A method for synthesizing a 2,3-dihydroindolizine compound

Abstract

The application provides a synthesis method of a 2,3-dihydrobenzo-f quinoline compound, which comprises the following steps: taking pyridine quaternary ammonium salt and olefin as raw materials, C6F5I as a catalyst, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as an additive, and reacting in air for 4-15 hours at a reaction temperature of 20-50 DEG C, removing the organic solvent by rotary evaporation, and separating the product by column chromatography. The raw materials are stable, cheap and easy to obtain; the raw material quaternary ammonium salt can be prepared from easily available pyridine and corresponding halide by a simple and efficient method, the raw material olefin is cheap and easy to obtain, the reaction is carried out in air, other oxidants are avoided, the additive DBU is cheap and easy to obtain, and the catalyst is used in a small amount. The method is simple, the target product is obtained by one-step synthesis, the reaction time is short, and the treatment is convenient. The reaction yield is considerable, and the method has industrial production potential.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for synthesizing 2,3-dihydronitrogen indene compounds. Background Technology

[0002] 2,3-Dihydroindene is an important organic intermediate used in the synthesis of downstream nitrogen-containing heterocyclic compounds. For example, its product after complete hydrogenation forms the main skeleton of many natural products, and its product after oxidation and dehydrogenation contains nitrogen-containing indene, an important structural unit in pharmaceuticals. Due to its structural characteristics, 2,3-dihydroindene can also react with some electron-deficient alkenes to construct bridged ring compounds. However, due to factors such as its extensive oxidation, synthetic methods for these compounds are rarely reported domestically or internationally. Given its potential applications in organic synthesis and pharmaceutical unit construction, developing synthetic methods for 2,3-dihydroindene compounds is of significant practical importance.

[0003] 2,3-Dihydronitrogen indene compounds can be used in the synthesis of a variety of downstream nitrogen heterocyclic compounds:

[0004] (1) Indene with 8 hydrogens is synthesized by hydrogenation. Indene with 8 hydrogens is the core structure of many natural products such as erythrine and sialic acid.

[0005] (2) Through further oxidation and dehydrogenation, medium-nitrogen indene compounds are formed. Medium-nitrogen indene is the core structure of many active pharmaceutical ingredients;

[0006] (3) Using cyclization addition with certain alkynyl esters to construct bridged ring molecules in organic synthesis;

[0007] .

[0008] The synthetic methods for 2,3-dihydro-nitrogen indene compounds currently known can be found in the reports by Subhabrata Sen et al. (S. Sar, S. Guha, T. Prabakar, D. Maiti, S. Sen, J. Org. Chem. 2021, 86 (11736–11747.), its general formula is as follows:

[0009]

[0010] Where R is a hydrocarbon group and Ar is an aromatic group.

[0011] This method uses pyridine a, diazonyl ester b, and olefin c as reactants, dichloromethane as solvent, and blue light irradiation to obtain a class of 2,3-dihydronitrogen indene compounds.

[0012] The current shortcomings of this method are:

[0013] 1. The reactant, diazonyl ester b, has poor stability and safety, and is expensive, resulting in a high overall reaction cost, which is not conducive to large-scale production.

[0014] 2. The reaction process requires high-energy blue light irradiation, which not only increases the reaction cost but also causes light pollution hazards, which are not friendly to the environment and health.

[0015] 3. Due to the structure of reactant b, the product at position 3 is double-substituted with aryl and aliphatic groups, thus limiting the product structure and restricting its potential for further chemical modification.

[0016] Therefore, it is of great significance to develop low-cost and environmentally friendly synthetic methods for 2,3-dihydro-nitrogen indene compounds. Summary of the Invention

[0017] The purpose of this invention is to provide a method for synthesizing 2,3-dihydronitrogen indene compounds.

[0018] To achieve the aforementioned objective, the present invention adopts the following technical solution:

[0019] This invention discloses a method for synthesizing 2,3-dihydro-nitrogen indene compounds. The method involves reacting pyridine quaternary ammonium salt and olefins in an organic solvent, using iodopentafluorobenzene C6F5I as a catalyst, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as an additive. The reaction is carried out in air for 4-15 hours at a temperature of 20°C to 50°C. The organic solvent is removed by rotary evaporation, and the product is obtained by column chromatography.

