A method for electrooxidation synthesis of fluoroalkyl-substituted benzo seven-membered nitrogen heterocycle

Abstract

The present invention relates to the technical field of chemical synthesis, and specifically discloses a method for electro-oxidative synthesis of a fluoroalkyl-substituted benzo-7-membered nitrogen heterocycle, which specifically comprises the following steps: Step 1, under the condition of passing an electric current, an aryl diazonium salt reacts with a fluorinated sodium methylsulfinate compound in an electrolyte and a solvent to obtain the benzo-7-membered nitrogen heterocycle. Step 2, using the fluorinated sodium methylsulfinate compound to react with a substituted aryl diazonium salt in an electrolyte under the promotion of electricity to generate a benzo-7-membered nitrogen heterocycle compound. In the present invention, no transition metal catalyst is required, and the reaction is carried out only under the action of electric current, which is energy-saving and economical; the free radical source used in the reaction is cheap and easy to obtain, and the cost is low, and the 7-membered nitrogen heterocycle compound can be directly synthesized, which reduces the synthesis cost compared with the prior art.

Description

Technical Field

[0001] The invention relates to the technical field of chemical synthesis, in particular to a method for electro-oxidative synthesis of fluoroalkyl-substituted benzo seven-membered nitrogen heterocycles. Background Art

[0002] Heterocyclic compounds are widely present in drug molecules and natural products. Finding greener and novel synthesis methods for heterocyclic compounds is the direction of efforts of many synthetic chemists.

[0003] Free radical chemistry has experienced a resurgence and has become a powerful tool for constructing new chemical bonds. The rapid development of free radical chemistry has opened up new pathways for synthesizing novel substituted heterocyclic compounds. Previously, Li Yi's research group at Fuzhou University designed a photocatalytic reaction between a diazonium salt and a trifluoroalkyl group to construct a benzo-7-membered nitrogen heterocycle. The reaction mechanism is shown below: (Reference: Org. Lett. 2024, 26, 3622-2627.)

[0004]

[0005] However, the above reaction requires the use of one equivalent of the chemical oxidant tert-butyl hydroperoxide to initiate the generation of free radicals, which has high reaction costs, low environmental friendliness, and does not achieve the direct synthesis of trifluoromethyl or difluoromethyl substituted products. Therefore, it is very necessary to obtain trifluoromethyl substituted benzo seven-membered nitrogen heterocyclic products through electrochemistry. Summary of the Invention

[0006] In view of the technical problems in the prior art that one equivalent of chemical oxidant tert-butyl hydroperoxide is required to initiate the generation of free radicals, the reaction cost is high, the environmental friendliness is low, and the direct synthesis of trifluoromethyl or difluoromethyl substituted products is not achieved, the present invention provides a method for electro-oxidation synthesis of fluoroalkyl substituted benzo seven-membered nitrogen heterocycles.

[0007] The technical solution adopted by the present invention is: a method for electrooxidation synthesis of fluoroalkyl-substituted benzo seven-membered nitrogen heterocycle, which specifically comprises the following steps:

[0008] Step 1: Under the condition of passing current, an aryl diazonium salt reacts with a fluorinated sodium methanesulfinate compound in an electrolyte and a solvent to obtain the benzo seven-membered nitrogen heterocycle.

[0009] The structure of the aryl diazonium salt is shown in formula (I):

[0010]

[0011] The structure of the fluorinated sodium methanesulfinate is shown in formula (II):

[0012]

[0013] In formula (I) to formula (II), R 1 It is an electron-withdrawing group such as a nitro group, a halogen atom, a cyano group, an acyl group, a carboxyl group, or an electron-donating group such as an amino group, a methyl group, or a methoxy group;

[0014] Among them, R 1 The substitution position can be at position 3, 4, 5, or 6 of the benzene ring.

[0015] R 2 is a H or fluorine atom;

[0016] X is O, S or a nitrogen atom;

[0017] Step 2: Using a fluorinated sodium methanesulfinate compound and a substituted aryl diazonium salt in an electrolyte, a benzo-7-membered nitrogen heterocyclic compound is generated under the promotion of electricity. The specific reaction formula is shown below:

[0018]

[0019] The present invention is further configured such that the reaction in step 1 is carried out under a constant current, and the current fluctuation range is 3-10 mA.

