A cyclic ether compound containing an indanone structure and a preparation method thereof

Abstract

This invention belongs to the field of compound preparation technology and discloses a method for preparing cyclic ether compounds containing an indanone structure. The method includes the following steps: using an indanedione diazo compound and a cyclic ether compound as raw materials, and under the action of a copper salt catalyst and in an argon atmosphere, a heated reaction is carried out to synthesize the cyclic ether compound containing an indanone structure shown in Formula II. This invention uses a copper salt as a catalyst, specifically copper carbene inserting into the diazo compound to form an oxonium ylide, which then undergoes a ring-expansion reaction with the cyclic ether, resulting in the efficient synthesis of cyclic ether compounds containing an indanone structure with high product yield.

Description

Technical Field

[0001] This invention belongs to the field of compound preparation technology, and relates to a cyclic ether compound containing an indanone structure and its preparation method. Background Technology

[0002] Macrocyclic molecules are an important class of compounds in nature, serving as the core skeletons of many natural products and bioactive molecules. Polycyclic ethers are a special subclass of macrocyclic molecules, acting as effective binding acceptors for cations or small molecules, and have diverse uses and applications in chemistry, materials science, and medicine. For example, lysine ethers have inhibitory effects on Escherichia coli and Bacillus subtilis, making them potential antibacterial drugs; 5-fluorouracil is a common and effective chemotherapeutic agent targeting various tumor types. Due to the potential biological and pharmacological activities of polycyclic ethers, developing efficient synthetic methods to construct these compounds is of great significance.

[0003] In 2010, Lacour's group developed a rhodium-catalyzed regioselective condensation of two molecules of α-diazo-β-keto ester and two molecules of cyclic ether to achieve the one-pot synthesis of 18-membered polyether rings (eghida W., Besnard C., Lacour J., Angew. Chem. Int. Ed., 2010, 49, 7253-7256).

[0004] Currently reported methods for synthesizing polycyclic ethers suffer from drawbacks such as poor substrate universality. Therefore, developing new methods for synthesizing polycyclic ethers is of great significance. Summary of the Invention

[0005] To address the aforementioned technical problems, this invention provides a cyclic ether compound containing an indanone structure and its preparation method. A copper salt is used as a catalyst, specifically, copper carbene inserts into a diazo compound to form an oxonium ylide, which then undergoes a ring-expansion reaction with the cyclic ether, resulting in the efficient synthesis of cyclic ether compounds containing an indanone structure with high product yield.

[0006] To achieve the above objectives, the present invention adopts the following technical solution:

[0007] This invention provides a cyclic ether compound containing an indanone structure, the chemical structural formula of which is as follows:

[0008]

[0009] Wherein, R is selected from H or halogen, n is 1 to 7, and m is 1 to 9.

[0010] This invention also provides a method for preparing the above-mentioned cyclic ether compounds containing an indanone structure, comprising the following steps: using an indanedione diazonium compound and a cyclic ether compound of formula I as raw materials, and under the action of a copper salt catalyst and in an argon atmosphere, heating reaction to synthesize the cyclic ether compound of formula II containing an indanone structure; the synthetic route is as follows:

[0011]

[0012] Wherein: R is selected from H or halogen, n is 1 to 7, and m is 1 to 9.

[0013] The copper salt catalyst described in the technical solution of this invention is selected from cuprous cyanide, copper hydroxide, cuprous bromide or cuprous chloride.

[0014] The cyclic ether compounds described in the technical solution of this invention are selected from trimethoxy esters, tetrahydrofuran, tetrahydropyran, dioxane, oxacyclohexane, 15-crown ether-5, or 18-crown ether-6.

[0015] The reaction temperature described in the technical solution of this invention is 90-120℃.

[0016] The amount of copper salt catalyst added in the technical solution of this invention is 10% of the molar amount of the indanedione diazo compound.

[0017] In the technical solution of this invention, the ratio of cyclic ether compounds to indanedione diazo compounds is 1 ml: 0.1 mmol.

[0018] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0019] This invention uses copper salts as catalysts, specifically copper carbenes inserting into diazo compounds to form oxonium ylides, which then undergo ring-expansion reactions with cyclic ethers to efficiently synthesize cyclic ether compounds containing indanone structures with high product yields. The reaction route in Example Twelve is shown below.

