A method for the synthesis of benzodiheteropentalenes

Abstract

The application provides a synthesis method of a benzodiheteropental ring and relates to the technical field of organic synthesis. The synthesis method provided by the application is used for reacting 2-substituted aniline compounds II with 2-chloropropene compounds III to generate benzodiheteropental rings I in a solvent environment and with the participation of alkali. The application provides a single carbon source by using the structure of the 2-chloropropene compounds III, and the 2-substituted aniline compounds II are subjected to carbon insertion [1+4] cyclization to synthesize the benzodiheteropental rings I. The reaction raw materials are easy to obtain, the reaction conditions are mild, the product is easy to separate, the yield is high, the reaction process is safe and pollution-free, and the method is suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for synthesizing benzo[a]pyrene five-membered rings. Background Technology

[0002] Statistics show that 59% of small molecule drugs approved by the U.S. Food and Drug Administration (FDA) contain at least one nitrogen heterocycle. Furthermore, nitrogen-containing heterocyclic compounds account for nearly half of the world's top 200 best-selling drugs. In particular, benzo[a]bis(heterocyclic) five-membered ring compounds, many natural and synthetic organic compounds with benzo[a]bis(heterocyclic) structural skeletons, possess a wide range of biological activities, including antibacterial, antitumor, antioxidant, antiviral, antituberculosis, and anthelmintic properties. Benzothiophene derivatives are widely used in pesticides, pharmaceuticals, and other fields, and are also the core framework for constructing many functional materials and natural products.

[0003] For example, mefenacet can effectively control barnyard grass and other gramineous weeds. Some 1,3-benzodiazoles also possess endothelin antagonist, anti-inflammatory, antibacterial, and antitumor activities. For example, S-Gboxin is used to treat diffuse midline gliomas. Currently, common methods for synthesizing benzodiazole five-membered ring compounds include cycloaddition using o-aminophenol derivatives as substrates, and synthesis using o-haloanilines as substrates. For example, o-aminophenol and benzyl alcohol can be condensed under noble metal catalysts to synthesize benzoxazole compounds, and allene compounds can undergo base-catalyzed double Michael reactions with various nucleophiles to obtain benzodiazole five-membered ring compounds.

[0004] However, these methods currently suffer from a series of problems, such as demanding reaction conditions, the need for precious metal catalysts, low reaction yields, and pollution during the reaction process. The complexity of the reaction substrates also prevents large-scale production applications. Therefore, there is an urgent need to provide a solution to improve these problems. Summary of the Invention

[0005] The purpose of this invention is to provide a method for synthesizing benzo[a]dihexane five-membered rings.

[0006] The present invention provides a method for synthesizing a benzodihexane five-membered ring, wherein a 2-substituted aniline compound II reacts with a 2-chloropropene compound III in a solvent environment and with the participation of a base to generate a benzodihexane five-membered ring I;

[0007]

[0008] Wherein, X is one of N, O, S or an amino-substituted derivative, R is one of C1-C6 alkyl or cycloalkyl, phenyl, sulfonyl, benzylbenzenesulfonyl, benzoyl, tert-butoxycarbonyl, benzyl or a substituted derivative thereof, and EWG is one of sulfone, sulfonyl fluoride, sulfonyl chloride, ester, cyano, trifluoromethyl, nitro, phosphate ester, phosphoryl chloride, phosphoryl fluoride.

[0009] The synthesis method provided by this invention uses a 2-chloropropene compound III structure as a single carbon source to perform carbon insertion [1+4] cyclization of a 2-substituted aniline compound II to synthesize a benzodihexane five-membered ring I. The reaction raw materials are readily available and the reaction conditions are mild. The product is easy to separate, the yield is high, and the reaction process is safe and pollution-free, making it suitable for large-scale industrial production.

[0010] Optionally, the alkali includes at least one of DIPEA, DABCO, Et3N, Cs2CO3, Na2CO3, NaHCO3, DBU, DBN, DMAP, NaOH, KOH, t-BuOK, t-BuONa, t-BuOLi, and Li2CO3.

