Method for synthesizing indole fused ring compound through light-induced continuous flow

Abstract

The invention discloses a method for synthesizing an indole fused ring compound through light-induced continuous flow, which comprises the following steps: dissolving a compound shown as a formula I and a compound shown as a formula II in an organic solvent to obtain a homogeneous solution; and pumping the obtained homogeneous solution into a micro-channel reaction device provided with a light source, and reacting to obtain the indole fused ring compound as shown in the formula III. The novel condensed ring indole compound is obtained by taking nitro-aromatic hydrocarbon as a photosensitizer, absorbing energy through ultraviolet irradiation, attacking double bonds on N-Boc indole by the excited nitro-aromatic hydrocarbon to generate triple double free radicals, and carrying out cyclization reaction after electron transition. Compared with the prior art, the light-induced continuous flow reaction device is innovatively applied, the method is green, efficient, free of metal residues and mild in reaction condition, and the synthesized novel product, namely the fused heterocycle indole, has a wide application prospect in the aspect of synthesizing medical products.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry and fine chemical synthesis, and relates to a method for photo-induced continuous flow synthesis of indole fused-ring compounds. Background Technology

[0002] Nitroaromatics are fundamental molecules and key structural units in organic chemistry, commonly used as precursors in coupling reactions to synthesize amine compounds. In recent years, it has been discovered that nitroaromatics can act as photosensitizers and oxidants in photodriven reactions, serving as a rich source of raw materials for photoreactions. In 2022, Ruffoni et al. found that photoexcited nitroaromatics can be a powerful tool for the oxidative cracking of olefins. Compared to photochemical reactions in the presence of catalysts, research on photochemical reactions of nitroaromatics without catalysts is relatively limited, necessitating the development of new reactions to explore the intrinsic potential of nitrobenzene.

[0003] Indole rings are among the most common heterocycles found in nature and in synthetic bioactive compounds. The lone pair of electrons in the nitrogen atom of the indole ring can form a conjugated system with the surrounding π electrons, thereby enhancing the stability and reactivity of the molecule. Fused-ring indole compounds have attracted increasing attention due to their unique chemical properties and broad bioactivity. Greaney et al. disclosed a Pd-catalyzed coupling reaction to obtain indole heterofused-ring compounds. Existing synthetic methods typically require complex steps, high temperatures and pressures, or harsh conditions using strong oxidants or transition metal catalysis. Developing a method for the efficient synthesis of heterofused-ring indoles under mild conditions has significant research and practical application value. Summary of the Invention

[0004] Objective: This invention primarily provides a novel, green, and efficient synthetic method for synthesizing indole fused-ring compounds via photoinduced continuous flow under visible light conditions. The method utilizes a visible-light-induced photoredox neutral radical addition reaction. In this reaction, nitroaromatic hydrocarbons act as photosensitizers, reacting with the double bonds of indole to form indole fused rings after ultraviolet light absorption. The advantages of this method include the innovative application of a microfluidic reaction apparatus, the use of visible-light catalysis, mild reaction conditions, green and efficient operation, and the absence of metal residues. It also demonstrates potential in drug discovery and development. This method is expected to become a highly practical tool and provide an alternative method for the formation of fused rings from nitroaromatic hydrocarbons and indole under catalyst-free conditions.

[0005] Technical solution: To achieve the above objectives, the technical solution adopted by the present invention is as follows: A method for photo-induced continuous flow synthesis of indole fused-ring compounds includes the following steps: Compounds of Formula I and Formula II are dissolved in an organic solvent to obtain a homogeneous solution; the obtained homogeneous solution is pumped into a microchannel reaction device equipped with a light source to carry out the reaction, thereby obtaining the indole fused-ring compound shown in Formula III;

[0006] R1 is selected from hydrogen or halogen, and R2 is selected from carboxyl or nitro.

[0007] In the above method, nitroaromatic hydrocarbons are used as photosensitizers. After absorbing energy under ultraviolet light, the excited-state nitroaromatic hydrocarbons attack the double bonds on N-Boc indole to generate triple diradicals. After electronic transition, a cyclization reaction occurs, yielding novel fused-ring indole compounds.