[0020]

[0021] The raw materials used in the synthesis method of this invention are widely available, the copper catalyst used is inexpensive, environmentally friendly, and easy to operate, with excellent product yield. It is suitable for large-scale preparation and has broad application prospects. Attached Figure Description

[0022] Figure 1 The above is the 1H NMR spectrum of 3,4,7,8,11,12-hexahydro-2H,6H,10H,18H-indeno[1,2-b][1,4,8,12]tetraoxanepentadecane-18-one in Example 1 of this invention.

[0023] Figure 2The image shows the carbon NMR spectrum of 3,4,7,8,11,12-hexahydro-2H,6H,10H,18H-indeno[1,2-b][1,4,8,12]tetraoxanepentadecane-18-one in Example 1 of this invention.

[0024] Figure 3 The above is the 1H NMR spectrum of 3,4,5,6,9,10,11,12-octahydro2H,8H,18H-indeno[1,2-b][1,4,10]trioxanepentadecane-18-one in Example 2 of this invention.

[0025] Figure 4 This is the carbon NMR spectrum of 3,4,5,6,9,10,11,12-octahydro2H,8H,18H-indeno[1,2-b][1,4,10]trioxanepentadecane-18-one in Example 2 of the present invention.

[0026] Figure 5 The above is the 1H NMR spectrum of 2,3,5,6,8,9,11,12-octahydro-18H-indeno[1,2-b][1,4,7,10,13]pentoxane-18-one in Example 3 of the present invention.

[0027] Figure 6 The image shows the carbon NMR spectrum of 2,3,5,6,8,9,11,12-octahydro-18H-indeno[1,2-b][1,4,7,10,13]pentoxane-18-one in Example 3 of this invention.

[0028] Figure 7 The above is the 1H NMR spectrum of 2,3,4,5,6,7,9,10,11,12,13,14-dodecano-20H-indeno[1,2-b][1,4,11]trihexacycloheptadecadien-20-one in Example 4 of this invention.

[0029] Figure 8 The image shows the carbon NMR spectrum of 2,3,4,5,6,7,9,10,11,12,13,14-dodecano-20H-indeno[1,2-b][1,4,11]trihexacycloheptadecene-20-one in Example 4 of this invention.

[0030] Figure 9 The above is the 1H NMR spectrum of 2,3,5,6,8,9,11,12,14,15-decahydro-21H-indeno[1,2-b][1,4,7,10,13,16]hexaoxane-oct-21-one in Example 5 of this invention.

[0031] Figure 10The image shows the carbon NMR spectrum of 2,3,5,6,8,9,11,12,14,15-decahydro-21H-indeno[1,2-b][1,4,7,10,13,16]hexaoxane-oct-21-one in Example 5 of this invention.

[0032] Figure 11 The above is the 1H NMR spectrum of 2,3,5,6,8,9,11,12,14,15,17,18-dodecano-24H-indeno[1,2-b][1,4,7,10,13,16,19]heptaoxane-24-one in Example 6 of the present invention.

[0033] Figure 12 The image shows the carbon NMR spectrum of 2,3,5,6,8,9,11,12,14,15,17,18-dodecano-24H-indeno[1,2-b][1,4,7,10,13,16,19]heptaoxane-24-one in Example 6 of this invention.

[0034] Figure 13 The above is the 1H NMR spectrum of 12,13,14,15-tetrachloro-2,3,4,5,7,8,9,10-octahydro-16H-indeno[1,2-b][1,4,9]triazole ring tridecene-16-one in Example 7 of the present invention.

[0035] Figure 14 This is the carbon NMR spectrum of 12,13,14,15-tetrachloro-2,3,4,5,7,8,9,10-octahydro-16H-indeno[1,2-b][1,4,9]triazole ring tridecene-16-one in Example 7 of the present invention. Detailed Implementation

[0036] The following embodiments are used to illustrate the present invention, but are not intended to limit the scope of protection of the present invention. Unless otherwise specified, the technical means used in the embodiments are conventional means well known to those skilled in the art. Unless otherwise specified, the test methods in the following embodiments are conventional methods.

[0037] The ninhydrin diazo in the following examples was synthesized according to the reference: MK Muthyala, S. Choudhary, A. Kumar, J. Org. Chem. 2012, 77, 8787-8791.