[0011] Optionally, the solvent environment includes at least one of dichloromethane, acetonitrile, ethyl acetate, toluene, tetrahydrofuran, dichloroethane, dioxane, cyclohexane, chloroform, methanol, 2-methyltetrahydrofuran, DMF, and DMSO.

[0012] Optionally, when reacting 2-substituted aniline compound II with 2-chloropropene compound III, the molar ratio of 2-substituted aniline compound II to 2-chloropropene compound III is 1:(1-3), preferably 1:(1.5-2).

[0013] Optionally, 2-substituted aniline compound II and 2-chloropropene compound III are reacted at 20-30°C for 3-6 hours.

[0014] Optionally, after the reaction generates benzodiazepine five-membered ring I, it is purified by silica gel rapid column chromatography, eluted with eluent and the eluent is collected, and then dried by rotary evaporation to obtain pure benzodiazepine five-membered ring I.

[0015] Optionally, the eluent comprises ethyl acetate and petroleum ether in a volume ratio of 1:(3-20). Attached Figure Description

[0016] Figure 1 The above is the 1H NMR spectrum of the benzo[a]-dihexane five-membered ring synthesized in Example 1 of this invention;

[0017] Figure 2 The carbon NMR spectrum of the benzo[a]-dihexane five-membered ring synthesized in Example 1 of this invention;

[0018] Figure 3 The NMR fluorine spectrum of the benzo[a]-dihexane five-membered ring synthesized in Example 1 of this invention;

[0019] Figure 4 The above is the 1H NMR spectrum of the benzo[a]-dihexane five-membered ring synthesized in Example 2 of this invention;

[0020] Figure 5 The carbon NMR spectrum of the benzo[a]-dihexane five-membered ring synthesized in Example 2 of this invention;

[0021] Figure 6 The NMR fluorine spectrum of the benzo[a]-dihexane five-membered ring synthesized in Example 2 of this invention;

[0022] Figure 7 The above is the 1H NMR spectrum of the benzo[a]-dihexane five-membered ring synthesized in Example 3 of this invention;

[0023] Figure 8 The carbon NMR spectrum of the benzo[a]-dihexane five-membered ring synthesized in Example 3 of this invention;

[0024] Figure 9 The NMR fluorine spectrum of the benzo[a]-dihexane five-membered ring synthesized in Example 3 of this invention;

[0025] Figure 10 The 1H NMR spectrum of the benzo[a]-dihexane five-membered ring synthesized in Example 4 of this invention;

[0026] Figure 11 The carbon NMR spectrum of the benzo[a]-dihexane five-membered ring synthesized in Example 4 of this invention;

[0027] Figure 12 The NMR fluorine spectrum of the benzo[a]-dihexane five-membered ring synthesized in Example 4 of this invention;

[0028] Figure 13 The 1H NMR spectrum of the benzo[a]-dihexane five-membered ring synthesized in Example 5 of this invention;

[0029] Figure 14 The carbon NMR spectrum of the benzo[a]-dihexane five-membered ring synthesized in Example 5 of this invention;

[0030] Figure 15 The NMR fluorine spectrum of the benzo[a]-dihexane five-membered ring synthesized in Example 5 of this invention;

[0031] Figure 16 The 1H NMR spectrum of the benzo[a]-dihexane five-membered ring synthesized in Example 6 of this invention;

[0032] Figure 17 The carbon NMR spectrum of the benzo[a]-dihexane five-membered ring synthesized in Example 6 of this invention;

[0033] Figure 18 The NMR fluorine spectrum of the benzo[a]-dihexane five-membered ring synthesized in Example 6 of this invention;

[0034] Figure 19 This invention provides a reaction formula for the synthesis of a benzo[a]-dihexane five-membered ring. Detailed Implementation

[0035] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Unless otherwise defined, the technical or scientific terms used herein should have the ordinary meaning understood by those skilled in the art to which this invention pertains.

