A method for photo-induced titanium-catalyzed addition synthesis of phenanthridine compounds

Abstract

This invention belongs to the field of organic synthesis technology, specifically a method for the photo-induced titanium-catalyzed addition reaction to synthesize phenanthridine compounds. The method uses 2-isocyano-1,1'-biphenyl and cyclohexane oxide as raw materials, titanium dichlorophenocene as a catalyst, 4CzIPN as a photocatalyst, and triethylamine as a base, and performs an addition-cyclization reaction under blue light to obtain phenanthridine compounds. This invention utilizes readily available and inexpensive titanium dichlorophenocene as a catalyst, starting with activated cyclohexane oxide, which undergoes an addition reaction with 2-isocyano-1,1'-biphenyl, followed by intramolecular cyclization to obtain the phenanthridine compound 2-(phenanthrene-6-yl)cyclohexane-1-ol. The catalytic system of this invention is inexpensive and readily available, with mild reaction conditions and safe and efficient steps, solving the problems of excessive oxidant, low reaction yield, and long reaction time in the traditional synthesis of 2-(phenanthrene-6-yl)cyclohexane-1-ol, and has broad application prospects.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically a method for photo-induced titanium-catalyzed addition synthesis of phenanthridine compounds. Background Technology

[0002] It is an intermediate that can be modified to yield an active drug molecule, such as diaminophenanthridine, with the following structural formula: Diaminophenanthridine compounds contain phenanthridine pharmacophore groups and are widely used as DNA intercalating agents in anti-inflammatory applications. In the context of... The modified 5-hydroxytryptamine receptor, used as a natural ligand, has the following structural formula: It is easy to combine with drugs, thereby enabling them to exert their medicinal effects.

[0003] Currently, Wang et al. have achieved the Minisci reaction of heteroaromatic hydrocarbons, alkenes, and water by photocatalysis in the presence of excess peroxide. The synthesis was carried out, but the product yield was only 50%, and the method used an excess of oxidant and the reaction time was 24 hours. Summary of the Invention

[0004] To address the shortcomings of existing technologies, this invention provides a method for the photo-induced titanium-catalyzed addition reaction to synthesize phenanthridine compounds. The method uses 2-isocyano-1,1'-biphenyl and cyclohexane oxide as raw materials, titanium dichlorophenocene as a catalyst, 4CzIPN as a photocatalyst, and triethylamine as a base, and performs an addition-cyclization reaction under blue light to obtain phenanthridine compounds. This method utilizes readily available and inexpensive titanium dichlorophenocene as a catalyst, starting with the activation of cyclohexane oxide, followed by intramolecular cyclization with 2-isocyano-1,1'-biphenyl. The catalytic system is inexpensive and readily available, the reaction conditions are mild, and the steps are safe and efficient. This method solves the problems of excessive oxidant, long reaction time, and low yield in the traditional synthesis of 2-(phenanthrene-6-yl)cyclohexane-1-ol, and has broad application prospects.

[0005] Based on the above technical objectives, the present invention adopts the following technical solution:

[0006] This invention protects a method for synthesizing phenanthridine compounds by photoinduced titanium-catalyzed addition, comprising the following steps:

[0007] In an inert atmosphere, 2-isocyano-1,1'-biphenyl and cyclohexane oxide were used as raw materials, with titanium dichlorophenocene as a catalyst, 4CzIPN as a photocatalyst, and triethylamine as a base. These were mixed in an organic solvent and subjected to an addition-cyclization reaction under blue light. During the addition-cyclization reaction, 2-isocyano-1,1'-biphenyl and cyclohexane oxide first underwent addition followed by intramolecular cyclization to yield phenanthridine compounds. .

[0008] Preferably, the conditions for the addition-cyclization reaction are heating at 50°C to 80°C for 6 to 12 hours. At lower temperatures, the reaction cannot proceed completely, resulting in a lower yield; in this invention, the reaction is relatively complete at 6 to 12 hours.

