A method for electrochemically synthesizing N-(alpha-alkoxyalkyl)azole compounds

Abstract

The application discloses an electrochemical synthesis N α A method for synthesizing azole compounds under mild electrochemical conditions through a three-component reaction of azole, aldehyde and alcohol N α In the electrolysis process, azole is oxidized into a nitrogen free radical at the anode, and aldehyde is reduced into a hydroxyalkyl free radical at the cathode, then the free radical coupling is carried out, and finally, intermolecular dehydration of alcohol is carried out to synthesize a series of azole compounds with an alkoxyalkyl group N α The reaction avoids the use of an acid catalyst, an additional oxidant and a reducing agent through a free radical active intermediate route, is low in production cost, is friendly to the environment, and is suitable for industrial large-scale production as shown by the feasibility of a kilogram-scale amplification experiment.​​​

Description

Technical Field

[0001] This invention relates to electrochemical synthesis technology, specifically a method for synthesizing N-(α-alkoxyalkyl)azole compounds via an electrochemical three-component reaction. Background Technology

[0002] In organic chemistry, the synthesis and functionalization of nitrogen-containing heterocycles is a common and attractive research area due to their wide applications in medicinal chemistry, agriculture, and materials science. Benzotriazoles are a unique class of nitrogen-containing heterocyclic compounds, and N-substituted benzotriazoles exhibit favorable biological properties in the pharmaceutical industry (Eur. J. Med. Chem. 2015, 97, 612; J. Chem. Pharm. Res. 2011, 3, 375; J. Heterocyclic Chem. 2023, 60, 705; Front. Chem. 2021, 9, 660424), including antibacterial, antitumor, antiviral, antiprotozoal, plant growth regulator, and anti-inflammatory activities. Therefore, N-substituted benzotriazoles have attracted widespread attention from medicinal chemists.

[0003] Currently, in research on N-substituted benzotriazole compounds, the construction of C(sp) 2 Significant progress has been made in C-N bonds. However, due to the limitations of C(sp... 3 The relative inertness of the C(sp)-H bond requires a relatively high activation energy from the substrate, therefore direct C(sp)-H bond activation is not feasible. 3 )-H amination to construct C(sp 3 The -N bond still faces challenges.

[0004] N-(α-alkoxyalkyl)benzotriazole is a class of C(sp... 3 N-substituted benzotriazoles constructed by α-N bonds are traditionally synthesized via acid catalysis (Chin. J. Chem. 2007, 25, 1041; Chin. Chem. Lett. 2005, 16, 155; J. Org. Chem. 1995, 60, 7619; J. Chem. Soc. Perkin Trans 1987, 791). First, an aldehyde and an alcohol undergo nucleophilic addition under acidic conditions to form a hemiacetal. Then, the active hydroxyl group of the hemiacetal reacts with H... + The combination process removes one water molecule to generate a positively charged alkoxyalkyl hemiacetal. Finally, the resulting carbocation adds to the N atom of benzotriazole to give N-(α-alkoxyalkyl)benzotriazole. Although this strategy achieves C(sp... 3While the construction of α-N bonds is possible, several limitations remain, such as the need for strong acids and long reflux times, poor stability and high production costs of acidic catalysts, the tendency to produce acetals as byproducts under acidic conditions, poor reaction selectivity, and the inherent toxicity and poor biodegradability of certain acidic ionic liquids. Therefore, there is an urgent need to develop economical and environmentally friendly, concise synthetic routes to address these shortcomings. Summary of the Invention

[0005] The purpose of this invention is to address the shortcomings of existing technologies by providing a method for the electrochemical three-component reaction synthesis of N-(α-alkoxyalkyl)azole compounds. This method requires no acid catalyst or redox agent, has low production costs, is environmentally friendly, and the feasibility of gram-scale experiments demonstrates its suitability for large-scale industrial production.

[0006] The technical solution to achieve the objective of this invention is:

[0007] A method for synthesizing N-(α-alkoxyalkyl)azole compounds via an electrochemical three-component reaction, wherein the general synthetic formula of the compounds is as follows:

[0008]

[0009] In the general formula, R 1 =Alkyl; R 2 =alkyl, aryl; R 3 =alkyl;

[0010] Aldehydes are aliphatic and aromatic; alcohols are chain alcohols.

[0011] The electrolyte is: tetrabutylammonium tetrafluoroborate or tetrabutylammonium hexafluorophosphate;

[0012] The solvent is methanol, ethanol, isopropanol, tert-butanol or n-pentanol.

[0013] The above-mentioned method for synthesizing N-(α-alkoxyalkyl)azole compounds via a three-component electrochemical reaction is as follows:

[0014] Benzotriazole (0.6 mmol), aliphatic aldehyde and aromatic aldehyde (2.4 mmol), chain alcohol (6 mL), and electrolyte (0.6 mmol) were added to a 10 mL three-necked round-bottom flask, respectively.

[0015] Alcohol was used as both the reaction substrate and the solvent. Platinum sheets (1 cm x 1 cm) were used as the anode and cathode. The reaction was carried out under argon protection and at 60 °C with a constant current of 12 mA. The reaction progress was monitored by thin-layer chromatography until the substrate was completely depleted.

[0016] After the reaction was completed, the crude product was obtained by concentration under reduced pressure, and the concentrate was purified by silica gel column chromatography with a mesh size of 300-400 to obtain the target product.

[0017] The column chromatography purification uses petroleum ether / ethyl acetate as the eluent, wherein the volume ratio of petroleum ether / ethyl acetate is 15:1.

[0018] During synthesis, raw materials can be added in multiples of the raw material ratios described in the above synthesis method.

[0019] N-(α-alkoxyalkyl)benzotriazole possesses important biochemical and antitumor activities (Tetrahedronlett. 1968, 38, 4089; Synthesis 1994, 597), thus making its synthesis practical.

