Preparation method of 1-aryl-2-arylformyl cyclopropane compound

Abstract

The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of a 1-aryl-2-arylformyl cyclopropane compound, which comprises the following steps: carrying out first-stage reaction on a formula 1, a formula 2 and a formula 3, then adding a formula 4 and an alkaline component into the first-stage reaction system, carrying out second-stage reaction, and synthesizing to obtain the 1-aryl-2-arylformyl cyclopropane compound with a structure as shown in a formula 5. The invention innovatively provides a metal-catalysis-free, mild and green method for synthesizing the 1-aryl-2-arylformyl cyclopropane compound, which comprises the following steps: by taking a formula 1 as an initial raw material, forming an active intermediate state under the assistance of a formula 2 and a formula 3 in advance, and then reacting the active intermediate state with a formula 4 in the presence of an alkaline component, thereby obtaining the 1-aryl-2-arylformyl cyclopropane compound. Therefore, the 1-aryl-2-aryl formyl cyclopropane compound can be efficiently and mildly synthesized in one pot.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis and relates to a method for synthesizing cyclopropane compounds. Background Technology

[0002] Cyclopropane has attracted increasing attention due to its highly strained ring system and unique bonds. It is widely found in natural products such as terpenes, pheromones, and fatty acid metabolites, and introducing cyclopropane ring structures is an important strategy in drug development. Furthermore, cyclopropane compounds containing multiple functional groups are important organic synthons, capable of synthesizing novel compounds such as polysubstituted cyclopentenes, furans, thiophenes, pyridines, and dihydroisoxazoles through ring-opening reactions. To expand the applications of cyclopropane, numerous synthetic methods for cyclopropane and its derivatives have been reported. The Simmons-Smith reaction utilizes diethylzinc or zinc-copper amalgam with diiodo(bromo)methane to generate a carbene intermediate, which then reacts with alkenes to produce cyclopropane. This type of reaction has high yields but generates large amounts of metal waste. The cycloaddition of diazomethane with alkenes is also an important method; however, diazo compounds pose an explosion risk. The Corey-Chaykovsky cyclopropane reaction is prepared by conjugation addition of dimethyl sulfoxide methylene ylide and α,β-unsaturated carbonyl compounds, but most of the starting materials are not commercially available, and this type of reaction is often carried out using hazardous sodium hydride as a strong base. Angelo Nacci et al. prepared cyclopropane from alkenes and acetophenones via palladium-catalyzed coupling reactions, but this requires expensive palladium catalysts and equivalent amounts of copper acetate, and the reaction temperature is high, limiting its widespread application in industrial production (Angew. Chem. Int. Ed., 2014, 53, 13563). Summary of the Invention

[0003] To address the problems of complex reaction systems, difficult-to-obtain raw materials, cumbersome post-processing, and safety hazards in existing cyclopropane preparation methods, this invention provides a method for preparing 1-aryl-2-arylcarboxylcyclopropane compounds. The aim is to provide a mild, safe, and high-conversion method for synthesizing 1-aryl-2-arylcarboxylcyclopropane compounds without metal catalysis.

[0004] A method for preparing 1-aryl-2-arcarboxylcyclopropane compounds involves performing a first-stage reaction on formulas 1, 2, and 3, followed by adding formula 4 and a basic component to the first-stage reaction system to perform a second-stage reaction, thereby synthesizing 1-aryl-2-arcarboxylcyclopropane compounds with the structure of formula 5.

[0005]

[0006]

[0007] Ar1 and Ar2 are aryl groups on their own or substituted aryl groups;

[0008] R1 and R2 are individually C1 to C6 alkyl, substituted alkyl, phenyl or substituted phenyl groups, or they may be cyclized together to form a cyclo group;

[0009] R3 and R4 are individually C1 to C6 alkyl, substituted alkyl, phenyl or substituted phenyl groups, or they may be cyclized together to form cyclogroups;

[0010] The substituents in the substituted aryl, substituted alkyl, and substituted phenyl groups include at least one of alkyl, alkoxy, halogen, nitro, trifluoromethyl, ester, and acyl groups;

[0011] The alkaline component is at least one of sodium hydroxide, potassium hydroxide, cesium carbonate, potassium carbonate, and DBU.