[0020] The structural formula of pyridine quaternary ammonium salt is R1 is hydrogen or a hydrocarbon group, preferably methyl, phenyl, tert-butyl, methyl ester or cyano, and Ar is an aryl group;

[0021] The olefin is acrylonitrile or methyl acrylate;

[0022] The structural formula of the 2,3-dihydronitrogen indene compound is:

[0023]

[0024] R1 is hydrogen or a hydrocarbon group, preferably methyl, phenyl, tert-butyl, methyl ester or cyano; R2 is cyano or methyl ester; Ar is aryl.

[0025] The organic solvent is toluene, 1,2-dichloroethane, 1,4-dioxane, ethyl acetate, acetone, or acetonitrile. The molar ratio of pyridine quaternary ammonium salt to olefin is 2:1 to 3:1. The molar amount of iodopentafluorobenzene is 5 to 50% of the molar amount of the olefin. The molar amount of 1,8-diazabicyclo[5.4.0]undec-7-ene is 1 to 2 times the molar amount of the olefin.

[0026] Pyridine quaternary ammonium salts can be rapidly prepared from the corresponding pyridine and halide in a 1:1 molar ratio. Simple filtration and rinsing with ethyl acetate yields the pyridine quaternary ammonium salt as a light-colored powder. The synthetic route is as follows:

[0027]

[0028] R1 is a hydrogen or hydrocarbon group, and Ar is an aryl group.

[0029] The 2,3-dihydro nitrogen-indene compounds synthesized in this invention have the same applications as those described in the background art. They are important organic intermediates that can be used in the synthesis of downstream nitrogen heterocyclic compounds.

[0030] The beneficial effects of this invention are:

[0031] 1. Stable, inexpensive and readily available raw materials: The quaternary ammonium salt used as raw material can be easily and efficiently prepared from readily available pyridine and its corresponding halogenated derivatives. The olefin used as raw material is inexpensive and readily available. The reaction takes place in air, avoiding the use of other oxidants. The additive DBU is inexpensive and readily available, and the amount of catalyst required is small.

[0032] 2. The method is simple, the target product is synthesized in one step, the reaction time is short, and the processing is convenient.

[0033] 3. This method has low energy consumption and the reaction can be carried out at normal pressure, room temperature or low temperature.

[0034] 4. The reaction yield is considerable, and it has the potential for industrial production.

[0035] 5. The product has high purity and low overall cost compared to similar products.

[0036] 6. The product is the result of partial oxidation of the nitrogen indene in tetrahydrogen, with a monosubstituent on the aromatic ring at position 3, indicating great potential for further chemical modification. Detailed Implementation

[0037] The present invention will be further described below through specific embodiments.

[0038] Example 1

[0039] Synthesis of nitrogen-indene from 1-cyano-3-phenyl-2,3-dihydro:

[0040]

[0041] A magnetic flask was added to a 25 mL reaction flask, followed by 2 mL of acetonitrile, and then 0.66 mmol of 1-benzylpyridine-1-bromide, 0.3 mmol of acrylonitrile, 0.06 mmol of C6F5I, and 0.6 mmol of 1,8-diazabicyclo[5.4.0]undec-7-ene. The reaction was carried out at room temperature in air for 9 hours. The organic solvent was then removed by rotary evaporation, followed by column chromatography (silica gel: 200-300 mesh, eluent volume ratio of petroleum ether: ethyl acetate = 1:1) to obtain a pure orange oily product with a yield of 71%.

[0042] The NMR data for this compound are as follows: 1 H NMR (400 MHz, DMSO-d6): δ 7.46 – 7.40(m,2H), 7.39 – 7.33 (m, 3H), 6.99 – 6.89 (m, 2H), 6.53 – 6.43 (m, 1H), 5.74 (td,J = 6.6, 1.2 Hz, 1H), 5.49 (dd, J = 11.9, 7.1 Hz, 1H), 3.35 – 3.30 (m, 1H), 2.65 (dd, J = 13.9, 7.1 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6): δ 155.2, 141.3,136.3, 135.9, 129.1, 128.4, 126.5, 121.5, 114.0, 105.3, 66.1, 57.2, 36.4.

[0043] Example 2:

[0044] Synthesis of indene from 1-cyano-6,8-dimethyl-3-phenyl-2,3-dihydro ...

