A method for preparing 2-aryl-3-sulfonyl-substituted pyrrolidine and piperidine compounds

Abstract

The present application discloses a preparation method of 2-aryl-3-sulfonyl-substituted pyrrolidine and piperidine compounds in the field of organic synthesis. The reaction general formula is as follows: Specifically, 2-aryl-3-sulfonyl-substituted pyrrolidine and piperidine compounds are prepared by a one-pot method from unsaturated amines and alkyl or aryl sodium sulfinates under organic electrochemical synthesis conditions. This method has mild conditions, cheap and easily available raw materials, simple operation, avoids the use of chemical oxidants and metal catalysts, has less pollutants, has good practical value and potential social and economic efficiency, and provides important reference significance for the synthesis process development of similar molecules and downstream molecules.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis, and particularly relates to a method for preparing 2-aryl-3-sulfonyl-substituted pyrrolidine and piperidine compounds. Background Art

[0002] Five- and six-membered nitrogen heterocycles are important skeletons of functional molecules such as pesticides, organic dyes, and drugs. For example, the antipsychotic sulpiride contains a five-membered nitrogen heterocycle pyrrolidine structure, and haloperidol for treating schizophrenia contains a six-membered nitrogen heterocycle piperidine structure. And 2-aryl-3-sulfonyl-substituted pyrrolidine and piperidine compounds are important five- and six-membered nitrogen heterocyclic compounds. The sulfonyl group with unique physical and chemical properties and the structurally diverse aryl substituents in such compounds can further expand the application scope of related compounds.

[0003] Currently, in the reports of the prior art, there are also few synthesis methods for 2-aryl-3-sulfonyl-substituted piperidine compounds. For the existing synthesis examples, for instance, 2-aryl-3-sulfonyl-substituted piperidine compounds are prepared by a (3+2) cycloaddition reaction of aryl vinyl sulfone and 1,3-dipolar reagent (Organic Letters, 2018, 20, 337); another example is that 2-aryl-3-sulfonyl-substituted piperidine compounds are prepared by multi-step reactions using piperidine compounds, sulfonylation reagents, and arylmagnesium bromide as raw materials (Chemical Science, 2018, 9, 2295). However, both components of the first synthesis method need to be prepared by relatively cumbersome methods and it is not easy to introduce structurally diverse functional group molecules. And the second synthesis method requires multi-step reactions, and active Grignard reagents and a large amount of chemical oxidants are used in the reaction process, resulting in relatively large pollution. Summary of the Invention

[0004] Aiming at the deficiencies of the prior art, the present invention provides a method for synthesizing 2-aryl-3-sulfonyl-substituted pyrrolidine and piperidine compounds with cheap and easily available starting materials, simple procedures, and capable of being synthesized in one step.

[0005] One of the purposes of the present invention is to provide a method for preparing 2-aryl-3-sulfonyl-substituted pyrrolidine and piperidine compounds. Specifically, an unsaturated amine, an aryl or alkyl sodium sulfonate, an electrolyte, and a solvent are sequentially added to an electrolytic cell equipped with electrode materials, and 2-aryl-3-sulfonyl-substituted pyrrolidine and piperidine compounds are prepared by a one-pot method under the conditions of organic electrochemical synthesis with constant current and gas protection atmosphere. The reaction formula is as follows:

[0006]

[0007] Wherein:

[0008] (1) Ar is selected from one of phenyl, o - methylphenyl, m - methylphenyl, p - methylphenyl, m - methoxyphenyl, p - methoxyphenyl, p - ethylphenyl, p - tert - butylphenyl, p - n - butoxyphenyl, 3,4 - dimethoxyphenyl, 3,4,5 - trimethoxyphenyl, 3 - chloro - 4 - methoxyphenyl or 3 - bromo - 4 - methoxyphenyl;

[0009] (2) R 1 is selected from one of phenyl, p - methylphenyl, p - methoxyphenyl, p - trifluoromethylphenyl, p - tert - butylphenyl, p - bromophenyl or p - cyanophenyl;

[0010] (3) R 2 is selected from one of methyl, ethyl, cyclopropyl, n - butyl, phenyl, m - methylphenyl, p - methylphenyl, m - methoxyphenyl, p - methoxyphenyl, p - trifluoromethylphenyl, m - trifluoromethylphenyl, p - tert - butylphenyl, o - fluorophenyl, m - fluorophenyl, p - fluorophenyl, m - bromophenyl, p - bromophenyl, p - iodophenyl, p - chlorophenyl or 3 - fluoro - 4 - methylphenyl.

[0011] Furthermore, the molar ratio of each substance in the reaction is: unsaturated amine: aryl or alkylsulfonate: electrolyte = 1:1 - 5:0.1 - 4; preferably, in the present invention, unsaturated amine: aryl or alkylsulfonate: electrolyte = 1:2:0.4.

