A method for electrocatalytic synthesis of sulfur-containing spirocyclic indoline compounds from thiophenol and isonitrile

Abstract

The application discloses a method for synthesizing a sulfur-containing spirocyclic indoline compound by electrocatalysis of thiophenol and isonitrile. The method uses a carbon rod as an anode, a platinum sheet as a cathode, thiophenol or thiol as a sulfur source, and an indole ethyl isonitrile as a reaction substrate, and performs an electric reaction in an electrolyte in an organic solvent to obtain the sulfur-containing spirocyclic indoline compound. The method does not need a transition metal catalyst and a stoichiometric oxidant, has the advantages of mild reaction conditions, simple experimental device, excellent functional group compatibility, good product yield and the like, and provides a new way for green synthesis of the sulfur-containing spirocyclic indoline compound.

Description

Technical Field

[0001] This invention belongs to the field of organic electrosynthesis technology, specifically relating to a method for electrocatalytic synthesis of sulfur-containing spirocyclic indoline compounds from thiophenols and isonitriles. Background Technology

[0002] Spirocyclic indoline is an important class of nitrogen-containing heterocyclic compounds with a unique three-dimensional rigid skeleton structure. It possesses a variety of pharmacological activities, including anti-inflammatory, analgesic, antimalarial, antithrombotic, and neuroprotective effects, making it a research hotspot in drug design and organic synthesis. This type of structure connects the indoline unit to another ring system via a spirocarbon atom, endowing the molecule with special conformations and physicochemical properties, demonstrating significant value in medicinal chemistry. Many natural alkaloids (such as strychnine) contain this skeleton and possess various biological activities such as antitumor, antibacterial, and analgesic effects, making them highly sought after in innovative drug development. Therefore, developing efficient synthetic methods is of great importance for drug development.

[0003] Isonitriles are an important class of nitrogen-containing organic compounds with unique molecular structures exhibiting both electrophilic and nucleophilic properties at their carbon atoms, resulting in extremely reactive chemical properties. Benefiting from this amphiphilic reactivity, isonitriles can participate in various organic transformations, including addition, cyclization, tandem, and multicomponent reactions, constructing diverse nitrogen-containing heterocycles and complex molecular skeletons. Furthermore, isonitriles possess advantages such as good functional group compatibility, mild reaction conditions, and easy structural modification, making them classic raw materials for constructing complex heterocycles and spirocycles in organic synthetic chemistry, playing an irreplaceable role in medicinal chemistry and natural product synthesis.

[0004] Spirocyclic indolines not only possess significant biological activity and are widely found in natural products, but they are also key intermediates in the construction of other complex heterocyclic structures. Koumine, a major alkaloid extracted from the traditional Chinese medicine *Gelsemium elegans*, exhibits anti-inflammatory, analgesic, and immunomodulatory activities. It can inhibit joint swelling and neuroinflammation, and its effects are related to TSPO with low toxicity, showing promising development potential (J. Nat. Prod. 2016, 79, 2635-2643). Aristoserratenine, derived from the leaf extract of the New Zealand plant *Aristotelia serrata*, possesses butyrylcholinesterase inhibitory and antioxidant activities, demonstrating potential in the adjunctive treatment of Alzheimer's disease (Food Bioprod. Process. 2020, 124, 445-454). Aspidospermidine is a monoterpenoid indole alkaloid belonging to the Apocynaceae family. It possesses good antimalarial activity, with its free ethyl side chain being the key active group. It also has potential application value in reversing Plasmodium resistance (Planta Med. 2002, 68, 142-144). (5-chloro-1H-indole-2-yl)((3R)-1'-(piperidin-3-yl)spiro[indoline-3,3'-pyrrolidine]-1-yl)methyl ketone is a SKY kinase inhibitor that exerts its antithrombotic effect by targeting the Gas6 signaling pathway. Although this compound has relatively weak activity and limitations such as CYP inhibition, it serves as a novel lead compound, providing an important template for developing antiplatelet drugs with low bleeding risk (Bioorg. Med. Chem. Lett. 2012, 22, 190-193). Spirocyclic indoline skeletons have shown important value in multiple disease areas. Developing efficient, simple, and green synthetic methods is of great scientific significance and application prospects for promoting drug research on this type of compound.