[0036] This invention provides a method for synthesizing a benzodiazepine five-membered ring, comprising reacting a 2-substituted aniline compound II with a 2-chloropropene compound III in a solvent environment and with the participation of a base to generate a benzodiazepine five-membered ring I. In fact, during the reaction, the electron-deficient structure of the 2-chloropropene compound III provides a single carbon source and performs carbon insertion [1+4] cyclization on the 2-substituted aniline compound II.

[0037] In fact, see Figure 19 The reaction formula of the synthesis method provided by the present invention is as follows:

[0038]

[0039] Wherein, X is one of N, O, S or an amino-substituted derivative, R is one of C1-C6 alkyl or cycloalkyl, phenyl, sulfonyl, benzylbenzenesulfonyl, benzoyl, tert-butoxycarbonyl, benzyl or a substituted derivative thereof, and EWG is one of sulfone, sulfonyl fluoride, sulfonyl chloride, ester, cyano, trifluoromethyl, nitro, phosphate ester, phosphoryl chloride, phosphoryl fluoride.

[0040] In some embodiments, the base used includes at least one of DIPEA, DABCO, Et3N, Cs2CO3, Na2CO3, NaHCO3, DBU, DBN, DMAP, NaOH, KOH, t-BuOK, t-BuONa, t-BuOLi, and Li2CO3, and the solvent environment used includes at least one of dichloromethane, acetonitrile, ethyl acetate, toluene, tetrahydrofuran, dichloroethane, dioxane, cyclohexane, chloroform, methanol, 2-methyltetrahydrofuran, DMF, and DMSO.

[0041] Specifically, when reacting 2-substituted aniline compound II with 2-chloropropene compound III, the molar ratio of 2-substituted aniline compound II to 2-chloropropene compound III is 1:(1-3), preferably 1:(1.5-2). In fact, setting an excess of 2-chloropropene compound III is beneficial for increasing the conversion rate of 2-substituted aniline compound II and improving the yield of benzo[a]pyrene five-membered ring I.

[0042] In some embodiments, 2-substituted aniline compound II and 2-chloropropene compound III are reacted at 20-30°C for 3-6 hours. Specifically, after the reaction generates benzodiazepine five-membered ring I, it is purified by silica gel rapid column chromatography, eluted with eluent, and the eluent is collected, dried by rotary evaporation, and the pure benzodiazepine five-membered ring I is obtained. The eluent actually consists of ethyl acetate and petroleum ether in a volume ratio of 1:(3-20).

[0043] Example 1

[0044] This embodiment 1 provides a method for synthesizing a benzo[a]-dihexane five-membered ring, comprising the following steps:

[0045] S1. Add 10 mmol (2-hydroxyphenyl)-4-methylbenzenesulfonamide (CAS: 3897-39-0), 20 mmol 2-chloropropenesulfonyl fluoride (CAS: 2137642-41-0), 30 mmol sodium bicarbonate (CAS: 144-55-8) and 50 mL methanol to a reaction vessel and stir for 3 h at room temperature (25°C) under air atmosphere.

[0046] S2. After purification by silica gel rapid column chromatography, the solution was eluted with an eluent prepared by mixing ethyl acetate and petroleum ether at a volume ratio of 1:6. The eluent was collected, and the solvent was removed by rotary evaporation. The solution was then dried under vacuum to obtain benzodiazepine five-membered rings with a calculated yield of 95%.

[0047] In fact, the structure of the benzo[a]bis(heterocyclic) five-membered ring obtained in Example 1 is shown in the following formula:

[0048]

[0049] The benzo[a]dihexane five-membered ring prepared in Example 1 was characterized by 1H NMR spectroscopy as follows: Figure 1 As shown, the carbon NMR characterization was performed as follows: Figure 2 As shown, the fluorine NMR spectroscopy characterization was performed as follows: Figure 3 As shown, and the NMR characterization data are as follows: 1H NMR(CDCl3,400MHz)δ7.78(d,J=8.4Hz,2H),7.44(m,J=7.5Hz,1H),7.30(d,J=8.2Hz,2H),7 .03–6.94(m,2H),6.85(m,J=7.4,Hz,1H),4.21(d,J=3.2Hz,2H),2.42(s,3H),2.03(s,3H). 13 C NMR (CDCl3, 100MHz) δ147.5,145.2,137.0,130.2,128.6,127.0,124.9,122.6,113.5,110.3,99.2,58.9,58.7,23.5,21.7. 19 F NMR (CDCl3, 376MHz) δ 64.46.