[0012] Furthermore, the electrolyte is selected from ammonium tetrabutylborate, ammonium tetrabutylhexafluorophosphate, ammonium tetrabutylacetate, ammonium tetrabutyl iodide, ammonium tetrabutyl bromide, ammonium tetrabutyl chloride or lithium perchlorate, and most preferably ammonium tetrabutylborate in the present invention.

[0013] Furthermore, the electrode material includes an anode electrode material and a cathode electrode material. The anode electrode material is a carbon rod electrode or a glassy carbon electrode, and preferably a carbon rod electrode in the present invention.

[0014] Furthermore, the cathode electrode material is a platinum sheet, a copper sheet, a nickel sheet or a zinc sheet, and preferably a platinum sheet in the present invention.

[0015] Furthermore, the solvent is one or more of acetonitrile, methanol, dichloromethane, N,N - dimethylformamide, dimethyl sulfoxide, hexafluoroisopropanol and water; preferably, acetonitrile: water = 12:1 (volume ratio) in the present invention

[0016] Furthermore, the current used is 1 mA to 15 mA, and preferably 4 mA in the present invention.

[0017] Furthermore, the heating temperature of the reaction is 0 - 60 °C, and preferably 25 °C in the present invention.

[0018] Furthermore, the reaction time is 1 - 10 hours, and preferably 3 hours in the present invention.

[0019] Further, the gas protection atmosphere used is oxygen, nitrogen, argon or air, and the present invention preferably uses argon.

[0020] Further, the electrolytic cell is selected from an integrated electrolytic cell or a separated electrolytic cell. The present invention preferably uses an integrated electrolytic cell.

[0021] Working principle and beneficial effects of the present invention: The present invention creatively prepares 2-aryl-3-sulfonyl-substituted pyrrolidine and piperidine compounds by a one-pot method from unsaturated amines and aryl or alkylsulfinic acid sodium salts under organic electrochemical synthesis conditions. This method has the advantages of inexpensive and easily available raw materials, mild conditions, avoiding the use of chemical oxidants and metal catalysts, and less pollution. Except for the end products, the intermediates in this transformation process do not need to be separated and purified, providing a green and efficient preparation method for 2-aryl-3-sulfonyl-substituted pyrrolidine and piperidine compounds. Therefore, the present invention has good practical value and potential social and economic efficiency, providing important reference significance for the synthesis process development of similar molecules and downstream molecules. Specific Embodiments

[0022] The following is a further detailed description through specific embodiments:

[0023] Examples

[0024] Using 4-phenyl-3-butenamine compounds as olefin substrates and sodium p-toluenesulfinate as the sulfonylation reagent to prepare 2-aryl-3-sulfonyl-substituted pyrrolidine molecules (Reaction Scheme 1)

[0025]

[0026] Add 4-phenyl-3-butenamine substrate (60.2 mg, 0.2 mmol), sodium p-toluenesulfinate (71.2 mg, 0.4 mmol), tetrabutylammonium tetrafluoroborate (26.3 mg, 0.08 mmol), acetonitrile (24 mL) and water (2 mL) successively into an integrated electrolytic cell equipped with electrode materials (the anode is a carbon rod and the cathode is a platinum sheet). After argon protection, react at a constant current of 4 mA and a temperature of 25 °C for 3 hours. The reaction system is extracted, dried, concentrated, and purified by silica gel column chromatography to obtain a white solid (dr>19:1, 46.5 mg, 51%).

[0027] The product detection data is as follows:

[0028] Melting range: 132.3–134.7 °C

[0029] 1 H NMR (400 MHz, CDCl 3) δ 7.68 (d, J = 8.1 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 7.33 (t, J = 8.1, Hz, 4H), 7.21 (dd, J = 5.1, 1.9 Hz, 3H), 7.03–7.01 (m, 2H), 5.01 (d, J = 2.9 Hz, 1H), 3.81–3.75 (m, 1H), 3.65–3.57 (m, 1H), 3.47–3.39 (m, 1H), 2.45 (s, 6H), 2.42–2.39 (m, 1H), 2.34–2.30 (m, 1H).

[0030] 13 C NMR (101 MHz, CDCl 3 ) δ 145.6, 144.0, 141.4, 134.4, 134.0, 130.2, 129.7, 128.83, 128.78, 128.1, 127.9, 125.9, 72.2, 63.0, 48.8, 25.0, 21.82, 21.79.

