Spiro pyrrolo-indolone derivative and preparation method thereof

Abstract

The invention discloses a spiro pyrrolo-indolone derivative and a preparation method thereof, and belongs to the field of chemical synthesis, a cyclic imine ylide derivative and a 2-alkenyl indole derivative are used as raw materials, a catalyst, a solvent and alkali are added, a reaction is performed for 6-24 h, and the spiro pyrrolo-indolone derivative is obtained through one-step efficient synthesis. The preparation method has the advantages of simple operation, few reaction steps, easily available raw materials, high yield, no need of a transition metal catalyst, and environmental protection; a new path is provided for synthesizing the compounds; the enantioselectivity and diastereoselectivity of the product obtained by the preparation method disclosed by the invention are high; the preparation method has wide substrate universality and strong compatibility with substituent groups on substrates, and through one-pot one-step reaction, a tedious separation process and an intermediate compound purification process in a post-treatment process are avoided, so that time and resources are saved, and the yield is improved.

Description

Technical Field

[0001] The invention relates to the field of chemical synthesis, and in particular to a spirocyclic pyrroloindolone derivative and a preparation method thereof. Background Art

[0002] The pyrroloindolone skeleton is the core structural unit of many important natural products and active pharmaceutical molecules, and is also the core fragment of many natural alkaloids. Due to its unique structure, this type of compound often exhibits very unique pharmacological activities and has a wide range of applications in the field of medicinal chemistry, such as potential applications in anti-cancer, anti-depression and antibacterial. On the other hand, spiro compounds are also very valuable structural units and important pharmacophores, widely present in many natural products and drugs and their intermediates. In addition, spiro skeleton compounds may also have application value in photochromic materials; due to the rigidity of the spiro structure and the many steric groups around the spiro atom center, the spiro atom contains a quaternary carbon center, and the construction of the quaternary carbon center is a difficulty in the field of synthetic chemistry.

[0003] The pyrroloindolone skeleton products reported in the current literature are mainly single pyrroloindolone structures. The literature One-Pot Organocatalytic Asymmetric Synthesis of 1H-Pyrrolo[1,2a]indol-3(2H)-ones via a Michael-Hemiaminalization-Oxidation Sequence. Synlett, 2011(4),469-472 synthesized the pyrroloindolone structure through organic amine catalysis and PCC relay catalysis. This method uses chiral amine catalysts, which are expensive and require the addition of PCC oxidant for further oxidation, and the post-oxidation treatment of PCC is more troublesome. The literature Chemo- and Regioselective Synthesis of Functionalized 1H-imidazo[1,5-a]indol-3(2H)-ones via a Redox-Neutral Rhodium(III)-Catalyzed [4+1] Annulationbetween Indoles and Alkynes. Advanced Synthesis & Catalysis , 2021, 363, 18, 4380-4389 A chemical and regioselective synthesis of functionalized 1H-imidazo[1,5-a]indol-3(2H)-ones was achieved via a redox-neutral rhodium(III)-catalyzed [4+1] cyclization reaction between indoles and alkynes, but this required the use of expensive rhodium metal and harsh reaction conditions.

[0004] In summary, only single-structure pyrroloindolone products have been reported in the literature, but the synthesis of pyrroloindolone skeletons with spirocyclic structures has not been reported. Therefore, it is of great research value to develop efficient synthesis and efficiently construct spirocyclic pyrroloindolone skeletons and their derivatives in one step. Summary of the invention

[0005] In order to solve the above technical problems, the present invention provides a simple, efficient and green spirocyclic pyrroloindolone derivative and a preparation method thereof. The preparation method has the advantages of simple reaction system, simple operation, green and mild conditions, readily available raw materials, low price, high yield, high selectivity and easy application expansion, and is expected to provide a new path for the efficient synthesis of such compounds.

[0006] The technical solution adopted by the present invention is as follows: A spirocyclic pyrroloindolone derivative, the general structural formula of which is shown in Formula 3: , Among them, R in formula 3 1 , R 2 , R 3 Independently selected from any one of hydrogen atom, alkyl group, alkoxy group and halogen; EWG is any one of nitro group, ester group and carbonyl group.

