and 3-(aminomethyl)pyridine afforded the corresponding products 3q and 3r with yields of 38% and 30%, respectively. The application of 1-aminohexane did not lead to the cyclization product. Subsequently, representative amines 2 with electron-donating and electron-withdrawing groups were evaluated (Scheme 3). The various benzyl amines 2 were suitable for this transformation, giving the desired products 3l-p, with yields of 35-55%. 2-(Aminomethyl)furan and 3-(aminomethyl)pyridine afforded the corresponding products 3q and 3r with yields of 38% and 30%, respectively. The application of 1-aminohexane did not lead to the cyclization product.
In order to determine the reaction mechanism, we conducted a series of control experiments (Scheme 4). Firstly, 1a and 2a were placed with iodine (4.0 eq.) as the oxidant, so the target product 3a was not observed, and acetophenone was isolated in a 20% yield (Scheme 4a). This result demonstrated the unique reactivity of the electrochemical system, which is far more complex than the iodine generation. Moreover, ω-iodoacetophenone 4 and acetophenone 5, instead of 1a, were investigated under electrochemical conditions (Scheme 4b,c). The reaction of ω-iodoacetophenone 4 with benzyl amine 2a did not lead to the desired imidazole 3a, unlike the reaction of acetophenone 5 with benzyl amine 2a.
The imidazole 3a was synthesized from acetophenone, 5 with a low yield of 14% under optimal conditions (Scheme 4c). These results implied that the iodination of α-carbon in the vinyl substrate might not be the required reaction step. The substrate 2a was employed to react with 3-phenyl-2H-azirine 6; the product 3a was obtained with a yield of 35%, thus 3-phenyl-2H-azirine 6 might be the intermediate in electrochemically induced synthesis of substituted imidazoles (Scheme 4d). In order to determine the reaction mechanism, we conducted a series of control experiments (Scheme 4). Firstly, 1a and 2a were placed with iodine (4.0 eq.) as the oxidant, so the target product 3a was not observed, and acetophenone was isolated in a 20% yield (Scheme 4a). This result demonstrated the unique reactivity of the electrochemical system, which is far more complex than the iodine generation. Moreover, ω-iodoacetophenone 4 and acetophenone 5, instead of 1a, were investigated under electrochemical conditions (Scheme 4b,c). The reaction of ω-iodoacetophenone 4 with benzyl amine 2a did not lead to the desired imidazole 3a, unlike the reaction of acetophenone 5 with benzyl amine 2a.
The imidazole 3a was synthesized from acetophenone, 5 with a low yield of 14% under optimal conditions (Scheme 4c). These results implied that the iodination of α-carbon in the vinyl substrate might not be the required reaction step. The substrate 2a was employed to react with 3-phenyl-2H-azirine 6; the product 3a was obtained with a yield of 35%, thus 3-phenyl-2H-azirine 6 might be the intermediate in electrochemically induced synthesis of substituted imidazoles (Scheme 4d). To understand the influence of the cathodic processes and p-TsOH on the yield of 3a, we performed comparative electrochemical experiments in undivided and divided electrochemical cells (Scheme 5). There is no significant difference in 3a yield between an undivided and divided electrochemical cells in the presence of p-TsOH. Without acid the reaction in the divided cell resulted in higher yields than in the undivided one. So, in the undivided cell, an acid is likely reduced on the cathode, preventing cathodic side processes.
Cyclic voltammetry (CV) was used to study the redox potentials of the substrates ( To understand the influence of the cathodic processes and p-TsOH on the yield of 3a, we performed comparative electrochemical experiments in undivided and divided electrochemical cells (Scheme 5). There is no significant difference in 3a yield between an undivided and divided electrochemical cells in the presence of p-TsOH. Without acid the reaction in the divided cell resulted in higher yields than in the undivided one. So, in the undivided cell, an acid is likely reduced on the cathode, preventing cathodic side processes.  To understand the influence of the cathodic processes and p-TsOH on the yield of 3a, we performed comparative electrochemical experiments in undivided and divided electrochemical cells (Scheme 5). There is no significant difference in 3a yield between an undivided and divided electrochemical cells in the presence of p-TsOH. Without acid the reaction in the divided cell resulted in higher yields than in the undivided one. So, in the undivided cell, an acid is likely reduced on the cathode, preventing cathodic side processes. potential below 1.5 V (curve d). The addition of KI to the mixture of benzyl amine 2a and p-TsOH·H2O led to decreased oxidation and reduction peaks of KI (curves b, d, e). The mixture vinyl azide 1a, benzyl amine 2a, KI, and p-TsOH·H2O (curves e, f) demonstrated increased oxidation peaks, which may indicate the oxidation of the reaction products from vinyl azide 1a with electrochemically generated intermediates from benzyl amine 2a, KI, and p-TsOH·H2O. Based on our experimental results and previous works, [17,25,46] a plausible reaction mechanism for electrochemical transformation of vinyl azides and benzyl amines into imidazoles was proposed in Scheme 6. First, molecular iodine is generated via the anodic oxidation of I − . [15,16,22] Generated I2 can further react with the Ito result in I3 − formation or with traces of water from the solvent, as well as OHgenerated on the cathode, to give electrophilic iodine species. [47,48] Then, molecular iodine oxidizes 2a to form imine 8. The vinyl azide 1a is converted to 2H-azirine 6 by thermal decomposition. A nucleophilic attack of starting benzyl amine 2a to 2H-azirine 6 leads to intermediate 7.   Based on our experimental results and previous works [17,25,46], a plausible reaction mechanism for electrochemical transformation of vinyl azides and benzyl amines into imidazoles was proposed in Scheme 6. First, molecular iodine is generated via the anodic oxidation of I − [15,16,22]. Generated I 2 can further react with the I − to result in I 3 − formation or with traces of water from the solvent, as well as OH − generated on the cathode, to give electrophilic iodine species [47,48]. Then, molecular iodine oxidizes 2a to form imine 8. The vinyl azide 1a is converted to 2H-azirine 6 by thermal decomposition. A nucleophilic attack of starting benzyl amine 2a to 2H-azirine 6 leads to intermediate 7 [25].
High-resolution mass spectra (HR-MS) were measured on a Bruker micrOTOF II instrument using electrospray ionization (ESI). The measurements were performed in a positive ion mode (interface capillary voltage-4500 V); mass range from m/z 50 to m/z 3000 Da; external calibration with Electrospray Calibrant Solution (Fluka). A syringe injection was used for all acetonitrile solutions (flow rate 3 µL/min). Nitrogen was applied as a dry gas; interface temperature was set at 180 °C.
FT-IR spectra were recorded on Bruker Alpha instrument. The TLC analysis was carried out on standard silica gel chromatography plates (DC-Fertigfolien ALUGRAM R Xtra SIL G/UV254). Column chromatography was performed using silica gel (0.040-0.060 mm, 60 A). Scheme 6. The proposed reaction mechanism.
High-resolution mass spectra (HR-MS) were measured on a Bruker micrOTOF II instrument using electrospray ionization (ESI). The measurements were performed in a positive ion mode (interface capillary voltage-4500 V); mass range from m/z 50 to m/z 3000 Da; external calibration with Electrospray Calibrant Solution (Fluka). A syringe injection was used for all acetonitrile solutions (flow rate 3 µL/min). Nitrogen was applied as a dry gas; interface temperature was set at 180 • C.
FT-IR spectra were recorded on Bruker Alpha instrument. The TLC analysis was carried out on standard silica gel chromatography plates (DC-Fertigfolien ALUGRAM R Xtra SIL G/UV 254 ). Column chromatography was performed using silica gel (0.040-0.060 mm, 60 A). DMF, p-TsOH • H 2 O, TBAI, KI, NH 4 I, NH 4 Br, LiClO 4 , H 2 SO 4, CH 3 SO 3 H, Amberlyst-15, and chlorobenzene were purchased from commercial sources and were used as is. All solvents were distilled before use using standard procedures.
Amines 2 were obtained from commercial suppliers and used without further purification.