[0031] Using 4-(3,4-dimethoxyphenyl)-3-butenylamine compounds as substrates and sodium cyclopropylsulfinate as the sulfonylation reagent to prepare 2-aryl-3-sulfonyl-substituted pyrrolidine molecules (Reaction Scheme 2)

[0032]

[0033] 4-(3,4-Dimethoxyphenyl)-3-butenylamine substrate (72.3 mg, 0.2 mmol), sodium cyclopropylsulfinate (51.2 mg, 0.4 mmol), tetrabutylammonium tetrafluoroborate (26.3 mg, 0.08 mmol), acetonitrile (24 mL) and water (2 mL) were successively added to an integrated electrolytic cell equipped with electrode materials (the anode is a carbon rod and the cathode is a platinum sheet). After being protected by argon, the reaction was carried out at a constant current of 4 mA and a temperature of 25 °C for 3 hours. The reaction system was subjected to extraction, drying, concentration, and silica gel column chromatography to obtain a white solid (dr > 19:1, 46.6 mg, 50%).

[0034] The product detection data are as follows:

[0035] Melting range: 136.2–138.3 °C

[0036] 1 H NMR (400 MHz, CDCl 3)δ 7.62 (d, J = 7.9 Hz, 2H), 7.27 (d, J = 8.1 Hz, 2H), 6.93 (d, J = 7.2 Hz, 1H), 6.84–6.77 (m, 2H), 5.20 (d, J = 3.8 Hz, 1H), 3.87 (s, 3H), 3.82 (s, 3H), 3.73–3.68 (m, 2H), 3.55–3.48 (m, 1H), 2.41 (s, 3H), 2.41–2.28 (m, 2H), 2.21–2.10 (m, 1H), 1.17–1.10 (m, 2H), 1.01–0.87 (m, 2H).

[0037] 13 C NMR (101 MHz, CDCl 3 )δ 149.2, 148.8, 143.9, 134.4, 133.4, 129.6, 127.8, 118.9, 111.1, 109.3, 70.6, 67.1, 62.7, 56.0, 55.9, 48.3, 28.5, 25.5, 21.6, 5.4, 5.0.

[0038] Using 5-(4-butoxyphenyl)-3-butenamine compounds as substrates and sodium p-toluenesulfinate as the sulfonylation reagent to synthesize 2-aryl-3-sulfonyl-substituted piperidine molecules (Reaction Scheme 3)

[0039]

[0040] 5-(4-Butoxyphenyl)-3-butenamine substrate (76.9 mg, 0.2 mmol), sodium p-toluenesulfinate (71.2 mg, 0.4 mmol) and tetrabutylammonium tetrafluoroborate (26.3 mg, 0.08 mmol), acetonitrile (24 mL) and water (2 mL) were successively added to an integrated electrolytic cell equipped with electrode materials (the anode is a carbon rod and the cathode is a platinum sheet). After argon protection, the reaction was carried out at a constant current of 4 mA and a temperature of 25 °C for 3 hours. The reaction system was subjected to extraction, drying, concentration, and silica gel column chromatography to obtain a light yellow liquid (dr > 19:1, 80.8 mg, 75%).

[0041] The product detection data are as follows:

[0042] 1 H NMR (400 MHz, CDCl 3)δ 7.83 (d, J = 8.6 Hz, 2H), 7.76 (d, J = 8.6 Hz, 2H), 7.57 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 6.90 (d, J = 8.6 Hz, 2H), 6.71 (d, J = 8.7 Hz, 2H), 5.11 (d, J = 2.3 Hz, 1H), 3.88 (t, J = 6.5 Hz, 2H), 3.76 (ddd, J = 9.3, 7.1, 4.4 Hz, 1H), 3.63 (dd, J = 17.1, 8.9 Hz, 1H), 3.43–3.38 (m, 1H), 2.43 (s, 3H), 2.35–2.26 (m, 2H), 1.73 (dd, J = 14.3, 7.3 Hz, 2H), 1.45 (dd, J = 15.0, 7.5 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H).

[0043] 13 C NMR (101 MHz, CDCl 3 )δ 159.0, 145.7, 141.6, 134.1, 132.7, 132.2, 130.3, 128.6, 128.4, 127.0, 117.6, 116.5, 114.7, 62.6, 48.4, 31.3, 25.0, 21.8, 19.3, 13.9.

[0044] Using 5-(3,4-dimethoxyphenyl)-4-pentenamine compounds as substrates and sodium p-fluorobenzenesulfinate as the sulfonylation reagent to synthesize 2-aryl-3-sulfonyl-substituted piperidine molecules (Reaction Scheme 4)

[0045]

[0046] 5-(3,4-Dimethoxyphenyl)-4-pentenamine substrate (75.1 mg, 0.2 mmol), sodium p-fluorobenzenesulfinate (72.5 mg, 0.4 mmol) and tetrabutylammonium tetrafluoroborate (26.3 mg, 0.08 mmol) were successively added to an integrated electrolytic cell equipped with electrode materials (the anode is a carbon rod and the cathode is a platinum sheet). After argon protection, the reaction was carried out at a constant current of 4 mA and a temperature of 25 °C for 3 hours. The reaction system was subjected to extraction, drying, concentration, and silica gel column chromatography to obtain a light yellow oil (dr > 19:1, 69.4 mg, 65%).