[0007] Furthermore, the general structural formula of the spirocyclic pyrroloindolone derivative is selected from any one of the following structures: .

[0008] The preparation method of the above-mentioned spirocyclic pyrroloindolone derivative comprises the following steps: using the cyclic imine ylide derivative shown in formula 1 and the 2-alkenyl indole derivative shown in formula 2 as raw materials, adding a catalyst, a solvent, and a base, reacting for 6 to 24 hours, and purifying the product to obtain the spirocyclic pyrroloindolone derivative shown in formula 3. The general synthetic formula is as follows: ; Among them, R in formula 1, formula 2 and formula 3 1 , R 2 , R 3 Independently selected from any one of a hydrogen atom, an alkyl group, an alkoxy group, and a halogen; EWG is any one of a nitro group, an ester group, and a carbonyl group.

[0009] Preferably, the catalyst is a phase transfer catalyst and / or a metal catalyst.

[0010] Preferably, the phase transfer catalyst includes at least one of a quaternary ammonium salt phase transfer catalyst, a quaternary phosphonium salt phase transfer catalyst, a crown ether catalyst and a chiral quaternary ammonium salt or quaternary phosphonium salt catalyst.

[0011] Preferably, the metal catalyst is at least one of a divalent copper salt (CuBr2, CuCl2, CuI2, Cu(OAc)2, Cu(OTf)2), a monovalent copper salt (CuBr, CuCl, CuI), a trivalent iron salt (FeCl3), a divalent iron salt (FeCl2, FeBr2), a divalent nickel salt (NiBr2, NiCl2) and a divalent cobalt salt (CoBr2, CoCl2, Co(OAc)2).

[0012] Preferably, the base is one of cesium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, cesium hydroxide, anhydrous potassium phosphate, potassium phosphate trihydrate, potassium phosphate heptahydrate, and potassium bicarbonate.

[0013] Preferably, the solvent is at least one of toluene, benzene, tetrahydrofuran, ether, petroleum ether, n-hexane, dichloromethane, chloroform, ethyl acetate and acetonitrile.

[0014] Preferably, the molar ratio of the cyclic imine ylide derivative to the 2-alkenyl indole derivative is 1-3:1-2; the amount of the catalyst is 0.01-0.5 of the molar amount of the cyclic imine ylide derivative; and the amount of the base is 1.0-5.0 times the molar amount of the cyclic imine ylide derivative.

[0015] Based on a general inventive concept, the present invention also provides a spirocyclic pyrroloindolone derivative or a stereoisomer thereof.

[0016] The preparation method mechanism of the spirocyclic pyrroloindolone derivatives of the present invention is as follows (eg Figure 1 As shown): The cyclic imine ylide derivative (substrate A) is deprotonated under the action of a catalyst and a base to obtain intermediate 1, and then the anion attacks the double bond of the 2-vinyl indole derivative (substrate B) to obtain intermediate 2; further deprotonation is performed under the action of a base to form intermediate 3; the N anion of intermediate 3 attacks the ester group, and the methoxy group leaves to obtain the target spirocyclic product.

[0017] Compared with the prior art, the present invention has the following beneficial effects: The present invention uses cyclic imine ylide derivatives and 2-alkenyl indole derivatives as raw materials, adds catalysts, solvents, and bases, reacts for 6 to 24 hours, and efficiently synthesizes spirocyclic pyrroloindolone and its derivatives in one step. The method is simple to operate, has few reaction steps, is easy to obtain raw materials, has a high yield, does not require transition metal catalysts, and is green and environmentally friendly. It provides a new path for synthesizing such compounds and has a high reaction yield.

[0018] The invention has wide substrate universality, strong compatibility with substituents on the substrate, and avoids lengthy separation processes and purification processes of intermediate compounds in post-treatment processes through a one-pot method and a one-step reaction, thereby saving time and resources and improving the yield.