[0020] The present invention provides a synthetic method for synthesizing N-(α-alkoxyalkyl)azole compounds by reacting azoles, aldehydes, and alcohols under mild electrochemical conditions. This method avoids the use of acidic catalysts and additional redox agents, and features mild reaction conditions, simple operation, low production cost, and high controllability. Furthermore, scale-up studies using a gram-scale electrochemical reactor demonstrate its suitability for large-scale industrial production. Detailed Implementation

[0021] The present invention will be further described below with reference to embodiments, but this is not intended to limit the scope of the invention.

[0022] Example 1:

[0023] Preparation and characterization of 1-(1-ethoxy-3-phenylpropyl)-1H-benzo[d][1,2,3]triazole (4aaa):

[0024]

[0025] Benzotriazole (0.6 mmol), phenylpropionaldehyde (2.4 mmol), and tetrabutylammonium tetrafluoroborate (0.6 mmol) were placed in 10 mL three-necked round-bottom flasks, respectively.

[0026] Then, 6.0 mL of ethanol solvent was added to dissolve the substrate. Platinum sheets (1 cm x 1 cm) were used as anode and cathode. The reaction was carried out under argon protection and at 60 °C with a constant current of 12 mA until the substrate was completely consumed (thin-layer chromatography monitoring, reaction time was 2 hours).

[0027] After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was then purified by column chromatography (300-400 mesh silica gel, petroleum ether / ethyl acetate = 15:1 elution) to obtain the target product 4aaa.

[0028] The product was characterized as follows:

[0029] Yellow liquid (143.5 mg, 85%). 1 H NMR(400MHz,Chloroform-d)δ8.08(dd,J=8.3,1.1,

[0030] 1H),7.77(dt,J=8.3,1.0,1H),7.49-7.45(m,1H),7.40-7.36(m,1H),7.29-7.25(m,2H),7.20-7.14(m,3H),6.03(t,J=6.6 ,1H),3.53-3.46(m,1H),3.31-3.24(m,1H),2.78-2.70(m,1H),2.65-2.57(m,2H),2.47-2.40(m,1H),1.14(t,J=7.0,3H). 13 C NMR(100MHz,Chloroform-d)δ146.89,140.15,131.47,128.63,128.52,127.56,126.37,12 4.32,120.20,111.29,89.91,64.71,36.26,31.11,14.82.HRMS(m / z)[ESI]:calculatedfor C 17 H 20 N3O + m / z[M+H] + :282.1601,found282.1611.

[0031] Example 2:

[0032] Preparation and characterization of 1-(1-ethoxy-3-phenylpropyl)-5-methyl-1H-benzo[d][1,2,3]triazole (4baa):

[0033]

[0034] 5-Methylbenzotriazole (0.6 mmol), phenylpropionaldehyde (2.4 mmol), and tetrabutylammonium tetrafluoroborate (0.6 mmol) were placed in 10 mL three-necked round-bottom flasks, respectively.

[0035] Then, 6.0 mL of ethanol solvent was added to dissolve the substrate. Platinum sheets (1 cm x 1 cm) were used as anode and cathode. The reaction was carried out under argon protection and at 60 °C with a constant current of 12 mA until the substrate was completely consumed (thin-layer chromatography monitoring, reaction time was 2 hours).

[0036] After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was then purified by column chromatography (300-400 mesh silica gel, petroleum ether / ethyl acetate = 15:1 elution) to obtain the target product 4baa.

[0037] The product was characterized as follows:

[0038] yellow liquid(136.5mg,77%)dr 1:1,as an inseparable diastereomeric mixture. 1 H NMR (500MHz, DMSO-d6) δ7.96 (d, J = 8.5, 0.47H), 7.86 (t, J = 1.7, 0.53H), 7.82 (d, J = 8.5, 0. 53H),7.72(t,J=1.7,0.47H),7.41-7.39(m,0.51H),7.28-7.25(m,2.49H),7.19-7.15(m,3 H),6.08(d,J=6.5,0.51H),6.05(d,J=6.5,0.49H),3.50-3.44(m,1H),3.17-3.08(m,1H), 2.69-2.61(m,1H),2.60-2.53(m,1H),2.50(s,3H),2.47-2.45(m,2H),1.03(q,J=7.1,3H). 13 C NMR (126MHz, DMSO-d6) δ146.39,144.45,140.30,137.98,133.99,132.04,130.05,129.79,128.41,128.30,128.27,126.50,126.07,118. 98,118.30,110.81,110.23,88.44,88.35,63.87,63.85,35.42,35.31,30.51,30.45,21.47,20.95,14.62.HRMS(m / z)[ESI]:calculated for C 18 H 22 N3O + m / z[M+H] + :296.1757,found 296.1750.

[0039] Example 3:

[0040] Preparation and characterization of 1-(1-ethoxy-3-phenylpropyl)-5,6-dimethyl-1H-benzo[d][1,2,3]triazole (4caa):

[0041]

[0042] 5,6-Dimethylbenzotriazole (0.6 mmol), phenylpropionaldehyde (2.4 mmol), and tetrabutylammonium tetrafluoroborate (0.6 mmol) were placed in 10 mL three-necked round-bottom flasks, respectively.

[0043] Then, 6.0 mL of ethanol solvent was added to dissolve the substrate. Platinum sheets (1 cm x 1 cm) were used as anode and cathode. The reaction was carried out under argon protection and at 60 °C with a constant current of 12 mA until the substrate was completely consumed (thin-layer chromatography monitoring, reaction time was 2 hours).

[0044] After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was then purified by column chromatography (300-400 mesh silica gel, petroleum ether / ethyl acetate = 15:1 elution) to obtain the target product 4caa.

[0045] The product was characterized as follows:

[0046] Yellow liquid (139.2 mg, 75%). 1 H NMR(500MHz,Chloroform-d)δ7.86(s,1H),7.57(s,1H),7.33(t,J=7.7,2H),7.26-7.20(m,3H),6.02(t,J=6.6,1H), 3.56-3.50(m,1H),3.35-3.29(m,1H),2.79-2.73(m,1H),2.68-2.68(m,2H),2.47(d,J=8.2,7H),1.19(t,J=7.0,3H). 13 CNMR(126MHz,Chloroform-d)δ146.17,140.28,137.94,134.17,130.47,128.63,128.57,126.36 ,119.22,110.66,89.66,64.61,36.14,31.17,21.06,20.56,14.86.HRMS(m / z)[ESI]:calculated for C 19 H 24 N3O + m / z[M+H] + :310.1914,found310.1914.