[0020] The present invention is further configured such that the electrolyte in step 1 is one of tetrabutylammonium tetrafluoroborate, lithium tert-butoxide, tetrabutylammonium iodate, tetraethylammonium perchlorate, tetraethylammonium hexafluorophosphate and tetrabutylammonium perchlorate, and the concentration is 0.05 to 1 mol / L.

[0021] The present invention is further configured such that the solvent in step 1 is one of acetonitrile, water, dichloroethane, methanol, isopropanol, ethyl acetate, N,N-dimethylformamide and tetrahydrofuran.

[0022] The present invention is further configured such that the reaction temperature in step 1 is 25-70°C.

[0023] The present invention is further configured such that the reaction atmosphere in step 1 is one of air and nitrogen; the anode material is a carbon electrode, and the cathode material is Ni or Pt.

[0024] The beneficial effects of the present invention are as follows: compared with the prior art, the present invention does not require a transition metal catalyst and is carried out only under the action of electric current, which is energy-saving and economical; the free radical source used in the reaction is cheap and easily available, and the cost is low, and a seven-membered nitrogen heterocyclic compound can be directly synthesized, thereby reducing the synthesis cost compared with the prior art. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 For the product obtained in Example 1 of the present invention 1 HNMR spectrum;

[0026] Figure 2 For the product obtained in Example 1 of the present invention 13 CNMR spectrum;

[0027] Figure 3 For the product obtained in Example 1 of the present invention 19 F-NMR spectrum;

[0028] Figure 4 For the product obtained in Example 2 of the present invention 1 HNMR spectrum;

[0029] Figure 5 For the product obtained in Example 2 of the present invention 1 CNMR spectrum;

[0030] Figure 6 For the product obtained in Example 2 of the present invention 19 F-NMR spectrum;

[0031] Figure 7 For the product obtained in Example 3 of the present invention 1 HNMR spectrum;

[0032] Figure 8 For the product obtained in Example 3 of the present invention 13 CNMR spectrum;

[0033] Figure 9 For the product obtained in Example 3 of the present invention 19 F-NMR spectrum;

[0034] Figure 10 For the product obtained in Example 4 of the present invention 1 HNMR spectrum;

[0035] Figure 11 For the product obtained in Example 4 of the present invention 1 CNMR spectrum;

[0036] Figure 12 For the product obtained in Example 4 of the present invention 19 F-NMR spectrum;

[0037] Figure 13 For the product obtained in Example 5 of the present invention 1 HNMR spectrum;

[0038] Figure 14 For the product obtained in Example 5 of the present invention 13 CNMR spectrum;

[0039] Figure 15For the product obtained in Example 5 of the present invention 19 F-NMR spectrum;

[0040] Figure 16 For the product obtained in Example 6 of the present invention 1 HNMR spectrum;

[0041] Figure 17 For the product obtained in Example 6 of the present invention 13 CNMR spectrum;

[0042] Figure 18 For the product obtained in Example 6 of the present invention 19 F-NMR spectrum;

[0043] Figure 19 It is a device diagram of the reaction process in the present invention. DETAILED DESCRIPTION

[0044] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0045] With reference to 1-19, in order to solve the problems existing in the background technology, the present application proposes the following technical solution: a method for electrooxidation synthesis of fluoroalkyl-substituted benzo seven-membered nitrogen heterocycle, specifically comprising the following steps:

[0046] Step 1: Under the condition of passing current, an aryl diazonium salt reacts with a fluorinated sodium methanesulfinate compound in an electrolyte and a solvent to obtain the benzo seven-membered nitrogen heterocycle.

[0047] The structure of the aryl diazonium salt is shown in formula (I):

[0048]

[0049] The structure of the fluorinated sodium methanesulfinate is shown in formula (II):

[0050]

[0051] In formula (I) to formula (II), R 1 It is an electron-withdrawing group such as a nitro group, a halogen atom, a cyano group, an acyl group, a carboxyl group, or an electron-donating group such as an amino group, a methyl group, or a methoxy group;

[0052] Among them, R 1 The substitution position can be at position 3, 4, 5, or 6 of the benzene ring.