[0019] The target product of the invention has a novel structure, the reaction is adaptable to water and air atmospheres, the product is easy to separate, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 It is the mechanism diagram of the reaction of the present invention; Figure 2 is the H NMR spectrum of the product obtained in Example 2; Figure 3 is the NMR carbon spectrum of the product obtained in Example 2; Figure 4 is the H NMR spectrum of the product obtained in Example 26; Figure 5 This is the NMR carbon spectrum of the product obtained in Example 26. DETAILED DESCRIPTION

[0021] In order to make the technical problems, technical solutions and advantages to be solved by the present invention more clear, a detailed description will be given below with reference to the accompanying drawings and specific embodiments.

[0022] The following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention. Without departing from the spirit and substance of the present invention, modifications or substitutions made to the methods, steps or conditions of the present invention are within the scope of the present invention.

[0023] Unless otherwise specified, the technical means used in the examples are conventional means well known to those skilled in the art; unless otherwise specified, the reagents used in the examples are commercially available.

[0024] Example 1-25 Preparation of Spirocyclic Pyrroloindolone Derivatives To a 25 mL reaction bottle, 0.1-0.3 mmol of a cyclic imine ylide derivative (substrate A), 0.1-0.2 mmol of an indole olefin derivative (substrate B), a catalyst, 0.2 mmol of a base, and 10 mL of a solvent were added in sequence. The molar ratio of the catalyst to substrate A was 0.01-0.5. The reaction was carried out at room temperature for 6-24 h. After the reaction, the reaction was directly post-processed for column chromatography separation. The reaction formula is as follows: ; After the reaction, post-treatment, separation of the product, weighing and calculation of the product yield, the catalyst, solvent and base are shown in Table 1 below.

[0025] Table 1 Catalyst, solvent, base, temperature, time and product yield of Examples 1-25

[0026] Taking the product obtained in Example 2 as a typical representative, the H NMR spectrum and C NMR spectrum are as follows: Figure 2 and Figure 3 , 7.26 (td, J = 7.2, 1.5 Hz, 2H), 7.19 (d, J = 7.2 Hz, 1H), 6.22 (d, J = 0.6 Hz, 1H), 4.14 (ddd, J = 14.2, 7.2 Hz, 2H), 4.70 (d, J = 0.6, 1.3 Hz, 1H), 4.66 (d, J = 1.2, 7.2 Hz, 2H), 4.85 (ddd, J = 1.2, 7.2 Hz, 2H), 4.54 (ddd, J = 1.2, 7.2 Hz, 2H), 4.63 (d, J = 1.2, 7.2 Hz, 2H), 4.82 (d, J = 1.2, 7.2 Hz, 2H), 4.61 (d, J = 1.2, 7.2 Hz, 2H), 4.63 (d 1H), 3.49 (d, J = 16.4 Hz, 1H), 3.28 (dd, J = 17.2, 9.6 Hz, 1H), 3.17 (dd, J = 17.2, 4.7 Hz, 1H), 3.07(d, J = 16.5 Hz, 1H), 2.48 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 196.57,172.18, 165.55, 143.72, 136.33, 135.11, 133.56, 133.45, 131.72, 130.80,129.15, 128.67, 127.94, 127.84, 127.77, 126.07, 124.32, 123.76, 120.85,114.11, 102.33, 71.55, 40.92, 40.57, 29.72, 23.35. HRMS (ESI) m / z calcd forC 28 H 22 N2O2 [M+H]+ = 419.1760, found = 419.1766. Combined with H NMR spectrum (such as Figure 2 As shown), carbon spectrum (as Figure 3 As shown), it is known that the above-mentioned target product structure is correct.

[0027] Example 26 Preparation of Spirocyclic Pyrroloindolone Derivatives To a 25 mL reaction bottle, 0.12 mmol of cyclic imine ylide derivative, 0.12 mmol of indole olefin derivative, 0.01 mmol of catalyst (tetrabutylammonium bromide), 0.2 mmol of base (cesium carbonate) and 10 mL of solvent (ethanol) were added in sequence. The reaction was carried out at room temperature for 12 h, and the reaction was directly post-processed for column chromatography separation. The reaction formula is as follows: ;