[0005] Existing electrochemical methods for synthesizing spirocyclic indolines (such as phosphonylation) rely on specific phosphorus-containing precursors, limiting substrate applicability. Previous studies have reported an electrochemical cyclization method for synthesizing 2-(thio)benzothiazole from isonitriles and thiophenols. However, this method, using benzothiazole as the product, cannot construct a spirocyclic indoline skeleton.

[0006] Currently, there are no reports of constructing sulfur-containing spirocyclic indoline compounds using thiophenols or thiols as sulfur sources via electrochemical methods. Summary of the Invention

[0007] This invention provides a method for the electrochemical synthesis of sulfur-containing spirocyclic indoline compounds, using readily available thiophenols or thiols as the sulfur source, achieving broader functional group compatibility, and providing a new route for the green synthesis of sulfur-containing spirocyclic indoline compounds.

[0008] This invention discloses a method for the electrocatalytic synthesis of sulfur-containing spirocyclic indoline compounds from thiophenols and isonitriles, comprising the following steps:

[0009] Indoleethyl isonitrile compound (I) and thiophenol or thiol are dissolved in an organic solvent in the presence of an electrolyte;

[0010] After dissolution, a carbon rod was used as the anode and a platinum sheet as the cathode. Electrolysis was carried out with constant current and stirring at room temperature. The reaction process was monitored by thin-layer chromatography.

[0011] After the reaction was completed, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain a sulfur-containing spirocyclic indoline compound with the structure shown in formula (II).

[0012] The synthetic route for the sulfur-containing spirocyclic indoline compound is as follows:

[0013] ;

[0014] Wherein, R is selected from methyl, tert-butyl, n-butyl, benzyl, naphthyl, p-tolyl, o-tolyl, and m-tolyl.

[0015] Furthermore, the molar ratio of the indoleethyl isonitrile compound to thiophenol or thiol is 1:(1.2~1.8).

[0016] Furthermore, the electrolyte is selected from at least one of ammonium bromide, ammonium iodide, and tetrabutylammonium iodide.

[0017] Furthermore, the organic solvent is selected from at least one of dimethyl sulfoxide, acetonitrile, and methanol.

[0018] Furthermore, the current for the constant current electrolysis is 5~15 mA.

[0019] Furthermore, the stirring reaction time is 2 to 4 hours.

[0020] Furthermore, the silica gel column chromatography purification uses petroleum ether and ethyl acetate as eluents, wherein the volume ratio of petroleum ether to ethyl acetate is 2:1.

[0021] The method of the present invention has the following beneficial effects:

[0022] (1) No metal catalysts or exogenous oxidants are required, making it green and environmentally friendly;

[0023] (2) The reaction conditions are mild and can be carried out at room temperature;

[0024] (3) It has good functional group compatibility and can be compatible with a variety of substituents;

[0025] (4) The product yield is good and the separation is simple;

[0026] (5) High atom economy and environmentally friendly. Detailed Implementation

[0027] The present invention will be further described below with reference to embodiments, but this is not intended to limit the scope of the invention.

[0028] Example 1:

[0029] Preparation and characterization of 2-methyl-2'-(p-toluenethio)-4',5'-dihydrospiro[indole-3,3'-pyrrole] (3a):

[0030] ;

[0031] 0.3 mmol of 3-(2-isocyanoethyl)-2-methylindole, 0.45 mmol of p-methylthiophenol, and 0.6 mmol of ammonium bromide were added to a 10 mL three-necked flask, dissolved in 6 mL of methanol. The flask was stirred for 2 hours at a constant current of 15 mA at room temperature using a carbon rod as the anode and a platinum sheet as the cathode. The reaction was monitored by TLC. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 2:1 elution) to obtain the target product 3a.

[0032] Product 3a characterization: colorless liquid (yield = 76%, 69.9 mg). 1 H NMR (600 MHz, CDCl3) δ7.57 (d, J = 7.7 Hz, 1H), 7.41 - 7.38 (m, 1H), 7.33 - 7.30 (m, 3H), 7.28 -7.25 (m, 1H), 7.14 (d, J = 7.9 Hz, 2H), 4.29 - 4.24 (m, 1H), 4.18 - 4.13 (m,1H), 2.51 - 2.47 (m, 1H), 2.43 - 2.39 (m, 1H), 2.35 (s, 3H), 2.32 (s, 3H). 13 CNMR (150 MHz, CDCl3) δ 180.68, 172.34, 155.64, 140.19, 139.68, 134.74,130.13, 129.01, 126.18, 124.67, 122.34, 120.35, 75.77, 61.12, 34.45, 21.41,16.42. HRMS (m / z) (ESI): calcd for C 19 H 18 N2S +[M+H] + 307.1264, found 307.1271.