[0047] Example 4:

[0048] Preparation and characterization of 2-(1-ethoxy-3-phenylpropyl)-5-phenyl-2H-tetrazole (4daa):

[0049]

[0050] 5-Phenylacetazole (0.6 mmol), phenylpropionaldehyde (2.4 mmol), and tetrabutylammonium tetrafluoroborate (0.6 mmol) were placed in 10 mL three-necked round-bottom flasks, respectively.

[0051] Then, 6.0 mL of ethanol solvent was added to dissolve the substrate. Platinum sheets (1 cm x 1 cm) were used as anode and cathode. The reaction was carried out under argon protection and at 60 °C with a constant current of 12 mA until the substrate was completely consumed (thin-layer chromatography monitoring, reaction time was 2 hours).

[0052] After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was then purified by column chromatography (300-400 mesh silica gel, petroleum ether / ethyl acetate = 15:1 elution) to obtain the target product 4daa.

[0053] The product was characterized as follows:

[0054] Yellow liquid (116.6 mg, 63%). 1 H NMR(400MHz,Chloroform-d)δ8.22-8.19(m,2H),7.52-7.48(m,3H),7.33-7.29(m,2H),7.24-7.18(m,3H),5.85(t,J=6 .2,1H),3.62-3.54(m,1H),3.50-3.42(m,1H),2.69(qd,J=15.1,14.1,6.8,3H),2.57-2.46(m,1H),1.20(t,J=7.0,3H). 13 C NMR(100MHz,Chloroform-d)δ165.50,140.00,130.58,129.02,128.76,128.59,127. 42,127.12,126.52,91.64,65.65,36.00,30.82,14.77.HRMS(m / z)[ESI]:calculated for C 18 H 20 N4NaO + m / z[M+Na] + :331.1529,found 331.1524.

[0055] Example 5:

[0056] Preparation and characterization of 1-(cyclohexyl(ethoxy)methyl)-1H-benzo[d][1,2,3]triazole (4aba):

[0057]

[0058] Benzotriazole (0.6 mmol), cyclohexyl formaldehyde (2.4 mmol), and tetrabutylammonium tetrafluoroborate (0.6 mmol) were placed in 10 mL three-necked round-bottom flasks, respectively.

[0059] Then, 6.0 mL of ethanol solvent was added to dissolve the substrate. Platinum sheets (1 cm x 1 cm) were used as anode and cathode. The reaction was carried out under argon protection and at 60 °C with a constant current of 12 mA until the substrate was completely consumed (thin-layer chromatography monitoring, reaction time was 3 hours).

[0060] After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was then purified by column chromatography (300-400 mesh silica gel, petroleum ether / ethyl acetate = 15:1 elution) to obtain the target product 4aba.

[0061] The product was characterized as follows:

[0062] Yellow liquid (121.4 mg, 78%). 1 H NMR(400MHz,Chloroform-d)δ8.06(dt,J=8.3,1.0,1H),

[0063] 7.77(dt,J=8.3,1.0,1H),7.47-7.43(m,1H),7.38-7.34(m,1H),5.69(d,J=8.6,1H),3.51-3.43(m,1H),3.33- 3.25(m,1H),2.26-2.14(m,2H),1.84-1.75(m,1H),1.66-1.55(m,2H),1.13(t,J=7.0,6H),1.00-0.84(m,2H). 13 C NMR(100MHz,Chloroform-d)δ146.81,131.68,127.39,124.21,120.07,111.60,65.00,29.45,27.95,26.13,25.52,25.42,14.75.HRMS(m / z)[ESI]:calculated for C 15 H 22 N3O + m / z[M+H] + :260.1757,found260.1757.

[0064] Example 6:

[0065] Preparation and characterization of 1-(cyclopropyl(ethoxy)methyl)-1H-benzo[d][1,2,3]triazole (4aca):

[0066]

[0067] Benzotriazole (0.6 mmol), cyclopropylformaldehyde (2.4 mmol), and tetrabutylammonium tetrafluoroborate (0.6 mmol) were placed in 10 mL three-necked round-bottom flasks, respectively.

[0068] Then, 6.0 mL of ethanol solvent was added to dissolve the substrate. Platinum sheets (1 cm x 1 cm) were used as anode and cathode. The reaction was carried out under argon protection and at 60 °C with a constant current of 12 mA until the substrate was completely consumed (thin-layer chromatography monitoring, reaction time was 2 hours).

[0069] After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was then purified by column chromatography (300-400 mesh silica gel, petroleum ether / ethyl acetate = 15:1 elution) to obtain the target product 4aca.

[0070] The product was characterized as follows:

[0071] Yellow liquid (106.9 mg, 82%). 1 H NMR(500MHz,DMSO-d6)δ8.08(dt,J=8.4,0.9,1H),

[0072] 7.97(dt,J=8.3,0.9,1H),7.57-(m,1H),7.43-7.40(m,1H),5.62(d,J=7.7,1H),3.51-3.45(m,1H),3.17-3.11( m,1H),1.79-1.73(m,1H),1.01(t,J=7.0,3H),0.81-0.69(m,2H),0.47-0.40(m,1H),0.31(td,J=9.5,5.4,1H). 13 C NMR(126MHz,DMSO-d6)δ145.74,131.45,127.61,124.23,119.36,111.45,92.19,63.81,15.15,14.54,3.96,1.83.HRMS(m / z)[ESI]:calculated for C 12 H 16 N3O + m / z[M+H] + :218.1288,found 218.1297.

[0073] Example 7:

[0074] Preparation and characterization of 1-(1-ethoxy-3-methylbutyl)-1H-benzo[d][1,2,3]triazole (4ada):

[0075]

[0076] Benzotriazole (0.6 mmol), 3-methylbutyraldehyde (2.4 mmol), and tetrabutylammonium tetrafluoroborate (0.6 mmol) were placed in 10 mL three-necked round-bottom flasks, respectively.