[0028] After the reaction, post-treatment, separation of products, weighing and calculation of product yield, the reaction product characterization data are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 7.4 Hz, 1H), 7.66 (d, J = 8.2 Hz, 2H), 7.57(d, J = 7.4 Hz, 1H), 7.44 (dd, J = 6.7, 1.6 Hz, 1H), 7.37 (dd, J = 7.5, 1.2Hz, 1H), 7.32 (dd, J = 7.5, 1.2 Hz, 1H), 7.30 – 7.23 (m, 3H), 7.21 (d, J =8.2 Hz, 3H), 6.21 (s, 1H), 4.08 (dd, J = 9.8, 4.5 Hz, 1H), 3.48 (d, J = 16.4Hz, 1H), 3.25 (dd, J = 17.0, 9.8 Hz, 1H), 3.13 (dd, J = 17.0, 4.6 Hz, 1H),3.06 (d, J = 16.5 Hz, 1H), 2.48 (s, 3H), 2.39 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 196.24, 172.21, 165.50, 144.34, 143.81, 135.13, 133.92, 133.63,131.69, 130.79, 129.34, 129.15, HRMS (ESI) m / z calcd for C 29 H 24 N2O2 [M+H]+ = 433.1916, found = 433.1918. Combined with H NMR spectrum (such as Figure 4 As shown), carbon spectrum (as Figure 5 As shown), it is known that the above-mentioned target product structure is correct.

[0029] Example 27 Preparation of Spirocyclic Pyrroloindolone Derivatives To a 25 mL reaction bottle, 0.12 mmol of cyclic imine ylide derivative, 0.15 mmol of indole olefin derivative, 0.01 mmol of catalyst (tetrabutylammonium bromide), 0.2 mmol of base (cesium carbonate) and 10 mL of solvent (ethanol) were added in sequence. The reaction was carried out at room temperature for 12 h, and the reaction was directly post-processed for column chromatography separation. The reaction formula is as follows: ;

[0030] After the reaction, post-treatment, separation of products, weighing and calculation of product yield, the reaction product characterization data are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 7.4 Hz, 1H), 7.62 (d, J = 8.2 Hz, 2H), 7.53(d, J = 7.2 Hz, 1H), 7.44 (dd, J = 6.7, 1.6 Hz, 1H), 7.37 (dd, J = 7.5, 1.2Hz, 1H), 7.32 (dd, J = 7.5, 1.2 Hz, 1H), 7.30 – 7.23 (m, 3H), 7.21 (d, J=8.2 Hz, 3H), 6.21 (s, 1H), 4.08 (dd, J = 9.8, 4.5 Hz, 1H), 3.48 (d, J = 16.4Hz, 1H), 3.25 (dd, J = 17.0, 9.8 Hz, 1H), 3.13 (dd, J = 17.0, 4.6 Hz, 1H),3.06 (d, J = 16.5 Hz, 1H), 2.48 (s, 3H), 2.39 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 196.20, 172.22, 165.30, 144.34, 143.81, 135.13, 133.92, 133.63,131.69, 130.79, 129.34, 129.10, HRMS (ESI) m / z calcd for C 29 H 24 N2O2 [M+H]+ = 433.1916, found = 433.1918. It can be seen that the above target product structure is correct.

[0031] Example 28 Preparation of Spirocyclic Pyrroloindolone Derivatives To a 25 mL reaction bottle, 0.12 mmol of cyclic imine ylide derivative, 0.1 mmol of 4-chloro-substituted indole olefin derivative, 0.01 mmol of catalyst (tetrabutylammonium bromide), 0.2 mmol of base (cesium carbonate) and 10 mL of solvent (ethanol) were added in sequence. The reaction was carried out at room temperature for 12 h, and the reaction was directly post-processed for column chromatography separation. The reaction formula is as follows: ;

[0032] The product characterization data are as follows: 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 7.2 Hz, 1H),7.73 (d, J = 7.2 Hz, 2H), 7.43 (dd, J= 14.2, 7.2 Hz, 2H), 7.56–7.32 (m, 2H), 7.37–7.31 (m, 2H), 7.26 (td, J = 7.2, 1.5 Hz, 2H), 7.19 (d, J = 7.2 Hz, 1H),6.22 (d, J = 0.6 Hz, 1H), 4.10 (ddd, J = 9.5, 4.5, 1.3 Hz, 1H), 3.49 (d, J =16.4 Hz, 1H), 3.28 (dd, J = 17.2, 9.6 Hz, 1H), 3.17 (dd, J = 17.2, 4.7 Hz, 1H), 3.07 (d, J = 16.5 Hz, 1H), 2.48 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ196.67, 172.30, 165.22, 143.42, 136.33, 135.31, 133.56, 132.45, 131.70,130.81, 129.15, 128.57, HRMS (ESI) m / zcalcd for C 28 H 21 ClN2O2 [M+H]+ = 453.1370, found = 453.1365. It can be seen that the above target product structure is correct.