[0033] To further verify the scale-up application potential of this invention, product 3a was prepared on a gram-scale basis:

[0034] 6.0 mmol of 3-(2-isocyanoethyl)-2-methylindole, 9.0 mmol of p-toluenethiophenol, and 12.0 mmol of ammonium bromide were placed in a 100 mL three-necked flask, dissolved in 100 mL of acetonitrile, and reacted at room temperature for 2 hours at a constant current of 150 mA using a carbon rod as the anode and a platinum sheet as the cathode. After the reaction, the product was purified using the same post-treatment method, successfully obtaining 1.18 g of the target product 3a with a separation yield of 64%.

[0035] Example 2:

[0036] Preparation and characterization of 2-methyl-2'-(o-tolylthio)-4',5'-dihydrospiro[indole-3,3'-pyrrole] (3b):

[0037] ;

[0038] 0.3 mmol of 3-(2-isocyanoethyl)-2-methylindole, 0.54 mmol of o-methylthiophenol, and 0.6 mmol of ammonium iodide were added to a 10 mL three-necked flask, dissolved in 6 mL of dimethyl sulfoxide. The mixture was stirred for 3 hours at a constant current of 15 mA at room temperature using a carbon rod as the anode and a platinum sheet as the cathode. The reaction was monitored by TLC. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 2:1 elution) to obtain the target product 3b.

[0039] Product 3b characterization: colorless liquid (yield = 82%, 75.4 mg). 1 H NMR (400 MHz, CDCl3) δ7.57 (d, J = 7.7 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.38 - 7.33 (m, 1H), 7.29(d, J = 7.4 Hz, 1H), 7.24 - 7.22 (m, 3H), 7.14 - 7.10 (m, 1H), 4.24 - 4.16(m, 1H), 4.13 - 4.05 (m, 1H), 2.46 - 2.40 (m, 1H), 2.38 - 2.35 (m, 1H), 2.34(d, J = 2.0 Hz, 3H), 2.30 (s, 3H).13 C NMR (100 MHz, CDCl3) δ 180.28, 170.42,155.26, 141.99, 140.06, 135.83, 130.50, 129.89, 128.67, 127.26, 126.37,125.82, 121.85, 120.02, 75.38, 60.82, 34.13, 20.47, 16.11. HRMS (m / z) (ESI):calcd for C 19 H 18 N2S + [M+H] + 307.1264, found 307.1263.

[0040] Example 3:

[0041] Preparation and characterization of 2-methyl-2'-(m-toluenethio)-4',5'-dihydrospiro[indole-3,3'-pyrrole] (3c):

[0042] ;

[0043] 0.3 mmol of 3-(2-isocyanoethyl)-2-methylindole, 0.54 mmol of m-methylthiophenol, and 0.6 mmol of tetrabutylammonium iodide were added to a 10 mL three-necked flask, dissolved in 6 mL of acetonitrile. The reaction was carried out with a carbon rod as the anode and a platinum sheet as the cathode, under constant current of 15 mA and at room temperature for 3.5 hours with stirring. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 2:1 elution) to obtain the target product 3c.

[0044] Product 3C characterization: colorless liquid (yield = 54%, 49.6 mg). 1 H NMR (400 MHz, CDCl3) δ7.45 (d, J = 7.7 Hz, 1H), 7.26 (d, J = 15.0 Hz, 1H), 7.20 (d, J = 7.3 Hz,1H), 7.15 - 7.07 (m, 4H), 7.01 (d, J = 7.2 Hz, 1H), 4.18 - 4.11 (m, 1H), 4.07- 4.00 (m, 1H), 2.36 - 2.31 (m, 1H), 2.29 - 2.25 (m, 1H), 2.23 (s, 3H), 2.18(s, 3H). 13C NMR (100 MHz, CDCl3) δ 180.34, 171.66, 155.45, 139.98, 138.77,134.94, 131.57, 130.10, 128.81, 128.77, 127.65, 125.93, 122.10, 120.10,75.61, 60.90, 34.19, 21.17, 16.20. HRMS (m / z) (ESI): calcd for C 19 H 18 N2S + [M+H] + 307.1264, found 307.1264.