[0009] Preferably, the molar ratio of 2-isocyano-1,1'-biphenyl to cyclohexane oxide is 1:1 to 4.

[0010] Preferably, the molar ratio of dichlorodicyclopentadiene to 2-isocyano-1,1'-biphenyl is 0.2 to 1:1. The reaction is optimal within this ratio range.

[0011] Preferably, the molar ratio of 4CzIPN to 2-isocyano-1,1'-biphenyl is 1:5~40. This invention also explored other photocatalysts, such as Ir[dF(CF3)ppy]2(dtbbpy)PF6, Ir[(dFCF3ppy)2-(5,5'dCF3bpy)]PF6, Ir(ppy)3, and Ru(bpy)3(PF6)2. Compared with other photocatalysts, the 4CzIPN photocatalyst is the cheapest, has the highest catalytic efficiency, and the best product selectivity, thus it is irreplaceable; without the photocatalyst, the reaction will not occur, and the yield will be 0.

[0012] Preferably, the molar ratio of triethylamine to 2-isocyano-1,1'-biphenyl is 1:1 to 10. Triethylamine acts as a reducing agent, reducing the photocatalyst 4CzIPN, thus enabling the photocatalyst to cycle. Without triethylamine, the photocatalyst cannot cycle. The reason for using triethylamine as a reducing agent is that it is relatively inexpensive, and during the reaction, it is converted to triethylamine hydrochloride, which is generally insoluble in organic solvents, reducing impurities introduced into the reaction system. Therefore, it is a suitable reagent.

[0013] Preferably, the organic solvent is selected from dichloroethane, acetonitrile, toluene, or tetrahydrofuran.

[0014] Preferably, the wavelength of blue light is 450nm.

[0015] Compared with the prior art, the present invention has the following beneficial effects:

[0016] 0. This invention uses 4CzIPN as a photocatalyst, which has the advantages of being inexpensive, having the highest catalytic efficiency, and exhibiting the best product selectivity. Titanium dichlorocerocene is used as the catalyst, and triethylamine is used as the base. Triethylamine acts as a reducing agent, reducing the 4CzIPN photocatalyst and enabling its recycling. Without triethylamine, the photocatalyst cannot be recycled. 2-Isocyano-1,1'-biphenyl is added to cyclohexane oxide, followed by intramolecular cyclization, to prepare phenanthridine compounds. .

[0017] 2. This invention is the first to propose a photo-induced titanium-catalyzed addition synthesis of 2-isocyano-1,1'-biphenyl with cyclohexane oxide. This method utilizes an inexpensive and readily available catalytic system, employs mild reaction conditions, and features safe and efficient procedures, resulting in high yields of the target product and short reaction times. It solves the problems of traditional... The synthesis process suffers from problems such as the need for excess oxidant, low reaction yield, and long reaction time. Furthermore, the catalyst used in this invention is not only highly efficient but also inexpensive, and has broad application prospects. Attached Figure Description

[0018] Figure 1 This is a schematic diagram illustrating the preparation principle of the phenanthridine compounds of this invention.

[0019] Figure 2 The hydrogen spectrum of 2-(phenanthrene-6-yl)cyclohexane-1-ol from Example 1 is shown.

[0020] Figure 3 The carbon spectrum of 2-(phenanthrene-6-yl)cyclohexane-1-ol is shown in Example 1. Detailed Implementation

[0021] The specific embodiments of the present invention are described in detail below, but it should be understood that the scope of protection of the present invention is not limited to the specific embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention. Unless otherwise specified, the experimental methods described in the embodiments of the present invention are conventional methods.

[0022] Phenyridines are nitrogen-containing heterocycles with physiological and photoelectric properties, found in many natural products such as alkaloids, and possess a range of medicinal values ​​including anticancer, antifungal, and antitumor effects. Simultaneously, phenyridines can also serve as structural frameworks for organic solar cells and molecular probes in the field of optoelectronic materials, thus exhibiting strong potential application value.

