A method for photocatalytic synthesis of 6-methylphenanthridine compounds

Abstract

The present invention discloses a method for photocatalytic synthesis of 6-methylphenanthridine compounds, comprising the following steps: dissolving a biphenyl isocyanide compound in a dimethyl sulfoxide solvent, adding a photosensitizer and a base, reacting at room temperature for 24 hours under blue light irradiation, and after the reaction is completed, column chromatography is performed to separate and obtain 6-methylphenanthridine compounds. The raw materials used in this preparation method are cheap and easy to obtain, the reaction system is mild, the operation is simple, and the yield is high. 6-methylphenanthridine compounds have a wide range of uses and can also be used as a synthetic intermediate.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthetic chemistry and relates to a method for photocatalytically synthesizing 6-methylphenanthridine compounds, and specifically relates to a method for synthesizing 6-methylphenanthridine compounds by reacting biphenyl isonitrile compounds in a dimethyl sulfoxide solution in the presence of a photosensitizer and a base and under the irradiation of a blue light LED. Background Art

[0002] Phenanthridine compounds possess unique physiological activities and, therefore, hold valuable applications in numerous important fields, including medicinal chemistry and natural product chemistry. Numerous methods have been reported for synthesizing phenanthridine derivatives, including the one-pot cascade method, the benzylene method, and transition metal-catalyzed methods. However, while these traditional methods offer high yields, they still suffer from limitations, such as harsh reaction conditions and significant pollution. Therefore, the search for efficient and environmentally friendly methods for synthesizing phenanthridine derivatives is of vital importance. Recently, many literatures have reported methods for preparing quinoline derivatives by photocatalytic reaction, such as: (1) In 2018, Barriault et al. described the use of dimerized gold (II) photoredox catalyst [Au2(dppm)2]Cl2 to photocatalyze the generation of alkyl radicals from unactivated bromoalkanes, and then perform addition cyclization of isonitriles to obtain 6-alkylphenanthridine derivatives ((J.Org.Chem., 2018, 83(17):10015-10024.). However, this reaction requires the synergistic action of expensive gold salts, photocatalysts and additives in an inert atmosphere, and the reaction system is complex. (2) In 2022, Pe i et al. also reported the use of visible light and palladium salt dual synergistic catalysis to synthesize 6-alkylphenanthridine derivatives by free radical addition cyclization reaction with iodinated hydrocarbons (Tetrahedron, 2022, 123, 132939.). In this reaction, the synergistic effect of expensive palladium salts, additives and photocatalysts is required for the reaction to occur. The reaction system is complex, its substrate applicability is poor, and it is difficult to promote and apply on a large scale. Invention patents CN107778239A, CN106518761A, CN110627721A, etc. also reported the synthesis of related phenanthridine compounds, but the source of starting materials is inconvenient, and the reaction conditions and the catalytic system used are also complex.

[0003] Therefore, there is still a need to develop and optimize new methods for preparing 6-alkylphenanthridine compounds. Summary of the Invention

[0004] The purpose of the present invention is to provide a simple method for preparing 6-methylphenanthridine compounds in view of the shortcomings and defects of the above-mentioned prior art.

[0005] The present invention uses biphenyl isocyanide compounds as raw materials. In a dimethyl sulfoxide solution, in the presence of a photosensitizer and a base, and under blue LED irradiation, the reaction is carried out at room temperature for 24 hours to produce 6-methylphenanthridine compounds through an addition cyclization reaction. This reaction method uses inexpensive and readily available raw materials, operates under mild reaction conditions, does not require the use of an oxidant, has a simple post-processing process, has a wide product range, and has good industrial potential.