[0038] Example 1: Preparation of 3,4,7,8,11,12-hexahydro-2H,6H,10H,18H-indeno[1,2-b][1,4,8,12]tetraoxane-pentadecane-18-one

[0039] Prepare a 25 mL Schlenk tube, add a magnetic stir bar, then add 0.2 mmol of indanedione diazonium, 0.02 mmol of cuprous cyanide, and finally add 1 mL of trimethoxy ester. Using a double-row tube, fill the 25 mL Schlenk tube with argon gas and stir with a magnetic stirrer. Heat to 110 °C for 48 h. Separate the product (3,4,7,8,11,12-hexahydro-2H,6H,10H,18H-inden[1,2-b][1,4,8,12]tetraoxanepentadecane-18-one) by column chromatography in a yield of 46%.

[0040] The above reaction equation is as follows:

[0041]

[0042] 1H NMR spectrum of 3,4,7,8,11,12-hexahydro-2H,6H,10H,18H-indeno[1,2-b][1,4,8,12]tetraoxane-pentadecane-18-one (see spectrum) Figure 1 The characteristics are as follows: 1 H NMR (300MHz, CDCl3) δ7.30-7.24(m,2H),7.22-7.13(m,1H),7.05(d,J=6.9Hz,1H),4.68(t,J =6.6Hz,2H),4.10(t,J=5.7Hz,2H),3.72-3.53(m,8H),2.12-1.93(m,4H),1.82-1.75(m,2H).

[0043] 2,3,4,5,7,8,9,10-octahydro-16H-indeno[1,2-b][1,4,9]triazole ring tridecene 16-one NMR spectrum (see spectrum) Figure 2 The characteristics are as follows: 13 C NMR (101MHz, CDCl3) δ191.7,160.5,138.3,132.6,130.4,129.0,128.1,120.4,118.0,69.7,69.6,67.0,66.8,66.4,66.1,30.6,29.93,29.92.

[0044] Example 2: Preparation of 3,4,5,6,9,10,11,12-octahydro2H,8H,18H-indeno[1,2-b][1,4,10]trioxanepentadecan-18-one

[0045] Prepare a 25 mL Schlenk tube, add a magnetic stir bar, then add 0.2 mmol of indanedione diazonium, 0.02 mmol of cuprous cyanide, and finally 2 mL of tetrahydropyran. Using a double-row tube, fill the 25 mL Schlenk tube with argon gas and stir with a magnetic stirrer. Heat to 110 °C for 48 h. Separate the product (3,4,5,6,9,10,11,12-octahydro2H,8H,18H-inden[1,2-b][1,4,10]trioxanepentadecane-18-one) by column chromatography, with a yield of 61%.

[0046] The above reaction equation is as follows:

[0047]

[0048] 1H NMR spectrum of 3,4,5,6,9,10,11,12-octahydro2H,8H,18H-inden[1,2-b][1,4,10]trioxanepentadecane-18-one (see spectrum) Figure 3 The characteristics are as follows: 1 H NMR (400MHz, CDCl3) δ7.26-7.17(m,2H),7.13(t,J=7.2Hz,1H),7.00(d,J=7.2Hz,1H),4.61-4.47(m,2 H), 4.25 (t, J = 5.6Hz, 2H), 3.57-3.38 (m, 4H), 1.94-1.84 (m, 2H), 1.79-1.70 (m, 2H), 1.68-1.49 (m, 8H).

[0049] 3,4,5,6,9,10,11,12-octahydro2H,8H,18H-inden[1,2-b][1,4,10]trioxanepentadecane-18-one NMR spectrum (see spectrum) Figure 4 The characteristics are as follows: 13 C NMR (101MHz, CDCl3) δ191.5,158.7,138.6,132.6,129.9,128.6,128.3,120.1,117.6,72.3,72.1,70.1,68.5,29.2,28.9,28.8,28.4,23.2,20.7.

