Cis-hydrogen benzofuran compound with novel structure and preparation method thereof

Abstract

The invention discloses a cis-hydrogen benzofuran compound with a novel structure and a preparation method thereof, and belongs to the technical field of organic synthesis.A benzoxazole-pyridine complex of palladium is used as a catalyst, an alkynyl cyclohexadienone compound and a carboxylic acid compound are used as substrates, and the cis-hydrogen benzofuran compound is prepared through a one-step reaction. According to the invention, different ligands are selected to realize the series cyclization reactions with completely different reaction paths, and the cis-hydrogen benzofuran compound with the novel structure is obtained at high yield. The method has the advantages of wide substrate range, simple and easy operation, mild reaction conditions, low energy consumption, environmental friendliness and good yield.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a method for preparing a class of cis-hydrobenzofuran compounds with novel structures by ligand-regulated palladium-catalyzed tandem cyclization reaction of alkynyl cyclohexadienone and carboxylic acid. Background Art

[0002] Cis-hydrobenzofuran is a ubiquitous structural unit in natural products and bioactive molecules. Transition metal-catalyzed tandem reactions of alkynylcyclohexadienones are an effective way to obtain cis-hydrobenzofuran. In 2023, our group reported that planar chiral oxazole-pyridine ligands based on cycloarethane skeletons achieved palladium-catalyzed asymmetric acylation cyclization of alkynylcyclohexadienones. This reaction can synthesize chiral cis-hydrobenzofuran compounds with excellent yields and enantioselectivity, and this type of compound can be used as an inhibitor of NF-κB signaling. It is particularly important to study and develop new cis-hydrobenzofuran compounds and their preparation methods. Summary of the invention

[0003] In view of this, the purpose of the present invention is to provide a class of novel cis-hydrobenzofuran compounds and a preparation method thereof. The inventors found in their research that when a benzoxazole-pyridine ligand containing a substituent at the 6-position of pyridine is used, a cyclization product with a completely different reaction path can be obtained, which provides a convenient way to study the biological activity of novel cis-hydrobenzofuran compounds.

[0004] In order to achieve the above object, the present invention provides the following technical solutions:

[0005] The present invention provides a novel cis-hydrobenzofuran compound, the structure of which is shown in Formula I;

[0006]

[0007] Where:

[0008] R is selected from benzyl, phenyl or C1-C 20 One of alkyl and tert-butyldimethylsilyloxy;

[0009] R' is selected from cyclohexyl, phenyl, substituted phenyl Ph1, heteroaryl or substituted heteroaryl; the heteroaryl is a five-membered heterocyclic group containing a heteroatom S in the skeleton; the substituents of the substituted phenyl Ph1 and the substituted heteroaryl are independently selected from at least one of methyl, methoxy, acetyl, fluorine, chlorine and bromine; the heteroaryl is preferably thienyl;

[0010] R" is selected from C1-C 20 Alkyl, phenyl or substituted phenyl Ph2; the substituent of substituted phenyl Ph2 is selected from methyl, methoxy and acetoxy;

[0011] X is oxygen or p-toluenesulfonylamide.

[0012] The term "C1-C 20 "Alkyl" refers to a straight or branched chain alkyl group having 1 to 20 carbon atoms; preferably "C1 to C 20 The "alkyl" includes methyl, ethyl, n-propyl, isopropyl, n-butyl and the like.

[0013] The term "heteroaryl" as used herein is selected from 5-membered ring heteroaryl, which refers to a 5-membered monocyclic aromatic heterocycle containing one or more (e.g. 1-3) sulfur atoms in addition to carbon atoms, such as thienyl, etc. Examples include 2-thienyl, etc.