[0045]

[0046] Add a magnetic flask to a 25 mL reaction flask, add 2 mL of acetonitrile, and then add 1-benzyl-3,5-dimethylpyridine-1-bromide (0.66 mmol), acrylonitrile (0.3 mmol), C6F5I (0.06 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.6 mmol), 50 o The reaction was carried out in air at C for 5 hours, and then the organic solvent was removed by rotary evaporation. The product was then separated by column chromatography (silica gel: 200~300 mesh, eluent volume ratio of petroleum ether: ethyl acetate = 2:1) to obtain a pure orange oily product with a yield of 64%.

[0047] The NMR data for this compound are as follows: 1 H NMR (400 MHz, Chloroform-d): δ 7.39 (qd, J=7.7, 6.8, 3.7 Hz, 3H), 7.32 – 7.28 (m, 2H), 6.43 (s, 1H), 6.27 (s, 1H), 5.15 (dd, J = 12.0, 9.0 Hz, 1H), 3.36 (dd, J =14.2, 12.0 Hz, 1H), 2.86 (dd, J =14.2, 9.0 Hz, 1H), 2.30 (s, 3H), 1.79 (s, 3H). 13 C NMR (101 MHz, Chloroform-d): δ 153.8, 140.9, 136.8, 129.2, 129.1, 128.7, 126.8, 125.6, 124.2, 114.9, 67.6,57.6,38.4, 18.9, 17.0.

[0048] Example 3

[0049] Synthesis of nitrogen-indene from 1-cyano-7-methyl ester-3-phenyl-2,3-dihydro:

[0050]

[0051] A magnetic stir bar was added to a 25 mL reaction flask, followed by 2 mL of acetonitrile. Then, 0.66 mmol of 1-benzyl-4-methyl ester pyridine-1-bromide, 0.3 mmol of acrylonitrile, 0.06 mmol of C6F5I, and 0.6 mmol of 1,8-diazabicyclo[5.4.0]undec-7-ene were added sequentially. The mixture was reacted in air at room temperature for 13 hours. The organic solvent was then removed by rotary evaporation, followed by column chromatography (silica gel: 200-300 mesh, eluent volume ratio of petroleum ether: ethyl acetate = 2:1) to obtain a pure orange oily product with a yield of 58%.

[0052] The NMR data for this compound are as follows: 1 H NMR (400 MHz, Chloroform- d ): δ 7.43 – 7.36(m, 3H), 7.31 (dd, J = 7.8, 1.7 Hz, 2H), 7.23 (s, 1H), 6.51 (dd, J = 7.0, 0.9 Hz, 1H), 5.99 (dd,J = 7.0, 1.7 Hz, 1H), 5.21 (dd, J = 12.3, 9.3 Hz, 1H), 3.84 (s,3H), 3.38 (dd, J = 15.0, 12.3 Hz, 1H), 2.90 (dd, J = 15.0, 9.3 Hz, 1H). 13 C NMR (101 MHz, Chloroform- d ): δ 164.6, 154.8, 139.9, 136.1, 134.7, 129.4, 129.1,126.8, 120.6, 118.8, 103.5,67.4, 63.9, 52.6, 37.8.

[0053] Example 4

[0054] Synthesis of nitrogen-indene from 1,7-dicyano-3-phenyl-2,3-dihydro:

[0055]

[0056] Add a magnetic flask to a 25 mL reaction flask, add 2 mL of acetonitrile, then add 1-benzyl-4-cyanopyridine-1-bromide (0.66 mmol) and acrylonitrile (0.3 mmol), C6F5I (0.06 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.6 mmol), 50 o The mixture was reacted in air at C for 5 hours, and then the organic solvent was removed by rotary evaporation. The mixture was then separated by column chromatography (silica gel: 200~300 mesh, eluent volume ratio of petroleum ether: ethyl acetate = 3:1) to obtain a pure orange oily product with a yield of 80%.

[0057] The NMR data for this compound are as follows: 1 H NMR (400 MHz, Chloroform- d ): δ 7.46 – 7.39(m, 3H), 7.34 (dd, J = 7.8, 1.8 Hz, 2H), 6.83 (s, 1H), 6.50 (dd, J = 7.0, 1.0 Hz, 1H), 5.50 (dd, J = 7.0, 1.6 Hz, 1H), 5.20 (dd, J = 12.4, 9.7 Hz, 1H), 3.37 (dd,J =15.4, 12.5 Hz, 1H), 2.91 (dd, J = 15.4, 9.7 Hz, 1H). 13 C NMR (101 MHz, Chloroform- d ): δ 152.7, 139.2, 136.0, 129.6, 129.5, 126.9, 122.8, 119.2,116.1, 103.4, 67.7, 66.4, 37.7.

