Method for synthesizing phenanthridine compound through photo-induced titanium catalytic addition

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing a phenanthridine compound through photo-induced titanium catalytic addition, which comprises the following steps: by taking 2-isocyanato-1, 1 '-biphenyl and cyclohexane oxide as raw materials, titanocene dichloride as a catalyst, 4CzIPN as a photocatalyst and triethylamine as alkali, carrying out an addition cyclization reaction under blue light to obtain the phenanthridine compound. The phenanthridine compound is prepared. According to the method disclosed by the invention, cheap and easily available titanocene dichloride is used as a catalyst, activated oxidized cyclohexane and 2-isocyano-1, 1 '-biphenyl are subjected to addition and intramolecular cyclization, and the phenanthridine compound 2-(phenanthrene-6-yl) cyclohexane-1-alcohol is obtained. A catalytic system is low in cost and easy to obtain, reaction conditions are mild, steps are safe and efficient, the problems that in traditional 2-(phenanthrene-6-yl) cyclohexane-1-alcohol synthesis, excessive oxidizing agents are needed, the reaction yield is low, and the reaction time is long are solved, and the method has wide application prospects.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a method for synthesizing phenanthridine compounds by light-induced titanium catalytic addition. Background Art

[0002] It is an intermediate that can be modified to obtain active drug molecules, such as diaminoethylbenzenephenanthridine compounds, with the structural formula: Diaminoethylbenzenephenanthridine compounds contain phenanthridine pharmacophores, and diaminoethylbenzenephenanthridine compounds are also widely used as DNA intercalators in anti-inflammatory treatment. The modified 5-HT receptor is used as a natural ligand, and its structural formula is: It is easy to combine with drugs to make them effective.

[0003] At present, Wang et al. have achieved the Minisci reaction of heteroaromatic hydrocarbons, olefins and water by photocatalysis in the presence of excess peroxide. However, the product yield was only 50%, and an excess of oxidant was used in this method, and the reaction time was 24 h. Summary of the Invention

[0004] In response to the deficiencies in the above-mentioned prior art, the present invention provides a method for synthesizing phenanthridine compounds by light-induced titanium-catalyzed addition. The method of the present invention uses 2-isocyanato-1,1'-biphenyl and cyclohexane oxide as raw materials, dichlorotitanocenes as catalysts, 4CzIPN as photocatalysts, and triethylamine as bases, and performs an addition cyclization reaction under blue light to prepare phenanthridine compounds. The method of the present invention utilizes cheap and readily available dichlorotitanocenes as a catalyst, starting from activated cyclohexane oxide, and then adds 2-isocyanato-1,1'-biphenyl to form an intramolecular ring. The catalytic system is cheap and readily available, the reaction conditions are mild, and the steps are safe and efficient. This method solves the problems of the traditional synthesis of 2-(phenanthrene-6-yl)cyclohexane-1-ol, such as the need for excessive oxidants, long reaction times, and low yields, and has broad application prospects.

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

[0006] The present invention provides a method for synthesizing a phenanthridine compound by light-induced titanium catalytic addition, comprising the following steps:

[0007] In an inert atmosphere, 2-isocyanato-1,1'-biphenyl and cyclohexane oxide are used as raw materials, dichlorodiphenylmethane is used as a catalyst, 4CzIPN is used as a photocatalyst, and triethylamine is used as a base. They are mixed together in an organic solvent and subjected to an addition cyclization reaction under blue light. During the addition cyclization reaction, 2-isocyanato-1,1'-biphenyl and cyclohexane oxide first add and then undergo intramolecular cyclization to obtain a phenanthridine compound.

[0008] Preferably, the conditions for the addition ring reaction are: heating at 50°C to 80°C for 6 to 12 hours. At lower temperatures, the reaction cannot proceed completely and the yield is low; the present invention achieves a relatively complete reaction within 6 to 12 hours.

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

[0010] Preferably, the molar ratio of titanocene dichloride 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-isocyanato-1,1'-biphenyl is 1:5 to 40. The present invention also tried 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, 4CzIPN photocatalyst is the cheapest, has the highest catalytic efficiency, and the best product selectivity, making it irreplaceable; without the photocatalyst, the reaction will not proceed and the yield is 0.

[0012] Preferably, the molar ratio of triethylamine to 2-isocyanato-1,1'-biphenyl is 1:1 to 10. Triethylamine acts as a reducing agent, reducing the photocatalyst 4CzIPN, allowing the photocatalyst 4CzIPN to circulate; without triethylamine, the photocatalyst cannot circulate. Triethylamine is used as a reducing agent because it is relatively inexpensive and converts to triethylamine hydrochloride during the reaction, which is generally insoluble in organic solvents. This reduces the amount of impurities introduced into the reaction system, making it a viable reagent.

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

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

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

[0016] 1. The present invention uses 4CzIPN as a photocatalyst. 4CzIPN has the advantages of being cheap, having the highest catalytic efficiency, and having the best product selectivity. Dichlorotitanocene is used as a catalyst, and triethylamine is used as a base. Triethylamine acts as a reducing agent to reduce the photocatalyst 4CzIPN and enable the photocatalyst to circulate. Without triethylamine, the photocatalyst cannot circulate. 2-isocyanato-1,1'-biphenyl is added to cyclohexane oxide, and intramolecular cyclization is performed to obtain a phenanthridine compound.