[0014] Based on the above technical solution, further, the novel cis-hydrobenzofuran compound is selected from any one of the structures shown below;

[0015]

[0016] On the other hand, the present invention provides a method for preparing the novel cis-hydrobenzofuran, wherein a benzoxazole-pyridine complex of palladium is used as a catalyst, an alkynyl cyclohexadienone compound and a carboxylic acid compound are used as substrates, and a novel cis-hydrobenzofuran is synthesized by a tandem cyclization reaction, and the reaction formula is as follows:

[0017]

[0018] Where:

[0019] R is selected from benzyl, phenyl or C1-C 20 One of alkyl and tert-butyldimethylsilyloxy;

[0020] R' is selected from cyclohexyl, phenyl, substituted phenyl Ph1, heteroaryl or substituted heteroaryl; the heteroaryl is a five-membered heterocyclic group containing a heteroatom S in the skeleton; the substituents of the substituted phenyl Ph1 and the substituted heteroaryl are independently selected from at least one of methyl, methoxy, acetyl, fluorine, chlorine and bromine; the heteroaryl is preferably thienyl;

[0021] R" is selected from C1-C 20 Alkyl, phenyl or substituted phenyl Ph2; the substituent of substituted phenyl Ph2 is selected from methyl, methoxy and acetoxy;

[0022] X is oxygen or p-toluenesulfonylamide.

[0023] Based on the above technical solution, further, an additive is added to the reaction, and the additive is a monovalent copper salt or N-iodosuccinimide.

[0024] Based on the above technical solution, further, the monovalent copper salt includes cuprous chloride, cuprous bromide, cuprous iodide, and cuprous acetate.

[0025] Based on the above technical scheme, further, the molar ratio of the alkynyl cyclohexadienone compound to the carboxylic acid compound is 1:5 to 1:17, the molar ratio of the additive to the alkynyl cyclohexadienone compound is 0.05 to 0.2:1, the molar ratio of the palladium metal precursor to the alkynyl cyclohexadienone compound is 0.01 to 0.1:1, and the molar ratio of the benzoxazole-pyridine ligand to the palladium metal precursor is 1 to 1.2:1.

[0026] Based on the above technical solution, further, the reaction solvent is selected from at least one of 1,2-dichloroethane, ethyl acetate, toluene, and methyl tert-butyl ether.

[0027] Based on the above technical solution, further, the reaction temperature is 60-100°C.

[0028] Based on the above technical solution, further, the reaction time is 1 to 96 hours.

[0029] Based on the above technical scheme, the method further comprises the following steps: under nitrogen protection, adding a palladium metal precursor, a benzoxazole-pyridine ligand and a carboxylic acid compound into a sealed tube, then adding a solvent, stirring and reacting at room temperature for 30 to 150 minutes, adding an alkynyl cyclohexadienone compound and an additive under nitrogen protection, continuing to stir and react at 60 to 100° C. in a nitrogen atmosphere for 1 to 96 hours, spinning the solvent dry, and separating by column chromatography to obtain pure cis-hydrobenzofuran.

[0030] Based on the above technical scheme, further, R is methyl, R' is phenyl, X is oxygen, R'' is methyl, the catalyst is a complex formed by palladium acetate (Pd(OAc)2) and benzoxazole-pyridine ligand, the organic solvent is toluene, the temperature is 80°C, the additive is cuprous iodide, and the reaction time is 1h.

[0031] Based on the above technical solution, further, the alkynyl cyclohexadienone compound includes the following structure:

[0032]

[0033] Based on the above technical solution, further, the benzoxazole-pyridine comprises the following structure:

[0034]

[0035] Based on the above technical solution, further, the preparation method of the benzoxazole-pyridine compounds L1, L2, L5, L6, L7, and L8 comprises the following steps;

[0036] A mixed solution a of the compound represented by formula II, the compound represented by formula III and the solvent Y2 is subjected to a condensation reaction a in an inert atmosphere to obtain benzoxazole-pyridine compounds L1, L2, L5, L6, L7 and L8;

[0037]

[0038] In the formula, R1 is selected from hydrogen and methyl, and R2 is selected from methoxy, tert-butoxy, benzyl, dimethylamino, and N-pyrrolidinyl.

[0039] Based on the above technical solution, further, the molar ratio of the compound represented by formula II to the compound represented by formula III is 1:1.1 to 1:2.

[0040] Based on the above technical solution, further, the molar concentration of the compound represented by formula II in the solvent Y2 is 0.2 to 1.5 mol / L.