[0058] Example 5

[0059] Synthesis of nitrogen-indene from 1-cyano-3,7-diphenyl-2,3-dihydro:

[0060]

[0061] Add a magnetic flask to a 25 mL reaction flask, add 2 mL of acetonitrile, and then add 1-benzyl-4-phenylpyridine-1-bromide (0.66 mmol), acrylonitrile (0.3 mmol), C6F5I (0.06 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.6 mmol), 50 o The mixture was reacted in air at C for 9 hours, and then the organic solvent was removed by rotary evaporation. The product was then separated by column chromatography (silica gel: 200~300 mesh, eluent volume ratio of petroleum ether: ethyl acetate = 2:1) to obtain a pure orange oily product with a yield of 83%.

[0062] The NMR data for this compound are as follows: 1 H NMR (400 MHz, Chloroform- d ): δ 7.54 – 7.48(m, 2H), 7.40 (dddd, J = 17.0, 7.5, 4.6, 2.8 Hz, 8H), 6.76 (s, 1H), 6.62 (d, J =7.0 Hz, 1H), 5.89 (dd, J = 7.1, 1.8 Hz, 1H), 5.22 (dd, J = 11.9, 8.8 Hz, 1H), 3.39 (dd, J = 14.2, 11.8 Hz, 1H), 2.91 (dd, J = 14.2, 8.8 Hz, 1H). 13C NMR (101MHz, Chloroform- d ): δ 155.9, 147.2, 140.3, 134.4, 129.4, 129.3, 128.8, 128.8,126.8, 126.2, 111.8, 105.2, 67.3,59.5, 37.8.

[0063] Example 6:

[0064] Synthesis of nitrogen-indene from 1-cyano-7-tert-butyl-3-phenyl-2,3-dihydro:

[0065]

[0066] Add a magnetic flask to a 25 mL reaction flask, add 2 mL of acetonitrile, and then add 1-benzyl-4-tert-butylpyridine-1-bromide (0.66 mmol), acrylonitrile (0.3 mmol), C6F5I (0.06 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.6 mmol), 50 o The mixture was reacted in air at C for 9 hours, and then the organic solvent was removed by rotary evaporation. The product was then separated by column chromatography (silica gel: 200~300 mesh, eluent volume ratio of petroleum ether: ethyl acetate = 1:1) to obtain a pure orange oily product with a yield of 66%.

[0067] The NMR data for this compound are as follows: 1 H NMR (400 MHz, Chloroform- d ): δ 7.45 – 7.38(m, 3H), 7.36 – 7.33 (m, 2H), 6.58 – 6.44 (m, 2H), 5.71 (dd, J = 7.2, 2.0 Hz, 1H), 5.18 (dd, J = 11.7, 8.9 Hz, 1H), 3.38 (dd, J = 14.0, 11.7 Hz, 1H), 2.90 (dd, J = 14.0, 8.9 Hz, 1H), 1.20 (s, 9H). 13 C NMR (101 MHz, Chloroform- d ): δ 158.8,156.3, 140.5, 133.3, 129.3, 128.8, 127.0, 109.7, 105.1, 67.4, 58.1,37.8,34.9, 29.4.

[0068] Example 7

[0069] Synthesis of nitrogen-indene from 1-cyano-3-(4-nitrophenyl)-2,3-dihydro:

[0070]

[0071] A magnetic stir bar was added to a 25 mL reaction flask, followed by 2 mL of acetonitrile. Then, 1-(4-nitrobenzyl)pyridine-1-bromide (0.66 mmol), acrylonitrile (0.3 mmol), C6F5I (0.06 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.6 mmol) were added sequentially. The mixture was reacted in air at room temperature for 13 hours. The organic solvent was then removed by rotary evaporation, followed by column chromatography (silica gel: 200-300 mesh, eluent volume ratio of petroleum ether: ethyl acetate = 1:1) to obtain a pure orange oily product with a yield of 75%.

[0072] The NMR data for this compound are as follows: 1 H NMR (400 MHz, CDCl3): δ 8.28 (d, J = 8.7 Hz, 2H), 7.53 (d, J =8.7 Hz, 2H), 6.82 (ddd, J = 9.4, 6.3, 1.2 Hz, 1H), 6.64 –6.52 (m, 2H), 5.68 (td, J = 6.6, 1.2 Hz, 1H), 5.37 (dd, J = 12.1, 7.5 Hz, 1H), 3.47 (dd, J = 14.4, 12.1 Hz, 1H), 2.79 (dd, J = 14.4,7.6 Hz, 1H). 13 C NMR (101 MHz, CDCl3): δ 155.7, 148.0, 147.3, 135.3, 133.9, 127.5, 124.6, 121.0,115.8, 105.9, 66.5, 59.5, 37.4.