[0077] Then, 6.0 mL of ethanol solvent was added to dissolve the substrate. Platinum sheets (1 cm x 1 cm) were used as anode and cathode. The reaction was carried out under argon protection and at 60 °C with a constant current of 12 mA until the substrate was completely consumed (thin-layer chromatography monitoring, reaction time was 2 hours).

[0078] After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was then purified by column chromatography (300-400 mesh silica gel, petroleum ether / ethyl acetate = 15:1 elution) to obtain the target product 4ada.

[0079] The product was characterized as follows:

[0080] Yellow liquid (99.4 mg, 71%). 1 H NMR(400MHz,Chloroform-d)δ8.07(dt,J=8.4,1.0,1H),

[0081] 7.78(dt,J=8.3,1.0,1H),7.49-7.45(m,1H),7.40-7.36(m,1H),6.13(t,J =6.9,1Hzz),3.55-3.47(m,1H),3.29-3.22(m,1H),2.20-2.13(m,1H),2.01 -1.95(m,1H),1.61-1.51(m,1H),1.13(t,J=7.0,3H),1.00(d,J=6.7,3H),0.89(d,J=6.7,3H). 13 C NMR(100MHz,Chloroform-d)δ146.93,131.41,127.49,124.29,120.19,111.44,89.68,64.64,43.43,24.57,22.54,22.41,14.86.HRMS(m / z)[ESI]:calculated for C 13 H 20 N3O +m / z[M+H] + :234.1601,found234.1621.

[0082] Example 8:

[0083] Preparation and characterization of 1-(1-ethoxy-2,2-dimethylpropyl)-1H-benzo[d][1,2,3]triazole 4aea):

[0084]

[0085] Benzotriazole (0.6 mmol), 2,2-dimethylpropionaldehyde (2.4 mmol), and tetrabutylammonium tetrafluoroborate (0.6 mmol) were placed in 10 mL three-necked round-bottom flasks, respectively.

[0086] Then, 6.0 mL of ethanol solvent was added to dissolve the substrate. Platinum sheets (1 cm x 1 cm) were used as anode and cathode. The reaction was carried out under argon protection and at 60 °C with a constant current of 12 mA until the substrate was completely consumed (thin-layer chromatography monitoring, reaction time was 2 hours).

[0087] After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was then purified by column chromatography (300-400 mesh silica gel, petroleum ether / ethyl acetate = 15:1 elution) to obtain the target product 4aea.

[0088] The product was characterized as follows:

[0089] Yellow liquid (95.2 mg, 68%). 1 H NMR(400MHz,Chloroform-d)δ8.05(dd,J=8.3,1.0,1H),

[0090] 7.79(dt,J=8.4,1.0,1H),7.46-7.41(m,1H),7.37-7.33(m,1H),5.73(s,1 H),3.48-3.40(m,1H),3.36-3.29(m,1H),1.18(t,J=7.0,3H),1.03(s,9H). 13 C NMR(100MHz,Chloroform-d)δ146.23,132.70,127.30,123.99,119.81,112.91,98.85,65.76,37.99,25.99,14.70.HRMS(m / z)[ESI]:calculated for C 13 H 20 N3O + m / z[M+H] +:234.1601,found234.1621.

[0091] Example 9:

[0092] Preparation and characterization of 1-(1-ethoxyoctyl)-1H-benzo[d][1,2,3]triazole (4afa):

[0093]

[0094] Benzotriazole (0.6 mmol), n-octanal (2.4 mmol), and tetrabutylammonium tetrafluoroborate (0.6 mmol) were placed in 10 mL three-necked round-bottom flasks, respectively.

[0095] Then, 6.0 mL of ethanol solvent was added to dissolve the substrate. Platinum sheets (1 cm x 1 cm) were used as anode and cathode. The reaction was carried out under argon protection and at 60 °C with a constant current of 12 mA until the substrate was completely consumed (thin-layer chromatography monitoring, reaction time was 2 hours).

[0096] After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was then purified by column chromatography (300-400 mesh silica gel, petroleum ether / ethyl acetate = 15:1 elution) to obtain the target product 4afa.

[0097] The product was characterized as follows:

[0098] Yellow liquid (132.2 mg, 80%). 1 H NMR(400MHz,Chloroform-d)δ8.06(dd,J=8.3,1.1,

[0099] 1H),7.78(dt,J=8.3,1.1,1H),7.48-7.4(m,1H),7.39-7.35(m,1H),6.04(t,J=6.8,1H),3.54-3.46(m,1H),3.30-3.22(m, 1H),2.29-2.20(m,1H),2.15-2.06(m,1H),1.44-1.41(m,1H),1.29-1.18(m,8H),1.12(t,J=7.0,4H),0.83(t,J=6.9,3H). 13C NMR(100MHz,Chloroform-d)δ=146.90,131.37,127.46,124.26,120.15,111.41,91.01,64 .66,34.85,31.73,29.08,29.02,24.92,22.66,14.82,14.14.HRMS(m / z)[ESI]:calculated forC 16 H 26 N3O + m / z[M+H] + :276.2070,found276.2073.

[0100] Example 10:

[0101] Preparation and characterization of 1-(1-ethoxydecyl)-1H-benzo[d][1,2,3]triazole (4aga):

[0102]

[0103] Benzotriazole (0.6 mmol), decanal (2.4 mmol), and tetrabutylammonium tetrafluoroborate (0.6 mmol) were placed in 10 mL three-necked round-bottom flasks, respectively.

[0104] Then, 6.0 mL of ethanol solvent was added to dissolve the substrate. Platinum sheets (1 cm x 1 cm) were used as anode and cathode. The reaction was carried out under argon protection and at 60 °C with a constant current of 12 mA until the substrate was completely consumed (thin-layer chromatography monitoring, reaction time was 3 hours).

