Preparation method of 2-aza [5] helicene
By using the Vilsmeier-Haack reaction, oxidative aromatization and Suzuki coupling reaction and Aldol reaction, the problem of low synthesis efficiency of 2-aza[5]spiroene was successfully solved, and a high-yield and industrially suitable synthesis of 2-aza[5]spiroene was achieved.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-12-26
- Publication Date
- 2026-03-31
AI Technical Summary
The synthesis efficiency of 2-aza[5]spiroene in the existing technology is low, the yield is low and the tin reagent used is highly toxic, which is not suitable for industrial production.
Commercial 2,3-dihydrophenanthrene-4(1H)-one was subjected to a Vilsmeier-Haack reaction with phosphorus tribromooxy and N,N-dimethylformamide, followed by oxidative aromatization with 2,3-dichloro-5,6-dicyanobenzoquinone, and then Suzuki coupling reaction with 4-methylpyridine-3-boronic acid pinacol ester was carried out using a palladium catalyst. Finally, 2-azaspirene was synthesized by Aldol reaction under alkaline conditions.[5]
A high-yield synthesis of 2-aza[5]spiroene was achieved. The synthesis conditions were mild and the operation was simple, making it suitable for industrial production.
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Figure CN121758367A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of preparation methods of functional organic molecules, specifically relating to a preparation method of 2-aza[5]helicene. Background Technology
[0002] As a type of fused-ring aromatic hydrocarbon with a helical chiral structure, helicene has shown important application value in fields such as optoelectronic materials, supramolecular self-assembly, chiral catalysis and biomolecular recognition due to its unique spatial arrangement and photoelectric properties. However, due to the large steric hindrance and strain that accompany the formation of fused rings, the synthesis of 2-aza[5]helicene has long suffered from problems such as low efficiency and many by-products.
[0003] Therefore, it is of great significance to develop an efficient, economical and green production method to prepare 2-aza[5]spiroene.
[0004] 2-aza[5]helicene has the following structural formula:
[0005]
[0006] The article Abbate, S.; Bazzini, C.; Caronna, T.; Fontana, F.; Gambarotti, C.; Gangemi, F.; Longhi, G.; Mele, A.; Sora, IN; Panzeri, W. Monoaza[5]helicenes. Part 2: Synthesis, Characterisation and The oretical Calculations. Tetrahedron 2006, 62, 139-148. reports the following synthetic route:
[0007]
[0008] This route first involves a Wittig reaction between terephthalaldehyde and pyridine ylides to generate a cis-olefin, followed by cyclization under light to yield a benzo[h]isoquinoline-9-formaldehyde intermediate. This intermediate then undergoes a Wittig reaction with aryl ylides to generate a brominated cis-olefin. t Bu3SnH promotes the cyclization reaction to give 2-aza[5]spiroene.
[0009] The biggest drawback of this route is that... t The cyclization step promoted by Bu3SnH is extremely inefficient, with a yield of only 5%, resulting in an overall synthetic yield of only 2%. Furthermore, tin reagents are highly toxic, making them unsuitable for industrial production. This severely restricts their functional research and application expansion. Summary of the Invention
[0010] In view of the above, this invention addresses the aforementioned problems in the prior art by providing a method for preparing 2-aza[5]helicene. The synthesis method of this invention is simple, the synthesis conditions are mild, the operation is straightforward, the steps are short, and the yield of synthesized 2-aza[5]helicene is high.
[0011] The method for preparing 2-aza[5]hexaene products of the present invention includes the following steps:
[0012] Step 1: Commercial 2,3-dihydrophenanthrene-4(1H)-one was reacted with phosphorus tribromooxyphosphine and N,N-dimethylformamide via a Vilsmeier-Haack reaction to synthesize 4-bromo-1,2-dihydrophenanthrene-3-carboxaldehyde compound.
[0013] Step 2: 4-Bromo-1,2-dihydrophenanthrene-3-carboxaldehyde and 2,3-dichloro-5,6-dicyanobenzoquinone undergo an oxidative aromatization reaction to synthesize 4-bromophenanthrene-3-carboxaldehyde.
[0014] Step 3: Construct axially chiral 4-(4-methylpyridin-3-yl)phenanthrene-3-carboxaldehyde by palladium-catalyzed Suzuki coupling reaction of 4-bromophenanthrene-3-carboxaldehyde with pinacol 4-methylpyridin-3-boronic acid.
[0015] Step 4: The axially chiral 4-(4-methylpyridin-3-yl)phenanthrene-3-carboxaldehyde undergoes an Aldol reaction under alkaline conditions to obtain the target product 2-aza[5]spiroene.
[0016] The reaction route is shown below:
[0017] .