[0041] Based on the above technical solution, further, the reaction conditions of the condensation reaction a are a temperature of 40 to 60° C. and a reaction time of 24 to 72 hours.

[0042] Based on the above technical solution, further, the inactive atmosphere in the condensation reaction a is selected from at least one of nitrogen and argon.

[0043] Based on the above technical solution, further, the solvent Y2 is selected from at least one of methanol, tetrahydrofuran and dioxane.

[0044] Based on the above technical solution, further, the preparation method of the benzoxazole-pyridine compound L3 comprises the following steps: subjecting a mixed solution b of the compound represented by formula IV, the compound represented by formula V, a base and a solvent Y3 to a condensation reaction b in an oxygen atmosphere to obtain the benzoxazole-pyridine compound L3;

[0045]

[0046] Based on the above technical solution, further, the molar ratio of the compound represented by formula IV to the compound represented by formula V is 1:1.

[0047] Based on the above technical solution, further, the molar ratio of the compound represented by formula V to the base is 1:2 to 1:3.

[0048] Based on the above technical solution, further, the molar concentration of the compound represented by formula IV in the solvent Y3 is 0.3 to 0.6 mol / L.

[0049] Based on the above technical solution, further, the reaction conditions of the condensation reaction b are 60-80° C. and the reaction time is 24-48 hours.

[0050] Based on the above technical solution, further, the base is selected from at least one of N,N-diisopropylethylamine, diisopropylamine, and triethylamine.

[0051] Based on the above technical solution, further, the solvent Y3 is selected from at least one of methanol, ethanol and dioxane.

[0052] Based on the above technical scheme, further, the preparation method of the benzoxazole-pyridine compound L4 includes the following steps: a mixed solution c of the benzoxazole-pyridine compound L5, acid, and solvent Y4 undergoes a tert-butyl removal reaction c in an air atmosphere to obtain the benzoxazole-pyridine compound L4.

[0053] Based on the above technical solution, further, the volume ratio of solvent Y4 and acid is 0.5:1 to 1:1.

[0054] Based on the above technical solution, further, the reaction conditions of the removal of the tert-butyl group in reaction c are 20 to 30° C. and the reaction time is 30 to 60 minutes.

[0055] Based on the above technical solution, further, the acid is selected from at least one of trifluoroacetic acid and formic acid.

[0056] Based on the above technical solution, further, the solvent Y4 is selected from at least one of dichloromethane and 1,2-dichloroethane.

[0057] Compared with the prior art, the present invention has the following beneficial effects:

[0058] The method of the invention realizes the ligand-regulated palladium-catalyzed tandem cyclization reaction of alkynyl cyclohexadienone and carboxylic acid, and obtains a cis-hydrobenzofuran compound with a novel structure in high yield; the invention has a wide substrate range, is simple and practical to operate, has readily available raw materials, has high catalyst reaction activity, has complete raw material conversion, is convenient to separate, and can obtain a high-purity product; the reaction conditions are mild, the energy consumption is low, it is environmentally friendly and the yield is high. BRIEF DESCRIPTION OF THE DRAWINGS

[0059] Figure 1 This is the X-ray single crystal diffraction test pattern of compound 3aa of the present invention. DETAILED DESCRIPTION

[0060] The present invention is described in detail below by examples, but the present invention is not limited to the following examples.

[0061] Synthesis of the raw materials alkynyl cyclohexadienone compounds in the following examples References (a) Gollapelli, KK; Donikela, S.; Manjula, N.; Chegondi, R. ACS Catal.2018,8,1440-1447. (b) Xu, D.; Zhao, Y.; Song, D.; Zhong, Z.: Feng, S.; Xie, X.; Wa ng, X.; She, X. Org. Lett. 2017, 19, 3600-3603. (c) Banfield, SC; 4,82,131-138. (d) Tello-Aburto, R.; Kalstabakken, KA; Harned, AMOrg.Biomol.Chem.2 013,11,5596-5604.(e)Wu,W.;Chen,T.;Chen,J.;Han,XJOrg.Chem.2018,83,1033-1040.