[0073] Example 8

[0074] Synthesis of nitrogen-containing indene from 1-methyl ester-3-(4-nitrophenyl)-2,3-dihydro:

[0075]

[0076] Add a magnetic flask to a 25 mL reaction flask, add 2 mL of acetonitrile, and then add 1-(4-nitrobenzyl)pyridine-1-bromide (0.66 mmol), methyl acrylate (0.3 mmol), C6F5I (0.06 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.6 mmol), 50 o The mixture was reacted in air at C for 3 hours, and then the organic solvent was removed by rotary evaporation. Column chromatography was then performed (silica gel: 200-300 mesh, eluent volume ratio of petroleum ether: ethyl acetate = 1:1) to obtain a pure orange oily product with a yield of 54%.

[0077] The NMR data for this compound are as follows: 1 H NMR (400 MHz, Chloroform- d ): δ 8.22 (d, J = 8.6Hz, 2H), 7.46 (d, J = 8.6 Hz, 2H), 6.90 (dd, J = 9.4, 6.3 Hz, 1H), 6.65 (d, J = 6.8Hz, 1H), 5.76 (t, J = 6.6 Hz, 1H), 5.33 (dd, J = 12.1, 6.9 Hz, 1H), 3.66 (s, 3H), 3.46 (dd, J = 15.0, 12.1 Hz, 1H), 2.81 (dd, J = 15.0, 7.0 Hz, 1H). 13 C NMR (101MHz, Chloroform- d ): δ 166.3, 148.4, 147.9, 135.6, 134.0, 127.4, 124.5, 118.1,106.6, 66.5, 50.0, 37.1.

[0078] Comparative Example 1

[0079] As in Example 1, with other conditions unchanged, the solvent was replaced with 1,2-dichloroethane, and the amount of C6F5I was reduced to 0.3 mmol, resulting in a decrease in the yield of the target product to 15%.

[0080] Comparative Example 2

[0081] As in Example 1, with other conditions unchanged, when the additive 1,8-diazabicyclo[5.4.0]undec-7-ene was replaced with common substitutes such as triethylamine, N,N-diisopropylethylamine, or 4-dimethylaminopyridine, the target product was almost impossible to obtain.

[0082] Comparative Example 3

[0083] As in Example 1, the target product cannot be obtained without adding C6F5I, while other conditions remain unchanged.

[0084] Comparative Example 4

[0085] As in Example 1, with other conditions unchanged, the target product could not be obtained when C6F5I was replaced with C6F5Br or C6F6.

Claims

1. A method for synthesizing a 2,3-dihydro nitrogen-indene compound, comprising reacting in an organic solvent with pyridine quaternary ammonium salt and olefin as raw materials, iodopentafluorobenzene C6F5I as catalyst, 1,8-diazabicyclo[5.4.0]undec-7-ene as additive, reacting in air for 4-15 hours at a reaction temperature of 20℃-50℃, removing the organic solvent by rotary evaporation, and obtaining the product by column chromatography; The olefin is acrylonitrile or methyl acrylate; the organic solvent is acetonitrile; The structural formula of pyridine quaternary ammonium salt is: The structural formula of the 2,3-dihydro nitrogen-indene compound is: In the formula, R1 is H, methyl, cyano, tert-butyl, methyl ester, or phenyl, R2 is cyano, and Ar is nitro-substituted or unsubstituted phenyl.

2. The method for synthesizing 2,3-dihydronitrogen indene compounds according to claim 1, characterized in that: The molar ratio of pyridine quaternary ammonium salt to olefin is 2:1 to 3:

1.

3. The method for synthesizing 2,3-dihydronitrogen indene compounds according to claim 1, characterized in that: The molar amount of iodopentafluorobenzene is 5 to 50% of the molar amount of the olefin.

4. The method for synthesizing 2,3-dihydronitrogen indene compounds according to claim 1, characterized in that: The molar amount of 1,8-diazabicyclo[5.4.0]undec-7-ene is 1 to 2 times the molar amount of olefins.

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