[0033] The above is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above embodiments. For those skilled in the art, improvements and changes obtained without departing from the technical concept of the present invention should also be regarded as the protection scope of the present invention.

Claims

1. A spirocyclic pyrroloindolone derivative, characterized in that: The general structural formula of the spirocyclic pyrroloindolone derivative is shown in Formula 3: ， Among them, R in formula 3 1 , R 2 , R 3 Independently selected from any one of hydrogen atom, alkyl group, alkoxy group and halogen; EWG is any one of nitro group, ester group and carbonyl group.

2. The spirocyclic pyrroloindolone derivative according to claim 1, characterized in that: The general structural formula of the spirocyclic pyrroloindolone derivative is selected from any one of the following structures: 。 3. The method for preparing the spirocyclic pyrroloindolone derivative according to claim 1 or 2, characterized in that: The following steps are involved: The cyclic imine ylide derivative shown in formula 1 and the 2-alkenyl indole derivative shown in formula 2 are used as raw materials, a catalyst, a solvent, and a base are added, and the reaction is carried out for 6 to 24 hours. The product is purified to obtain a spirocyclic pyrroloindolone derivative shown in formula 3. The general synthesis formula is as follows: ； Among them, R in formula 1, formula 2 and formula 3 1 , R 2 , R 3 Independently selected from any one of hydrogen atom, alkyl group, alkoxy group and halogen; EWG is any one of nitro group, ester group and carbonyl group.

4. The preparation method according to claim 3, characterized in that: The catalyst is a phase transfer catalyst and / or a metal catalyst.

5. The preparation method according to claim 4, characterized in that: The phase transfer catalyst is at least one of a quaternary ammonium salt phase transfer catalyst, a quaternary phosphonium salt phase transfer catalyst, a crown ether catalyst and a chiral quaternary ammonium salt or quaternary phosphonium salt catalyst; the metal catalyst is at least one of a divalent copper salt, a monovalent copper salt, a trivalent iron salt, a divalent iron salt, a divalent nickel salt and a divalent cobalt salt.

6. The preparation method according to claim 4, characterized in that: The divalent copper salt is at least one of CuBr2, CuCl2, CuI2, Cu(OAc)2, and Cu(OTf)2; the monovalent copper salt is at least one of CuBr, CuCl, and CuI; the trivalent iron salt is FeCl3; the divalent iron salt is at least one of FeCl2 and FeBr2; the divalent nickel salt is at least one of NiBr2 and NiCl2; and the divalent cobalt salt is at least one of CoBr2, CoCl2, and Co(OAc)2.

7. The preparation method according to claim 3, characterized in that: The base is one of cesium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, cesium hydroxide, anhydrous potassium phosphate, potassium phosphate trihydrate, potassium phosphate heptahydrate, and potassium bicarbonate.

8. The preparation method according to claim 3, characterized in that: The solvent is at least one of toluene, benzene, tetrahydrofuran, ether, petroleum ether, n-hexane, dichloromethane, chloroform, ethyl acetate and acetonitrile.

9. The preparation method according to claim 3, characterized in that: The molar ratio of the cyclic imine ylide derivative to the 2-alkenyl indole derivative is 1-3:1-2; the amount of the catalyst is 0.01-0.5 of the molar amount of the cyclic imine ylide derivative; and the amount of the base is 1.0-5.0 times the molar amount of the cyclic imine ylide derivative.

10. A stereoisomer of the spirocyclic pyrroloindolone derivative according to claim 1 or 2 or a spirocyclic pyrroloindolone derivative obtained by the preparation method according to any one of claims 3 to 9.

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