[0045] Example 4:

[0046] Preparation and characterization of 2'-((2,4-dimethylphenyl)thio)-2-methyl-4',5'-dihydrospiro[indole-3,3'-pyrrole] (3d):

[0047] ;

[0048] 0.3 mmol of 3-(2-isocyanoethyl)-2-methylindole, 0.45 mmol of 2,4-dimethylthiophenol, and 0.6 mmol of ammonium bromide were added to a 10 mL three-necked flask, dissolved in 6 mL of methanol. The reaction was carried out with a carbon rod as the anode and a platinum sheet as the cathode, under constant current of 5 mA and at room temperature for 4 hours with stirring. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 2:1 elution) to obtain the target product 3d.

[0049] Product 3D characterization: colorless liquid (yield = 64%, 61.5 mg). 1H NMR (400 MHz, CDCl3) δ7.58 (d, J = 7.7 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.30 - 7.28 (m, 2H), 7.23(d, J = 6.7 Hz, 1H), 7.06 (s, 1H), 6.96 (d, J = 7.8 Hz, 1H), 4.26 - 4.19 (m,1H), 4.15 - 4.08 (m, 1H), 2.50 - 2.44 (m, 1H), 2.39 (dd, J = 8.2, 6.3 Hz,1H), 2.35 (s, 3H), 2.27 (s, 6H). 13 C NMR (100 MHz, CDCl3) δ 180.67, 171.21,155.45, 142.05, 140.35, 140.33, 136.05, 131.71, 128.87, 127.51, 126.05,123.96, 122.09, 120.25, 75.58, 61.05, 34.44, 21.25, 20.60, 16.34. HRMS (m / z)(ESI): calcd for C 20 H 20 N2S + [M+H] + 321.1420, found 321.1421.

[0050] Example 5:

[0051] Preparation and characterization of 2'-((4-tert-butylphenyl)thio)-2-methyl-4',5'-dihydrospiro[indole-3,3'-pyrrole](3e):

[0052] ;

[0053] 0.3 mmol of 3-(2-isocyanoethyl)-2-methylindole, 0.36 mmol of p-tert-butylthiophenol, and 0.6 mmol of ammonium iodide were added to a 10 mL three-necked flask, dissolved in 6 mL of dimethyl sulfoxide. The mixture was stirred for 3 hours at room temperature with a carbon rod as the anode and a platinum sheet as the cathode, under a constant current of 5 mA. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 2:1 elution) to obtain the target product 3e.

[0054] Product 3e characterization: colorless liquid (yield = 40%, 41.8 mg). 1 H NMR (400 MHz, CDCl3) δ7.56 (d, J = 7.7 Hz, 1H), 7.41 - 7.35 (m, 5H), 7.33 - 7.31 (m, 1H), 7.27 -7.23 (m, 1H), 4.33 - 4.26 (m, 1H), 4.22 - 4.14 (m, 1H), 2.53 - 2.46 (m, 1H), 2.43 - 2.38 (m, 1H), 2.36 (s, 3H), 1.29 (s, 9H). 13 C NMR (100 MHz, CDCl3) δ180.64, 172.03, 155.61, 152.38, 140.22, 134.18, 128.98, 126.39, 126.16,124.76, 122.31, 120.35, 75.84, 61.11, 34.77, 34.44, 31.24, 16.41. HRMS (m / z)(ESI): calcd for C 22 H 24 N2S + [M+H] + 349.1733, found 349.1731.

[0055] Example 6:

[0056] Preparation and characterization of 2'-((4-chlorophenyl)thio)-2-methyl-4',5'-dihydrospiro[indole-3,3'-pyrrole] (3f):

[0057] ;

[0058] 0.3 mmol of 3-(2-isocyanoethyl)-2-methylindole, 0.36 mmol of p-chlorothiophenol, and 0.6 mmol of tetrabutylammonium iodide were added to a 10 mL three-necked flask, dissolved in 6 mL of acetonitrile. The reaction was carried out with a carbon rod as the anode and a platinum sheet as the cathode, under constant current of 5 mA and at room temperature for 2 hours with stirring. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 2:1 elution) to obtain the target product 3f.

