Preparation method of thiocyano-containing pyrrolidine compound

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of a thiocyano-containing pyrrolidine compound, which comprises the following steps: adding sulfonamide, trimethylsilyl isothiocyanate, electrolyte and solvent into a reactor, reacting under the action of constant current, and after the reaction is finished, separating by silica gel column chromatography to obtain a pure target product. The skeleton structure of the target product has antibacterial, antiviral and other biological activities, and meanwhile, the heterocyclic structure of the target product has a surface adsorption corrosion inhibition effect, so that the target product has a relatively good application prospect in the fields of corrosion protection and medicine; the compound for preparing the equipment corrosion protection corrosion inhibitor in the marine atmospheric environment and the dry-wet alternate environment is synthesized through electrocatalysis, the synthesis method is scientific and reasonable, raw materials are easy to obtain, operation is easy, reaction conditions are mild, and functional groups are good in universality.

Description

Technical fields:

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing thiocyanopyrrolidine compounds, which uses electrocatalysis to synthesize compounds for formulating corrosion inhibitors for equipment in marine atmospheric environments and alternating wet and dry environments. Background technology:

[0002] Pyrrolidines are common skeletal structures in drug molecules and preservative compounds, possessing bioactivities such as anticancer, antibacterial, and antiviral properties (J. Med. Chem. 2024, 67, 11622). Furthermore, their heterocyclic structure provides surface adsorption and corrosion inhibition. Thiocyanates are widely found in natural products and bioactive compounds, serving as important structural units in the synthesis of sulfur- and nitrogen-containing compounds.

[0003] (Chem. Soc. Rev. 2016, 45, 494).

[0004] In the existing technology, the preparation of thiocyanopyrrolidine compounds by Zhao Xiaodan's research group using unstable electrophilic thiocyanating reagents under selenium catalysis (Org. Lett. 2019, 21, 7846-7850) has obvious drawbacks and shortcomings: first, it requires the use of unstable electrophilic reagents; second, the substrate needs to be prefunctionalized; third, it requires the use of catalysts and ligands; and fourth, the reaction conditions are harsh.

[0005] Therefore, it is of great significance to develop and design a green and efficient method for synthesizing thiocyanopyrrolidine compounds. Summary of the Invention:

[0006] The purpose of this invention is to overcome the shortcomings of existing technologies, develop and design a method for preparing thiocyanopyrrolidine compounds, and establish a new route for preparing thiocyanopyrrolidine compounds by electrocatalysis.

[0007] To achieve the above objectives, the present invention relates to a method for preparing thiocyanopyrrolidine compounds by reacting sulfonamide, trimethyl isothiocyanate, tetrabutylammonium dihydrogen phosphate, hexafluoroisopropanol, and dichloroethane at room temperature under constant current conditions, resulting in a synthetic structural formula as follows: Thiocyanopyrrolidine compounds, wherein R 1 The substituents are selected from methyl, hydrogen atom, fluorine, chlorine, bromine, tert-butyl, methoxy, and trifluoromethyl;

[0008] The specific preparation process is as follows:

[0009] Add 0.2 mmol of sulfonamide, 0.4 mmol of trimethylsilyl isothiocyanate (TMSNCS), and 0.4 mmol of tetrabutylammonium dihydrogen phosphate to the reactor. nBu4NH2PO4), 0.5 mL of hexafluoroisopropanol (HFIP), and 3.5 mL of dichloroethane (DCE) were reacted at room temperature under constant current conditions. The reaction equation is as follows:

[0010]

[0011] Compared with existing technologies, this invention involves adding sulfonamide, trimethyl isothiocyanate, electrolyte, and solvent to a reactor and reacting under constant current. After the reaction is complete, the pure target product is obtained by silica gel column chromatography. The target product has antibacterial and antiviral biological activities due to its skeletal structure. At the same time, due to its heterocyclic structure, it has surface adsorption and corrosion inhibition effects, showing good application prospects in corrosion protection and pharmaceutical fields. Its synthesis method is scientific and reasonable, the raw materials are readily available, the operation is simple, the reaction conditions are mild, and the functional groups are universal. Attached image description:

[0012] Figure 1 The NMR (nuclear magnetic resonance) spectrum of the thiocyanopyrrolidine compound 3a prepared in Example 1 of this invention is shown.

[0013] Figure 2 The NMR spectrum of compound 3b containing thiocyanopyrrolidine prepared in Example 2 of this invention is shown.

[0014] Figure 3 The NMR spectrum of the thiocyanopyrrolidine compound 3d prepared in Example 4 of this invention is shown. Detailed implementation method:

[0015] The present invention will be further described below with reference to the embodiments and accompanying drawings.