[0050] Example 2

[0051] This embodiment 2 provides a method for synthesizing a benzo[a]-dihexane five-membered ring, comprising the following steps:

[0052] S1. Add 10 mmol (2-hydroxyphenyl)benzamide (CAS: 3743-70-2), 15 mmol 2-chloropropenesulfonyl fluoride (CAS: 2137642-41-0), 20 mmol cesium carbonate (CAS: 534-17-8) and 50 mL tetrahydrofuran into a reaction vessel and stir for 3 h at room temperature (25°C) under air atmosphere.

[0053] S2. After purification by silica gel rapid column chromatography, the product was eluted with an eluent prepared by mixing ethyl acetate and petroleum ether at a volume ratio of 1:5. The eluent was collected, and the solvent was removed by rotary evaporation. The product was then dried under vacuum to obtain benzodiazepine five-membered rings with a calculated yield of 97%.

[0054] In fact, the structure of the benzo[2]hexa-5-membered ring obtained in Example 2 is shown in the following formula:

[0055]

[0056] The benzo[2]hexa-5-membered ring obtained in Example 2 was characterized by 1H NMR spectroscopy as follows: Figure 4 As shown, the carbon NMR characterization was performed as follows: Figure 5 As shown, the fluorine NMR spectroscopy characterization was performed as follows: Figure 6 As shown, and the NMR characterization data are as follows: 1H NMR(CDCl3,400MHz)δ7.52(m,J=7.3Hz,3H),7.46–7.40(m,2H),6.83(m,J=8.0Hz,2H),6.51(m, J=7.3Hz,1H),5.67(m,J=8.0Hz,1H),4.85(m,J=4.7Hz,1H),4.15(m,J=1.4Hz,1H),2.02(s,3H). 13 C NMR (CDCl3, 100MHz) δ167.5,131.8,129.1,128.7,127.6,124.9,121.5,114.0,110.4,98.9,54.8,54.6,24.4,24.4. 19 F NMR (CDCl3, 376MHz) δ64.97 (d, J=5.1Hz).

[0057] Example 3

[0058] This embodiment 3 provides a method for synthesizing a benzo[a]-dihexane five-membered ring, comprising the following steps:

[0059] S1. Add 10 mmol of 2-[(dimethylaminosulfonyl)amino]phenol (CAS: 105295-03-2), 20 mmol of 2-chloropropenesulfonyl fluoride (CAS: 2137642-41-0), 20 mmol of DBU (CAS: 6674-22-2) and 50 mL of ethyl acetate into a reaction vessel, and stir the mixture for 3 h at room temperature (25°C) under air atmosphere.

[0060] S2. After purification by silica gel rapid column chromatography, the solution was eluted with an eluent prepared by mixing ethyl acetate and petroleum ether at a volume ratio of 1:3. The eluent was collected, and the solvent was removed by rotary evaporation. The solution was then dried under vacuum to obtain benzodiazepine five-membered rings with a calculated yield of 85%.

[0061] In fact, the structure of the benzo[2]hexa-5-membered ring obtained in Example 3 is shown in the following formula:

[0062]

[0063] The benzo[a]dihexane five-membered ring obtained in Example 3 was characterized by 1H NMR spectroscopy as follows: Figure 7 As shown, the carbon NMR characterization was performed as follows: Figure 8 As shown, the fluorine NMR spectroscopy characterization was performed as follows: Figure 9 As shown, and the NMR characterization data are as follows: 1H NMR(CDCl3,400MHz)δ6.98–6.93(m,1H),6.91(m,J=7.6Hz,1H),6.87(m,J=7 .6Hz,1H),6.85–6.79(m,1H),4.25–4.08(m,2H),2.91(s,6H),2.05(s,3H). 13 C NMR (CDCl3, 100MHz) δ147.2,129.4,124.3,122.5,112.7,110.2,99.6,57.4,57.2,37.8,24.5,24.5. 19 F NMR (CDCl3, 376MHz) δ 65.14.