[0059] Product 3f characterization: white solid (yield = 68%, 66.7 mg). mp: 115.1 - 117.3 ℃.1 HNMR (400 MHz, CDCl3) δ 7.55 (d, J = 7.7 Hz, 1H), 7.37 (dd, J = 7.5, 1.4 Hz,1H), 7.34 (d, J = 1.9 Hz, 1H), 7.33 (t, J = 2.0 Hz, 1H), 7.29 - 7.27 (m, 2H),7.24 - 7.21 (m, 2H), 4.29 - 4.22 (m, 1H), 4.17 - 4.09 (m, 1H), 2.49 - 2.42(m, 1H), 2.40 - 2.35 (m, 1H), 2.31 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 180.05,171.00, 155.38, 139.66, 135.53, 135.38, 129.18, 128.88, 126.55, 126.00,122.06, 120.15, 75.48, 60.88, 34.05, 16.14. HRMS (m / z) (ESI): calcd forC 18 H 15 ClN2S + [M+H] + 327.0717, found 327.0715.

[0060] Example 7:

[0061] Preparation and characterization of 2'-((4-bromophenyl)thio)-2-methyl-4',5'-dihydrospiro[indole-3,3'-pyrrole] (3 g):

[0062] ;

[0063] 0.3 mmol of 3-(2-isocyanoethyl)-2-methylindole, 0.45 mmol of p-bromothiophenol, and 0.6 mmol of ammonium bromide were added to a 10 mL three-necked flask, dissolved in 6 mL of dimethyl sulfoxide. The reaction was carried out with a carbon rod as the anode and a platinum sheet as the cathode, under constant current of 10 mA and at room temperature with stirring for 2 hours. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 2:1 elution) to obtain 3 g of the target product.

[0064] Product 3g characterization: colorless liquid (yield = 47%, 52.4 mg). 1H NMR (400 MHz, CDCl3) δ7.57 (d, J = 7.7 Hz, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7.41 - 7.37 (m, 1H), 7.30- 7.27 (m, 3H), 7.25 (t, J = 7.3 Hz, 1H), 4.32 - 4.24 (m, 1H), 4.20 - 4.12(m, 1H), 2.53 - 2.46 (m, 1H), 2.44 - 2.37 (m, 1H), 2.33 (s, 3H). 13 C NMR (100MHz, CDCl3) δ 180.29, 171.20, 155.59, 139.86, 135.97, 132.38, 129.12, 127.40,126.23, 123.98, 122.27, 120.40, 75.73, 61.12, 34.29, 16.37. HRMS (m / z) (ESI):calcd for C 18 H 15 BrN2S + [M+H] + 371.0212, found 371.0213.

[0065] Example 8:

[0066] Preparation and characterization of 2-methyl-2'-((4-trifluoromethylphenyl)thio)-4',5'-dihydrospiro[indole-3,3'-pyrrole] (3h):

[0067] ;

[0068] 0.3 mmol of 3-(2-isocyanoethyl)-2-methylindole, 0.45 mmol of p-trifluoromethylthiophenol, and 0.6 mmol of ammonium iodide were added to a 10 mL three-necked flask, dissolved in 6 mL of acetonitrile. The reaction was carried out with a carbon rod as the anode and a platinum sheet as the cathode, under constant current of 10 mA and at room temperature with stirring for 2 hours. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 2:1 elution) to obtain the target product.

[0069] Product characterization after 3 hours: colorless liquid (yield = 45%, 48.7 mg). 1H NMR (400 MHz, CDCl3) δ7.62 - 7.53 (m, 5H), 7.40 (t, J = 7.5 Hz, 1H), 7.31 (d, J = 6.9 Hz, 1H), 7.26(d, J = 14.7 Hz, 1H), 4.35 - 4.28 (m, 1H), 4.23 - 4.15 (m, 1H), 2.55 - 2.48(m, 1H), 2.46 - 2.39 (m, 1H), 2.35 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 180.14,170.46, 155.66, 139.74, 134.19, 133.37 (d, J = 1.0 Hz), 130.96 (q, J = 32.7Hz), 129.20, 126.27, 125.91 (q, J = 3.7 Hz), 123.78 (q, J = 271.0 Hz), 122.28, 120.70, 120.45, 75.87, 61.20, 34.12, 16.33. 19 F NMR (376 MHz, CDCl3) δ-62.91. HRMS (m / z) (ESI): calcd for C 19 H 15 F3N2S + [M+H] + 361.0981, found361.0979.