[0023] This invention proposes a photo-induced titanium-catalyzed addition synthesis of 2-isocyano-1,1'-biphenyl with cyclohexane oxide. The method described herein features an inexpensive and readily available catalytic system, mild conditions, safe and efficient steps, high synthesis yield, and short reaction time. Furthermore, this invention screened the amount of titanium dichlorodicyclopentadiene catalyst used and the type of photocatalyst 4CzIPN. The results showed that the phenanthridine compound 2-(phenanthrene-6-yl)cyclohexane-1-ol could be obtained in a yield of 98% using the method of this invention.

[0024] The technical solution of the present invention will be further explained and illustrated below with examples and comparative examples, as detailed below:

[0025] Example 1

[0026] A method for photo-induced titanium-catalyzed addition synthesis of phenanthridine compounds, wherein the phenanthridine compound is 2-(phenanthrene-6-yl)cyclohexane-1-ol, with the following structural formula: It includes the following steps:

[0027] Under argon protection, 2-isocyano-1,1'-biphenyl (0.0358 g, 0.2 mmol), cyclohexane oxide (42 μL, 0.4 mmol), titanium dichlorocerophenone (0.0102 g, 0.04 mmol), 4CzIPN (0.0081 g, 0.01 mmol), triethylamine (5.6 μL, 0.04 mmol), and dichloroethane (1 mL) were added to a Shrek tube. The glass stopper of the Shrek tube was tightened, and the reaction was stirred at 70 °C for 12 h. After the reaction was completed, the reaction mixture was filtered through a silica gel liner and purified by rapid column chromatography using petroleum ether and ethyl acetate as eluents to give 2-(phenanthrene-6-yl)cyclohexane-1-ol in 98% yield (trans isomer: cis isomer = 85:13).

[0028] The preparation principle of the main product 2-(phenanthrene-6-yl)cyclohexane-1-ol is as follows: Figure 1 As shown, the spectrum is as follows Figure 2 and Figure 3 As shown, the spectral data is as follows: 1 H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.53 (s, 1H), 8.25 (s, 1H), 8.11 (s, 1H), 7.82 (s, 1H), 7.67 (d, J = 24.0 Hz, 3H), 4.62 (s, 1H), 3.60 (d, J =36.0 Hz, 2H), 2.25 (s, 2H), 1.96 (s, 1H), 1.82 (s, 1H), 1.62 (d, J = 32.0 Hz, 4H). 13 C{ 1 H} NMR (101 MHz, CDCl3) δ 163.1, 143.4, 133.4, 130.5, 129.9, 128.7,127.4, 126.7, 126.0, 125.2, 123.6, 122.8, 122.1, 71.4, 50.7, 33.3, 32.7,26.5, 25.2.

[0029] Example 2

[0030] A method for photoinduced titanium-catalyzed addition synthesis of phenanthridine compounds is identical to the preparation steps in Example 1, except that the amount of titanium dichlorodecane is replaced from 0.04 mmol to 0.2 mmol, in which case the molar ratio of titanium dichlorodecane to 2-isocyano-1,1'-biphenyl is 1:1, and includes the following steps:

[0031] Under argon protection, 2-isocyano-1,1'-biphenyl (0.0358 g, 0.2 mmol), cyclohexane oxide (42 μL, 0.4 mmol), dichlorodicyclopentadiene (0.051 g, 0.2 mmol), 4CzIPN (0.0081 g, 0.01 mmol), triethylamine (5.6 μL, 0.04 mmol), and dichloroethane (1 mL) were added to a Shrek tube. The glass stopper of the Shrek tube was tightened, and the reaction was stirred at 70 °C for 12 h. After the reaction was completed, the reaction mixture was filtered through a silica gel liner and purified by rapid column chromatography using petroleum ether and ethyl acetate as eluents to give 2-(phenanthrene-6-yl)cyclohexane-1-ol in 80% yield (trans isomer: cis isomer = 60:20).