[0053] R 2 is a H or fluorine atom;

[0054] X is O, S or a nitrogen atom;

[0055] Step 2: Using a fluorinated sodium methanesulfinate compound and a substituted aryl diazonium salt in an electrolyte, a benzo-7-membered nitrogen heterocyclic compound is generated under the promotion of electricity. The specific reaction formula is shown below:

[0056]

[0057] The above technical solution is explained as follows: During the reaction, the fluorinated methanesulfinate anion first loses electrons at the anode to become a fluorinated free radical A. Free radical A then attacks the terminal olefin carbon to form a thermodynamically more stable free radical B. Free radical B then strikes the nitrogen-nitrogen double bond and cyclizes to form a relatively stable new free radical cation C. Free radical C then reacts with the fluorinated methanesulfinate anion to form a benzo-7-membered nitrogen heterocycle. The hypothesized reaction mechanism is as follows:

[0058]

[0059] The reaction in step 1 is carried out under a constant current with a current fluctuation range of 3-10 mA. The actual current is 3-10 mA, preferably 4 mA, as the product yield is the highest.

[0060] The electrolyte in step 1 is one of tetrabutylammonium tetrafluoroborate, lithium tert-butoxide, tetrabutylammonium iodide, tetraethylammonium perchlorate, tetraethylammonium hexafluorophosphate, and tetrabutylammonium perchlorate, and the concentration is 0.05 to 1 mol / L. The actual electrolyte selected is tetrabutylammonium tetrafluoroborate, and the solution concentration thereof is 0.1M.

[0061] The solvent in step 1 is one of acetonitrile, water, dichloroethane, methanol, isopropanol, ethyl acetate, N,N-dimethylformamide and tetrahydrofuran. The actual solvent used is an acetonitrile system.

[0062] The reaction temperature in step 1 is 25-70° C. The reaction temperature is 25-70° C. If the reaction temperature is too high or too low, the conversion rate of the reactants will be reduced. As a further preferred embodiment, the reaction temperature is 45° C.

[0063] The reaction atmosphere in step 1 is one of air and nitrogen; the reaction atmosphere is air, and the reactor is open to the air environment, that is, the reaction process is an open system to avoid the accumulation of hydrogen generated at the cathode causing excessive pressure or explosion hazard; in addition, the reaction time can be monitored by TLC, and the reaction can be completed by stirring at 45°C for 2 to 5 hours. As a further preferred embodiment, the reaction time is 2 hours.

[0064] The anode material is a carbon electrode, and the cathode material is Ni or Pt. In practice, the anode material is graphite felt (GF), and the cathode material is a platinum sheet or nickel foam. As a further preferred embodiment, the cathode uses a platinum sheet.

[0065] Example 1:

[0066] To a reaction tube, diazonium salt 1a (157.2 mg, 0.6 mmol, 2.0 equiv.), NaSO₂CF₃₂a (46.8 mg, 0.3 mmol, 1.0 equiv.), and nBu₄NBF₄ (131 mg, 0.4 mmol, 1.3 equiv.) were accurately added and dissolved in MeCN (4 mL). The anode was a graphite felt GF electrode (10 mm × 15 mm × 6 mm), and the cathode was a platinum sheet electrode (10 mm × 15 mm × 0.25 mm). Electrooxidation was carried out at 45°C with a current maintained at 4 mA for 2 hours. The solvent was transferred to a round-bottom flask. Silica gel was added to the flask, and the solvent was evaporated in vacuo. Purification by silica gel column chromatography using PE / EA (v / v, 5:1) as the eluent afforded the corresponding product 3aa in 78% yield. The reaction equation is as follows:

[0067]

[0068] The product 3aa prepared in this example 1 H NMR spectrum is shown in Figure 1 , 13 C NMR spectrum is shown in Figure 2 , 19 F NMR spectrum is shown in Figure 3 ; NMR data of product 3a: 1 H NMR (400MHz, CDCl3) δ7.52 (s, 1H), 6.92 (d, J = 8.1Hz, 1H), 6.73 (d, J = 8.1Hz, 1H), 6.59 (s, 1H), 4.69 (s, 2H), 3.06 (q, J = 10.8Hz, 2H), 2.29 (s, 3H); 13CNMR(151MHz, CDCl3)δ147.5,137.1,137.0,134.1,125.9(q,J=277.8Hz),122.7,121.3,118.1,72.3,41.7(q,J=30.2Hz),20.7; 19 F NMR (565MHz,CDCl3)δ-64.39.