[0018] In step 1, the molar ratio of 2,3-dihydrophenanthrene-4(1H)-one, phosphorus tribromooxyphosphine, and N,N-dimethylformamide is 1:2.5:3.0.
[0019] In step 1, the reaction solvent is selected from any one of dichloromethane, carbon tetrachloride, dichloroethane, and phosphorus trichloride. Dichloromethane is preferred.
[0020] In step 2, the molar ratio of 4-bromo-1,2-dihydrophenanthrene-3-carboxaldehyde and 2,3-dichloro-5,6-dicyanobenzoquinone is 1:5-8, for example 1:5, 1:6, 1:7, 1:8, with a preferred ratio of 1:5.
[0021] In step 2, the reaction temperature is 120℃-130℃, such as 120℃, 110℃ or 130℃. 120℃ is preferred.
[0022] In step 2, the solvent used in the reaction is any one of 1,4-dioxane, toluene, benzene, and ethylbenzene. 1,4-dioxane is preferred.
[0023] Step 2 is carried out in the presence of an oxidant, which is any one of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), tin dioxide (SeO2), and palladium on carbon catalyst. Preferably, it is 2,3-dichloro-5,6-dicyanobenzoquinone.
[0024] In step 3, the palladium catalyst is tetrakis(triphenylpalladium). The molar ratio of 4-bromophenanthrene-3-carboxaldehyde, the palladium catalyst, and 4-methylpyridine-3-boronic acid pinacol ester is 1:(0.01-0.2):(1.0-3.0). For example, 1:0.1:1.1, 1:0.1:1.5, 1:0.2:1.5, with a preferred ratio of 1:0.1:1.1.
[0025] In step 3, the reaction is carried out in the presence of a base, which is either barium hydroxide monohydrate or potassium carbonate.
[0026] In step 3, the solvent used in the reaction is any one or a mixture of two of 1,4-dioxane and water. For example, the volume ratio of 1,4-dioxane to water is 5:1, 1,4-dioxane to water is 10:1, and the preferred ratio is 5:1.
[0027] In step 4, the molar ratio of axially chiral 4-(4-methylpyridin-3-yl)phenanthrene-3-carboxaldehyde to tert-butanol is 1:1-4, for example, 1:1, 1:2, 1:3, 1:4. Preferably, it is 1:2.
[0028] In step 4, the alkali used is any one of potassium tert-butoxide, sodium tert-butoxide, potassium hydroxide, sodium hydride, and barium hydroxide.
[0029] In step 4, the reaction temperature is from room temperature to 50°C, such as room temperature, 40°C, or 50°C. Room temperature is preferred.
[0030] Further, in step 1, 2,3-dihydrophenanthrene-4(1H)-one reacts with phosphorus tribromooxyphosphine and N,N-dimethylformamide via a Vilsmeier-Haack reaction to synthesize 4-bromo-1,2-dihydrophenanthrene-3-carboxaldehyde, specifically including the following steps:
[0031] Take a dry Shrek tube and add anhydrous N,N-dimethylformamide and anhydrous dichloromethane sequentially under a nitrogen atmosphere. After stirring thoroughly in an ice-water bath at 0°C, slowly add phosphorus oxybromide dropwise through a constant-pressure dropping funnel, maintaining uniform mixing with magnetic stirring. After the addition is complete, continue the reaction at 0°C for 1 h to allow DMF and PBr3 to fully form Vilsmeier's reagent. Subsequently, add a dichloromethane solution of 2,3-dihydrophenanthrene-4(1H)-one to the mixture, transfer the reaction system to a temperature-controlled metal bath, and react at 50°C for 18 h. After the reaction is complete, quench the reaction with a pre-prepared saturated sodium hydroxide solution cooled to room temperature. Continuously monitor the reaction with pH paper and TLC thin-layer silica gel plates until the product spot appears clearly and the pH value reaches between 7 and 8. The mixture was then extracted three times with a dichloromethane / water relative reaction mixture. The organic phases were combined, dried thoroughly with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (hexane / ethyl acetate = 80:1, V / V) to give a yellow oily product, 4-bromo-1,2-dihydrophenanthrene-3-carboxaldehyde.
[0032] Further, in step 2, 4-bromo-1,2-dihydrophenanthrene-3-carboxaldehyde and 2,3-dichloro-5,6-dicyanobenzoquinone undergo oxidative aromatization to generate 4-bromophenanthrene-3-carboxaldehyde, specifically including the following steps:
[0033] Add 4-bromo-1,2-dihydrophenanthrene-3-carboxaldehyde, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, and then 1,4-dioxane to a dry 250 mL three-necked round-bottom flask. Transfer the reaction apparatus to a temperature-controlled metal bath equipped with a reflux condenser and reflux the reaction at 120 °C. Maintain the reaction temperature precisely using an oil bath temperature control system and stir continuously for 24 hours. Monitor the reaction progress by thin-layer chromatography. After the reaction mixture has cooled naturally to room temperature, filter under reduced pressure through a sintered glass funnel filled with diatomaceous earth to remove insoluble solid impurities. Wash the filter cake three times with a small amount of dichloromethane to ensure complete product transfer. Combine the filtrates and concentrate under reduced pressure. Purify the residue by column chromatography (hexane / ethyl acetate = 20:1, V / V) to give the yellow oily product 4-bromophenanthrene-3-carboxaldehyde.
