Method for efficiently synthesizing eleven-membered cyclic imide compound

Abstract

The invention discloses a method for efficiently synthesizing an eleven-membered cyclic imide compound, which relates to the technical field of organic chemistry and is technically characterized in that the eleven-membered cyclic imide compound is obtained by one-pot reaction of an imide compound and a halogenated pentyne compound in the presence of a palladium catalyst and an alkali additive; the method provided by the invention has the advantages of easily available raw materials, high yield, wide substrate application range, mild reaction conditions, simple operation, one-step reaction ring formation and high reaction activity, and can efficiently synthesize various substituted 11-membered cyclic imide compounds.

Description

Technical Field

[0001] The present invention relates to the technical field of organic chemistry, and in particular to a method for efficiently synthesizing an 11-membered cyclic imide compound. Background Art

[0002] Among natural products and drug molecules, mid-ring compounds occupy an important position, and therefore the synthesis methods of mid-ring compounds are increasingly valued, such as the synthesis of azalactams (Eur. J. Org. Chem. 2023, 26, e202300142), the total synthesis of the diterpenoid (+)-vibsanin A (Org. Lett. 2015, 17(3):756–759), and the total synthesis of the terpenoid Buddledone A (Org. Lett. 2012, 14(7):1661–1663).

[0003] However, due to the bond tension of mesocyclic compounds, and the unfavorable enthalpy and entropy factors of molecular structure bring thermodynamic and kinetic mismatch, usually accompanied by the generation of small rings or side chain by-products in preparation process, or the situation of temperature increase can be accompanied by the generation of dimer. The method of currently commonly used synthesis of mesocyclic compounds is more of intramolecular σ rearrangement, metathesis ring closure reaction, the fracture of fused dicyclic system and the ring expansion mediated by free radicals, but the product prepared by intramolecular annulation reaction ubiquity yield is not high, there is the problem that substrate is difficult for preparation (CN112142683A). Intermolecular reaction is then accompanied by more uncertain factors and needs to be able to be cyclized through multistep reaction.

[0004] To this end, the present invention aims to provide a method for efficiently synthesizing an 11-membered cyclic imide compound to solve the above problems. Summary of the Invention

[0005] The purpose of the present invention is to solve the above-mentioned problems and provide a method for efficiently synthesizing an 11-membered cyclic imide compound, which is obtained by a one-pot reaction of an imide compound and a halopentyne compound in the presence of a palladium catalyst and a base additive. The preparation method is simple, efficient, and low-cost, can be efficiently applied to the synthesis of macrocyclic compounds, and has great application value in the synthesis of similar drugs.

[0006] In order to achieve the above object, the technical solution of the present invention is as follows:

[0007] The present invention provides a method for efficiently synthesizing an 11-membered cyclic imide compound, the synthesis method comprising the following steps:

[0008] S1. Add compound 1, compound 2, and a base additive to a pressure-resistant reaction tube filled with a solvent, add a palladium catalyst under nitrogen protection, and conduct a closed reaction at the reaction temperature;

[0009] S2. After the reaction is completed by TLC monitoring, the mixture is cooled to room temperature, water is added, and the mixture is extracted with dichloromethane. The organic phases are combined and dried, and separated by column chromatography to obtain the undecylic compound 3;

[0010] The general synthesis formula of the 11-membered cyclic imide compound is as follows:

[0011]

[0012] R in the compound 1 1 is an aryl or alkyl group, R 2 is an aryl or alkyl group, R 3 is bromine or iodine; the compound 2 is one of 5-chloro-1-pentyne, 5-bromo-1-pentyne, and 5-iodo-1-pentyne; the base additive is various inorganic bases or organic bases; and the palladium catalyst is palladium acetate, tetrakis(triphenylphosphine)palladium, bistriphenylphosphine palladium dichloride, palladium chloride, and the like.

[0013] The molar ratio of the compound 1 to the compound 2 is 1:(1-2), the molar ratio of the compound 1 to the base additive is 1:(2-4), and the molar ratio of the compound 1 to the palladium catalyst is 1:(0.01-0.5).