[0064] Example 4

[0065] This embodiment 4 provides a method for synthesizing a benzo[a]-dihexane five-membered ring, comprising the following steps:

[0066] S1. Add 10 mmol (2-hydroxyphenyl)-4-methylbenzamide (CAS: 57709-82-7), 10 mmol 2-chloropropenesulfonyl fluoride (CAS: 2137642-41-0), 15 mmol sodium hydroxide (CAS: 1310-73-2) and 50 mL toluene into a reaction vessel and stir the mixture for 3 h at room temperature (25°C) under air atmosphere.

[0067] S2. After purification by silica gel rapid column chromatography, the product was eluted with an eluent prepared by mixing ethyl acetate and petroleum ether at a volume ratio of 1:8. The eluent was collected, and the solvent was removed by rotary evaporation. The product was then dried under vacuum to obtain benzodiazepine five-membered rings with a calculated yield of 88%.

[0068] In fact, the structure of the benzo[2]hexa-5-membered ring obtained in Example 4 is shown in the following formula:

[0069]

[0070] The benzo[a]dihexane five-membered ring prepared in Example 4 was characterized by 1H NMR spectroscopy as follows: Figure 10 As shown, the carbon NMR characterization was performed as follows: Figure 11 As shown, the fluorine NMR spectroscopy characterization was performed as follows: Figure 12 As shown, and the NMR characterization data are as follows: 1H NMR(CDCl3,400MHz)δ7.4(d,J=8.2Hz,2H),7.2(d,J=8.0Hz,2H),6.9–6.8(m,2H),6.5(m,J=7.7H z,1H),5.8(m,J=8.0Hz,1H),4.8(m,J=4.4Hz,1H),4.2(m,J=1.7Hz,1H),2.4(s,3H),2.0(s,3H). 13 C NMR (CDCl3, 100MHz) δ167.6,148.4,142.4,129.6,127.8,124.7,121.4,114.1,110.3,98.9,54.8,54.7,24.3,24.3,21.7. 19 F NMR (CDCl3, 376MHz) δ64.93 (d, J=4.6Hz).

[0071] Example 5

[0072] This embodiment 5 provides a method for synthesizing a benzo[a]-dihexane five-membered ring, comprising the following steps:

[0073] S1. Add 10 mmol of 2-(methylamino)phenol (CAS: 611-24-5), 12 mmol of 2-chloropropenesulfonyl fluoride (CAS: 2137642-41-0), 15 mmol of cesium carbonate (CAS: 534-17-8), 25 mL of acetonitrile and 25 mL of dichloromethane into a reaction vessel, and stir the mixture for 3 h at room temperature (25°C) under air atmosphere.

[0074] S2. After purification by silica gel rapid column chromatography, the solution was eluted with an eluent prepared by mixing ethyl acetate and petroleum ether at a volume ratio of 1:6. The eluent was collected, and the solvent was removed by rotary evaporation. The solution was then dried under vacuum to obtain benzo[a]hexa-5-membered rings with a calculated yield of 86%.

[0075] In fact, the structure of the benzo[2]hexa-5-membered ring obtained in Example 5 is shown in the following formula:

[0076]

[0077] The benzo[a]dihexane five-membered ring prepared in Example 5 was characterized by 1H NMR spectroscopy as follows: Figure 13 As shown, the carbon NMR characterization was performed as follows: Figure 14 As shown, the fluorine NMR spectroscopy characterization was performed as follows: Figure 15 As shown, and the NMR characterization data are as follows: 1H NMR (CDCl3, 400MHz) δ7.20 (m, J = 8.3Hz, 2H), 6.71 (d, J = 8.4Hz, 1H), 6.70–6.61 (m, 1H), 4.31 (s, 2H), 2.86 (s, 3H), 2.44 (s, 3H). 13 C NMR (CDCl3, 100MHz) δ195.4,141.9,136.1,128.7,122.7,116.4,112.0,60.9,31.3,30.1. 19 F NMR (CDCl3, 376MHz) δ 70.70.