[0034] Further, in step 3, the axially chiral 4-(4-methylpyridin-3-yl)phenanthrene-3-carboxaldehyde is constructed by palladium-catalyzed Suzuki coupling reaction of the 4-bromophenanthrene-3-carboxaldehyde compound with pinacol 4-methylpyridin-3-boronate, specifically including the following steps:
[0035] Under a nitrogen atmosphere, a mixed solution of 4-bromophenanthrene-3-carboxaldehyde, 4-methylpyridin-3-boronic acid pinacol ester, barium hydroxide monohydrate, tetra(triphenylphosphine)palladium, 1,4-dioxane, and water, prepared in step 2, was added to a dry 250 mL Schlenk flask. The reaction system was placed in liquid nitrogen and purged three times with inert gas using a double-row tube, followed by thawing in a water bath while maintaining a nitrogen atmosphere. The reaction system was then transferred to a temperature-controlled metal bath and reacted at 100 °C for 12 hours. After the reaction, the mixture was extracted three times with ethyl acetate / aqueous phase. The combined organic phases were thoroughly dried over anhydrous sodium sulfate, filtered under reduced pressure, and the residue was purified by column chromatography (hexane / ethyl acetate = 20:1, V / V) to give a yellow oily product, axially chiral 4-(4-methylpyridin-3-yl)phenanthrene-3-carboxaldehyde.
[0036] Further, in step 4, the axially chiral 4-(4-methylpyridin-3-yl)phenanthrene-3-carboxaldehyde undergoes an Aldol reaction under alkaline conditions to obtain the target product 2-aza[5]spiroene, specifically including the following steps:
[0037] In a dry 100 mL flask, add the axially chiral 4-(4-methylpyridin-3-yl)phenanthrene-3-carboxaldehyde, potassium tert-butoxide, and anhydrous N,N-dimethylformamide prepared in step 3. Place the reaction system on a magnetic stirrer and stir at room temperature for 24 hours. After the reaction is complete, extract three times with ethyl acetate / saturated sodium chloride solution. Combine the organic phases and dry thoroughly with anhydrous sodium sulfate. Filter under reduced pressure. Purify the residue by column chromatography (hexane / ethyl acetate = 20:1, V / V) to obtain a yellow solid 2-aza[5]spirene.
[0038] Compared with the prior art, the beneficial effects of the present invention are reflected in:
[0039] The synthesis process of 2-aza[5]spiroene product of the present invention has mild synthesis conditions, simple and controllable operation, high yield, and is easy to repeat and scale up, meeting the needs of industrial production. Attached Figure Description
[0040] Figure 1 The NMR spectrum is for 4-bromo-1,2-dihydrophenanthrene-3-carboxaldehyde.
[0041] Figure 2 The NMR spectrum of 4-bromophenanthrene-3-carboxaldehyde is shown.
[0042] Figure 3 The NMR spectrum of axially chiral 4-(4-methylpyridin-3-yl)phenanthrene-3-carboxaldehyde is shown.
[0043] Figure 4 The NMR spectrum of 2-aza[5]helicene is shown. Detailed Implementation
[0044] The technical solution of the present invention will be further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments are merely illustrative of the present invention and should not be construed as limiting the invention.