[0017] 2. This invention proposes for the first time the synthesis of 2-isocyanato-1,1'-biphenyl and cyclohexane oxide by photoinduced titanium catalysis. The method has the advantages of cheap and easy-to-obtain catalytic system, mild reaction conditions, safe and efficient steps, high yield of target product and short reaction time. The problems of excessive oxidant required in the synthesis, low reaction yield and long reaction time are solved. The catalyst used in the present invention not only has high catalytic efficiency but also is low in price, and has broad application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 Schematic diagram of the preparation principle of the phenanthridine compounds of the present invention.

[0019] Figure 2 This is the hydrogen spectrum of 2-(phenanthrene-6-yl)cyclohexane-1-ol in Example 1.

[0020] Figure 3 This is the carbon spectrum of 2-(phenanthrene-6-yl)cyclohexane-1-ol in Example 1. DETAILED DESCRIPTION

[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 by the specific embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention. The experimental methods described in the embodiments of the present invention are all conventional methods unless otherwise specified.

[0022] Phenanthridines are a class of nitrogen-containing heterocycles with physiological and optoelectronic properties. Found in many natural products, such as alkaloids, they possess a range of medical benefits, including anticancer, antifungal, and antitumor properties. Furthermore, phenanthridines have strong potential applications in optoelectronic materials, serving as structural backbones for organic solar cells and molecular probes.

[0023] The present invention proposes a method for synthesizing 2-isocyanato-1,1'-biphenyl by addition of cyclohexane oxide using photoinduced titanium catalyst. The method features an inexpensive and readily available catalytic system, mild conditions, safe and efficient procedures, high synthesis yield, and a short reaction time. Furthermore, the present invention screened the amount of the catalyst, titanocene dichloride, and the type of photocatalyst, 4CzIPN. The results demonstrated that the method can produce a 98% yield of the phenanthridine compound, 2-(phenanthrene-6-yl)cyclohexane-1-ol.

[0024] The technical solution of the present invention is further explained below using examples and comparative examples, as shown below:

[0025] Example 1

[0026] A method for synthesizing a phenanthridine compound by light-induced titanium catalytic addition, wherein the phenanthridine compound is 2-(phenanthrene-6-yl)cyclohexane-1-ol, and has the structural formula: The steps include:

[0027] Under argon protection, 2-isocyanato-1,1'-biphenyl (0.0358 g, 0.2 mmol), cyclohexane oxide (42 μL, 0.4 mmol), titanocene dichloride (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 at the mouth of the Shrek tube was tightened, and the reaction was stirred at 70°C for 12 h. After the reaction, the reaction mixture was filtered through a silica gel pad and purified by flash column chromatography using petroleum ether and ethyl acetate as eluents to obtain 2-(phenanthren-6-yl)cyclohexan-1-ol with a yield of 98% (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 Figure 2 and Figure 3 As shown, the spectral data is: 1 H NMR (400MHz, CDCl3) δ8.65(s,1H),8.53(s,1H),8.25(s,1H),8.11(s,1H),7.82(s,1H),7.67(d,J=24.0Hz, 3H),4.62(s,1H),3.60(d,J=36.0Hz,2H),2.25(s,2H),1.96(s,1H),1.82(s,1H),1.62(d,J=32.0Hz,4H).; 13 C{ 1 H}NMR(101MHz,CDCl3)δ163.1,143.4,133.4,130.5,129.9,128.7,127.4,12 6.7,126.0,125.2,123.6,122.8,122.1,71.4,50.7,33.3,32.7,26.5,25.2.

[0029] Example 2

[0030] A method for synthesizing a phenanthridine compound by photoinduced titanium-catalyzed addition is the same as the preparation steps in Example 1, except that the amount of dichlorotitanocene is replaced by 0.2 mmol from 0.04 mmol, and the molar ratio of dichlorotitanocene to 2-isocyano-1,1'-biphenyl is 1:1. The method comprises the following steps:

[0031] Under argon protection, 2-isocyanato-1,1'-biphenyl (0.0358 g, 0.2 mmol), cyclohexane oxide (42 μL, 0.4 mmol), dichlorotitanocene (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 Shrek tube was stoppered tightly with a glass stopper, and the reaction was stirred at 70°C for 12 h. After the reaction, the reaction mixture was filtered through a silica gel pad and purified by flash column chromatography using petroleum ether and ethyl acetate as eluents to obtain 2-(phenanthren-6-yl)cyclohexan-1-ol with a yield of 80% (trans isomer: cis isomer = 60:20).