[0050] Example 3: Preparation of 2,3,5,6,8,9,11,12-octahydro-18H-indeno[1,2-b][1,4,7,10,13]pentaoxetine-18-one

[0051] Prepare a 25 mL Schlenk tube, add a magnetic stir bar, then add 0.2 mmol of indanedione diazonium, 0.02 mmol of cuprous cyanide, and finally add 2 mL of dioxane. Using a double-row tube, fill the 25 mL Schlenk tube with argon gas and stir with a magnetic stirrer. Heat to 110 °C and react for 48 h. Separate the product (2,3,5,6,8,9,11,12-octahydro-18H-indenzo[1,2-b][1,4,7,10,13]pentaoxane-pentadecane-18-one) by column chromatography in 58% yield.

[0052] The above reaction equation is as follows:

[0053]

[0054] 1H NMR spectrum of 2,3,5,6,8,9,11,12-octahydro-18H-indeno[1,2-b][1,4,7,10,13]pentaoxane-18-one (see spectrum) Figure 5 The characteristics are as follows: 1 H NMR (400MHz, CDCl3) δ7.26-7.20(m,2H),7.15(t,J=7.2Hz,1H),7.07(d,J=7.2Hz,1H),4.87(t,J=5 .6Hz, 2H), 4.36 (t, J = 3.6Hz, 2H), 3.94 (t, J = 5.6Hz, 2H), 3.78 (t, J = 4.0Hz, 1H), 3.74-3.45 (m, 8H).

[0055] 1H NMR spectrum of 2,3,5,6,8,9,11,12-octahydro-18H-indeno[1,2-b][1,4,7,10,13]pentaoxane-18-one (see spectrum) Figure 6 The characteristics are as follows: 13 C NMR (101MHz, CDCl3) δ191.7,160.1,138.2,132.7,129.3,128.9,128.2,120.2,118.1,72.1,71.9,71.6,71.3,70.9,70.2,70.0,69.5.

[0056] Example 4: Preparation of 2,3,4,5,6,7,9,10,11,12,13,14-dodecano-20H-indeno[1,2-b][1,4,11]trihexacycloheptadecene-20-one

[0057] Prepare a 25 mL Schlenk tube, add a magnetic stir bar, then add 0.2 mmol of indanedione diazonium, 0.02 mmol of cuprous cyanide, and finally add 2 mL of oxacyclohexane. Using a double-row tube, fill the 25 mL Schlenk tube with argon gas and stir with a magnetic stirrer. Heat to 110 °C and react for 48 h. Separate the product (2,3,4,5,6,7,9,10,11,12,13,14-dodecano-20H-indeno[1,2-b][1,4,11]trihexacycloheptadecene-20-one) by column chromatography, with a yield of 37%.

[0058] The above reaction equation is as follows:

[0059]

[0060] 1H NMR spectrum of 2,3,4,5,6,7,9,10,11,12,13,14-dodecano-20H-indeno[1,2-b][1,4,11]trihexacycloheptadecadien-20-one (see spectrum) Figure 7 The characteristics are as follows: 1 H NMR (300MHz, CDCl3) δ7.29-7.21(m,2H),7.15(t,J=7.2Hz,1H),7.02(d,J=6.9Hz,1H),4.57(t,J=7.8Hz, 2H), 4.11 (t, J = 5.7Hz, 2H), 3.51-3.38 (m, 4H), 1.97-1.83 (m, 2H), 1.78-1.69 (m, 2H), 1.64-1.45 (m, 12H).

[0061] 1H NMR spectrum of 2,3,4,5,6,7,9,10,11,12,13,14-dodecano-20H-indeno[1,2-b][1,4,11]trihexacycloheptadecadien-20-one (see spectrum) Figure 8 The characteristics are as follows: 13 C NMR (75MHz, CDCl3) δ191.6,159.3,138.4,132.6,130.2,128.7,128.2,120.2,1 17.8,73.2,71.4,70.4,69.5,30.7,29.19,29.17,29.1,27.2,25.9,25.4,24.4.

[0062] Example 5: Preparation of 2,3,5,6,8,9,11,12,14,15-decahydro-21H-indeno[1,2-b][1,4,7,10,13,16]hexaoxane-21-one

[0063] Prepare a 25 mL Schlenk tube, add a magnetic stir bar, then add 0.2 mmol of indanedione diazonium, 0.02 mmol of cuprous cyanide, and finally add 2 mL of 15-crown ether-5. Using a double-row tube, fill the 25 mL Schlenk tube with argon gas; heat to 110 °C for 48 h with magnetic stirring; and separate the product (2,3,5,6,8,9,11,12,14,15-decahydro-21H-indenzo[1,2-b][1,4,7,10,13,16]hexaoxane-oct-21-one) by preparative thin-layer chromatography, with a yield of 31%.