[0045] Example 1:
[0046] (1) Preparation of 4-bromo-1,2-dihydrophenanthrene-3-carboxaldehyde, the specific preparation method is as follows:
[0047]
[0048] Pretreatment of the 250 mL double-necked round-bottom flask: After vacuum drying at 120 °C, three "vacuum-nitrogen purging" cycles were performed using a dual-row tube system (each cycle lasting 5 min, vacuum degree ≤10). -3 A strictly inert gas atmosphere was established. Anhydrous N,N-dimethylformamide (DMF, 3.0 equivalent, 150.0 mmol) and anhydrous dichloromethane (DCM, 50 mL) were added sequentially under a nitrogen atmosphere. After thorough mixing in an ice-water bath at 0 °C, phosphorus oxybromide (2.5 equivalent, 125.0 mmol) was slowly added dropwise at a rate of 1 mL / min through a constant-pressure dropping funnel, maintaining homogeneity with magnetic stirring. After the addition was complete, the reaction was continued at 0 °C for 1 h to allow DMF and POBr3 to fully form the Vilsmeier reagent. Subsequently, a dichloromethane solution of 2,3-dihydrophenanthrene-4(1H)-one (1.0 equivalent, 50.0 mmol / 100 mL) was added to the mixture, and the reaction system was transferred to a temperature-controlled metal bath and reacted at 50 °C for 18 h. After the reaction was completed, a pre-prepared saturated sodium hydroxide solution cooled to room temperature was added to quench the reaction. The pH was continuously monitored using pH paper and TLC thin-layer silica gel plates until the product spot appeared clearly in the reaction system and the pH value reached between 7 and 8. Subsequently, the reaction mixture was extracted three times with dichloromethane / water. The combined organic phases were thoroughly dried with anhydrous sodium sulfate, filtered under reduced pressure, and the solvent and volatile substances were removed using a rotary evaporator. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 80 / 1) to give a yellow oily substance 4-bromo-1,2-dihydrophenanthrene-3-carboxaldehyde (22.5 mmol, 6.4611 g) in 45% yield.
[0049] 1H NMR (400 MHz, CDCl3 ) δ 10.32 (s, 1H), 8.71 (d, J = 8.4 Hz, 1H), 7.84 (t, J = 7.6 Hz, 2H), 7.57 (t, J = 7.6 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H),7.32 (d, J = 8.0 Hz, 1H), 2.85 – 2.79 (m, 2H), 2.62 – 2.56 (m, 2H). 13 C NMR(150 MHz, CDCl3) δ 192.9, 141.0, 137.9, 135.7, 133.8, 131.9, 130.4, 130.2,128.8, 126.4, 125.8, 125.8, 125.4, 29.7, 22.7.HRMS(ESI) m / z: [M + H] + Calcdfor C 15 H 11 BrOH + 287.0066; Found 287.0068.
[0050] (2) Preparation of 4-bromophenanthrene-3-carboxaldehyde, the specific preparation method is as follows:
[0051]
[0052] Add 4-bromo-1,2-dihydrophenanthrene-3-carboxaldehyde (1.0 equivalent, 22.5 mmol) to a dry 250 mL three-necked round-bottom flask, followed by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (5.0 equivalent, 112.5 mmol), and then 1,4-dioxane (180 mL). Transfer the reaction apparatus to a temperature-controlled metal bath equipped with a reflux condenser and reflux the reaction at 120 °C. Maintain the reaction temperature precisely using an oil bath temperature control system and stir continuously for 24 hours. Monitor the reaction progress by thin-layer chromatography (TLC) using petroleum ether / ethyl acetate = 5 / 1 as the developing solvent until the starting material spot disappears, indicating complete reaction. After the reaction mixture has cooled naturally to room temperature, filter under reduced pressure through a sintered glass funnel filled with diatomaceous earth (Celite G) to remove insoluble solid impurities. Wash the filter cake three times with a small amount of dichloromethane to ensure complete product transfer. After combining the filtrates, the volatile solvent was removed by rotary evaporation at 60°C under reduced pressure to obtain a brownish-yellow crude product. The crude product was purified by silica gel column chromatography with 200-300 mesh silica gel as the stationary phase and petroleum ether-ethyl acetate as the mobile phase (= 20 / 1). The eluent was monitored by UV detection, and the target component was collected. After removing residual solvent by vacuum drying, a yellow solid 4-bromophenanthrene-3-carboxaldehyde (12.2 mmol, 3.464 g) was obtained in 54% yield.
[0053] 1 H NMR (400 MHz, CDCl3) δ 10.78 (s, 1H), 9.82 (dd, J = 6.0, 3.6 Hz, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.92 (dd, J = 6.0, 3.6 Hz, 1H), 7.86 (d, J =10.0 Hz, 2H), 7.72 – 7.66 (m, 3H). 13 C NMR (100 MHz, CDCl3) δ 193.6, 138.6,134.2, 133.9, 131.3, 130.2, 129.6, 128.9, 128.8, 127.8, 127.7, 126.5, 126.2,125.8. HRMS(ESI) m / z: [M + Na] + Calcd for C 15 H9BrONa + 284.9910; Found 284.9915.