[0062] The structure of the alkynylcyclohexadienone 1 in the embodiment is as follows:

[0063]

[0064] Preparation Example 1 Synthesis of Ligand L1

[0065]

[0066] Under nitrogen protection, compound 4 (2.463 g, 20 mmol), compound 5a (2.108 g, 13 mmol) and 35 mL of anhydrous methanol were added to a 100 mL reaction bottle, the temperature was raised to 50 ° C, the reaction was carried out for 41 hours, the solvent was removed under reduced pressure, 10 mL of water was added, the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and column chromatography was performed to obtain 1.062 g of a pink solid, which was compound L1, with a yield of 34%.

[0067] Preparation Example 2 Synthesis of Ligand L2

[0068]

[0069] Under nitrogen protection, compound 6 (0.873 g, 8.0 mmol), compound 5a (0.665 g, 4.0 mmol) and 12 mL of anhydrous methanol were added to a 50 mL reaction bottle, the temperature was raised to 50 ° C, the reaction was carried out for 40 hours, the solvent was removed under reduced pressure, 5.0 mL of water was added, the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and column chromatography was performed to obtain 0.331 g of a yellow solid, which was compound L2, with a yield of 37%.

[0070] Preparation Example 3 Synthesis of Ligand L3

[0071]

[0072] Compound 7 (0.587 g, 3.0 mmol), compound 8 (0.411 g, 3.0 mmol), triethylamine (0.607 g, 6.0 mmol), and 6.0 mL of ethanol were added to a 50 mL reaction bottle, and an oxygen balloon was inserted to replace the reaction system with an oxygen atmosphere. The temperature was raised to 80 ° C and refluxed. The reaction was carried out for 24 hours, and the solvent was removed under reduced pressure. 5.0 mL of water was added, and the mixture was extracted with dichloromethane and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and column chromatography was performed to obtain 0.557 g of a light green solid, which was compound L3 with a yield of 67%.

[0073] Preparation Example 4 Synthesis of Ligand L5

[0074]

[0075] Under nitrogen protection, compound 4 (2.463 g, 20 mmol), compound 5b (2.644 g, 13 mmol), and 35 mL of anhydrous methanol were added to a 100 mL reaction bottle, and the temperature was raised to 50°C for 41 hours. The solvent was removed under reduced pressure, 10 mL of water was added, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Column chromatography was performed to obtain 1.188 g of a white solid, which was compound L5, with a yield of 32%.

[0076] Preparation Example 5 Synthesis of Ligand L4

[0077]

[0078] Compound L5 (0.279 g, 1.0 mmol), 1.0 mL trifluoroacetic acid, and 1.0 mL dichloromethane were added to a 25 mL reaction bottle and reacted at room temperature for 30 minutes. Saturated sodium bicarbonate aqueous solution was added to neutralize the reaction solution to a pH of about 7, extracted with dichloromethane, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Column chromatography gave 0.133 g of a light yellow solid, which was compound L4, with a yield of 59%.

[0079] Preparation Example 6 Synthesis of Ligand L6

[0080]

[0081] Under nitrogen protection, compound 4 (1.724 g, 14 mmol), compound 5c (2.083 g, 9.1 mmol) and 25 mL of anhydrous methanol were added to a 100 mL reaction bottle, the temperature was raised to 50 ° C, the reaction was carried out for 45 hours, the solvent was removed under reduced pressure, 10 mL of water was added, the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and column chromatography was performed to obtain 0.773 g of an orange solid, which was compound L6, with a yield of 28%.

[0082] Preparation Example 7 Synthesis of Ligand L7

[0083]

[0084] Under nitrogen protection, compound 4 (2.587 g, 21 mmol), compound 5d (14 mmol) and 14 mL of anhydrous methanol were added to a 50 mL reaction bottle, the temperature was raised to 50 ° C, the reaction was carried out for 59 hours, the solvent was removed under reduced pressure, 10 mL of water was added, the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and column chromatography was performed to obtain 0.835 g of a light yellow solid, which was compound L7, with a yield of 24%.