[0064] The above reaction equation is as follows:

[0065]

[0066] 1H NMR spectrum of 2,3,5,6,8,9,11,12,14,15-decahydro-21H-indenzo[1,2-b][1,4,7,10,13,16]hexaoxane-oct-21-one (see spectrum) Figure 9 The characteristics are as follows: 1 H NMR (400MHz, CDCl3) δ7.23-7.14(m,2H),7.09(t,J=7.4Hz,1H),7.03(d,J=7.1Hz, 1H),4.82-4.72(m,2H),4.28-4.18(m,2H),3.99-3.89(m,2H),3.69-3.51(m,14H).

[0067] 1H NMR spectrum of 2,3,5,6,8,9,11,12,14,15-decahydro-21H-indenzo[1,2-b][1,4,7,10,13,16]hexaoxane-oct-21-one (see spectrum) Figure 10 The characteristics are as follows: 13 C NMR (75MHz, CDCl3) δ191.7,160.0,138.0,132.7,129.4,128.9,128.2,120.2,118.3,72.0,71.9,71.4,70.7,70.5,70.4,70.0,69.9,69.5.

[0068] Example 6: Preparation of 2,3,5,6,8,9,11,12,14,15,17,18-dodecano-24H-indeno[1,2-b][1,4,7,10,13,16,19]heptaoxane-heptaoct-24-one

[0069] Prepare a 25 mL Schlenk tube, add a magnetic stir bar, then add 0.2 mmol of indanedione diazonium, 0.02 mmol of cuprous cyanide, and finally add 2 mL of 18-crown ether-6. Using a double-row tube, fill the 25 mL Schlenk tube with argon gas; heat to 110 °C for 48 h with magnetic stirring; and separate the product (2,3,5,6,8,9,11,12,14,15,17,18-dodecano-24H-indenzo[1,2-b][1,4,7,10,13,16,19]heptaoxane-heptaoct-24-one) by preparative thin-layer chromatography, with a yield of 26%.

[0070] The above reaction equation is as follows:

[0071]

[0072] 1H NMR spectrum of 2,3,5,6,8,9,11,12,14,15,17,18-dodecano-24H-indeno[1,2-b][1,4,7,10,13,16,19]heptaoxane-heptaoct-24-one (see spectrum) Figure 11 The characteristics are as follows: 1 H NMR (300MHz, CDCl3) δ7.19 (m, 2H), 7.13-6.99 (m, 2H), 4.83-4.71 (m, 2H), 4.28-4.17 (m, 2H), 3.90 (dd, J = 5.5, 3.7Hz, 2H), 3.73-3.51 (m, 18H).

[0073] 1H NMR spectrum of 2,3,5,6,8,9,11,12,14,15,17,18-dodecano-24H-indeno[1,2-b][1,4,7,10,13,16,19]heptaoxane-heptaoct-24-one (see spectrum) Figure 12 The characteristics are as follows: 13 C NMR (75MHz, CDCl3) δ191.6,160.0,138.1,132.7,129.3,128.9,128.2,120. 3,118.3,71.8,71.6,71.3,71.0,70.9,70.8,70.7,70.6,70.3,70.2,70.0.

[0074] Example 7: 12,13,14,15-Tetrachloro-2,3,4,5,7,8,9,10-Octahydro-16H-Indo[1,2-b][1,4,9]triazolecyclotridecene-16-one

[0075] Prepare a 25 mL Schlenk tube, add a magnetic stir bar, then add 0.2 mmol of tetrachloroindenedione diazonium, 0.02 mmol of cuprous cyanide, and finally add 2 mL of tetrahydrofuran. Using a double-row tube, fill the 25 mL Schlenk tube with argon gas and stir with a magnetic stirrer. Heat to 110 °C for 48 h. Separate the product (12,13,14,15-tetrachloro-2,3,4,5,7,8,9,10-octahydro-16H-inden[1,2-b][1,4,9]triazolecyclotridecene-16-one) by column chromatography, with a yield of 59%.