[0054] (3) Preparation of 4-(4-methylpyridin-3-yl)phenanthrene-3-carboxaldehyde, the specific preparation method is as follows:
[0055]
[0056] Add 1.0 equivalent (12.2 mmol) of 4-bromophenanthrene-3-carboxaldehyde, 1.1 equivalent (13.4 mmol) of 4-methylpyridine-3-boronic acid pinacol ester, 2.1 equivalent (25.5 mmol) of barium hydroxide monohydrate, and 0.1 equivalent (1.2 mmol) of tetrakis(triphenylphosphine)palladium to a dry 250 mL Schlenk flask. The flask was then treated using the Schlenk technique: three cycles of vacuuming and nitrogen purging were performed using a double-row tube system (each cycle lasting 5 minutes, with a vacuum level ≤10). -3 To ensure an anhydrous and oxygen-free reaction environment, a mixed solution of 1,4-dioxane (100 mL) and water (20 mL) was added under a nitrogen atmosphere. The reaction system was frozen in liquid nitrogen, purged with inert gas three times using a double-row tube, and then thawed in a water bath while maintaining a nitrogen atmosphere. The reaction system was then transferred to a temperature-controlled metal bath and reacted at 100 °C for 12 hours. After the reaction, the mixture was extracted three times with ethyl acetate / aqueous phase, and the combined organic phases were thoroughly dried over anhydrous sodium sulfate, filtered under reduced pressure, and the solvent and volatile substances were removed by rotary evaporation. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give a yellow oily substance 4-(4-methylpyridin-3-yl)phenanthrene-3-carboxaldehyde (7.2 mmol, 2.117 g) in 59% yield.
[0057] 1 H NMR (600 MHz, CDCl3) δ 9.70 (s, 1H), 8.73 (d, J = 5.2 Hz, 1H), 8.51(s, 1H), 8.24 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 7.6 Hz, 1H), 7.88 (t, J = 8.4Hz, 2H), 7.81 (d, J = 8.8 Hz, 1H), 7.51 – 7.46 (m, 1H), 7.39 – 7.34 (m, 2H), 7.19 – 7.14 (m, 1H), 1.95 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 191.9, 150.3,150.1, 146.5, 140.0, 137.4, 135.5, 133.8, 133.4, 131.3, 130.3, 129.5, 128.8,127.4, 126.9, 126.9, 126.0, 125.6, 124.5, 53.5, 24.9, 19.7. HRMS(ESI) m / z: [M+H] + Calcd for C 21 H 15 NOH + 298.1226; Found 298.1227.
[0058] (4) Preparation of 2-aza[5]helicene, the specific preparation method is as follows:
[0059]
[0060] Add 0.2 mmol of 4-(4-methylpyridin-3-yl)phenanthrene-3-carboxaldehyde (1.0 equivalence) to a dry 100 mL flask, followed by 0.4 mmol of potassium tert-butoxide (2.0 equivalence) and 1.0 mL of anhydrous tetrahydrofuran. Place the reaction system on a magnetic stirrer and stir at room temperature for 24 hours. After the reaction is complete, extract three times with ethyl acetate / saturated sodium chloride solution. Combine the organic phases and dry thoroughly with anhydrous sodium sulfate. Filter under reduced pressure. Purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give a yellow solid 2-aza[5]spirolene (41.9 mg, 75% yield).
[0061] 1 H NMR (600 MHz, CDCl3) δ 9.88 (s, 1H), 8.60 – 8.54 (m, 2H), 8.05 (d,J = 8.4 Hz, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.0 Hz, 1H), 7.87(dd, J = 8.4, 3.0 Hz, 2H), 7.84 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 4.4 Hz,1H), 7.54 (t, J = 6.8 Hz, 1H), 7.36 (t, J = 7.2 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 151.4, 143.9, 135.7, 132.8, 132.7, 132.6, 131.1, 128.4, 128.3,128.2, 127.8, 127.2, 126.9, 126.4, 126.2, 126.1, 125.9, 125.6, 125.6, 120.3.HRMS(ESI) m / z: [M + H] + Calcd for C 21 H 13 NH + 280.1121; Found 280.1121.
[0062] Example 2:
[0063] (1) Preparation of 4-bromo-1,2-dihydrophenanthrene-3-carboxaldehyde, the specific preparation method is as follows:
[0064] Compound 4-bromophenanthrene-3-carboxaldehyde was prepared using the same method as in step (1) of Example 1.
[0065] (2) Preparation of 4-bromophenanthrene-3-carboxaldehyde, the specific preparation method is as follows:
[0066] Compound 4-bromophenanthrene-3-carboxaldehyde was prepared using the same method as step (2) of Example 1.
[0067] (3) Preparation of 4-(4-methylpyridin-3-yl)phenanthrene-3-carboxaldehyde, the specific preparation method is as follows:
[0068] Compound 4-(4-methylpyridin-3-yl)phenanthrene-3-carboxaldehyde was prepared using the same method as step (3) in Example 1.