[0105] After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was then purified by column chromatography (300-400 mesh silica gel, petroleum ether / ethyl acetate = 15:1 elution) to obtain the target product 4aga.

[0106] The product was characterized as follows:

[0107] Yellow liquid (169.1 mg, 85%). 1 H NMR(500MHz,Chloroform-d)δ8.02(d,J=8.3,1H),

[0108] 7.75(d,J=8.3,1H),7.43-7.40(m,1H),7.34-7.31(m,1H),6.01(t,J=6.8,1H),3.50-3.44(m,1H),3.26-3.19(m,1H), 2.25-2.18(m,1H),2.11-2.04(m,1H),1.42-1.33(m,1H),1.29-1.19(m,16H),1.08(t,J=7.0,4H),0.81(t,J=6.9,3H). 13 C NMR(126MHz,Chloroform-d)δ146.81,131.30,127.33,124.13,120.05,111.29,90.88,64.53,34. 75,31.90,29.56,29.44,29.32,28.96,24.82,22.68,14.72,14.11.HRMS(m / z)[ESI]:calculated for C 20 H 34 N3O + m / z[M+H] + :323.2696,found 323.2696.

[0109] Example 11:

[0110] Preparation and characterization of 1-(ethoxy(phenyl)methyl)-1H-benzo[d][1,2,3]triazole (4aha):

[0111]

[0112] Benzotriazole (0.6 mmol), benzaldehyde (2.4 mmol), and tetrabutylammonium tetrafluoroborate (0.6 mmol) were placed in 10 mL three-necked round-bottom flasks, respectively.

[0113] Then, 6.0 mL of ethanol solvent was added to dissolve the substrate. Platinum sheets (1 cm x 1 cm) were used as anode and cathode. The reaction was carried out under argon protection and at 60 °C with a constant current of 12 mA until the substrate was completely consumed (thin-layer chromatography monitoring, reaction time was 3 hours).

[0114] After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was then purified by column chromatography (300-400 mesh silica gel, petroleum ether / ethyl acetate = 15:1 elution) to obtain the target product 4aha.

[0115] The product was characterized as follows:

[0116] Yellow liquid (110.9 mg, 73%).1 H NMR(400MHz,Chloroform-d)δ7.98-7.94(m,1H),7.35-7.32(m,2H),7.25-7.18 (m,6H),7.11(s,1H),3.69-3.61(m,1H),3.40-3.33(m,1H),1.14(t,J=7.0,3H). 13 C NMR(100MHz,Chloroform-d)δ147.00,136.40,131.10,129.02,128.59,127.46,125.96,1 24.22,119.91,111.69,89.55,77.48,76.84,65.01,14.73.HRMS(m / z)[ESI]:calculated for C 15 H 15 NNaO + m / z[M+Na] + :276.1107,found276.1104.

[0117] Example 12:

[0118] Preparation and characterization of 1-(1-ethoxy-4-(4-methylpent-3-en-1-yl)cyclohex-3-ene)-1H-benzo[d][1,2,3]triazole (4aia):

[0119]

[0120] Benzotriazole (0.6 mmol), 4-(4-methylpent-3-en-1-yl)cyclohex-3-en-1-al (2.4 mmol), and tetrabutylammonium hexafluorophosphate (0.6 mmol) were placed in 10 mL three-necked round-bottom flasks, respectively.

[0121] Then, 6.0 mL of ethanol solvent was added to dissolve the substrate. Platinum sheets (1 cm x 1 cm) were used as anode and cathode. The reaction was carried out under argon protection and at 60 °C with a constant current of 12 mA until the substrate was completely consumed (thin-layer chromatography monitoring, reaction time was 3 hours).

[0122] After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was then purified by column chromatography (300-400 mesh silica gel, petroleum ether / ethyl acetate = 15:1 elution) to obtain the target product 4aia.

[0123] The product was characterized as follows:

[0124] yellow liquid(121.2mg,75%).dr 1:1.3,as an inseparable diastereomeric mixture. 1 H NMR(400MHz,DMSO-d6)δ8.12-8.06(m,1H),7.96-7.94(m,1H),7.60-7.54(m,1H),7.47-7.4 1(m,1H),6.34-6.31(m,1H),6.22-6.20(m,0.43H),5.82-5.80(m,0.57H),5.33(dd,J=11.8 ,10.2,1H),3.45-3.38(m,1H),3.20-3.07(m,2H),2.87(d,J=4.4,0.51H),2.73(s,0.43H), 2.08(ddd,J=12.5,9.0,3.8,0.51H),1.84(s,0.57H),1.41-1.19(m,3H),1.08-0.95(m,4H). 13 C NMR(100MHz,DMSO-d6)δ145.84,145.76,138.53,138.42,132.15,131.71,131.66,131.41,127.83,127.76,124.37,119.55,119.49,111.36,11 1.34,93.44,92.97,64.02,63.74,48.89,48.68,44.09,43.25,43.19,42.75,42.10,41.69,29.99,27.50,14.58.HRMS(m / z)[ESI]:calculated for C 16 H 19 N3NaO + m / z[M+Na] + :292.1420,found 292.1422.

[0125] Example 13:

[0126] Preparation and characterization of 1-(1-ethoxy-3,7-dimethyl-6-en-1-yl)-1H-benzo[d][1,2,3]triazole (4aja):

[0127]

[0128] Benzotriazole (0.6 mmol), citronellal (2.4 mmol), and tetrabutylammonium tetrafluoroborate (0.6 mmol) were placed in 10 mL three-necked round-bottom flasks, respectively.

[0129] Then, 6.0 mL of ethanol solvent was added to dissolve the substrate. Platinum sheets (1 cm x 1 cm) were used as anode and cathode. The reaction was carried out under argon protection and at 60 °C with a constant current of 12 mA until the substrate was completely consumed (thin-layer chromatography monitoring, reaction time was 3 hours).

[0130] After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was then purified by column chromatography (300-400 mesh silica gel, petroleum ether / ethyl acetate = 15:1 elution) to obtain the target product 4aja.