[0085] Preparation Example 8 Synthesis of Ligand L8

[0086]

[0087] Under nitrogen protection, compound 4 (1.478 g, 12 mmol), compound 5e (8.0 mmol), and 8.0 mL of anhydrous methanol were added to a 50 mL reaction bottle, and the temperature was raised to 50°C for 48 hours. The solvent was removed under reduced pressure, 10 mL of water was added, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Column chromatography was performed to obtain 0.320 g of a yellow solid, which was compound L8, with a yield of 14%.

[0088] Example 1 Palladium-catalyzed tandem cyclization of alkynylcyclohexadienone 1a and acetic acid 2a

[0089] Under nitrogen protection, palladium acetate Pd(OAc)2 (0.004 mmol), benzoxazole-pyridine ligand L1 (0.0044 mmol) and acetic acid 2a (17 eq.) were added to a 10 mL sealed tube, and then toluene (0.9 mL) was added. After stirring at room temperature for 120 minutes, alkynyl cyclohexadienone 1a (0.1 mmol) was added under nitrogen. After stirring at 80°C for complete reaction, the solvent was spin-dried, internal standard trimethoxybenzene (0.1 mmol) was added, and the H NMR spectrum was measured. The H NMR yield was 57%.

[0090] Example 2 Palladium-catalyzed tandem cyclization of alkynylcyclohexadienone 1a and acetic acid 2a

[0091] Under nitrogen protection, palladium acetate Pd(OAc)2 (0.004 mmol), benzoxazole-pyridine ligand L1 (0.0044 mmol) and acetic acid 2a (17 eq.) were added to a 10 mL sealed tube, and then toluene (0.9 mL) was added. After stirring at room temperature for 120 minutes, alkynyl cyclohexadienone 1a (0.1 mmol) and cuprous chloride (0.01 mmol) were added under nitrogen. After stirring at 80°C for complete reaction, the solvent was spin-dried, internal standard trimethoxybenzene (0.1 mmol) was added, and the H NMR spectrum was measured. The H NMR yield was 75%.

[0092] Example 3-16 Palladium-catalyzed tandem cyclization of alkynylcyclohexadienone 1a and acetic acid 2a

[0093] Cis-hydrobenzofuran was prepared by the same method as in Example 2, except that the type of additive, ligand and organic solvent were changed. The results are shown in Table 1.

[0094]

[0095] Table 1. Condition parameters and experimental results of Examples 1-16

[0096]

[0097] Example 17 Palladium-catalyzed tandem cyclization of alkynylcyclohexadienone 1a and acetic acid 2a

[0098] Under nitrogen protection, palladium acetate Pd(OAc)2 (0.008 mmol), benzoxazole-pyridine ligand L1 (0.0088 mmol) and acetic acid 2a (3.4 mmol) were added to a 10 mL sealed tube, and then toluene (1.8 mL) was added. After stirring at room temperature for 120 minutes, alkynyl cyclohexadienone 1a (0.2 mmol) and cuprous iodide (0.02 mmol) were added under nitrogen. After stirring at 80° C. for complete reaction, the solvent was dried and separated by column chromatography to obtain pure cis-hydrobenzofuran 3aa in a yield of 80%.

[0099] Example 18 Palladium-catalyzed tandem cyclization of alkynylcyclohexadienone 1b and acetic acid 2a

[0100] Under nitrogen protection, palladium acetate Pd(OAc)2 (0.016 mmol), benzoxazole-pyridine ligand L1 (0.0176 mmol) and acetic acid 2a (3.4 mmol) were added to a 10 mL sealed tube, and then toluene (1.8 mL) was added. After stirring at room temperature for 120 minutes, alkynyl cyclohexadienone 1b (0.2 mmol) and N-iodosuccinimide (0.02 mmol) were added under nitrogen. After stirring at 80°C for completion of the reaction, the solvent was dried and separated by column chromatography to obtain pure cis-hydrobenzofuran 3ba in a yield of 76%.