[0069] (4) Preparation of 2-aza[5]helicene, the specific preparation method is as follows:
[0070]
[0071] Add 0.2 mmol of 4-(4-methylpyridin-3-yl)phenanthrene-3-carboxaldehyde (1.0 equivalence) to a dry 100 mL flask, followed by 0.6 mmol of potassium tert-butoxide (1.0 equivalence) and 1.0 mL of anhydrous tetrahydrofuran. Place the reaction system on a magnetic stirrer and stir at room temperature for 24 hours. After the reaction is complete, extract three times with ethyl acetate / saturated sodium chloride solution. Combine the organic phases and dry thoroughly with anhydrous sodium sulfate. Filter under reduced pressure. Purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give a yellow solid 2-aza[5]spirolene (35.8 mg, 64% yield).
[0072] 1 H NMR (600 MHz, CDCl3) δ 9.88 (s, 1H), 8.60 – 8.54 (m, 2H), 8.05 (d,J = 8.4 Hz, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.0 Hz, 1H), 7.87(dd, J = 8.4, 3.0 Hz, 2H), 7.84 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 4.4 Hz,1H), 7.54 (t, J = 6.8 Hz, 1H), 7.36 (t, J = 7.2 Hz, 1H). 13 C NMR (150 MHz, CDCl3) δ 151.4, 143.9, 135.7, 132.8, 132.7, 132.6, 131.1, 128.4, 128.3,128.2, 127.8, 127.2, 126.9, 126.4, 126.2, 126.1, 125.9, 125.6, 125.6, 120.3.HRMS(ESI) m / z: [M + H] + Calcd for C 21 H 13 NH + 280.1121; Found 280.1121.
[0073] Example 3:
[0074] (1) Preparation of 4-bromo-1,2-dihydrophenanthrene-3-carboxaldehyde, the specific preparation method is as follows:
[0075] Compound 4-bromophenanthrene-3-carboxaldehyde was prepared using the same method as in step (1) of Example 1.
[0076] (2) Preparation of 4-bromophenanthrene-3-carboxaldehyde, the specific preparation method is as follows:
[0077] Compound 4-bromophenanthrene-3-carboxaldehyde was prepared using the same method as step (2) of Example 1.
[0078] (3) Preparation of 4-(4-methylpyridin-3-yl)phenanthrene-3-carboxaldehyde, the specific preparation method is as follows:
[0079] Compound 4-(4-methylpyridin-3-yl)phenanthrene-3-carboxaldehyde was prepared using the same method as step (3) in Example 1.
[0080] (4) Preparation of 2-aza[5]helicene, the specific preparation method is as follows:
[0081]
[0082] Add 0.2 mmol of 4-(4-methylpyridin-3-yl)phenanthrene-3-carboxaldehyde (1.0 equivalence) to a dry 100 mL flask, followed by 0.6 mmol of potassium tert-butoxide (1.0 mL) and anhydrous tetrahydrofuran. Place the reaction system on a magnetic stirrer and stir at room temperature for 24 hours. After the reaction is complete, extract three times with ethyl acetate / saturated sodium chloride solution. Combine the organic phases and dry thoroughly with anhydrous sodium sulfate. Filter under reduced pressure. Purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give a yellow solid 2-aza[5]spirolene (41.3 mg, 74% yield).
[0083] 1 H NMR (600 MHz, CDCl3) δ 9.88 (s, 1H), 8.60 – 8.54 (m, 2H), 8.05 (d,J = 8.4 Hz, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.0 Hz, 1H), 7.87(dd, J = 8.4, 3.0 Hz, 2H), 7.84 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 4.4 Hz,1H), 7.54 (t, J = 6.8 Hz, 1H), 7.36 (t, J = 7.2 Hz, 1H). 13 C NMR (150 MHz, CDCl3) δ 151.4, 143.9, 135.7, 132.8, 132.7, 132.6, 131.1, 128.4, 128.3,128.2, 127.8, 127.2, 126.9, 126.4, 126.2, 126.1, 125.9, 125.6, 125.6, 120.3.HRMS(ESI) m / z: [M + H] + Calcd for C 21 H 13 NH + 280.1121; Found 280.1121.
[0084] Example 4:
[0085] (1) Preparation of 4-bromo-1,2-dihydrophenanthrene-3-carboxaldehyde, the specific preparation method is as follows:
[0086] Compound 4-bromophenanthrene-3-carboxaldehyde was prepared using the same method as in step (1) of Example 1.
[0087] (2) Preparation of 4-bromophenanthrene-3-carboxaldehyde, the specific preparation method is as follows:
[0088] Compound 4-bromophenanthrene-3-carboxaldehyde was prepared using the same method as step (2) of Example 1.
[0089] (3) Preparation of 4-(4-methylpyridin-3-yl)phenanthrene-3-carboxaldehyde, the specific preparation method is as follows:
[0090] Compound 4-(4-methylpyridin-3-yl)phenanthrene-3-carboxaldehyde was prepared using the same method as step (3) in Example 1.