[0069] Example 2:

[0070] To a reaction tube, diazonium salt 1b (148.2 mg, 0.6 mmol, 2.0 equiv.), NaSO₂CF₃₂a (46.8 mg, 0.3 mmol, 1.0 equiv.), and nBu₄NBF₄ (131 mg, 0.4 mmol, 1.3 equiv.) were accurately added and dissolved in MeCN (4 mL). The anode was a graphite felt GF electrode (10 mm × 15 mm × 6 mm), and the cathode was a platinum sheet electrode (10 mm × 15 mm × 0.25 mm). Electrooxidation was carried out at 45°C with a current maintained at 4 mA for 2 hours. The solvent was transferred to a round-bottom flask. Silica gel was added to the flask, and the solvent was evaporated in vacuo. Purification by silica gel column chromatography using PE / EA (v / v, 5:1) as the eluent afforded the corresponding product 3ba in 58% yield. The reaction equation is as follows:

[0071]

[0072] The product 3ba prepared in this example 1 H NMR spectrum is shown in Figure 4 , 13 C NMR spectrum is shown in Figure 5 , 19 F NMR spectrum is shown in Figure 6 ; NMR data of product 3ba: 1 HNMR (600MHz, CDCl3) δ7.47(s,1H),7.03–7.00(m,2H),6.92(td,J=7.7,1.3Hz,1H),6.80–6.78(m,1H),4.72(s,2H),3.06(q,J=10.8Hz,2H); 13 CNMR (151MHz, CDCl3) δ149.6,137.5,137.3,125.5(q,J=277.8Hz),124.4,123.0,121.6,117.8,72.15,41.8(q,J=30.2Hz); 19 F NMR (565MHz,CDCl3)δ-64.41.

[0073] Example 3:

[0074] To a reaction tube, diazonium salt 1c (195.0 mg, 0.6 mmol, 2.0 equiv.), NaSO₂CF₃₂a (46.8 mg, 0.3 mmol, 1.0 equiv.), and nBu₄NBF₄ (131 mg, 0.4 mmol, 1.3 equiv.) were accurately added and dissolved in MeCN (4 mL). The anode was a graphite felt GF electrode (10 mm × 15 mm × 6 mm), and the cathode was a platinum sheet electrode (10 mm × 15 mm × 0.25 mm). Electrooxidation was carried out at 45°C with a current maintained at 4 mA for 2 hours. The solvent was transferred to a round-bottom flask. Silica gel was added to the flask, and the solvent was evaporated in vacuo. Purification by silica gel column chromatography using PE / EA (v / v, 5:1) as the eluent afforded the corresponding product 3ca in 59% yield. The reaction equation is as follows:

[0075]

[0076] The product 3ca prepared in this example 1 H NMR spectrum is shown in Figure 7 , 13 C NMR spectrum is shown in Figure 8 , 19 F NMR spectrum is shown in Figure 9 ; NMR data of product 3ca: 1 H NMR (600MHz, CDCl3) δ7.43 (s, 1H), 6.99 (dd, J = 8.5, 2.2Hz, 1H), 6.92 (d, J = 2.2Hz, 1H), 6.87 (d, J = 8.5Hz, 1H), 4.68 (s, 2H), 3.06 (q, J = 10.2Hz, 2H); 13 C NMR (151MHz, CDCl3) δ148.5, 138.6, 138.2, 125.4 (q, J = 277.8Hz), 125.5, 123.0, 120.3, 116.5, 71.9, 41.8 (q, J = 30.2Hz). 19 F NMR (565MHz,CDCl3)δ-64.35.