[0012] This invention innovatively proposes a metal-free, mild, and green method for synthesizing 1-aryl-2-arylcarbamoylcyclopropane compounds. The method uses Formula 1 as the starting material, first forming an active intermediate with the assistance of Formulas 2 and 3, and then reacting it with Formula 4 under alkaline conditions. This allows for the one-pot, efficient, and mild synthesis of 1-aryl-2-arylcarbamoylcyclopropane compounds.

[0013] In this formulation, the aryl group includes monoaryl groups, or polycyclic aryl groups formed by the fusion or combination of two or more monoaryl groups;

[0014] Preferably, the monoaryl group includes phenyl, six-membered heterocyclic aryl, or five-membered heterocyclic aryl;

[0015] Preferably, Ar1 and Ar2 are either phenyl or substituted phenyl groups. The substituents in the substituted phenyl groups are, for example, at least one of C1-C6 alkyl groups, C1-C6 alkoxy groups, halogens, ester groups, and substituted alkyl groups; the substituted alkyl groups are, for example, substituents in C1-C6 alkyl groups containing at least one of hydroxyl groups and halogens.

[0016] In this invention, R1 and R2 in Formula 2 are trifluoromethyl (this compound can also be labeled as Tf2O). Studies have shown that using the preferred Formula 2, combined with the process of this invention, can further achieve synergy and optimize the synthesis effect.

[0017] In this invention, R3 and R4 are cyclically bonded to form a five- or six-membered cyclic base. For example, Formula 3 can be... (Tetramethylene sulfoxide). Studies have shown that using this preferred formula 3 in combination with the process of the present invention can further enhance the preparation effect.

[0018] In this invention, the molar ratio of Formula 1, Formula 2 and Formula 3 is 1:0.9-1.5:0.9-1.5, preferably 1:1-1.05:1-1.05.

[0019] In this invention, the solvent for the first stage reaction includes a non-water-soluble solvent with a boiling point below 150°C; preferably at least one of DCM (dichloromethane), CH3CN (acetonitrile), THF (tetrahydrofuran), acetone, and toluene, with DCM being the most preferred.

[0020] In this invention, the temperature of the first stage reaction is below 5°C, preferably -30°C to 5°C, and can be further set to -5°C to 5°C to consider preparation efficiency.

[0021] In this invention, the reaction time of the first stage can be reasonably adjusted as needed. For example, when the temperature is relatively low, the reaction time can be extended, for example, to 1 to 3 hours. Considering the preparation efficiency, the temperature can be -5 to 5°C and the reaction time can be 5 to 30 minutes. Considering the preparation efficiency, it can be further extended to 10 to 20 minutes.

[0022] In this invention, the alkaline component is cesium carbonate. Studies have shown that using cesium carbonate as the alkaline component, combined with the process of this invention, can further improve the synthesis effect.

[0023] In this invention, the molar ratio of Formula 1, Formula 4 and alkaline component is 1:1 to 3:1 to 3; further, it can be 1:1.3 to 1.6:1.8 to 2.2.

[0024] In this invention, the temperature of the second stage reaction is 20–80°C; for ease of operation, it can be further set to room temperature (e.g., 20–25°C).

[0025] In this invention, the reaction time of the second stage can be controlled according to existing central control methods, for example, it can be 8 to 15 hours, and further, it can be 11 to 13 hours.