[0091] (4) Preparation of 2-aza[5]helicene, the specific preparation method is as follows:
[0092]
[0093] Add 0.2 mmol of 4-(4-methylpyridin-3-yl)phenanthrene-3-carboxaldehyde (1.0 equivalence) to a dry 100 mL flask, followed by 0.8 mmol of potassium tert-butoxide (1.0 mL) and anhydrous tetrahydrofuran. Place the reaction system on a magnetic stirrer and stir at room temperature for 24 hours. After the reaction is complete, extract three times with ethyl acetate / saturated sodium chloride solution. Combine the organic phases and dry thoroughly with anhydrous sodium sulfate. Filter under reduced pressure. Purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain a yellow solid 2-aza[5]spirolene (40.2 mg, 72% yield).
[0094] 1 H NMR (600 MHz, CDCl3) δ 9.88 (s, 1H), 8.60 – 8.54 (m, 2H), 8.05 (d,J = 8.4 Hz, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.0 Hz, 1H), 7.87(dd, J = 8.4, 3.0 Hz, 2H), 7.84 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 4.4 Hz,1H), 7.54 (t, J = 6.8 Hz, 1H), 7.36 (t, J = 7.2 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 151.4, 143.9, 135.7, 132.8, 132.7, 132.6, 131.1, 128.4, 128.3,128.2, 127.8, 127.2, 126.9, 126.4, 126.2, 126.1, 125.9, 125.6, 125.6, 120.3.HRMS(ESI) m / z: [M + H] + Calcd for C 21 H 13 NH + 280.1121; Found 280.1121.
[0095] Example 5:
[0096] (1) Preparation of 4-bromo-1,2-dihydrophenanthrene-3-carboxaldehyde, the specific preparation method is as follows:
[0097] Compound 4-bromophenanthrene-3-carboxaldehyde was prepared using the same method as in step (1) of Example 1.
[0098] (2) Preparation of 4-bromophenanthrene-3-carboxaldehyde, the specific preparation method is as follows:
[0099] Compound 4-bromophenanthrene-3-carboxaldehyde was prepared using the same method as step (2) of Example 1.
[0100] (3) Preparation of 4-(4-methylpyridin-3-yl)phenanthrene-3-carboxaldehyde, the specific preparation method is as follows:
[0101] Compound 4-(4-methylpyridin-3-yl)phenanthrene-3-carboxaldehyde was prepared using the same method as step (3) in Example 1.
[0102] (4) Preparation of 2-aza[5]helicene, the specific preparation method is as follows:
[0103]
[0104] Add 0.2 mmol of 4-(4-methylpyridin-3-yl)phenanthrene-3-carboxaldehyde (1.0 equivalence) to a dry 25 mL reaction tube, followed by 0.4 mmol of potassium tert-butoxide (1.0 mL) and anhydrous tetrahydrofuran. Place the reaction system on a magnetic stirrer and stir at 50 °C for 24 hours. After the reaction is complete, extract three times with ethyl acetate / saturated sodium chloride solution, combine the organic phases and dry thoroughly with anhydrous sodium sulfate, filter under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give a yellow solid 2-aza[5]spirolene (40.8 mg, 73% yield).
[0105] 1 H NMR (600 MHz, CDCl3) δ 9.88 (s, 1H), 8.60 – 8.54 (m, 2H), 8.05 (d,J = 8.4 Hz, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.0 Hz, 1H), 7.87(dd, J = 8.4, 3.0 Hz, 2H), 7.84 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 4.4 Hz,1H), 7.54 (t, J = 6.8 Hz, 1H), 7.36 (t, J = 7.2 Hz, 1H). 13 C NMR (150 MHz, CDCl3) δ 151.4, 143.9, 135.7, 132.8, 132.7, 132.6, 131.1, 128.4, 128.3,128.2, 127.8, 127.2, 126.9, 126.4, 126.2, 126.1, 125.9, 125.6, 125.6, 120.3.HRMS(ESI) m / z: [M + H] + Calcd for C 21 H 13 NH + 280.1121; Found 280.1121.
[0106] Example 6:
[0107] (1) Preparation of 4-bromo-1,2-dihydrophenanthrene-3-carboxaldehyde, the specific preparation method is as follows:
[0108] Compound 4-bromophenanthrene-3-carboxaldehyde was prepared using the same method as in step (1) of Example 1.
[0109] (2) Preparation of 4-bromophenanthrene-3-carboxaldehyde, the specific preparation method is as follows:
[0110] Compound 4-bromophenanthrene-3-carboxaldehyde was prepared using the same method as step (2) of Example 1.
[0111] (3) Preparation of 4-(4-methylpyridin-3-yl)phenanthrene-3-carboxaldehyde, the specific preparation method is as follows:
[0112] Compound 4-(4-methylpyridin-3-yl)phenanthrene-3-carboxaldehyde was prepared using the same method as step (3) in Example 1.