[0131] The product was characterized as follows:

[0132] yellow liquid(126.1mg,70%).dr 1.1:1,as an inseparable diastereomeric mixture. 1 H NMR(500MHz,Chloroform-d)δ8.06(d,J=8.3,1H),7.77(d,J=8.1,1H),7.47-7.44(m,1H),7.38-7. 35(m,1H),6.16-6.13(m,1H),5.05(t,J=7.0,52H),4.91(t,J=7.0,0.48H),3.54-3.46(m,1H),3.29 -3.21(m,1H),2.35-2.29(m,1H),2.22-2.17(m,1H),2.06-1.80(m,2H),1.65-1.57(m,5H),1.48-1 .39(m,2H),1.32-1.18(m,2H),1.12(t,J=7.0,3H),0.99(d,J=6.4,1.52H),0.89(d,J=6.7,1.48H). 13 C NMR(126MHz,Chloroform-d)δ146.92,146.90,131.64,131.62,131.44,131.33, 127.46,127.43,124.40,124.25,124.22,124.17,120.17,111.41,111.36,89.6 5,89.45,64.61,41.79,41.43,36.90,36.86,28.92,28.78,25.80,25.70,25.29 ,25.18,19.66,19.22,17.77,17.67,14.84,14.82.HRMS(m / z)[ESI]:calculated for C 12 H16 N3O + m / z[M+H] + :218.1288,found 218.1280.

[0133] Example 14:

[0134] Preparation and characterization of 1-(3-(4-(tert-butyl)phenyl)-1-ethoxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazole (4aka):

[0135]

[0136] Benzotriazole (0.6 mmol), lily aldehyde (2.4 mmol), and tetrabutylammonium tetrafluoroborate (0.6 mmol) were placed in 10 mL three-necked round-bottom flasks, respectively.

[0137] Then, 6.0 mL of ethanol solvent was added to dissolve the substrate. Platinum sheets (1 cm x 1 cm) were used as anode and cathode. The reaction was carried out under argon protection and at 60 °C with a constant current of 12 mA until the substrate was completely consumed (thin-layer chromatography monitoring, reaction time was 2 hours).

[0138] After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was then purified by column chromatography (300-400 mesh silica gel, petroleum ether / ethyl acetate = 15:1 elution) to obtain the target product 4aka.

[0139] The product was characterized as follows:

[0140] yellow liquid(151.8mg,72%).dr 1:1,as an inseparable diastereomeric mixture. 1H NMR (500MHz, DMSO-d6) δ8.10-8.06(m,1H),7.94(dd,J=12.1,8.4,1H),7.56(t,J=8.2,1H),7.45-7. 41(m,1H),7.31(d,J=8.3,1H),7.18-7.15(m,2H),6.87(d,J=8.2,1H),5.94(d,J=8.0,0.51H),5.90 (d,J=8.0,0.49H),3.55-3.45(m,1H),3.20-3.15(m,1H),2.74-2.66(m,1H),2.28-2.23(m,0.5H),2 .18-2.14(m,0.5H),1.26-1.19(m,10H),1.08-1.04m,3H),1.00(d,J=6.6,2H),0.38(d,J=6.8,1H). 13 C NMR(126MHz,DMSO-d6)δ148.28,148.15,145.71,145.66,136.19,135.84,13 2.01,131.79,128.90,128.36,127.79,127.75,125.05,124.89,124.38,124 .29,119.50,119.46,111.46,92.99,92.83,64.35,64.28,37.57,36.97,34. 08,33.99,31.20,31.13,15.25,14.56,13.93.HRMS(m / z)[ESI]:calculated for C 13 H 20 N3O + m / z[M+H] + :234.1601,found234.1617.

[0141] Example 15:

[0142] Preparation and characterization of 1-(benzo[d][1,3]dioxo-4-(ethoxy)methyl)-1H-benzo[d][1,2,3]triazole (4ala):

[0143]

[0144] Benzotriazole (0.6 mmol), 1,3-benzodioxo-4-carboxaldehyde (2.4 mmol), and tetrabutylammonium tetrafluoroborate (0.6 mmol) were placed in 10 mL three-necked round-bottom flasks, respectively.

[0145] Then, 6.0 mL of ethanol solvent was added to dissolve the substrate. Platinum sheets (1 cm x 1 cm) were used as anode and cathode. The reaction was carried out under argon protection and at 60 °C with a constant current of 12 mA until the substrate was completely consumed (thin-layer chromatography monitoring, reaction time was 2 hours).

[0146] After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was then purified by column chromatography (300-400 mesh silica gel, petroleum ether / ethyl acetate = 15:1 elution) to obtain the target product 4ala.

[0147] The product was characterized as follows:

[0148] Yellow liquid (110.6 mg, 62%). 1 H NMR(400MHz,DMSO-d6)δ8.08(dd,J=8.3,1.1,1H),

[0149] 7.59(dt,J=8.4,1.1,1H),7.49(ddd,J=8.2,6.9,1.1,1H),7.43-7.37(m,2H),7.27(dd,J=5.2,4.1,1H),6.97-6 .96(m,2H),5.90(d,J=0.9,1H),5.79(d,J=0.9,1H),3.80-3.72(m,1H),3.42-3.37(m,1H),1.13(t,J=7.0,3H). 13 C NMR(100MHz,DMSO-d6)δ147.45,145.71,144.28,131.42,127.89,124.39,121.67,119.58,1 19.04,118.18,110.93,109.27,101.37,84.30,64.44,14.59.HRMS(m / z)[ESI]:calculated for C 16 H 16 N3O3 + m / z[M+H] + :298.1186,found 298.1190.

[0150] Example 16:

[0151] Preparation and characterization of 1-(1-methoxy-3-phenylpropyl)-1H-benzo[d][1,2,3]triazole (4aab):

[0152]

[0153] Benzotriazole (0.6 mmol), phenylpropionaldehyde (2.4 mmol), and tetrabutylammonium hexafluorophosphate (0.6 mmol) were placed in 10 mL three-necked round-bottom flasks, respectively.