[0008] As a specific implementation, the compound of formula I is 1-(tert-butyloxycarbonyl)-1H-indole-3-carboxylic acid or tert-butyl 3-nitro-1H-indole-1-carboxylic acid.

[0009] As a specific implementation scheme, the organic solvent is any one of ethyl acetate, dichloromethane, acetonitrile, and chloroform, preferably ethyl acetate.

[0010] As a specific implementation, the molar ratio of the compound of formula I to the compound of formula II is 1:(1.5~3), preferably 1:2.

[0011] As a specific implementation, the concentration of the compound of formula I in the homogeneous solution is 0.15~0.3 mmol / ml, preferably 0.2 mmol / ml.

[0012] As a specific implementation, the light source is violet light with a power of 8-12 W and a wavelength of 390-425 nm; preferably, the power is 10 W and the wavelength is 390 nm.

[0013] As a specific implementation, the microchannel reaction device includes a sampler, a microchannel reactor, a receiver, and a light source; the sampler, the microchannel reactor, and the receiver are connected in series via pipes; the light source is located outside the microchannel reactor, and its illumination range covers the microchannel reaction area, enabling it to provide uniform and effective illumination to the reaction system through the reactor wall, thereby achieving the continuous execution of the photoinduced reaction.

[0014] Furthermore, the microchannel reactor is a quartz coil with a diameter of 0.2~2 mm and a retention volume of 0.25~8 mL; the length of the connecting pipe between the injector and the microchannel reactor is 10 cm~50 cm; and the length of the connecting pipe between the microchannel reactor and the receiver is 10 cm~50 cm.

[0015] As a specific implementation, the flow rate of the homogeneous solution pumped into the microchannel reaction device is 0.05~0.2 mL / min, preferably 0.1 mL / min; the residence time of the reaction is 15~40 min, preferably 30 min, and the reaction temperature is room temperature. Beneficial effects

[0016] (1) Compared with the prior art, this invention proposes a photo-induced continuous flow synthesis method, which has significant advantages such as being green and efficient, having mild reaction conditions, requiring no additional photocatalyst and inert atmosphere protection, having no metal residues, and requiring no heating. This invention is the first to realize the construction of indole fused ring structures by radical rearrangement driven by nitroaromatics as an endogenous photosensitizer in a continuous flow system. With the help of the efficient mass transfer and uniform light environment of the microchannel reactor, excited-state nitroaromatics can participate in the reaction and be converted in a timely manner, thereby significantly reducing the occurrence of photoquenching and side reactions, and exhibiting better chemoselectivity and scalability than traditional batch photoreactors.

[0017] (2) The indole fused ring compounds prepared by this invention lay the foundation for the synthesis of pharmaceutical products, making them more competitive in the field of biomedical materials. Attached Figure Description

[0018] Figure 1 The 1H NMR spectrum of product III-1; Figure 2 The 1H NMR spectrum of product III-2; Detailed Implementation

[0019] The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments, and the advantages of the present invention in the above and / or other aspects will become clearer.

[0020] The reaction formula of this invention is as follows:

[0021] The structures of the fused-ring compound products shown in the following examples are illustrated in Table 1. Table 1

[0022] Unless otherwise specified, the experimental methods described in the following examples are conventional methods; unless otherwise specified, the reagents and materials are commercially available.

[0023] The method for synthesizing the compound represented by Formula I used in this invention is as follows:

[0024] Step (1): In a dry, double-necked 25 mL round-bottom flask equipped with a magnetic stir bar, add N-heterocyclic carbapenem catalyst (0.025 mmol) and tert-butyl 3-formyl-1H-indole-1-carboxylate (0.5 mmol). Add anhydrous tetrahydrofuran (3 mL) to the reaction vessel and then purge with O2 gas. Add DABCO (0.25 mmol) and purge with O2 gas again. Stir the reaction mixture under O2 (1 atm, O2 balloon) for 16 hours. After the reaction is complete as monitored by TLC, dilute the mixture with ethyl acetate (10 mL) and add 1.0 M sodium hydroxide aqueous solution. Separate the aqueous layer, wash with ethyl acetate (10 mL), and acidify with 3.0 M HCl aqueous solution (10 mL). The aqueous layer was extracted twice with ethyl acetate (10 mL), the combined organic layers were washed with brine, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to give the desired compound 1-(tert-butyloxycarbonyl)-1H-indole-3-carboxylic acid.