[0077] Example 4:

[0078] To a reaction tube, diazonium salt 1d (169.2 mg, 0.6 mmol, 2.0 equiv.), NaSO₂CF₃₂a (46.8 mg, 0.3 mmol, 1.0 equiv.), and nBu₄NBF₄ (131 mg, 0.4 mmol, 1.3 equiv.) were accurately added and dissolved in MeCN (4 mL). The anode was a graphite felt GF electrode (10 mm × 15 mm × 6 mm), and the cathode was a platinum sheet electrode (10 mm × 15 mm × 0.25 mm). Electrooxidation was carried out at 45°C with a current maintained at 4 mA for 2 hours. The solvent was transferred to a round-bottom flask. Silica gel was added to the flask, and the solvent was evaporated in vacuo. Purification by silica gel column chromatography using PE / EA (v / v, 5:1) as the eluent afforded the corresponding product 3da in 64% yield. The reaction equation is as follows:

[0079]

[0080] The product 3da prepared in this example 1 H NMR spectrum is shown in Figure 10 , 13 C NMR spectrum is shown in Figure 11 , 19 F NMR spectrum is shown in Figure 12 ; NMR data of product 3da: 1 H NMR (400MHz, CDCl3) δ7.42 (s, 1H), 6.93 (d, J = 8.5Hz, 1H), 6.85 (dd, J = 8.6, 2.1Hz, 1H), 6.78 (s, 1H), 4.68 (s, 2H), 3.06 (q, J = 10.7Hz, 2H); 13 CNMR (151MHz, CDCl3) δ148.0, 138.5, 137.9, 129.2, 126.4 (q, J = 277.8Hz), 122.7, 122.6, 117.4, 72.0, 41.8 (q, J = 30.2Hz). 19 F NMR (565MHz,CDCl3)δ-64.36.

[0081] Example 5:

[0082] To a reaction tube, diazonium salt 1e (182.4 mg, 0.6 mmol, 2.0 equiv.), NaSO₂CF₃₂a (46.8 mg, 0.3 mmol, 1.0 equiv.), and nBu₄NBF₄ (131 mg, 0.4 mmol, 1.3 equiv.) were accurately added and dissolved in MeCN (4 mL). The anode was a graphite felt GF electrode (10 mm × 15 mm × 6 mm), and the cathode was a platinum sheet electrode (10 mm × 15 mm × 0.25 mm). Electrooxidation was carried out at 45°C with a current maintained at 4 mA for 2 hours. The solvent was transferred to a round-bottom flask. Silica gel was added to the flask, and the solvent was evaporated in vacuo. Purification by silica gel column chromatography using PE / EA (v / v, 5:1) as the eluent afforded the corresponding product 3ea in 85% yield. The reaction equation is as follows:

[0083]

[0084] The product 3ea prepared in this example 1 H NMR spectrum is shown in Figure 13 , 13 C NMR spectrum is shown in Figure 14 , 19 F NMR spectrum is shown in Figure 15 ; NMR data of product 3ea: 1 HNMR (400MHz, CDCl3) δ7.44(s,1H),6.94(s,2H),6.77(s,1H),4.70(s,2H),3.05(q,J=10.8Hz,2H),1.30(s,9H). 13 C NMR (151MHz, CDCl3) δ147.6, 147.3, 137.1, 136.6, 125.5 (q, J = 277.8Hz), 121.0, 120.2, 114.7, 72.2, 41.9 (q, J = 28.7Hz), 34.4, 31.5. 19 F NMR (565MHz,CDCl3)δ-64.41.

[0085] Example 6:

[0086] To a reaction tube, diazonium salt 1f (232.2 mg, 0.6 mmol, 2.0 equiv.), NaSO₂CF₃₂a (46.8 mg, 0.3 mmol, 1.0 equiv.), and nBu₄NBF₄ (131 mg, 0.4 mmol, 1.3 equiv.) were accurately added and dissolved in MeCN (4 mL). The anode was a graphite felt GF electrode (10 mm × 15 mm × 6 mm), and the cathode was a platinum sheet electrode (10 mm × 15 mm × 0.25 mm). Electrooxidation was carried out at 45°C with a current maintained at 4 mA for 2 hours. The solvent was transferred to a round-bottom flask. Silica gel was added to the flask, and the solvent was evaporated in vacuo. Purification by silica gel column chromatography using PE / EA (v / v, 5:1) as the eluent afforded the corresponding product 3fa in 74% yield. The reaction equation is as follows:

[0087]