[0016] Example 1:

[0017] The specific process for preparing a thiocyanopyrrolidine compound involved in this embodiment is as follows:

[0018] First, sulfonamide 1a (51 mg, 0.2 mmol) and TMSNCS (53 mg, 0.4 mmol) were added sequentially to a 10 mL three-necked flask. n Bu4NH2PO4 (136 mg, 0.4 mmol), HFIP (0.5 mL), and DCE (3.5 mL);

[0019] Then, using graphite felt (1cm×1.5cm×0.3cm) as the anode and platinum sheet (1cm×1cm×0.1mm) as the cathode, electrolysis was carried out for 2.0h under nitrogen protection at room temperature with a constant current of 7mA.

[0020] Finally, the electrolytic mixture was concentrated under reduced pressure and subjected to rapid silica gel chromatography with petroleum ether and ethyl acetate as eluents to obtain thiocyanopyrrolidine compound 3a.

[0021] The reaction equation involved in this embodiment is:

[0022]

[0023] The spectral analysis data of the prepared thiocyanopyrrolidine compound 3a are as follows:

[0024] 1 H NMR (500MHz, CDCl3) δ7.71 (d, J=8.4Hz, 2H), 7.29 (d, J=8.0Hz, 2H), 3.65–3.60 (m, 1H) , 3.46–3.41(m, 2H), 2.46–2.40(m, 4H), 2.17–2.10(m, 1H), 1.56(s, 3H), 1.42(s, 3H). 13 CNMR (125MHz, CDCl3) δ143.6, 138.0, 129.8, 127.2, 110.8, 66.8, 57.7, 46.1, 29.2, 27.0, 23.4, 21.6.

[0025] Example 2:

[0026] The specific process for preparing a thiocyanopyrrolidine compound in this embodiment is the same as in Example 1, except that:

[0027] Replace sulfonamide 1a in Example 1 with sulfonamide 1b;

[0028] The reaction equation is:

[0029]

[0030] The spectral analysis data of the prepared thiocyanopyrrolidine compound 3b are as follows:

[0031] 1 H NMR (500MHz, CDCl3) δ7.85–7.83(m, 2H), 7.59–7.56(m, 1H), 7.53–7.49(m, 2H), 3.68–3.63( m, 1H), 3.48–3.43 (m, 2H), 2.47–2.41 (m, 1H), 2.19–2.11 (m, 1H), 1.56 (s, 3H), 1.43 (s, 3H). 13C NMR (125MHz, CDCl3) δ140.9, 132.8, 129.2, 127.2, 110.8, 66.9, 57.6, 46.1, 29.2, 27.0, 23.5.

[0032] Example 3:

[0033] The specific process for preparing a thiocyanopyrrolidine compound in this embodiment is the same as in Example 1, except that:

[0034] Replace sulfonamide 1a in Example 1 with sulfonamide 1c;

[0035] The reaction equation is:

[0036]

[0037] The spectral analysis data of the prepared thiocyanopyrrolidine compound 3c are as follows:

[0038] 1 H NMR (500MHz, CDCl3) δ7.86–7.83(m, 2H), 7.20–7.16(m, 2H), 3.65–3.60(m, 1H), 3.46–3.41(m, 2H), 2.47–2.42(m, 1H),

[0039] 2.19–2.12(m,1H), 1.56(s,3H), 1.43(s,3H). 13 C NMR (125MHz, CDCl3) δ165.1 (d, J C-F =255.5Hz), 137.0, 129.9 (d, J C-F =9.2Hz), 116.4 (d, J) C-F =22.8Hz), 110.7, 67.0, 57.6, 46.1, 29.1, 27.0, 23.5.

[0040] Example 4:

[0041] The specific process for preparing a thiocyanopyrrolidine compound in this embodiment is the same as in Example 1, except that:

[0042] Replace sulfonamide 1a in Example 1 with sulfonamide 1d;

[0043] The reaction equation is:

[0044]

[0045] The spectral analysis data of the prepared thiocyanopyrrolidine compounds at 3d are as follows:

[0046] 1 H NMR (500MHz, CDCl3) δ7.77 (d, J=8.6Hz, 2H), 7.48 (d, J=8.6Hz, 2H), 3.66–3.61 (m, 1H) , 3.46–3.41(m, 2H), 2.47–2.42(m, 1H), 2.20–2.12(m, 1H), 1.56(s, 3H), 1.43(s, 3H). 13 CNMR (125MHz, CDCl3) δ139.4, 139.3, 129.5, 128.6, 110.6, 67.1, 57.6, 46.2, 29.2, 27.0, 23.5.

[0047] Example 5:

[0048] The specific process for preparing a thiocyanopyrrolidine compound in this embodiment is the same as in Example 1, except that:

[0049] Replace sulfonamide 1a in Example 1 with sulfonamide 1e;

[0050] The reaction equation is:

[0051]

[0052] The spectral analysis data of the prepared thiocyanopyrrolidine compound 3e are as follows:

[0053] 1 H NMR (500MHz, CDCl3) δ7.69 (d, J=8.7Hz, 2H), 7.64 (d, J=8.7Hz, 2H), 3.66–3.61 (m, 1H) , 3.46–3.41(m, 2H), 2.48–2.42(m, 1H), 2.20–2.12(m, 1H), 1.55(s, 3H), 1.43(s, 3H). 13 C NMR (125MHz, CDCl3) δ140.0, 132.5, 128.7, 127.7, 110.6, 67.1, 57.6, 46.2, 29.2, 27.0, 23.5.