[0014] The base additive is various inorganic or organic bases, primarily one or more of potassium carbonate, cesium carbonate, sodium carbonate, triethylamine, and potassium tert-butoxide. The solvent is dioxane, dimethyl sulfoxide, N,N-dimethylformamide, acetone, methanol, or n-pentanol. The reaction temperature is 20-110°C, and the closed reaction time is 2-24 hours.

[0015] The eluent used in the column chromatography separation is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to ethyl acetate is (5-50):1.

[0016] Compared with the existing technology, this solution has the following beneficial effects:

[0017] 1. The 11-membered cyclic imide compound of the present invention forms a cyclic structure by reacting an imide derivative with a halopentyne in a single step. It has high reactivity and can efficiently synthesize various polysubstituted 11-membered ring compounds. It has broad application prospects in fields such as medicinal chemistry and materials science.

[0018] 2. The raw materials used in the synthesis method of the present invention are easily available, the yield is high, the substrate has a wide range of applicability, the reaction conditions are mild, and the operation is simple. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 Schematic diagram of the synthesis route of the undecacyclic imide compound in an embodiment of the present invention;

[0020] Figure 2 This is the single crystal diffraction pattern of the undecacyclic imide compound 2 in Example 2 of the present invention. DETAILED DESCRIPTION

[0021] In order to enable those skilled in the art to better understand the present invention, the technical solution of the present invention will be further described in detail below in conjunction with the embodiments of the present invention and the accompanying drawings. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts should fall within the scope of protection of the present invention.

[0022] It should be noted that, in the absence of conflict, the embodiments and features of the embodiments of the present invention can be combined with each other. The present invention will be described in detail below with reference to the embodiments.

[0023] Example 1: Preparation of raw material imide substrate 1

[0024]

[0025] To a 25 mL dry round-bottom flask, p-toluenesulfonyl azide (3.6 mmol), CuI (0.3 mmol), and Et4NI (0.3 mmol) were added. Under nitrogen, cyclopropylacetylene (3.6 mmol), o-iodobenzaldehyde (3.0 mmol), and DCM (15 mL) were added. After stirring, t-BuOLi (9.0 mmol) was added. After completion of the reaction, the reaction solution was quenched with saturated aqueous ammonium chloride solution, stirred, and separated. The aqueous phase was extracted three times with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The oil was separated and purified by silica gel column chromatography to obtain the desired product in an 87% yield. The corresponding H and C spectra of compound 1 are as follows:

[0026] 1 H NMR (400MHz, CDCl3) δ (ppm) 8.97 (s, 1H), 8.05 (d, J = 8.4Hz, 2H), 7.86 (d, J = 7.9Hz, 1H), 7.60 (s, 1H), 7.42–7. 31(m,4H),7.01(t,J=7.6Hz,1H),2.45(s,3H),1.58–1.47(m,1H),1.03–0.73(m,2H),0.28(d,J=5.2Hz,2H).

[0027] 13C NMR (101MHz, CDCl3) δ (ppm) 164.3, 145.2, 144.6, 139.1, 138.5, 135.5, 133.2, 130.7, 130.1, 129.7, 128.7, 127.5, 100.0, 21.8, 9.1, 9.0.

[0028] Example 2: Preparation of 11-membered ring compound 2

[0029]

[0030] To a pressure-resistant reaction tube, add the imide starting material (0.1 mmol), base (0.2 mmol, 2.0 eq), and 5-chloro-1-pentyne (0.2 mmol, 2.0 eq). Under nitrogen, add the palladium catalyst (0.01 mmol, 0.1 eq) and 2 mL of solvent. The reaction was sealed and allowed to react at 110°C for 8 h. After TLC monitoring, the reaction was cooled to room temperature, water was added, and the mixture was extracted with dichloromethane. The combined organic phases were dried, the solvent removed, and column chromatography (PE:EA = 10:1) was performed to yield 85% of the product. The corresponding H and C spectra of compound 2 are as follows:

[0031] 1 H NMR (400MHz, CDCl3) δ (ppm) 9.10 (s, 1H), 8.03 (d, J = 8.3Hz, 2H), 7.94 (d, J = 1.6Hz ,1H),7.57–7.51(m,1H),7.43–7.39(m,1H),7.36(d,J=8.1Hz,2H),7.28–7.24(m ,2H),4.21(t,J=6.2Hz,2H),2.52(t,J=6.9Hz,2H),2.45(s,3H),2.07(s,3H),1. 92(p,J=6.6Hz,2H),1.61–1.55(m,1H),0.97–0.87(m,2H),0.33(q,J=5.4Hz,2H).

[0032] 13 C NMR (101MHz, CDCl3) δ (ppm) 171.4, 165.0, 145.0, 139.7, 136.0, 135.8, 133.1, 132.3, 129. 8,129.6,128.7,128.6,127.0,124.7,95.2,79.3,63.1,27.7,21.7,21.0,16.4,9.5,9.4.

[0033] Example 3:

[0034]

[0035] To a pressure-resistant reaction tube, add the imide starting material (0.1 mmol), potassium carbonate (0.2 mmol, 2.0 eq), and 5-bromo-1-pentyne (0.17 mmol, 1.7 eq). Under nitrogen, add the palladium catalyst (0.01 mmol, 0.1 eq) and 2 mL of solvent. The mixture was sealed and reacted at 100°C for 10 h. After completion of the reaction, monitored by TLC, the mixture was cooled to room temperature, water was added, and the mixture was extracted with dichloromethane. The combined organic phases were dried, the solvent removed, and the mixture was separated by column chromatography (PE:EA = 10:1) to yield 80% of the product.

[0036] Example 4: Preparation of 11-membered ring compound 3

[0037]

[0038] The corresponding imide starting material (0.1 mmol), base (0.2 mmol, 2.0 eq), and 5-halopentyne (0.2 mmol, 2.0 eq) were added to a pressure-resistant reaction tube. Under nitrogen, palladium catalyst (0.01 mmol, 0.1 eq) and 2 mL of solvent were added. The mixture was sealed and reacted at 110°C for 16 h. After completion of the reaction, the reaction was monitored by TLC. The mixture was cooled to room temperature, water was added, and the mixture was extracted with dichloromethane. The organic phases were combined, dried, and the solvent removed. The mixture was then separated by column chromatography (PE:EA = 10:1) to yield 90% of the product. The corresponding H and C spectra of compound 3 are as follows:

[0039] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.95 (d, J = 8.3Hz, 2H), 7.35 (t, J = 8.0Hz, 3H), 7.23 (t, J = 7.6Hz, 1H), 7.16 (dt, J = 12.4, 7.4Hz, 2H),7.09(t,J=7.6Hz,2H),6.94(d,J=7.9Hz,3H),6.88(s,1H),4.10(s,2H),2.47(s,3H),2.45–2.22(m,3H),1.59(s,1H).

[0040] 13 C NMR (101MHz, CDCl3) δ (ppm) 170.1, 144.9, 140.7, 136.9, 135.8, 132.1, 130.5, 129.3, 129.1, 128.6,128.6,128.5,128.4,128.1,127.7,127.1,123.5,98.2,82.2,46.9,32.6,21.7,17.7.

[0041] Example 5: Preparation of Undecyl Cyclic Compound 4

[0042]

[0043] The method for preparing the compound is the same as in Example 2, and the method for preparing the imide raw material is the same as in Example 1. The corresponding hydrogen spectrum of compound 4 is as follows:

[0044] 1 H NMR (400MHz, CDCl3) δ (ppm) 8.02 (d, J = 8.4Hz, 2H), 7.48–7.36 (m, 3H), 7.36–7.27 (m, 3H), 7.23–7.19 (m, 1H), 7.12 (dd, J = 5.1, 0.9 Hz,1H),6.79(dd,J=5.1,3.8Hz,1H),6.67(s,1H),6.58–6.53(m,1H),4.04(s,2H),2.48(s,3H),2.40–2.23(m,2H),1.57(s,2H).