[0088] The product 3fa prepared in this example 1 H NMR spectrum is shown in Figure 16 , 13 C NMR spectrum is shown in Figure 17 , 19 F NMR spectrum is shown in Figure 18 ; NMR data of product 3fa: 1 HNMR(400MHz, CDCl3)δ7.37–7.32(m,3H),7.15–7.08(m,3H),6.96–6.90(m,2 H), 6.55 (d, J = 8.0Hz, 1H), 4.38 (s, 2H), 2.87 (q, J = 10.8Hz, 2H), 2.31 (s, 3H). 13 C NMR (101MHz, CDCl3) δ 144.0, 142.3, 136.1, 130.5 (q, J = 175.7Hz) 133.2, 129. 4,128.6,127.7,126.8,124.0,123.1,117.9,52.1,42.7(q,J=29.2Hz),21.7. 19 F NMR (565MHz,CDCl3)δ-64.21.

[0089] Example 7:

[0090] The same as Example 1, except that the reaction conditions (Table 1) were changed, and the yield of the benzo-7-membered nitrogen heterocycle prepared by electrochemical free radical reaction under different reaction conditions was statistically analyzed.

[0091]

[0092] Table 1 Optimization of reaction conditions

[0093] Grouping solvent electrolytes temperature Yield / % 1 MeCN <![CDATA[Et4NClO4]]> 45℃ 41 2 <![CDATA[MeCN:H2O=4:1]]> <![CDATA[Et4NClO4]]> 45℃ 0 3 1,4-dioxane <![CDATA[Et4NClO4]]> 45℃ 27 4 DCE <![CDATA[Et4NClO4]]> 45℃ 34 5 DCE:MeCN=1:1 <![CDATA[Et4NClO4]]> 45℃ 40 6 MeCN <![CDATA[nBu4NF4]]> 45℃ 78 7 MeCN <![CDATA[nBu4NPF6]]> 45℃ 40 8 MeCN <![CDATA[nBu4NF4]]> 20℃ 29 9 MeCN <![CDATA[nBu4NF4]]> 60℃ 40 <![CDATA[10 [b] ]]> MeCN <![CDATA[nBu4NF4]]> 45℃ 24 <![CDATA[11 [c] ]]> MeCN <![CDATA[nBu4NF4]]> 45℃ 50

[0094] Reaction parameters:

[0095] Reaction parameter conditions [a] for groups 1 to 9: 1a (0.60 mmol, 2.0 equiv), 2a (0.30 mmol, 1.0 equiv), solvent (4 mL), air, the amount of electrolyte is 1.3 times the amount of 2a, current (4.0 mA), 2 h.

[0096] [b] is the reaction time of 1.5 h.

[0097] [c] is the reaction time of 2.5h.

[0098] In summary, the reaction in the present invention does not require a transition metal catalyst and is carried out only under the action of electric current, which is energy-saving and economical. The free radical source used in the reaction is cheap and easily available, and the cost is low, and a seven-membered nitrogen heterocyclic compound can be directly synthesized, which reduces the synthesis cost compared with the existing technology.

[0099] While the embodiments of the present invention have been shown and described, it will be apparent to those skilled in the art that the scope of the invention is defined by the appended claims and their equivalents.

Claims

1. A method for electrooxidation synthesis of fluoroalkyl-substituted benzo seven-membered nitrogen heterocycles, characterized in that: The specific steps include: Step 1: Under the condition of passing current, an aryl diazonium salt reacts with a fluorinated sodium methanesulfinate compound in an electrolyte and a solvent to obtain the benzo seven-membered nitrogen heterocycle; The structure of the aryl diazonium salt is shown in formula (I): （I）； The structure of the fluorinated sodium methanesulfinate is shown in formula (II): (II); In formula (I) to formula (II), R 1 It is a nitro group, a halogen atom, a cyano group, an acyl group, a carboxyl group electron-withdrawing group, or an amino group, a methyl group, or a methoxy group electron-donating group; Among them, R 1 The substitution positions are at positions 3, 4, 5, and 6 of the benzene ring; R 2 is a H or fluorine atom; X is O, S or a nitrogen atom; Step 2: Using a fluorinated sodium methanesulfinate compound and a substituted aryl diazonium salt in an electrolyte, a benzo-7-membered nitrogen heterocyclic compound is generated under the promotion of electricity. The specific reaction formula is shown below: 。

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