[0032] Example 3

[0033] A method for synthesizing a phenanthridine compound by light-induced titanium catalytic addition comprises the following steps:

[0034] Under argon protection, 2-isocyanato-1,1'-biphenyl (0.2 mmol), cyclohexane oxide (0.6 mmol), dichlorotitanocene (0.1 mmol), 4CzIPN (0.01 mmol), triethylamine (0.1 mmol) and tetrahydrofuran (1 mL) were added to a Shrek tube. The glass stopper at the mouth of the Shrek tube was tightened, and the reaction was stirred at 80°C for 6 h. After the reaction, the reaction mixture was filtered through a silica gel pad and purified by flash column chromatography using petroleum ether and ethyl acetate as eluents to obtain 2-(phenanthrene-6-yl)cyclohexan-1-ol.

[0035] Example 4

[0036] A method for synthesizing a phenanthridine compound by light-induced titanium catalytic addition comprises the following steps:

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

[0038] Comparative Example 1

[0039] A method for synthesizing phenanthridine compounds by light-induced titanium-catalyzed addition 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 instead of 4CzIPN.

[0040] Comparative Example 2

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

[0042] Comparative Example 3

[0043] A method for synthesizing phenanthridine compounds by light-induced titanium-catalyzed addition 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 synthesizing phenanthridine compounds by light-induced titanium-catalyzed addition 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 instead of 4CzIPN.

[0046] Comparative Example 5

[0047] A method for synthesizing phenanthridine compounds by light-induced titanium-catalyzed 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 synthesizing a phenanthridine compound by light-induced titanium-catalyzed addition is the same as the preparation steps in Example 1, except that the molar ratio of dichlorotitanocene to 2-isocyano-1,1'-biphenyl is replaced from 0.2:1 to 0.05:1.

[0050] Comparative Example 7

[0051] A method for synthesizing a phenanthridine compound by light-induced titanium-catalyzed addition is the same as the preparation steps in Example 1, except that the molar ratio of dichlorotitanocene to 2-isocyano-1,1'-biphenyl is replaced from 0.2:1 to 0.1:1.

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

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

[0054] Table 1 Comparative yield of samples of Example 1 and Comparative Examples 1 to 5

[0055]

[0056]

[0057] The results in Table 1 show that the photocatalyst 4CzIPN of the present invention is irreplaceable.

[0058] The usage of titanocene dichloride was studied below, and the yields of 2-(phenanthrene-6-yl)cyclohexane-1-ol in Examples 1 to 2 and Comparative Examples 6 to 7 were compared, as shown in Table 2.

[0059] Table 2 Comparison of the yields of samples from Examples 1 to 2 and Comparative Examples 6 to 7

[0060] sample Titanocene dichloride (mol%) Yield (trans:cis) Comparative Example 6 5 23(15：8) Comparative Example 7 10 41(31:10) Example 1 20 98(85:13) Example 2 100 80(60:20)

[0061] The results in Table 2 show that when the molar ratio of dichlorotitanocene to 2-isocyano-1,1'-biphenyl is 0.05:1, the yield is only 23%; when the molar ratio of dichlorotitanocene to 2-isocyano-1,1'-biphenyl is 0.1:1, the yield is only 41%; when the molar ratio of dichlorotitanocene to 2-isocyano-1,1'-biphenyl is 0.2:1, the yield reaches 98%; when the molar ratio of dichlorotitanocene to 2-isocyano-1,1'-biphenyl is 1:1, the yield is reduced to 80%; so the use of dichlorotitanocene is not the more the better, and the best yield is obtained when the molar ratio to 2-isocyano-1,1'-biphenyl is 0.2:1.

[0062] Obviously, those skilled in the art may make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if such changes and modifications of the present invention fall within the scope of the claims and their equivalents, such changes and modifications are intended to be included.

Claims

1. A method for synthesizing phenanthridine compounds by light-induced titanium catalytic addition, characterized in that: The steps include: In an inert atmosphere, 2-isocyanato-1,1'-biphenyl and cyclohexane oxide are used as raw materials, dichlorodiphenylmethane is used as a catalyst, 4CzIPN is used as a photocatalyst, and triethylamine is used as a base. They are mixed together in an organic solvent and subjected to an addition cyclization reaction under blue light. During the addition cyclization reaction, 2-isocyanato-1,1'-biphenyl and cyclohexane oxide first add, and then undergo intramolecular cyclization to obtain a phenanthridine compound.

2. The method for synthesizing phenanthridine compounds by light-induced titanium catalytic addition according to claim 1, characterized in that: The conditions for the addition ring-closing reaction are: heating at 50°C to 80°C for 6h to 12h.

3. The method for synthesizing phenanthridine compounds by light-induced titanium catalytic addition 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 synthesizing phenanthridine compounds by light-induced titanium catalytic addition according to claim 1, characterized in that: The molar ratio of titanocene dichloride to 2-isocyano-1,1'-biphenyl is 0.2 to 1:

1.

5. The method for synthesizing phenanthridine compounds by light-induced titanium catalytic addition according to claim 4, characterized in that: The molar ratio of titanocene dichloride to 2-isocyano-1,1'-biphenyl is 0.2:

1.

6. The method for synthesizing phenanthridine compounds by light-induced titanium catalytic addition 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 light-induced titanium catalytic 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 synthesizing phenanthridine compounds by light-induced titanium catalytic addition 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 light-induced titanium catalytic addition according to claim 1, characterized in that: The wavelength of blue light is 450nm.

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