[0054] Example 6:

[0055] The specific process for preparing a thiocyanopyrrolidine compound in this embodiment is the same as in Example 1, except that:

[0056] Replace sulfonamide 1a in Example 1 with sulfonamide 1f;

[0057] The reaction equation is:

[0058]

[0059] The spectral analysis data of the prepared thiocyanopyrrolidine compound 3f are as follows:

[0060] 1 H NMR (500MHz, CDCl3) δ7.74 (d, J=8.7Hz, 2H), 7.50 (d, J=

[0061] 8.6Hz, 2H), 3.65–3.61(m, 1H), 3.45–3.40(m, 2H), 2.45–2.39(m, 1H), 2.18–2.10(m, 1H), 1.57(s, 3H), 1.43(s, 3H), 1.33(s, 9H).

[0062] 13 C NMR (125MHz, CDCl3) δ156.5, 137.8, 127.0, 126.1, 110.8, 66.8, 57.5, 46.0, 35.2, 31.2, 29.2, 26.9, 23.5.

[0063] Example 7:

[0064] The specific process for preparing a thiocyanopyrrolidine compound in this embodiment is the same as in Example 1, except that:

[0065] Replace sulfonamide 1a in Example 1 with 1g of sulfonamide;

[0066] The reaction equation is:

[0067]

[0068] The spectral analysis data of the prepared thiocyanopyrrolidine compound 3f are as follows:

[0069] 1 H NMR (500MHz, CDCl3) δ7.77–7.74(m, 2H), 6.97–6.94(m, 2H), 3.86(s, 3H), 3.61–3.57(m, 1H), 3.45–3.39(m, 2H), 2.45–2.39(m, 1H), 2.16–2.09(m, 1H), 1.55(s, 3H), 1.41(s, 3H). 13 CNMR (125MHz, CDCl3) δ162.9, 132.6, 129.3, 114.3, 110.9, 66.7, 57.7, 55.7, 46.0, 29.1, 26.9, 23.3.

[0070] Example 8:

[0071] The specific process for preparing a thiocyanopyrrolidine compound in this embodiment is the same as in Example 1, except that:

[0072] Replace sulfonamide 1a in Example 1 with sulfonamide 1h;

[0073] The reaction equation is:

[0074]

[0075] The spectral analysis data of the prepared thiocyanopyrrolidine compound 3f are as follows:

[0076] 1 H NMR (500MHz, CDCl3) δ7.97 (d, J=8.1Hz, 2H), 7.78 (d, J

[0077] =8.3Hz, 2H), 3.71–3.66(m, 1H), 3.49–3.44(m, 2H), 2.50–2.44(m, 1H), 2.22–2.15(m, 1H), 1.57(s, 3H), 1.45(s, 3H). 13 C NMR (125MHz, CDCl3) δ144.4, 134.2 (q, J C-F =33.6Hz), 127.6, 126.5 (q, J C-F =3.5Hz), 122.2(q, J C-F =273.5Hz), 110.5, 67.4, 57.5, 46.3, 29.2, 27.0, 23.6.

[0078] The yield test results of Examples 1-8 are as follows:

[0079]

[0080]

Claims

1. A method for preparing a thiocyanopyrrolidine compound, characterized in that, A thiocyano-containing pyrrolidine compound was synthesized by reacting sulfonamide, trimethyl isothiocyanate, tetrabutylammonium dihydrogen phosphate, hexafluoroisopropanol, and dichloroethane at room temperature under constant current conditions.

2. The method for preparing a thiocyanopyrrolidine compound according to claim 1, characterized in that, The specific preparation process is as follows: 0.2 mmol of sulfonamide, 0.4 mmol of trimethyl isothiocyanate, 0.4 mmol of tetrabutylammonium dihydrogen phosphate, 0.5 mL of hexafluoroisopropanol, and 3.5 mL of dichloroethane are added to the reactor, and the reaction is carried out at room temperature under constant current conditions.

3. A method for preparing a thiocyanopyrrolidine compound according to claim 1 or 2, characterized in that, The reaction equation is:

4. The method for preparing a thiocyanopyrrolidine compound according to claim 3, characterized in that, The structural formula of thiocyanopyrrolidine compounds is:

5. The method for preparing a thiocyanopyrrolidine compound according to claim 4, characterized in that, R 1 The substituents are selected from methyl, hydrogen atom, fluorine, chlorine, bromine, tert-butyl, methoxy, and trifluoromethyl.

Images