[0025] Step (2): Add aromatic hydrocarbon or heteroaromatic hydrocarbon (1 mmol) and NMe4NO3 (150 mg, 1.1 mmol) to the reaction tube and immediately dissolve in 1 mL of acetonitrile. Cool the reaction system to 0-5 °C and add trifluoroacetic anhydride solution (420 mg dissolved in 1 mL of acetonitrile). Incubate the reaction system at 0-5 °C for 4 hours. Monitor the reaction by thin-layer chromatography (TLC). After the reaction is complete, quench the reaction with saturated sodium carbonate solution. Extract with ethyl acetate and transfer to a round-bottom flask. Wash the combined organic layers with brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the desired compound, tert-butyl 3-nitro-1H-indole-1-carboxylate.

[0026] Example 1 At room temperature, 3,5-dinitrotrifluorotoluene (4 mmol, 2 equivalents) and 1-(tert-butyloxycarbonyl)-1H-indole-3-carboxylic acid (2 mmol, 1 equivalent) were added to ethyl acetate (10 mL) and mixed to obtain a homogeneous solution. This homogeneous solution was pumped into a microchannel reactor at a flow rate of 0.1 mL / min. The microchannel reactor was irradiated with a UV lamp (LED, wavelength 390 nm, 10 W) for 30 min, and the effluent was collected in a sample flask. The filtrate was concentrated under reduced pressure, and the residue was separated chromatographically on silica gel using a 6:1 eluent of petroleum ether and ethyl acetate to obtain the desired product III-1 with a conversion of 82%. The 1H NMR spectrum of product III-1 is shown below. Figure 1 As shown. Example

[0027] At room temperature, 3,5-dinitrotrifluorotoluene (4 mmol, 2 equivalents) and tert-butyl 3-nitro-1H-indole-1-carboxylate (2 mmol, 1 equivalent) were added to ethyl acetate (10 mL) and mixed to obtain a homogeneous solution. This homogeneous solution was pumped into a microchannel reactor at a flow rate of 0.1 mL / min. The microchannel reactor was irradiated with a UV lamp (LED, wavelength 390 nm, 10 W) for 30 min, and the effluent was collected in a sample flask. The filtrate was concentrated under reduced pressure, and the residue was separated chromatographically on silica gel using a 6:1 eluent of petroleum ether and ethyl acetate to obtain the desired product III-2 with a conversion of 76%. The 1H NMR spectrum of product III-2 is shown below. Figure 2 As shown.

[0028] 3,5-Dinitrotrifluorotoluene (4 mmol, 2 equivalents) was packed into a dry Schlenk tube equipped with a magnetic dome. The Schlenk tube was connected to a pipeline and purged with nitrogen three times. Then, 1-(tert-Butoxycarbonyl)-1H-indole-3-carboxylic acid (2 mmol, 1 equivalent) and ethyl acetate (10 mL) were added, the Schlenk tube was sealed, and a purple LED lamp was turned on for 24 h at room temperature. Subsequently, the reaction solution was extracted with water and ethyl acetate, the organic phase was collected, washed with saturated brine and anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was separated by silica gel chromatography using a 6:1 eluent of petroleum ether and ethyl acetate to obtain the desired product III-1 with a conversion of 40%.

[0029] 3,5-dinitrotrifluorotoluene (4 mmol, 2 equivalents) was packed into a dry Schlenk tube equipped with a magnetic dowel. The Schlenk tube was connected to a pipeline and purged with nitrogen three times. Then, tert-butyl 3-nitro-1H-indole-1-carboxylate (2 mmol, 1 equivalent) and ethyl acetate (10 mL) were added, the Schlenk tube was sealed, and a purple LED lamp was turned on for 24 h at room temperature. Subsequently, the reaction solution was extracted with water and ethyl acetate, the organic phase was collected, washed with saturated brine and anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was separated by silica gel chromatography using petroleum ether and ethyl acetate in a 6:1 eluent to obtain the desired product III-2 with a conversion of 37%.