[0032] Example 3

[0033] A method for photo-induced titanium-catalyzed addition synthesis of phenanthridine compounds includes the following steps:

[0034] Under argon protection, 2-isocyano-1,1'-biphenyl (0.2 mmol), cyclohexane oxide (0.6 mmol), dichlorodicyclopentadiene (0.1 mmol), 4CzIPN (0.01 mmol), triethylamine (0.1 mmol), and tetrahydrofuran (1 mL) were added to a Shrek tube, the glass stopper of the Shrek tube was tightened, and the reaction was stirred at 80 °C for 6 h. After the reaction was completed, the reaction mixture was filtered through a silica gel liner, purified by rapid column chromatography, and eluted with petroleum ether and ethyl acetate to obtain 2-(phenanthrene-6-yl)cyclohexane-1-ol.

[0035] Example 4

[0036] A method for photo-induced titanium-catalyzed addition synthesis of phenanthridine compounds includes the following steps:

[0037] Under argon protection, 0.2 mmol of 2-isocyano-1,1'-biphenyl, 0.8 mmol of cyclohexane oxide, 0.2 mmol of dichlorodicyclopentadiene, 0.04 mmol of 4CzIPN, 0.2 mmol of triethylamine, and 1 mL of acetonitrile were added to a Shrek tube. The glass stopper of the Shrek tube was tightened, and the mixture was stirred at 50 °C for 12 h. After the reaction was completed, the reaction mixture was filtered through a silica gel liner and purified by rapid column chromatography using petroleum ether and ethyl acetate as eluents to obtain 2-(phenanthrene-6-yl)cyclohexane-1-ol.

[0038] Comparative Example 1

[0039] A method for photoinduced titanium-catalyzed addition synthesis of phenanthridine compounds is the same as the preparation steps in Example 1, except that the photocatalyst is replaced by an equal amount of Ir[(dFCF3ppy)2-(5,5'dCF3bpy)]PF6.

[0040] Comparative Example 2

[0041] A method for photo-induced titanium-catalyzed addition synthesis of phenanthridine compounds is the same as the preparation steps in Example 1, except that the photocatalyst is replaced by an equal amount of Ir(ppy)3 instead of 4CzIPN.

[0042] Comparative Example 3

[0043] A method for photo-induced titanium-catalyzed addition synthesis of phenanthridine compounds is the same as the preparation steps in Example 1, except that the photocatalyst is replaced by an equal amount of Ru(bpy)3(PF6)2 instead of 4CzIPN.

[0044] Comparative Example 4

[0045] A method for photo-induced titanium-catalyzed addition synthesis of phenanthridine compounds is the same as the preparation steps in Example 1, except that the photocatalyst is replaced by an equal amount of Ir[dF(CF3)ppy]2(dtbbpy)PF6.

[0046] Comparative Example 5

[0047] A method for synthesizing phenanthridine compounds by photoinduced titanium catalytic addition is the same as the preparation steps in Example 1, except that the photocatalyst 4CzIPN is not added.

[0048] Comparative Example 6

[0049] A method for photoinduced titanium-catalyzed addition synthesis of phenanthridine compounds is the same as the preparation steps in Example 1, except that the molar ratio of titanium dichlorodicyclopentadiene to 2-isocyano-1,1'-biphenyl is replaced by 0.05:1 instead of 0.2:1.

[0050] Comparative Example 7

[0051] A method for photoinduced titanium-catalyzed addition synthesis of phenanthridine compounds is the same as the preparation steps in Example 1, except that the molar ratio of titanium dichlorodicyclopentadiene to 2-isocyano-1,1'-biphenyl is replaced by 0.1:1 instead of 0.2:1.