[0006] The principle of the synthetic route of the present invention is as follows:

[0007]

[0008] where R 1 R represents H, or fluorine, chlorine, bromine, methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, methoxy, ethoxy, trifluoromethyl, or substituted phenyl. These substituents may be substituted at the ortho, meta, or para position or multiple positions of the phenyl ring. 2 It is represented by H, or fluorine, chlorine, bromine, methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, methoxy, ethoxy, trifluoromethyl, or substituted phenyl. These substituents can be substituted at the ortho, meta, para, or multiple positions of the benzene ring; the light source used is a blue LED lamp; the photosensitizer is terpyridine ruthenium chloride hexahydrate, or one of di(2-phenylpyridine)iridium acetylacetonate, erythrosine B, eosin Y, and rose Bengal; the base is triethylamine, or one of diisopropylamine, piperidine, and pyridine.

[0009] In order to achieve the above object, the present invention adopts the following technical scheme to synthesize the above compound:

[0010] To a reaction tube, biphenyl isocyanide compound 1, solvent dimethyl sulfoxide, and a photosensitizer were added in sequence, followed by a base. After addition, the tube was placed under blue light (Blue LED) and reacted at room temperature for 24 hours. After completion of the reaction, 6-methylphenanthridine compound 2 was obtained by rapid column chromatography.

[0011] The reaction light source described in the above method is a 24W blue light LED lamp.

[0012] Among the photosensitizers described in the above method, terpyridine ruthenium chloride hexahydrate is selected as the reaction photosensitizer.

[0013] Among the bases described in the above method, triethylamine is selected as the base for the reaction.

[0014] The molar ratio of the biphenyl isocyanide compound 1, the photosensitizer, and the base in the above method is 1:0.05:10-50.

[0015] Compared with the existing technical route, the present invention has the following advantages:

[0016] (1) The method of the present invention has a wide range of substrate applicability, mild reaction conditions, simple post-processing process, high product yield, and a wide range of product expansion.

[0017] (2) A simple, green, efficient and superior synthesis method to that reported in existing literature is provided, which does not require the use of an oxidant and is a method for preparing 6-methylphenanthridine compounds by an addition cyclization reaction of biphenyl isocyanide compounds in a dimethyl sulfoxide solution under blue light irradiation. DETAILED DESCRIPTION

[0018] The invention is further described in detail with reference to specific examples, but the scope of protection claimed by the present invention is not limited thereto.

[0019] Example 1: 0.1 mmol of biphenyl isocyanide 1a, 2 mL of DMSO, 0.01 mmol of terpyridine ruthenium chloride hexahydrate, and 0.2 mL of triethylamine were added sequentially to a 10 mL reaction tube. The reaction was stirred magnetically under 24 W blue LED illumination for 24 hours, and the reaction progress was monitored by TLC. After completion of the reaction, column chromatography was performed to obtain 6,8-dimethylphenanthridine 2a in a 30% yield. 1 H NMR (400Hz, CDCl3) (δ, ppm) 8.51 (d, J = 8.3Hz, 2H), 8.11 (dd, J = 8.1, 1.4Hz, 1H), 8.01-7.96 (m, 1H), 7.69 (m, 2H), 7.61 (m, 1H), 3.04 (s, 3H), 2.62 (s, 3H); 13 C NMR (Chloroform-d, 101 MHz): δ (ppm) 158.61, 143.38, 137.23, 132.19, 130.38, 129.27, 128.18, 126.25, 126.10, 126.05, 123.89, 122.22, 121.78, 77.38, 77.06, 76.75, 23.43, 21.84. The reaction principle of Example 1 is as follows:

[0020]

[0021] Example 2: 0.1 mmol of biphenyl isocyanide 1a, 2 mL of DMSO, 0.03 mmol of terpyridine ruthenium chloride hexahydrate, and 0.2 mL of triethylamine were added sequentially to a 10 mL reaction tube. The reaction was stirred magnetically under 24 W blue LED illumination for 24 hours, and the reaction progress was monitored by TLC. After completion of the reaction, column chromatography was performed to obtain 6,8-dimethylphenanthridine 2a in a 60% yield.