[0070] Example 9:

[0071] Preparation and characterization of 2-methyl-2'-(methylthio)-4',5'-dihydrospiro[indole-3,3'-pyrrole] (3i):

[0072] ;

[0073] 0.3 mmol of 3-(2-isocyanoethyl)-2-methylindole, 0.54 mmol of methanethiol, and 0.6 mmol of tetrabutylammonium iodide were added to a 10 mL three-necked flask, dissolved in 6 mL of methanol. The flask was stirred for 4 hours at a constant current of 15 mA at room temperature using a carbon rod as the anode and a platinum sheet as the cathode. The reaction was monitored by TLC. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 2:1 elution) to obtain the target product 3i.

[0074] Product 3i characterization: colorless liquid (yield = 53%, 36.6 mg). 1 H NMR (400 MHz, CDCl3) δ7.54 (d, J = 7.7 Hz, 1H), 7.37 - 7.33 (m, 1H), 7.24 - 7.18 (m, 2H), 4.35 -4.28 (m, 1H), 4.25 - 4.17 (m, 1H), 2.54 - 2.47 (m, 1H), 2.44 - 2.39 (m, 1H), 2.35 (s, 3H), 2.25 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 180.89, 172.90, 155.54,140.47, 128.93, 126.08, 122.17, 120.28, 75.67, 60.82, 34.63, 16.25, 13.70.HRMS (m / z) (ESI): calcd for C 13 H 14 N2S + [M+H] + 231.0951, found 231.0948.

[0075] Example 10:

[0076] Preparation and characterization of 2'-(butyrothio)-2-methyl-4',5'-dihydrospiro[indole-3,3'-pyrrole] (3j):

[0077] ;

[0078] 0.3 mmol of 3-(2-isocyanoethyl)-2-methylindole, 0.54 mmol of n-butanethiol, and 0.6 mmol of ammonium bromide were added to a 10 mL three-necked flask, dissolved in 6 mL of acetonitrile. The reaction was carried out with a carbon rod as the anode and a platinum sheet as the cathode, under constant current of 15 mA and at room temperature for 3 hours with stirring. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 2:1 elution) to obtain the target product 3j.

[0079] Product 3j characterization: colorless liquid (yield = 50%, 49.9 mg). 1H NMR (400 MHz, CDCl3) δ7.48 (d, J = 7.6 Hz, 1H), 7.30 - 7.26 (m, 1H), 7.14 (q, J = 7.5 Hz, 2H), 4.26- 4.21 (m, 1H), 4.18 - 4.12 (m, 1H), 2.97 - 2.92 (m, 1H), 2.88 - 2.81 (m,1H), 2.42 - 2.37 (m, 1H), 2.34 - 2.27 (m, 1H), 2.19 (d, J = 2.0 Hz, 3H), 1.52- 1.45 (m, 2H), 1.29 - 1.24 (m, 2H), 0.82 - 0.78 (m, 3H). 13 C NMR (100 MHz, CDCl3) δ 180.72, 172.01, 155.43, 140.35, 128.64, 125.84, 121.99, 120.01,75.68, 60.70, 34.16, 30.70, 30.51, 21.79, 16.05, 13.49. HRMS (m / z) (ESI):calcd for C 16 H 20 N2S + [M+H] + 273.1420, found 273.1421.

[0080] Example 11:

[0081] Preparation and characterization of 2'-(tert-butylthio)-2-methyl-4',5'-dihydrospiro[indole-3,3'-pyrrole] (3k):

[0082] ;

[0083] 0.3 mmol of 3-(2-isocyanoethyl)-2-methylindole, 0.45 mmol of tert-butyl mercaptan, and 0.6 mmol of ammonium iodide were added to a 10 mL three-necked flask, dissolved in 6 mL of methanol. The flask was stirred for 3.5 hours at a constant current of 15 mA at room temperature using a carbon rod as the anode and a platinum sheet as the cathode. The reaction was monitored by TLC. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 2:1 elution) to obtain the target product 3k.

[0084] Product 3K characterization: colorless liquid (yield = 64%, 52.3 mg). 1H NMR (400 MHz, CDCl3) δ7.51 (d, J = 7.7 Hz, 1H), 7.33 - 7.29 (m, 1H), 7.21 - 7.14 (m, 2H), 4.37 -4.30 (m, 1H), 4.25 - 4.17 (m, 1H), 2.37 - 2.30 (m, 1H), 2.27 - 2.22 (m, 4H), 1.44 (s, 9H). 13 C NMR (100 MHz, CDCl3) δ 180.86, 170.50, 155.43, 140.44,128.47, 125.72, 121.90, 119.88, 77.01, 61.38, 47.64, 33.07, 29.81, 16.10.HRMS (m / z) (ESI): calcd for C 16 H 20 N2S + [M+H] + 273.1420, found 273.1420.