[0045] Example 6: Preparation of Undecyl Cyclic Compound 5

[0046]

[0047] The method for preparing the compound is the same as in Example 2, and the method for preparing the imide raw material is the same as in Example 1. The corresponding hydrogen spectrum of compound 5 is as follows:

[0048] 1 H NMR (400MHz, CDCl3) δ7.97 (ppm) (d, J = 8.4Hz, 2H), 7.38 (t, J = 7.6Hz, 3H), 7.26 (d, J = 7.4Hz, 1H), 7.20 (td, J = 7.6, 1.2Hz, 1H), 7.01 (d ,J=7.5Hz,1H),6.89–6.83(m,2H),6.78(s,1H),6.66–6.59(m,2H),4.09(s,2H),3.74(s,3H),2.49(s,3H),2.43(s,2H),1.59(s,2H).

[0049] The above specific embodiments are merely explanations of the present invention and are not limitations of the present invention. After reading this specification, those skilled in the art may make non-creative modifications to the embodiments as needed. However, as long as they are within the scope of the claims of the present invention, they are protected by patent law.

Claims

1. A method for efficiently synthesizing an 11-membered cyclic imide compound, characterized in that: The synthesis method comprises the following steps: S1. Add compound 1, compound 2, and a base additive to a pressure-resistant reaction tube filled with a solvent, add a palladium catalyst under nitrogen protection, and conduct a closed reaction at the reaction temperature; S2. After the reaction is completed by TLC monitoring, the mixture is cooled to room temperature, water is added, and the mixture is extracted with dichloromethane. The organic phases are combined and dried, and separated by column chromatography to obtain the undecylic compound 3; The synthesis formula of the 11-membered cyclic imide compound is as follows:

2. A method for efficiently synthesizing an 11-membered cyclic imide compound as claimed in claim 1, characterized in that: R in the compound 1 1 is an aryl or alkyl group, R 2 is an aryl or alkyl group, R 3 is bromine or iodine; The compound 2 is one of 5-chloro-1-pentyne, 5-bromo-1-pentyne and 5-iodo-1-pentyne.

3. A method for efficiently synthesizing an 11-membered cyclic imide compound as claimed in claim 2, characterized in that: The base additive is various inorganic bases or organic bases, and the palladium catalyst is palladium acetate, tetrakis(triphenylphosphine)palladium, bistriphenylphosphine palladium dichloride and palladium chloride.

4. A method for efficiently synthesizing an 11-membered cyclic imide compound as claimed in claim 3, characterized in that: The molar ratio of the compound 1 to the compound 2 is 1:(1-2), the molar ratio of the compound 1 to the base additive is 1:(2-4), and the molar ratio of the compound 1 to the palladium catalyst is 1:(0.01-0.5).

5. A method for efficiently synthesizing an 11-membered cyclic imide compound as claimed in claim 3, characterized in that: The organic base is triethylamine, the inorganic base is potassium carbonate, cesium carbonate, sodium carbonate, potassium tert-butoxide, and the alkaline additive is one or more of the above inorganic bases or organic bases.

6. A method for efficiently synthesizing an 11-membered cyclic imide compound as claimed in claim 1, characterized in that: The solvent is dioxane, dimethyl sulfoxide, N,N-dimethylformamide, acetone, methanol or n-pentanol.

7. A method for efficiently synthesizing an 11-membered cyclic imide compound as claimed in claim 1, characterized in that: The reaction temperature is 20-110° C., and the closed reaction time is 2-24 hours.

8. A method for efficiently synthesizing an 11-membered cyclic imide compound as claimed in claim 1, characterized in that: The eluent used in the column chromatography separation is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to ethyl acetate is (5-50):1.

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