[0026] In this invention, Ar1 / Ar2 is exemplified by phenyl or substituted phenyl groups, and its reaction formula is as follows:

[0027]

[0028] The Ar1 / Ar2 mentioned above, taking phenyl as an example, is based on the following reasonable principle:

[0029] First, styrene 1a reacts with trifluorosulfonic anhydride and tetramethylene sulfoxide 2a to form an alkenyl thioonium salt 3a. Acetophenone, under the influence of a strongly basic component, forms a nucleophilic carbanion IM-1', which then undergoes a nucleophilic addition reaction with 1a to generate intermediate IM-2'. The carbanion of intermediate IM-2' undergoes an intramolecular nucleophilic addition reaction with a carbonyl group to give intermediate IM-3'. Intermediate IM-3' is an unstable four-membered ring intermediate and further isomerizes to form intermediate IM-4', which then undergoes an intramolecular nucleophilic substitution reaction to give a cyclopropane product 4a and release one molecule of tetrahydrothiophene.

[0030]

[0031] Beneficial effects

[0032] This invention innovatively uses Formula 1 as the starting material, pre-forming it into an active intermediate with the assistance of Formula 2 and Formula 3, and then reacting it with Formula 4. In this way, 1-aryl-2-arcarboxylcyclopropane compounds can be synthesized in a one-pot, efficient and mild manner. Attached Figure Description

[0033] Figure 1 The product of Example 1 1 1H NMR (400M, CDCl3) spectrum;

[0034] Figure 2 The product of Example 1 13 C NMR (100M, CDCl3) spectrum;

[0035] Figure 3 The product of Example 6 1 1H NMR (400M, CDCl3) spectrum;

[0036] Figure 4 The product of Example 6 13 C10 NMR (100M, CDCl3) spectrum. Detailed Implementation

[0037] Example 1:

[0038]

[0039] Styrene (0.5 mmol, 52 mg) and tetramethylene sulfoxide (0.5 mmol, 52 mg) were added to a 10 mL round-bottom flask and dissolved in dichloromethane (5 mL). The reaction solution was cooled to 0 °C, and trifluoromethanesulfonic anhydride (0.5 mmol, 141 mg) was added dropwise, maintaining the temperature below 5 °C. After reacting for 15 min, acetophenone (0.75 mmol, 90 mg) and cesium carbonate (1 mmol, 326 mg) were added, and the mixture was stirred at room temperature for 12 h. After the reaction was complete, water (10 mL) was added, and the mixture was extracted. The aqueous phase was extracted twice with dichloromethane (2 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The product was purified by silica gel column chromatography in 77% yield. 1HNMR(400MHz,Chloroform-d)δ7.92(d,J=7.8Hz,2H),7.43(dt,J=40.1,7.5Hz,3H),7.26– 7.08(m,5H),2.87–2.79(m,1H),2.69–2.59(m,1H),1.90–1.80(m,1H),1.51–1.45(m,1H); 13 C NMR (101MHz, Chloroform-d) δ198.52,140.47,137.72,139.09,132.87,128.54,128.09,126.57,126.21,29.98,29.28,19.22.

[0040] Example 2

[0041] Compared to Example 1, the difference lies in that single-factor screening of the conditions is performed according to the conditions in Table 1 below, and the results are shown in Table 1:

[0042]

[0043]

[0044] Unless otherwise specified, 1a (0.3 mmol) and the activator (0.3 mmol, 1 eq) were dissolved in DCM (3 mL), stirred at 0 °C, and sulfoxide (0.3 mmol, 1 eq) was added dropwise. After the addition was complete, stirring was continued for 0.5 h. 2a (0.45 mmol, 1.5 eq) and the basic component (0.6 mmol, 2 eq) were added at room temperature and stirred for 12 h. a Add 1.5 equivalents of Cs₂CO₃; b Add 1.0 equivalent of Cs₂CO₃. c Add 1.2 equivalents of Tf₂O and 1.2 equivalents of tetramethylene sulfoxide. The first step of the reaction was carried out at -20°C for 2 hours.