[0154] Then, 6.0 mL of methanol solvent was added to dissolve the substrate. Platinum sheets (1 cm x 1 cm) were used as anode and cathode. The reaction was carried out under argon protection and at 60 °C with a constant current of 12 mA until the substrate was completely consumed (thin-layer chromatography monitoring, reaction time was 2 hours).

[0155] After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was then purified by column chromatography (300-400 mesh silica gel, petroleum ether / ethyl acetate = 15:1 elution) to obtain the target product 4aab.

[0156] The product was characterized as follows:

[0157] Yellow liquid (115.5 mg, 72%) 1 H NMR(500MHz,DMSO-d6)δ8.10(dt,J=8.4,1.0,1H),

[0158] 7.94(dt,J=8.4,1.0,1H),7.58-7.56(m,1H),7.47-7.44(m,1H),7.27-7.24(m,2H),7.1 9-7.15(m,3H),6.04(t,J=6.5,1H),3.14(s,3H),2.67-2.57(m,2H),2.48-2.42(m,2H). 13 C NMR(126MHz,DMSO-d6)δ=145.77,140.28,131.69,128.42,128.27,127.88,126.09,1 24.45,119.56,111.26,89.92,55.91,35.25,30.45.HRMS(m / z)[ESI]:calculatedfor C 16 H 18 N3O + m / z[M+H] + :268.1444,found 268.1445.

[0159] Example 17:

[0160] Preparation and characterization of 1-(1-isopropoxy-3-phenylpropyl)-1H-benzo[d][1,2,3]triazole (4aac):

[0161]

[0162] Benzotriazole (0.6 mmol), phenylpropionaldehyde (2.4 mmol), and tetrabutylammonium tetrafluoroborate (0.6 mmol) were placed in 10 mL three-necked round-bottom flasks, respectively.

[0163] Then, 6.0 mL of isopropanol solvent was added to dissolve the substrate. Platinum sheets (1 cm x 1 cm) were used as the anode and cathode. The reaction was carried out under argon protection and at 60 °C with a constant current of 12 mA until the substrate was completely consumed (thin-layer chromatography monitoring, reaction time was 2 hours).

[0164] After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was then purified by column chromatography (300-400 mesh silica gel, petroleum ether / ethyl acetate = 15:1 elution) to obtain the target product 4aac.

[0165] The product was characterized as follows:

[0166] Yellow liquid (124.1 mg, 70%). 1 H NMR(400MHz,Chloroform-d)δ8.07(d,J=8.3,1H),

[0167] 7.80(d,J=8.3,1H),7.49-7.45(m,1H),7.40-7.35(m,1H),7.28-7.24(m,2H),7.20-7.14(m,3H),6.18-6.15(m,1H), 3.58-3.48(m,1H),2.81-2.72(m,1H),2.63-2.53(m,2H),2.42-2.34(m,1H),1.22(d,J=6.1,3H),0.92(d,J=6.2,3H). 13 C NMR(100MHz,Chloroform-d)δ146.93,140.19,131.41,128.60,128.46,127.42,126.33,124.28,120 .13,111.60,87.93,77.48,76.84,70.46,36.61,31.17,22.78,21.21.HRMS(m / z)[ESI]:calculated for C 15 H 15 N3NaO + m / z[M+Na] + :276.1107,found 276.1109.

[0168] Example 18:

[0169] Preparation and characterization of 1-(1-tert-butoxy-3-phenylpropyl)-1H-benzo[d][1,2,3]triazole (4aad):

[0170]

[0171] Benzotriazole (0.6 mmol), phenylpropionaldehyde (2.4 mmol), and tetrabutylammonium tetrafluoroborate (0.6 mmol) were placed in 10 mL three-necked round-bottom flasks, respectively.

[0172] Then, 6.0 mL of tert-butanol solvent was added to dissolve the substrate. A platinum sheet (1 cm x 1 cm) was used as the anode and cathode. The reaction was carried out under argon protection and at 60 °C with a constant current of 12 mA until the substrate was completely consumed (thin-layer chromatography monitoring, reaction time was 3 hours).

[0173] After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was then purified by column chromatography (300-400 mesh silica gel, petroleum ether / ethyl acetate = 15:1 elution) to obtain the target product 4aad.

[0174] The product was characterized as follows:

[0175] Yellow liquid (126.2 mg, 68%). 1 H NMR (400MHz, DMSO-d6) δ8.06 (dt, J = 8.4, 1.0, 1H),

[0176] 7.94(dd,J=8.3,1.1,1H),7.57-7.53(m,1H),7.43-7.39(m,1H),7.26-7.22(m,2H),7.17-7.14(m ,3H),6.41(t,J=6.5,1H),2.72-2.64(m,1H),2.46-2.40(m,2H),2.32-2.24(m,1H),1.00(s,9H). 13 C NMR(101MHz,DMSO-d6)δ145.88,140.37,131.12,128.35,128.19,127.43,125.99,124 .14,119.40,111.92,83.57,75.96,37.29,30.46,27.47.HRMS(m / z)[ESI]:calculated for C 18 H 28 N3O + m / z[M+H] + :302.2227,found 302.2229.

[0177] Example 19:

[0178] Preparation and characterization of 1-(1-n-pentoxy-3-phenylpropyl)-1H-benzo[d][1,2,3]triazole (4aae):

[0179]

[0180] Benzotriazole (0.6 mmol), phenylpropionaldehyde (2.4 mmol), and tetrabutylammonium tetrafluoroborate (0.6 mmol) were placed in 10 mL three-necked round-bottom flasks, respectively.

[0181] Then, 6.0 mL of n-pentanol solvent was added to dissolve the substrate. A platinum sheet (1 cm x 1 cm) was used as the anode and cathode. The reaction was carried out under argon protection and at 60 °C with a constant current of 12 mA until the substrate was completely consumed (thin-layer chromatography monitoring, reaction time was 3 hours).

[0182] After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was then purified by column chromatography (300-400 mesh silica gel, petroleum ether / ethyl acetate = 15:1 elution) to obtain the target product 4aae.