[0078] Example 6

[0079] This embodiment 6 provides a method for synthesizing a benzo[a]-dihexane five-membered ring, comprising the following steps:

[0080] S1. Add 10 mmol (2-hydroxyphenyl)acetamide (CAS: 714-80-2), 15 mmol 2-chloropropenesulfonyl fluoride (CAS: 2137642-41-0), 15 mmol DIPEA (CAS: 7087-68-5) and 50 mL chloroform into a reaction vessel and stir for 3 h in air at room temperature (25°C).

[0081] S2. After purification by silica gel rapid column chromatography, the solution was eluted with an eluent prepared by mixing ethyl acetate and petroleum ether at a volume ratio of 1:5. The eluent was collected, and the solvent was removed by rotary evaporation. The solution was then dried under vacuum to obtain benzodiazepine five-membered rings with a calculated yield of 80%.

[0082] In fact, the structure of the benzo[2]hexa-5-membered ring obtained in Example 6 is shown in the following formula:

[0083]

[0084] The benzo[a]dihexane five-membered ring prepared in Example 6 was characterized by 1H NMR spectroscopy as follows: Figure 16 As shown, the carbon NMR characterization was performed as follows: Figure 17 As shown, the fluorine NMR spectroscopy characterization was performed as follows: Figure 18 As shown, and the NMR characterization data are as follows: 1 H NMR (CDCl3, 400MHz) δ7.09–6.98(m,2H),6.91(m,J=7.8Hz,2H),4.82(m,J=5.0Hz,1H),4.09(m,J=1.5Hz,1H),2.47(s,3H),1.97(s,3H). 13C NMR (CDCl3, 100MHz) δ167.8, 148.8, 128.3, 124.9, 121.9, 113.0, 110.3, 98.6, 55.0 (d, J = 15.0Hz), 25.7, 24.9 (d, J = 2.4Hz). 19 F NMR (CDCl3, 376MHz) δ64.15 (d, J=4.8Hz).

[0085] While embodiments of the present invention have been described in detail above, it will be apparent to those skilled in the art that various modifications and variations can be made to these embodiments. However, it should be understood that such modifications and variations fall within the scope and spirit of the invention as set forth in the claims. Furthermore, the invention described herein may have other embodiments and can be implemented or carried out in various ways.

Claims

1. A method for synthesizing a benzo[a]dihexane five-membered ring, characterized in that, In a solvent environment and with the participation of alkali, 2-substituted aniline compound II and 2-chloropropene compound III in a molar ratio of 1:(1-3) react for 3-6 h to generate benzodiazepine five-membered ring I. After purification by silica gel rapid column chromatography, the eluent is used for elution and the eluent is collected. After rotary evaporation and drying, the pure benzodiazepine five-membered ring I is obtained. The eluent consists of ethyl acetate and petroleum ether in a volume ratio of 1:(3-20). ； Wherein, R is one of C1-C6 alkyl or cycloalkyl, phenyl, sulfonyl, benzyl, tert-butoxycarbonyl, benzyl, and EWG is sulfonyl fluoride; the base is one of sodium bicarbonate, cesium carbonate, DBU, sodium hydroxide, and N,N-diisopropylethylamine.

2. The synthesis method according to claim 1, characterized in that, The solvent environment includes at least one of dichloromethane, acetonitrile, ethyl acetate, toluene, tetrahydrofuran, dichloroethane, dioxane, cyclohexane, chloroform, methanol, 2-methyltetrahydrofuran, DMF, and DMSO.

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