[0022] Example 3: 0.1 mmol of biphenyl isocyanide 1a, 2 mL of DMSO, 0.05 mmol of terpyridine ruthenium chloride hexahydrate, and 0.2 mL of triethylamine were added sequentially to a 10 mL reaction tube. The reaction was stirred magnetically under 24 W blue LED illumination for 24 hours, and the reaction progress was monitored by TLC. After completion of the reaction, column chromatography was performed to obtain 6,8-dimethylphenanthridine 2a in a 68% yield.

[0023] Example 4: 0.1 mmol of biphenyl isocyanide 1a, 2 mL of DMSO, 0.05 mmol of terpyridine ruthenium chloride hexahydrate, and 0.4 mL of triethylamine were added sequentially to a 10 mL reaction tube. The reaction was stirred magnetically under 24 W blue LED illumination for 24 hours, and the reaction progress was monitored by TLC. After completion of the reaction, column chromatography was performed to obtain 6,8-dimethylphenanthridine 2a in a 72% yield.

[0024] Example 5: 0.1 mmol of biphenyl isocyanide 1a, 2 mL of DMSO, 0.05 mmol of terpyridine ruthenium chloride hexahydrate, and 0.6 mL of triethylamine were added sequentially to a 10 mL reaction tube. The reaction was stirred magnetically under 24 W blue LED illumination for 24 hours, and the reaction progress was monitored by TLC. After completion of the reaction, column chromatography was performed to obtain 6,8-dimethylphenanthridine 2a in a yield of 78%.

[0025] Example 6: 0.1 mmol of biphenyl isocyanide 1b, 2 mL of DMSO, 0.05 mmol of terpyridine ruthenium chloride hexahydrate, and 0.6 mL of triethylamine were added sequentially to a 10 mL reaction tube. The reaction was stirred magnetically under 24 W blue LED illumination for 24 hours, and the reaction progress was monitored by TLC. After completion of the reaction, column chromatography was performed to obtain 6-methyl-8-methoxyphenanthridine 2b in 83% yield. 1 H NMR(400MHz,Chloroform-d)δ8.53(d,J=8.8Hz,1H),8.45(d,J=8.1Hz,1H),8.11(d,J=8.1Hz ,1H),7.66(t,J=7.5Hz,1H),7.63–7.56(m,1H),7.56–7.40(m,2H),4.00(s,3H),3.02(s,3H); 13 C NMR (Chloroform-d, 101 MHz): δ (ppm) 158.69, 158.01, 142.47, 129.04, 127.76, 127.15, 126.93, 126.53, 124.08, 123.88, 121.49, 120.99, 106.84, 77.37, 77.06, 76.74, 55.58, 23.36. The reaction principle of Example 6 is as follows:

[0026]

[0027] Example 7: 0.1 mmol of biphenyl isocyanide 1c, 2 mL of DMSO, 0.05 mmol of terpyridine ruthenium chloride hexahydrate, and 0.6 mL of triethylamine were added sequentially to a 10 mL reaction tube. The reaction was stirred magnetically under 24 W blue LED illumination for 24 hours, and the reaction progress was monitored by TLC. After completion of the reaction, column chromatography was performed to obtain 6-methyl-8-chlorophenanthridine 2c in a yield of 71%. 1 H NMR(400MHz,Chloroform-d)δ8.51(d,J=8.8Hz,1H),8.44(dd,J=8.1,1.4Hz,1H),8.14(d,J=2.1Hz,1H) ,8.10(dd,J=8.2,1.4Hz,1H),7.76(dd,J=8.9,2.2Hz,1H),7.74–7.68(m,1H),7.62(m,1H),3.00(s,3H); 13 C NMR (Chloroform-d, 101 MHz): δ (ppm) 158.97, 143.34, 132.64, 130.74, 129.13, 128.78, 127.44, 126.67, 126.49, 125.86, 123.81, 122.38, 122.01, 77.38, 77.06, 76.74, 23.27. The reaction principle of Example 7 is as follows:

[0028]

[0029] Example 8: 0.1 mmol of biphenyl isocyanide 1d, 2 mL of DMSO, 0.05 mmol of terpyridine ruthenium chloride hexahydrate, and 0.6 mL of triethylamine were added sequentially to a 10 mL reaction tube. The reaction was stirred magnetically under 24 W blue LED illumination for 24 hours, and the reaction progress was monitored by TLC. After completion of the reaction, column chromatography was performed to obtain 6-methyl-8-tert-butylphenanthridine 2d in a yield of 66%. 1 H NMR(400MHz,Chloroform-d)δ8.57(d,J=8.7Hz,1H),8.52(d,J=8.1Hz,1H),8.17(s,1H),8.11(d,J=8.1 Hz,1H),7.94(d,J=8.7Hz,1H),7.69(t,J=7.5Hz,1H),7.61(t,J=7.5Hz,1H),3.08(s,3H),1.48(s,9H); 13C NMR (Chloroform-d, 101 MHz): δ (ppm) 159.04, 150.49, 143.19, 130.44, 129.07, 128.33, 126.35, 125.78, 123.83, 122.21, 122.02, 121.88, 77.38, 77.07, 76.75, 35.16, 31.38, 23.37. The reaction principle of Example 8 is as follows:

[0030]

[0031] Example 9: 0.1 mmol of biphenyl isocyanide 1e, 2 mL of DMSO, 0.05 mmol of terpyridine ruthenium chloride hexahydrate, and 0.6 mL of triethylamine were added sequentially to a 10 mL reaction tube. The reaction was stirred magnetically under 24 W blue LED illumination for 24 hours, and the reaction progress was monitored by TLC. After completion of the reaction, column chromatography was performed to obtain 6-methyl-8-trifluoromethylphenanthridine 2e in a yield of 59%. 1 HNMR(400MHz,Chloroform-d)δ8.70(d,J=8.6Hz,1H),8.52(d,J=8.2Hz,1H),8.46(s,1H),8.14(d ,J=8.1Hz,1H),8.02(d,J=8.8Hz,1H),7.78(t,J=7.6Hz,1H),7.67(t,J=7.6Hz,1H),3.08(s,3H); 13 C NMR (Chloroform-d, 101 MHz): δ (ppm) 158.67, 144.19, 134.83, 129.93, 129.51, 127.01, 126.44, 126.41, 125.19, 124.03, 123.99, 123.45, 122.79, 122.35, 77.37, 77.05, 76.73, 23.25. The reaction principle of Example 9 is as follows:

[0032]

[0033] Example 10: 0.1 mmol of biphenyl isocyanide 1f, 2 mL of DMSO, 0.05 mmol of terpyridine ruthenium chloride hexahydrate, and 0.6 mL of triethylamine were added sequentially to a 10 mL reaction tube. The reaction was stirred magnetically under 24 W blue LED illumination for 24 hours, and the reaction progress was monitored by TLC. After completion of the reaction, column chromatography was performed to obtain 6-methyl-8-phenylphenanthridine 2f in a 59% yield. 1H NMR (400MHz, Chloroform-d) δ8.67(d,J=8.6Hz,1H),8.54(d,J=8.1Hz,1H),8.38(d,J=1.8Hz,1H),8.13(d,J=8.1Hz,1H),8.08(dd,J=8.7,1.9H z,1H),7.76(d,J=1.0Hz,1H),7.74(s,1H),7.73–7.69(m,1H),7.66–7.61(m,1H),7.54(dd,J=8.4,6.7Hz,2H),7.47–7.40(m,1H),3.10(s,3H); 13 C NMR (Chloroform-d, 101 MHz): δ (ppm) 159.05, 143.40, 140.41, 140.29, 131.64, 129.95, 129.20, 129.12, 128.76, 127.94, 127.51, 126.59, 126.26, 124.71, 123.67, 123.00, 122.05, 77.38, 77.06, 76.74, 23.37. The reaction principle of Example 10 is as follows:

[0034]

[0035] Example 11: 1 g of biphenyl isocyanide (0.1 mmol), 2 mL of DMSO, 0.05 mmol of terpyridine ruthenium chloride hexahydrate, and 0.6 mL of triethylamine were added sequentially to a 10 mL reaction tube. The reaction was stirred magnetically under 24 W blue LED illumination for 24 hours, and the reaction progress was monitored by TLC. After completion of the reaction, column chromatography was performed to obtain 2 g of 2,6,8-trimethylphenanthridine in a yield of 59%. 1 H NMR(400MHz,Chloroform-d)δ8.51(d,J=8.3Hz,1H),8.28(s,1H),7.96(d,J=8.3Hz,1H),7 .65(t,J=7.7Hz,1H),7.49(dd,J=15.8,7.8Hz,2H),3.19(s,3H),2.98(s,3H),2.60(s,3H); 13 CNMR (Chloroform-d, 101 MHz): δ (ppm) 157.98, 137.26, 136.16, 134.24, 131.52, 130.36, 129.82, 128.39, 126.49, 123.71, 121.91, 120.82, 77.38, 77.06, 76.75, 30.44, 26.37, 22.04. The reaction principle of Example 11 is as follows:

[0036]

[0037] Example 12: 0.1 mmol of biphenyl isocyanide 1h, 2 mL of DMSO, 0.05 mmol of terpyridine ruthenium chloride hexahydrate, and 0.6 mL of triethylamine were added sequentially to a 10 mL reaction tube. The reaction was stirred magnetically under 24 W blue LED illumination for 24 hours, and the reaction progress was monitored by TLC. After completion of the reaction, column chromatography was performed to obtain 2-chloro-6,8-dimethylphenanthridine 2h in a yield of 56%. 1 HNMR(400MHz,Chloroform-d)δ8.41(t,J=2.0Hz,1H),8.38(d,J=8.4Hz,1H),8.00(d,J=8.7H z,1H),7.96(s,1H),7.66(d,J=8.4Hz,1H),7.60(d,J=8.7Hz,1H),3.00(s,3H),2.61(s,3H); 13 C NMR (Chloroform-d, 101 MHz): δ (ppm) 158.97, 138.14, 132.58, 132.10, 130.59, 129.37, 128.68, 126.21, 126.08, 124.96, 122.26, 121.45, 77.38, 77.06, 76.74, 23.32, 21.89. The reaction principle of Example 12 is as follows:

[0038] .

Claims

1. A method for photocatalytic synthesis of 6-methylphenanthridine compounds, characterized in that: The following steps are involved: The biphenyl isocyanide compound 1 was dissolved in dimethyl sulfoxide (DMSO) solvent, and then a photosensitizer and a base were added. The reaction was carried out at room temperature for 24 hours under blue light (Blue LED). After the reaction was completed, column chromatography was performed to obtain the target product 6-methylphenanthridine compound 2. The reaction formula is as follows: where R 1 R represents H, or fluorine, chlorine, bromine, methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, methoxy, ethoxy, trifluoromethyl, or substituted phenyl, wherein these substituents are substituted at the ortho, meta, para, or multiple positions of the phenyl ring; 2 It is represented by H, or fluorine, chlorine, bromine, methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, methoxy, ethoxy, trifluoromethyl, or substituted phenyl. These substituents are substituted at the ortho, meta, para, or multiple positions of the benzene ring. The light source used is a 24W blue light LED lamp. The photosensitizer is terpyridine ruthenium chloride hexahydrate. The base is triethylamine.

2. The method for photocatalytic synthesis of 6-methylphenanthridine compounds 2 according to claim 1, characterized in that: The molar ratio of the biphenyl isocyanide compound 1, the photosensitizer and the base is 1:0.05:10-50.

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