[0045] Example 3:

[0046]

[0047] In a 10 mL round-bottom flask, 0.5 mmol (81 mg) of p-methyl styrene and 0.5 mmol (52 mg) of tetramethylene sulfoxide were added and dissolved in 5 mL of dichloromethane. The reaction solution was cooled to 0 °C, and trifluoromethanesulfonic anhydride (0.5 mmol (141 mg) was added dropwise while maintaining the temperature below 5 °C. After reacting for 15 min, 0.75 mmol (90 mg) of acetophenone and cesium carbonate (1 mmol (326 mg)) were added, and the mixture was stirred at room temperature for 12 h. After the reaction was complete, 10 mL of water was added, and the mixture was extracted. The aqueous phase was extracted twice with dichloromethane (2 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The product was purified by silica gel column chromatography in 73% yield. 1 HNMR(400MHz,Chloroform-d)δ7.96–7.88(m,4H),7.51(t,J=7.1Hz,1H),7.40(t,J=7.6Hz,2H),7.16(d, J=8.0Hz,2H),3.84(s,3H),2.93–2.86(m,1H),2.71–2.63(m,1H),1.94–1.87(m,1H),1.57–1.52(m,1H); 13 C NMR (101MHz, Chloroform-d) δ198.03,166.84,146.00,137.44,133.09,129.87,128.61,128.39,128.10,126.00,52.10,29.64,29.56,19.68.

[0048] Example 4:

[0049]

[0050] In a 10 mL round-bottom flask, p-chloromethylstyrene (0.5 mmol, 76 mg) and diphenyl sulfoxide (0.5 mmol, 101 mg) were added and dissolved in dichloromethane (5 mL). The reaction solution was cooled to 0 °C, and trifluoromethanesulfonic anhydride (0.5 mmol, 141 mg) was added dropwise, maintaining the temperature below 5 °C. After reacting for 15 min, acetophenone (0.75 mmol, 90 mg) and cesium carbonate (1 mmol, 326 mg) were added, and the mixture was stirred at room temperature for 12 h. After the reaction was complete, water (10 mL) was added, and the mixture was extracted. The aqueous phase was extracted twice with dichloromethane (2 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The product was purified by silica gel column chromatography in 62% yield. 1HNMR(400MHz,Chloroform-d)δ7.92(d,J=7.8Hz,2H),7.50(t,J=7.1Hz,1H),7.40(t,J=7.6Hz,2H),7.27(d,J=7.9Hz,2 H),7.10(d,J=7.9Hz,2H),4.51(s,2H),2.90–2.77(m,1H),2.63(t,J=9.7Hz,1H),1.95–1.79(m,1H),1.52–1.44(m,1H); 13 C NMR (101MHz, Chloroform-d) δ198.36,140.90,137.55,132.99,128.86,128.57,128.08,126.55,46.00,29.62,29.34,19.26.

[0051] Example 5:

[0052]

[0053] Styrene (0.5 mmol, 52 mg) and diphenyl sulfoxide (0.5 mmol, 101 mg) were added to a 10 mL round-bottom flask and dissolved in dichloromethane (5 mL). The reaction solution was cooled to 0 °C, and trifluoromethanesulfonic anhydride (0.5 mmol, 141 mg) was added dropwise, maintaining the temperature below 5 °C. After reacting for 15 min, p-bromoacetophenone (0.75 mmol, 149 mg) and cesium carbonate (1 mmol, 326 mg) were added, and the mixture was stirred at room temperature for 12 h. After the reaction was complete, water (10 mL) was added, and the mixture was extracted. The aqueous phase was extracted twice with dichloromethane (2 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The product was purified by silica gel column chromatography in 70% yield. 1 HNMR(400MHz,Chloroform-d)δ7.78(d,J=8.4Hz,2H),7.52(d,J=8.4Hz,2H),7.24(t,J=7.4Hz,2H),7.16(d,J= 7.4Hz,1H),7.10(d,J=7.6Hz,2H),2.82–2.72(m,1H),2.68–2.58(m,1H),1.91–1.80(m,1H),1.53–1.47(m,1H); 13 C NMR (101MHz, Chloroform-d) δ197.48,140.17,136.33,131.82,129.61,128.58,128.06,126.69,126.15,30.28,29.27,19.41.