[0030] At room temperature, 3,5-dinitrotrifluorotoluene (4 mmol, 2 equivalents) and 1-(tert-butyloxycarbonyl)-1H-indole-3-carboxylic acid (2 mmol, 1 equivalent) were added to ethyl acetate (10 mL) and mixed to obtain a homogeneous solution. The homogeneous solution was pumped into a microchannel reactor with a flow rate of 0.1 mL / min. The retention time in the microreactor without purple LED illumination was 30 min. The effluent was collected in a sample flask, but the desired product was not obtained.

[0031] At room temperature, 3,5-dinitrotrifluorotoluene (4 mmol, 2 equivalents) and tert-butyl 3-nitro-1H-indole-1-carboxylate (2 mmol, 1 equivalent) were added to ethyl acetate (10 mL) and mixed to obtain a homogeneous solution. The homogeneous solution was pumped into a microchannel reactor with a flow rate of 0.1 mL / min. The retention time in the microreactor without purple LED illumination was 30 min. The effluent was collected in a sample flask, but the desired product was not obtained.

[0032] This invention provides a method for photo-induced fused ring formation of nitroaromatic hydrocarbons and indole. Many methods and approaches exist for implementing this technical solution; the above description is merely a preferred embodiment of the invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principle of this invention, and these improvements and modifications should also be considered within the scope of protection of this invention. All components not explicitly stated in this embodiment can be implemented using existing technologies.

Claims

1. A method for synthesizing indole fused-ring compounds via photoinduced continuous flow, characterized in that, Includes the following steps: Compounds of Formula I and Formula II are dissolved in an organic solvent to obtain a homogeneous solution; the obtained homogeneous solution is pumped into a microchannel reaction device equipped with a light source to carry out the reaction, thereby obtaining the indole fused-ring compound shown in Formula III; R1 is selected from hydrogen or halogen, and R2 is selected from carboxyl or nitro.

2. The method for synthesizing indole fused-ring compounds by photoinduced continuous flow according to claim 1, characterized in that, The compound of Formula I is 1-(tert-butyloxycarbonyl)-1H-indole-3-carboxylic acid or tert-butyl 3-nitro-1H-indole-1-carboxylic acid.

3. The method for synthesizing indole fused-ring compounds by photoinduced continuous flow according to claim 1, characterized in that, The organic solvent is any one of ethyl acetate, dichloromethane, acetonitrile, and chloroform.

4. The method for synthesizing indole fused-ring compounds by photoinduced continuous flow according to claim 1, characterized in that, The molar ratio of the compound of formula I to the compound of formula II is 1:(1.5~3).

5. The method for synthesizing indole fused-ring compounds by photoinduced continuous flow according to claim 1, characterized in that, In the homogeneous solution, the concentration of compound I is 0.15~0.3 mmol / ml.

6. The method for synthesizing indole fused-ring compounds by photoinduced continuous flow according to claim 1, characterized in that, The light source is violet light, with a power of 8-12 W and a wavelength of 390-425 nm.

7. The method for synthesizing indole fused-ring compounds by photoinduced continuous flow according to claim 1, characterized in that, The microchannel reaction device includes a sample injector, a microchannel reactor, a receiver, and a light source; the sample injector, microchannel reactor, and receiver are connected in series via pipes; the light source is located outside the microchannel reactor, and its illumination range covers the microchannel reaction area, enabling it to provide uniform and effective illumination to the reaction system through the reactor wall, thereby achieving continuous photoinduced reaction.

8. The method for synthesizing indole fused-ring compounds by photoinduced continuous flow according to claim 7, characterized in that, The microchannel reactor is a quartz coil with a diameter of 0.2-2 mm and a retention volume of 0.25-8 mL; the length of the connecting pipe between the injector and the microchannel reactor is 10 cm-50 cm; the length of the connecting pipe between the microchannel reactor and the receiver is 10 cm-50 cm.

9. The method for synthesizing indole fused-ring compounds by photoinduced continuous flow according to claim 1, characterized in that, The homogeneous solution is pumped into the microchannel reaction device at a flow rate of 0.05~0.2 mL / min; the residence time of the reaction is 15~40 min, and the reaction temperature is room temperature.

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