[0113] (4) Preparation of 2-aza[5]helicene, the specific preparation method is as follows:
[0114]
[0115] Add 0.2 mmol of 4-(4-methylpyridin-3-yl)phenanthrene-3-carboxaldehyde (1.0 equivalence) to a dry 25 mL reaction tube, followed by 0.4 mmol of potassium tert-butoxide (1.0 mL) and anhydrous tetrahydrofuran. Place the reaction system on a magnetic stirrer and stir at room temperature for 24 hours. After the reaction is complete, extract three times with ethyl acetate / saturated sodium chloride solution, combine the organic phases, dry thoroughly with anhydrous sodium sulfate, filter under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give a yellow solid 2-aza[5]spirolene (17.9 mg, 32% yield).
[0116] 1 H NMR (600 MHz, CDCl3) δ 9.88 (s, 1H), 8.60 – 8.54 (m, 2H), 8.05 (d,J = 8.4 Hz, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.0 Hz, 1H), 7.87(dd, J = 8.4, 3.0 Hz, 2H), 7.84 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 4.4 Hz,1H), 7.54 (t, J = 6.8 Hz, 1H), 7.36 (t, J = 7.2 Hz, 1H). 13 C NMR (150 MHz, CDCl3) δ 151.4, 143.9, 135.7, 132.8, 132.7, 132.6, 131.1, 128.4, 128.3,128.2, 127.8, 127.2, 126.9, 126.4, 126.2, 126.1, 125.9, 125.6, 125.6, 120.3.HRMS(ESI) m / z: [M + H] + Calcd for C 21 H 13 NH + 280.1121; Found 280.1121.
[0117] The present invention illustrates the preparation method of 2-aza[5]hexaene through the above embodiments, but the present invention is not limited to the above embodiments, that is, it does not mean that the present invention must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvement to the present invention, equivalent substitution of each raw material of the product of the present invention, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.
Claims
1. A process for the preparation of a 2-aza[5]spiroulen product, characterized in that Comprising the following steps: Step 1: Vilsmeier-Haack reaction of 2,3-dihydrophenanthrene-4(1H)-one with phosphorus oxybromide and N, N-dimethylformamide to synthesize 4-bromo-1,2-dihydrophenanthrene-3-carbaldehyde compound; Step 2: oxidative aromatization reaction of 4-bromo-1,2-dihydrophenanthrene-3-carbaldehyde and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone to synthesize 4-bromo-phenanthrene-3-carbaldehyde compound; Step 3: Suzuki coupling reaction of 4-bromo-phenanthrene-3-carbaldehyde compound with 4-methylpyridine-3-boronic acid pinacol ester using palladium catalyst to construct axially chiral 4-(4-methylpyridine-3-yl)phenanthrene-3-carbaldehyde; Step 4: Aldol reaction of axially chiral 4-(4-methylpyridine-3-yl)phenanthrene-3-carbaldehyde under basic conditions to obtain the target product 2-aza[5]spiroulen; The reaction route is as follows: 。 2. The preparation method according to claim 1, characterized in that: In step 1, the molar ratio of 2,3-dihydrophenanthrene-4(1H)-one, phosphorus oxybromide and N, N-dimethylformamide is 1:2.5:3.
0.
3. The preparation method according to claim 1, characterized in that: In step 2, the molar ratio of 4-bromo-1,2-dihydrophenanthrene-3-carbaldehyde and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone is 1:5-8.
4. The preparation method according to claim 1, characterized in that: The reaction in step 2 is carried out in the presence of an oxidizing agent, which is any one of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, tin dioxide and palladium carbon catalyst.
5. The preparation method according to claim 1, characterized in that: In step 3, the palladium catalyst is tetra(triphenylphosphine)palladium.
6. The preparation method according to claim 1 or 5, characterized in that: In step 3, the molar ratio of 4-bromo-phenanthrene-3-carbaldehyde, palladium catalyst and 4-methylpyridine-3-boronic acid pinacol ester is 1:(0.01-0.2):(1.0-3.0).
7. The preparation method according to claim 1, characterized in that: In step 3, the reaction is carried out in the presence of a base, which is any one of barium hydroxide monohydrate and potassium carbonate.
8. The preparation method according to claim 1, characterized in that: In step 4, the molar ratio of axially chiral 4-(4-methylpyridine-3-yl)phenanthrene-3-carbaldehyde and tert-butyl alcohol is 1:1-4.
9. The preparation method according to claim 1, characterized in that: In step 4, the base used is any one of potassium tert-butoxide, sodium tert-butoxide, potassium hydroxide, sodium hydride and barium hydroxide.
10. The preparation method according to claim 1, characterized in that: In step 4, the reaction temperature is room temperature to 50℃.