[0047] The product detection data are as follows:

[0048] 1 H NMR (400 MHz, CDCl 3)δ 7.99 (dd, J = 8.7, 5.0 Hz, 2H), 7.62 (d, J = 8.2 Hz, 2H), 7.23 (dd, J = 15.0, 6.6 Hz, 2H), 7.14 (d, J = 8.1 Hz, 2H), 6.60 (d, J = 8.9 Hz, 1H), 6.49–6.43 (m, 2H), 5.76 (s, 1H), 3.73 (s, 3H), 3.58 (s, 3H), 3.41 (s, 1H), 3.21–3.11 (m, 1H), 2.31 (s, 3H), 2.22–2.13 (m, 1H), 2.01–1.91 (m, 1H), 1.86–1.73 (m, 1H), 1.53–1.44 (m, 1H).

[0049] 13 C NMR (101 MHz, CDCl 3 ) δ 165.8 (d, J = 256.9 Hz), 148.8, 148.2, 143.3, 136.5, 133.8 (d, J = 3.1 Hz), 131.8 (d, J = 9.6 Hz), 130.8, 129.2, 127.6, 118.5, 116.7 (d, J = 22.6 Hz), 111.0, 110.0, 63.9, 55.8, 55.5, 53.2, 41.1, 21.4, 19.7, 18.6.

[0050] 19 F NMR (376 MHz, CDCl 3 ) δ –102.80.

[0051] The above are only embodiments of the present invention, and common knowledge such as specific structures and characteristics known in the art are not described in detail herein. It should be noted that for those skilled in the art, without departing from the structure of the present invention, several modifications and improvements can be made, which should also be regarded as the protection scope of the present invention, and these will not affect the implementation effect of the present invention and the practicality of the patent. The protection scope required by this application shall be subject to the content of its claims, and the specific implementation manners described in the specification can be used to interpret the content of the claims.

Claims

1. A method for preparing 2-aryl-3-sulfonyl-substituted pyrrolidine and piperidine compounds, characterized in that, an unsaturated amine, an aryl or alkyl sodium sulfonate, an electrolyte, and a solvent are sequentially added to an electrolytic cell equipped with electrode materials, and 2-aryl-3-sulfonyl-substituted pyrrolidine and piperidine compounds are prepared by a one-pot method under the conditions of constant current and organic electrochemical synthesis in a gas protection atmosphere. The electrolyte is selected from tetrabutylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium acetate, tetrabutylammonium iodide, tetrabutylammonium bromide, tetrabutylammonium chloride, or lithium perchlorate. The solvent is a mixed solution of acetonitrile and water. The reaction formula is as follows: Wherein: (1) Ar is selected from one of phenyl, o-methylphenyl, m-methylphenyl, p-methylphenyl, m-methoxyphenyl, p-methoxyphenyl, p-ethylphenyl, p-tert-butylphenyl, p-n-butoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3-chloro-4-methoxyphenyl, or 3-bromo-4-methoxyphenyl; (2)R 1 selected from one of phenyl, p-methylphenyl, p-methoxyphenyl, p-trifluoromethylphenyl, p-tert-butylphenyl, p-bromophenyl or p-cyanophenyl; (3)R 2 selected from methyl, ethyl, cyclopropyl, n-butyl, phenyl, m-methylphenyl, p-methylphenyl, m-methoxyphenyl, p-methoxyphenyl, p-trifluoromethylphenyl, m-trifluoromethylphenyl, p-tert-butylphenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-bromophenyl, p-bromophenyl, p-iodophenyl, p-chlorophenyl or 3-fluoro-4-methylphenyl.

2. The preparation method according to claim 1, characterized in that: The molar ratio of each substance in the reaction is: unsaturated amine: aryl or alkyl sodium sulfonate: electrolyte = 1: 1-5: 0.1-4.

3. The preparation method according to claim 2, characterized in that: The electrode materials include an anode electrode material and a cathode electrode material. The anode electrode material is a carbon rod electrode or a glassy carbon electrode, and the cathode electrode material is a platinum sheet, a copper sheet, a nickel sheet, or a zinc sheet.

4. The preparation method according to any one of claims 1 to 3, characterized in that: The current used is 1 mA to 15 mA.

5. The preparation method according to claim 4, characterized in that: The heating temperature of the reaction is 0 to 60 °C.

6. The preparation method according to claim 5, characterized in that: The reaction time is 1 to 10 hours.

7. The preparation method according to claim 6, characterized in that: The gas protection atmosphere is oxygen, nitrogen, argon, or air.

8. The preparation method according to claim 7, characterized in that: The electrolytic cell is selected from an integrated electrolytic cell or a separated electrolytic cell.

Images