[0052] Examples 1 to 4 of this invention all yielded 2-(phenanthrene-6-yl)cyclohexane-1-ol in high yield. The 2-(phenanthrene-6-yl)cyclohexane-1-ol from Examples 1 and 2 are used as examples, and compared with comparative examples. The specific research methods and results are shown below:

[0053] The selection of photocatalysts is investigated below, and the yields of 2-(phenanthrene-6-yl)cyclohexane-1-ol in Example 1 and Comparative Examples 1 to 5 are compared, as shown in Table 1:

[0054] Table 1. Comparison of yields of Samples from Example 1 and Comparative Examples 1 to 5

[0055]

[0056] The results in Table 1 show that the photocatalyst 4CzIPN of the present invention is irreplaceable.

[0057] The following study investigated the amount of titanium dichloropentane used, comparing the yields of 2-(phenanthrene-6-yl)cyclohexane-1-ol in Examples 1-2 and Comparative Examples 6-7, as shown in Table 2:

[0058] Table 2. Yield Comparison of Samples from Examples 1-2 and Comparative Examples 6-7

[0059]

[0060] Table 2 shows that when the molar ratio of titanium dichlorocerocene to 2-isocyano-1,1'-biphenyl is 0.05:1, the yield is only 23%; when the molar ratio is 0.1:1, the yield is only 41%; when the molar ratio is 0.2:1, the yield reaches 98%; and when the molar ratio is 1:1, the yield decreases to 80%. Therefore, the amount of titanium dichlorocerocene used is not necessarily better the more it is used; the optimal yield is obtained under the condition of a molar ratio of 0.2:1 with 2-isocyano-1,1'-biphenyl.

[0061] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, it is intended to include any modifications and variations that fall within the scope of the claims and their equivalents.

Claims

1. A method for synthesizing phenanthridine compounds by photoinduced titanium-catalyzed addition, characterized in that, Includes the following steps: In an inert atmosphere, 2-isocyano-1,1'-biphenyl and cyclohexane oxide were used as raw materials, with titanium dichlorophenocene as a catalyst, 4CzIPN as a photocatalyst, and triethylamine as a base. These were mixed in an organic solvent and subjected to an addition-cyclization reaction under blue light. During the addition-cyclization reaction, 2-isocyano-1,1'-biphenyl and cyclohexane oxide first undergo addition, followed by intramolecular cyclization to yield phenanthridine compounds. .

2. The method for photo-induced titanium-catalyzed addition synthesis of phenanthridine compounds according to claim 1, characterized in that, The conditions for the addition cyclization reaction are: heating at 50℃~80℃ for 6h~12h.

3. The method for photo-induced titanium-catalyzed addition synthesis of phenanthridine compounds according to claim 1, characterized in that, The molar ratio of 2-isocyano-1,1'-biphenyl to cyclohexane oxide is 1:1~4.

4. The method for photo-induced titanium-catalyzed addition synthesis of phenanthridine compounds according to claim 1, characterized in that, The molar ratio of dichlorodicyclopentadiene to 2-isocyano-1,1'-biphenyl is 0.2~1:

1.

5. The method for photo-induced titanium-catalyzed addition synthesis of phenanthridine compounds according to claim 4, characterized in that, The molar ratio of dichlorodicyclopentadiene to 2-isocyano-1,1'-biphenyl is 0.2:

1.

6. The method for photo-induced titanium-catalyzed addition synthesis of phenanthridine compounds according to claim 1, characterized in that, The molar ratio of 4CzIPN to 2-isocyano-1,1'-biphenyl is 1:5~40.

7. The method for synthesizing phenanthridine compounds by photoinduced titanium-catalyzed addition according to claim 1, characterized in that, The molar ratio of triethylamine to 2-isocyano-1,1'-biphenyl is 1:1~10.

8. The method for photo-induced titanium-catalyzed addition synthesis of phenanthridine compounds according to claim 1, characterized in that, The organic solvent is selected from dichloroethane, acetonitrile, toluene, or tetrahydrofuran.

9. The method for synthesizing phenanthridine compounds by photoinduced titanium-catalyzed addition according to claim 1, characterized in that, Blue light has a wavelength of 450nm.

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