[0054] Example 6:

[0055]

[0056] Styrene (0.5 mmol, 52 mg) and diphenyl sulfoxide (0.5 mmol, 101 mg) were added to a 10 mL round-bottom flask and dissolved in dichloromethane (5 mL). The reaction solution was cooled to 0 °C, and trifluoromethanesulfonic anhydride (0.5 mmol, 141 mg) was added dropwise, maintaining the temperature below 5 °C. After reacting for 15 min, 3,4-dichloroacetophenone (0.75 mmol, 141 mg) and cesium carbonate (1 mmol, 326 mg) were added, and the mixture was stirred at room temperature for 12 h. After the reaction was complete, water (10 mL) was added, and the mixture was extracted. The aqueous phase was extracted twice with dichloromethane (2 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The product was purified by silica gel column chromatography in 68% yield. 1 HNMR(400MHz,Chloroform-d)δ7.98(s,1H),7.72(d,J=8.4Hz,1H),7.45(d,J=8.3Hz,1H),7.24 (t,J=7.5Hz,2H),7.18–7.05(m,3H),2.76–2.60(m,2H),1.90–1.81(m,1H),1.56–1.49(m,1H); 13 CNMR(101MHz,Chloroform-d)δ196.26,139.86,137.42,137.11,133.20,130.63,130.04,128.61,127.11,126.79,126.14,30.58,29.29,19.74.

[0057] Example 7:

[0058]

[0059] Styrene-3,5-di-tert-butylstyrene (0.5 mmol, 108 mg) and diphenyl sulfoxide (0.5 mmol, 101 mg) were added to a 10 mL round-bottom flask and dissolved in dichloromethane (5 mL). The reaction solution was cooled to 0 °C, and trifluoromethanesulfonic anhydride (0.5 mmol, 141 mg) was added dropwise, maintaining the temperature below 5 °C. After reacting for 15 min, acetophenone (0.75 mmol, 90 mg) and KOH (1 mmol, 56 mg) were added, and the mixture was stirred at room temperature for 12 h. After the reaction was complete, water (10 mL) was added, and the mixture was extracted. The aqueous phase was extracted twice with dichloromethane (2 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The product was purified by silica gel column chromatography in 63% yield. 1HNMR(400MHz,Chloroform-d)δ7.94(d,J=7.7Hz,2H),7.48(t,J=7.3Hz,1H),7.39(t,J=7.6Hz,2H),7.24(s, 1H),6.96(s,2H),2.91–2.79(m,1H),2.72–2.60(m,1H),1.91–1.74(m,1H),1.55–1.49(m,1H),1.25(s,18H); 13 C NMR (101MHz, Chloroform-d) δ198.83,150.95,139.35,137.73,132.82,128.49,128.12,120.88,120.45,34.84,31.44,30.70,29.30,19.34.

[0060] Example 8:

[0061]