[0183] The product was characterized as follows:

[0184] Yellow liquid (137.8 mg, 71%). 1 H NMR(400MHz,Chloroform-d)δ8.08(d,J=8.3,1H),

[0185] 7.77(d,J=8.4,1H),7.49-7.45(m,1H),7.40-7.36(m,1H),7.29-7.25(m,2H),7.20-7.14(m,3H),6.02(t,J=6.6,1H),3.46-3.41(m,1H) ,3.22-3.16(m,1H),2.79-2.71(m,1H),2.65-2.58(m,2H),2.47-2.39(m,1H),1.54-1.48(m,2H),1.25-1.20(m,4H),0.84-0.79(m,3H). 13CNMR(100MHz,Chloroform-d)δ146.87,140.15,131.41,128.61,128.49,127.50,126.35,124.31,120.16,1 11.32,90.13,77.48,76.84,69.25,36.24,31.13,28.95,28.14,22.34,13.98.HRMS(m / z)[ESI]:calculated for C 22 H 30 N3O + m / z[M+H] + :352.2383,found 352.2387.

[0186] Example 20:

[0187] Preparation and characterization of 1-(cyclohexyl(methoxy)methyl)-1H-benzo[d][1,2,3]triazole (4abb):

[0188]

[0189] Benzotriazole (0.6 mmol), cyclohexyl formaldehyde (2.4 mmol), and tetrabutylammonium tetrafluoroborate (0.6 mmol) were placed in 10 mL three-necked round-bottom flasks, respectively.

[0190] Then, 6.0 mL of methanol solvent was added to dissolve the substrate. A platinum sheet (1 cm x 1 cm) was used as the anode and cathode. The reaction was carried out under argon protection and at 60 °C with a constant current of 12 mA until the substrate was completely consumed (thin-layer chromatography monitoring, reaction time was 3 hours).

[0191] After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was then purified by column chromatography (300-400 mesh silica gel, petroleum ether / ethyl acetate = 15:1 elution) to obtain the target product 4abb.

[0192] The product was characterized as follows:

[0193] Yellow liquid (101.6 mg, 69%). 1 H NMR(400MHz,Chloroform-d)δ8.07(dt,J=8.3,1.0,

[0194] 1H),7.74(dt,J=8.3,1.0,1H),7.48-7.44(m,1H),7.40-7.35(m,1H),5.60(d,J=8.7,1H),3.23(s,3 H),2.25-2.14(m,2H),1.84-1.78(m,1H),1.65-1.57(m,2H),1.26-1.03(m,6H),0.97-0.88(m,2H). 13 C NMR(100MHz,Chloroform-d)δ146.84,131.61,127.53,124.30,120.17,111.49,96. 79,57.08,42.12,29.40,27.95,26.12,25.51,25.41.HRMS(m / z)[ESI]:calculated for C 14 H 20 N3O + m / z[M+H] + :246.1601,found 246.1607.

[0195] Example 21:

[0196] Scale-up preparation process of 1-(cyclohexyl(ethoxy)methyl)-1H-benzo[d][1,2,3]triazole (4aba):

[0197]

[0198] Benzotriazole (12 mmol), cyclohexyl formaldehyde (48 mmol), and tetrabutylammonium tetrafluoroborate (24 mmol) were placed in a 350 mL single-chamber electrolytic cell, respectively.

[0199] Then, 120 mL of ethanol solvent was added to dissolve the substrate. A platinum sheet (1 cm x 1 cm) was used as the anode and cathode. The reaction was carried out at 60 °C with a constant current of 120 mA until the substrate was completely consumed (thin-layer chromatography monitoring, reaction time was 8 hours).

[0200] After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was then purified by column chromatography (300-400 mesh silica gel, petroleum ether / ethyl acetate = 15:1 elution) to obtain the target product 4aba (2.18 g, 70%).

[0201] The above examples demonstrate the synthesis of N-(α-alkoxyalkyl)azole compounds via a three-component reaction of azole, aldehyde, and alcohol under mild electrochemical conditions. This synthetic method avoids the use of acidic catalysts and additional oxidizing / reducing agents, and features mild reaction conditions, simple operation, low production cost, and high controllability. Furthermore, further scale-up studies using a gram-scale electrochemical reactor indicate its suitability for large-scale industrial production.

Claims

1. An electrochemical synthesis N -( α The method for using (-alkoxyalkyl)azole compounds is characterized by... The general formula for the synthesis of the compound is as follows: ； In the general formula, R 1 = Alkyl; R 2 = Alkyl, aryl; R 3 = Alkyl; Aldehydes are aliphatic and aromatic; alcohols are chain alcohols. The electrolyte is: tetrabutylammonium tetrafluoroborate or tetrabutylammonium hexafluorophosphate; Solvents include: methanol, ethanol, isopropanol, tert-butanol, or n-pentanol; The method uses platinum sheets as the anode and cathode, and carries out a stirred reaction under an argon atmosphere and at a temperature of 60 °C with a constant current of 12 mA.

2. The electrochemical synthesis according to claim 1 N -( α The method for using (-alkoxyalkyl)azole compounds is characterized by... The specific operating steps are as follows: Add 0.6 mmol of benzotriazole, 2.4 mmol of aliphatic aldehyde and aromatic aldehyde, and 0.6 mmol of electrolyte to a 10 mL three-necked round-bottom flask, respectively. Then, 6.0 mL of chain alcohol was added to dissolve it. The alcohol was both the reaction substrate and the solvent. After dissolution, a platinum sheet was used as the anode and cathode. The reaction was carried out under argon atmosphere and 60 °C with a constant current of 12 mA. The reaction progress was monitored by thin-layer chromatography until the substrate was completely consumed. After the reaction was completed, the solution was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (300-400 mesh) to obtain the target product.

3. The electrochemical synthesis according to claim 2 N -( α The method for using (-alkoxyalkyl)azole compounds, characterized in that: The column chromatography purification uses petroleum ether / ethyl acetate as the eluent, wherein the volume ratio of petroleum ether / ethyl acetate is 15:1.

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