[0085] Example 12:

[0086] Preparation and characterization of 2'-(cyclohexylthio)-2-methyl-4',5'-dihydrospiro[indole-3,3'-pyrrole] (3l):

[0087] ;

[0088] 0.3 mmol of 3-(2-isocyanoethyl)-2-methylindole, 0.45 mmol of cyclohexanethiol, and 0.6 mmol of tetrabutylammonium iodide were added to a 10 mL three-necked flask, dissolved in 6 mL of dimethyl sulfoxide. The reaction was carried out with a carbon rod as the anode and a platinum sheet as the cathode, under constant current of 15 mA and at room temperature for 2 hours with stirring. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 2:1 elution) to obtain 3 μL of the target product.

[0089] Product 3L characterization: white solid (yield = 64%, 57.3 mg). mp: 91.4 - 93.3 ℃. 1H NMR(400 MHz, CDCl3) δ 7.51 (d, J = 7.7 Hz, 1H), 7.32 - 7.28 (m, 1H), 7.19 - 7.14(m, 2H), 4.32 - 4.25 (m, 1H), 4.21 - 4.14 (m, 1H), 3.61 - 3.56 (m, 1H), 2.43- 2.37 (m, 1H), 2.34 - 2.27 (m, 1H), 2.22 (s, 3H), 1.99 - 1.97 (m, 1H), 1.93- 1.89 (m, 1H), 1.64 - 1.57 (m, 2H), 1.53 - 1.49 (m, 1H), 1.36 - 1.17 (m, 5H). 13 C NMR (100 MHz, CDCl3) δ 180.72, 171.21, 155.39, 140.29, 128.54,125.76, 121.93, 119.90, 75.80, 60.83, 43.69, 33.80, 32.80, 32.41, 25.63,25.57, 25.46, 16.01. HRMS (m / z) (ESI): calcd for C 18 H 22 N2S + [M+H] + 299.1577, found 299.1577.

[0090] Example 13:

[0091] Preparation and characterization of 2'-(benzylthio)-2-methyl-4',5'-dihydrospiro[indole-3,3'-pyrrole] (3m):

[0092] ;

[0093] 0.3 mmol of 3-(2-isocyanoethyl)-2-methylindole, 0.36 mmol of benzyl thiol, and 0.6 mmol of ammonium bromide were added to a 10 mL three-necked flask, dissolved in 6 mL of acetonitrile. The reaction was carried out with a carbon rod as the anode and a platinum sheet as the cathode, under constant current of 5 mA and at room temperature with stirring for 2 hours. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 2:1 elution) to obtain the target product 3m.

[0094] Product 3M characterization: colorless liquid (yield = 66%, 60.7 mg). 1 H NMR (400 MHz, CDCl3) δ7.51 (d, J = 7.7 Hz, 1H), 7.30 - 7.26 (m, 1H), 7.21 - 7.11 (m, 7H), 4.32 -4.23 (m, 2H), 4.19 - 4.13 (m, 1H), 4.09 (d, J = 13.2 Hz, 1H), 2.40 - 2.28 (m, 2H), 2.12 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 180.38, 171.13, 155.34, 139.86,136.60, 128.64, 128.58, 128.15, 127.03, 125.73, 121.94, 119.87, 75.31, 60.56,35.00, 34.06, 15.86. HRMS (m / z) (ESI): calcd for C 19 H 18 N2S + [M+H] + 307.1264, found 307.1262.

[0095] Example 14:

[0096] Preparation and characterization of 2-methyl-2'-(naphthyl-2-thio)-4',5'-dihydrospiro[indole-3,3'-pyrrole] (3n):

[0097] ;

[0098] 0.3 mmol of 3-(2-isocyanoethyl)-2-methylindole, 0.45 mmol of 2-naphthiophenol, and 0.6 mmol of ammonium iodide were added to a 10 mL three-necked flask, dissolved in 6 mL of dimethyl sulfoxide. The reaction was carried out with a carbon rod as the anode and a platinum sheet as the cathode, under constant current of 10 mA and at room temperature for 2 hours with stirring. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 2:1 elution) to obtain the target product 3n.