[0062] Styrene (0.5 mmol, 52 mg) and diphenyl sulfoxide (0.5 mmol, 101 mg) were added to a 10 mL round-bottom flask and dissolved in dichloromethane (5 mL). The reaction solution was cooled to 0 °C, and trifluoromethanesulfonic anhydride (0.5 mmol, 141 mg) was added dropwise while maintaining the temperature below 5 °C. After reacting for 15 min, p-trifluoromethylacetophenone (0.75 mmol, 141 mg) and Cs₂CO₃ (1 mmol, 326 mg) were added, and the mixture was stirred at room temperature for 12 h. After the reaction was complete, water (10 mL) was added, and the mixture was extracted. The aqueous phase was extracted twice with dichloromethane (2 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The product was purified by silica gel column chromatography in 72% yield. 1 H NMR(400MHz,Chloroform-d)δ8.01(d,J=8.1Hz,2H),7.65(d,J=8.1Hz,2H),7.25(t,J=7.5Hz,2H),7.17(d,J=8 .7Hz,1H),7.11(d,J=7.7Hz,2H),2.85–2.76(m,1H),2.71–2.62(m,1H),1.96–1.85(m,1H),1.60–1.53(m,1H); 13C NMR(101MHz,Chloroform-d)δ197.66,140.32,139.95,134.16(q,J=32.6Hz),128.63,128.40,126.81,126.17,125.61(q,J=3.7Hz),123.59,30.70,29.69(q,J=273.71Hz),19.63; 19 F NMR(376MHz,Chloroform-d)δ-63.03.

Claims

1. Process for the preparation of 1-aryl-2-aroylcyclopropanes, characterized in that, The first stage reaction of formula 1, formula 2 and formula 3, then adding formula 4 and basic component to the first stage reaction system, the second stage reaction, synthesis of formula 5 structure 1-aryl-2-aromatic formyl cyclopropane compounds; Ar1, Ar2 are independently aryl or substituted aryl; R1, R2 are independently C1-C6 alkyl, substituted alkyl, phenyl or substituted phenyl, or cyclically form a ring group; R3, R4 are independently C1-C6 alkyl, substituted alkyl, phenyl or substituted phenyl, or cyclically form a ring group; The substituents of the substituted aryl, substituted alkyl, substituted phenyl include at least one of alkyl, alkoxy, halogen, nitro, trifluoromethyl, ester group, acyl group; The basic component is at least one of sodium hydroxide, potassium hydroxide, cesium carbonate, potassium carbonate, DBU.

2. The method for preparing 1-aryl-2-arylcarboxylcyclopropane compounds as described in claim 1, characterized in that, The aryl includes monoaryl, or polycyclic aryl formed by combining or combining two or more monoaryls; Preferably, the monoaryl includes phenyl, six-membered heterocyclic aryl or five-membered heterocyclic aryl; Preferably, Ar1, Ar2 are independently phenyl or substituted phenyl.

3. The method for preparing 1-aryl-2-arylcarboxylcyclopropane compounds as described in claim 1, characterized in that, In formula 2, R1, R2 are trifluoromethyl.

4. The method for preparing 1-aryl-2-arylcarboxylcyclopropane compounds as described in claim 1, characterized in that, R3, R4 cyclically form a five or six-membered ring group.

5. The method for preparing 1-aryl-2-arylcarboxylcyclopropane compounds as described in claim 1, characterized in that, The molar ratio of formula 1, formula 2 and formula 3 is 1:0.9-1.5:0.9-1.

5.

6. The method for preparing 1-aryl-2-arylcarboxylcyclopropane compounds as described in claim 1, characterized in that, The solvent of the first stage reaction includes non-water soluble solvent with boiling point below 150℃; preferably at least one of DCM, acetonitrile, THF, acetone, toluene.

7. The method for preparing 1-aryl-2-arylcarboxylcyclopropane compounds as described in claim 1, characterized in that, The temperature of the first stage reaction is below 5℃, preferably -30℃-5℃.

8. The method for preparing 1-aryl-2-arylcarboxylcyclopropane compounds as described in claim 1, characterized in that, The basic component is cesium carbonate.

9. The method for preparing 1-aryl-2-arylcarboxylcyclopropane compounds as described in claim 1, characterized in that, The molar ratio of formula 1, formula 4 and basic component is 1:1-3:1-3.

10. The method for preparing 1-aryl-2-arylcarboxylcyclopropane compounds as described in claim 1, characterized in that, The temperature of the second stage reaction is 20-80℃; Preferably, the time of the second stage reaction is 8-15h.

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