[0076] The above reaction equation is as follows:

[0077]

[0078] 1H NMR spectrum of 12,13,14,15-tetrachloro-2,3,4,5,7,8,9,10-octahydro-16H-indeno[1,2-b][1,4,9]triazole ring tridecene-16-one (see spectrum) Figure 13 The characteristics are as follows: 1 H NMR (400MHz, CDCl3) δ4.80(t,J=8.4Hz,2H),4.24(t,J=5.6Hz,2H),3.56(t,J=4.8Hz,2H),3.47(t,J=5.6Hz,2H),2.04-1.83(m,4H),1.80-1.63(m,4H).

[0079] The carbon NMR spectrum of 12,13,14,15-tetrachloro-2,3,4,5,7,8,9,10-octahydro-16H-indeno[1,2-b][1,4,9]triazole ring tridecene-16-one (see spectrum) Figure 14 The characteristics are as follows: 13 C NMR (101MHz, CDCl3) δ185.4,158.4,138.0,134.5,134.1,131.7,126.6,124.7,123.6,72.8,72.1,71.1,69.3,28.8,27.3,24.7,24.6.

[0080] Optimization of reaction conditions in Examples 8 to 13

[0081] Examples 8 through 13 are essentially the same as Example 1, except that the trimethoxy ester is replaced with tetrahydrofuran, and the metal salt catalysts used are rhodium acetate, nickel chloride, cuprous chloride, cuprous bromide, cuprous cyanide, and copper hydroxide, respectively. The reaction equations are as follows:

[0082]

[0083] The yields of the product (2,3,4,5,7,8,9,10-octahydro-16H-indeno[1,2-b][1,4,9]trihexacyclic trilactone-16-one) under different catalyst conditions are shown in Table 1.

[0084] Table 1 Product yield under different catalyst conditions

[0085] Example Metal salt catalysts Yield (%) Example 8 Rhodium acetate 22 Example 9 Nickel chloride 0 Example 10 Cuprous chloride 55 Example 11 Cuprous bromide 51 Example 12 Cuprous cyanide 83 Example 13 copper hydroxide 60

[0086] As can be seen from Table 1, copper catalysts can be used to obtain products under different catalyst conditions, and the yield of products is the highest when the catalyst is cuprous cyanide.

[0087] Examples 14-16: Screening of Reaction Temperature

[0088] Examples 14 through 16 are basically the same as Example 12, except that the reaction temperature is changed to 120°C, 100°C, and 90°C. The yields of the products under different temperature conditions are shown in Table 2.

[0089] Table 2 Product yield under different temperature conditions

[0090] Serial Number Temperature (°C) Yield (%) Example 12 110 83 Example 14 120 79 Example 15 100 63 Example 16 90 58

[0091] As can be seen from Table 2, the product can be obtained under different temperature conditions, with the optimal yield reaching 110℃.

[0092] The embodiments described above are merely preferred embodiments of the present invention and are only used to explain the present invention. They are not intended to limit the scope of the present invention. For those skilled in the art, other implementation methods can be easily made by substitution or modification based on the technical content disclosed in this specification. Therefore, all changes and improvements made on the principle of the present invention should be included within the scope of the patent application of the present invention.

Claims

1. A method for preparing a cyclic ether compound containing an indanone structure, characterized in that, Includes the following steps: Using diazo compounds and cyclic ether compounds of Formula I as starting materials, cyclic ether compounds containing ninhydrin structures as shown in Formula II were synthesized by heating under an argon atmosphere and in the presence of a copper salt catalyst. The copper salt catalyst was selected from cuprous cyanide, copper hydroxide, cuprous bromide, or cuprous chloride. The cyclic ether compounds were selected from trimethoxy esters, tetrahydrofuran, tetrahydropyran, dioxane, oxacyclohexane, 15-crown ether-5, or 18-crown ether-6. The synthetic route is as follows: ， Wherein: R is selected from H or halogen, n is 1~7, and m is 1~9.

2. The preparation method according to claim 1, characterized in that, The reaction temperature is 90~120℃.

3. The preparation method according to claim 1, characterized in that, The amount of copper salt catalyst added is 10% of the molar amount of the ninhydrin diazo compound.

4. The preparation method according to claim 1, characterized in that, The ratio of the cyclic ether compound to the indanedione diazo compound is 1 ml: 0.1 mmol.

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