[0099] Product 3n characterization: colorless liquid (yield = 35%, 36.0 mg). 1H NMR (400 MHz, CDCl3) δ7.95 (s, 1H), 7.82 - 7.80 (m, 2H), 7.77 - 7.75 (m, 1H), 7.58 (d, J = 7.7 Hz,1H), 7.51 - 7.45 (m, 3H), 7.43 - 7.39 (m, 1H), 7.37 (d, J = 6.8 Hz, 1H), 7.31- 7.27 (m, 1H), 4.33 - 4.26 (m, 1H), 4.22 - 4.14 (m, 1H), 2.56 - 2.49 (m,1H), 2.47 - 2.42 (m, 1H), 2.40 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 180.63,171.96, 155.66, 140.17, 134.20, 133.60, 133.40, 131.20, 129.14, 128.90,128.02, 127.88, 127.21, 126.64, 126.29, 125.63, 122.39, 120.44, 75.92, 61.23,34.42, 16.50. HRMS (m / z) (ESI): calcd for C 22 H 18 N2S + [M+H] + 343.1264, found343.1266.

[0100] The electrochemical synthesis method provided by this invention can be used for the large-scale preparation of sulfur-containing spirocyclic indoline compounds. Given the important pharmacological activities of this skeleton in anti-inflammatory, antimalarial, and antithrombotic fields, this method, validated through gram-scale reactions (see preparation in 3a), can provide a stable source of compounds for medicinal chemistry research and has practical synthetic applicability. Furthermore, this method operates under mild conditions and exhibits good functional group compatibility, possessing the potential for later-stage structural modification of molecules containing thiol functional groups. This facilitates the rapid construction of a library of structurally diverse spirocyclic indoline derivatives, accelerating structure-activity relationship studies and the discovery of novel lead compounds in this class of compounds.

Claims

1. A method for the electrocatalytic synthesis of sulfur-containing spirocyclic indoline compounds from thiophenols and isonitriles, characterized in that, Includes the following steps: Indoleethyl isonitrile compound (I) and thiophenol or thiol are dissolved in an organic solvent in the presence of an electrolyte; After dissolution, a carbon rod was used as the anode and a platinum sheet as the cathode. Electrolysis was carried out with constant current and stirring at room temperature. The reaction process was monitored by thin-layer chromatography. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain a sulfur-containing spirocyclic indoline compound with the structure shown in formula (II). The indoleethyl isonitrile compound has the structure shown in formula (I): ； The sulfur-containing spirocyclic indoline compound has the structure shown in formula (II): ； Wherein, R is selected from methyl, tert-butyl, n-butyl, benzyl, naphthyl, p-tolyl, o-tolyl, and m-tolyl.

2. The method according to claim 1, characterized in that, The molar ratio of the indoleethyl isonitrile compound to thiophenol or thiol is 1:(1.2~1.8).

3. The method according to claim 1, characterized in that, The electrolyte is selected from at least one of ammonium bromide, ammonium iodide, and tetrabutylammonium iodide.

4. The method according to claim 1, characterized in that, The organic solvent is selected from at least one of dimethyl sulfoxide, acetonitrile, and methanol.

5. The method according to claim 1, characterized in that, The constant current electrolysis current is 5~15 mA.

6. The method according to claim 1, characterized in that, The stirring reaction time is 2 to 4 hours.

7. The method according to claim 1, characterized in that, The silica gel column chromatography purification uses petroleum ether and ethyl acetate as eluents, wherein the volume ratio of petroleum ether to ethyl acetate is 2:

1.

8. The method according to claim 1, characterized in that, The thiophenol is selected from at least one of p-methylthiophenol, o-methylthiophenol, m-methylthiophenol, 2,4-dimethylthiophenol, p-tert-butylthiophenol, p-chlorothiophenol, p-bromothiophenol, p-trifluoromethylthiophenol, and 2-naphthiophenol. The thiol is selected from at least one of methanethiol, n-butanethiol, tert-butanethiol, cyclohexanethiol, and benzylthiol.

9. The method according to claim 1, characterized in that, The indole ethyl isonitrile compound is 3-(2-isocyanoethyl)-2-methylindole.

10. A sulfur-containing spirocyclic indoline compound prepared by the method according to any one of claims 1 to 9.

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