Electrochemical Cell
For the electrosynthesis glassy carbon and platinum plates from Russian commercial suppliers were used as electrodes (glassy carbon: CУ-2000: TУ 1916-027-27208846-01; platinum grade: AISI 304). The reactions were performed in a common chemical tube. Undivided electrochemical cell equipped with glassy carbon plate anode and platinum plate cathode with reaction mixture during electrolysis under constant current conditions. The detailed electrochemical equipment was presented in our previous study [44].
Before all electrochemical reactions, the electrodes were placed into a 5 M solution of KOH and this mixture was electrolyzed for 10 min at j = 200 mA/cm 2 . After that, the polarity of electrodes was changed and the mixture was electrolyzed under these conditions again. After electrolysis, the electrodes were washed with running water and then with acetone. All these procedures help to clean the electrodes from the impurities from the previous electrolysis.

General Experimental Procedure for Schemes 2 and 3
An undivided cell was equipped with a glassy carbon anode (3 cm 2 ) and a platinum plate cathode (3 cm 2 ) and connected to a DC regulated power supply. The solution of 1a  13

Conclusions
In summary, we have disclosed the electrochemical synthesis of imidazoles from vinyl azides and benzyl amines in moderate to high yields. Application of an electric current makes it possible to conduct the reaction without application of unrecoverable chemical oxidants. The process was carried out under constant current conditions in an experimentally simple undivided electrochemical cell equipped with a platinum cathode and a glassy carbon anode. Potassium iodide served as both a supporting electrolyte and a redox catalyst. With the use of cyclic voltammetry and control experiments, a possible reaction pathway was proposed. Presumably, during the reaction, 2H-azirine is generated from the vinyl azide followed by its reaction with benzyl amine and the corresponding imine. The cyclization and aromatization of the obtained intermediate lead to the target imidazole.