[0101] Example 19-30 Palladium-catalyzed tandem cyclization of alkynylcyclohexadienone 1 and acetic acid 2a

[0102] The same method and conditions as in Example 17 were used to prepare cis-hydrobenzofurans 3 of different structures, the only difference being that the type of alkynyl cyclohexadienone 1 in the reaction was changed, and chiral cis-hydrobenzofurans 3ca, 3da, 3ea, 3fa, 3ga, 3ha, 3ia, 3ja, 3ka, 3la, 3ma, and 3na were obtained in sequence.

[0103] Example 31 Palladium-catalyzed tandem cyclization of alkynylcyclohexadienone 1o with acetic acid 2a

[0104] Under nitrogen protection, palladium acetate Pd(OAc)2 (0.016 mmol), benzoxazole-pyridine ligand L1 (0.0176 mmol) and acetic acid 2a (3.4 mmol) were added to a 10 mL sealed tube, and then toluene (1.8 mL) was added. After stirring at room temperature for 120 minutes, alkynyl cyclohexadienone 1o (0.2 mmol) and cuprous iodide (0.02 mmol) were added under nitrogen. After stirring at 80° C. for complete reaction, the solvent was dried and separated by column chromatography to obtain pure cis-hydrobenzofuran 3oa in a yield of 77%.

[0105] Example 32-34 Palladium-catalyzed tandem cyclization of alkynylcyclohexadienone 1 and acetic acid 2a

[0106] The same method and conditions as in Example 17 were used to prepare cis-hydrobenzofurans 3 of different structures, except that the type of alkynyl cyclohexadienone 1 in the reaction was changed, and chiral cis-hydrobenzofurans 3pa, 3qa, and 3ra were obtained in turn.

[0107] Example 35 Palladium-catalyzed tandem cyclization of alkynylcyclohexadienone 1s and acetic acid 2a

[0108] Under nitrogen protection, palladium acetate Pd(OAc)2 (0.016 mmol), benzoxazole-pyridine ligand L1 (0.0176 mmol) and acetic acid 2a (3.4 mmol) were added to a 10 mL sealed tube, and then toluene (1.8 mL) was added. After stirring at room temperature for 120 minutes, alkynyl cyclohexadienone 1s (0.2 mmol) and N-iodosuccinimide (0.02 mmol) were added under nitrogen. After stirring at 100° C. for completion of the reaction, the solvent was spin-dried and separated by column chromatography to obtain pure cis-hydrobenzofuran 3sa in a yield of 54%.

[0109] Example 36 Palladium-catalyzed tandem cyclization of alkynylcyclohexadienone 1t and acetic acid 2a

[0110] Under nitrogen protection, palladium acetate Pd(OAc)2 (0.016 mmol), benzoxazole-pyridine ligand L1 (0.0176 mmol) and acetic acid 2a (3.4 mmol) were added to a 10 mL sealed tube, and then toluene (1.8 mL) was added. After stirring at room temperature for 120 minutes, alkynyl cyclohexadienone 1s (0.2 mmol) and N-iodosuccinimide (0.02 mmol) were added under nitrogen. After stirring at 100° C. for completion of the reaction, the solvent was dried and separated by column chromatography to obtain pure cis-hydrobenzofuran 3ta in a yield of 61%.

[0111] Example 37 Palladium-catalyzed tandem cyclization of alkynylcyclohexadienone 1a and propionic acid 2b

[0112] Under nitrogen protection, palladium acetate Pd(OAc)2 (0.008 mmol), benzoxazole-pyridine ligand L1 (0.0088 mmol) and propionic acid 2b (2.0 mmol) were added to a 10 mL sealed tube, and then toluene (2.0 mL) was added. After stirring at room temperature for 120 minutes, alkynyl cyclohexadienone 1a (0.2 mmol) and cuprous iodide (0.02 mmol) were added under nitrogen. After stirring at 80°C for completion of the reaction, the solvent was dried and separated by column chromatography to obtain pure cis-hydrobenzofuran 3ab in a yield of 83%.

[0113] Examples 38-41 Palladium-catalyzed tandem cyclization of alkynylcyclohexadienone 1a and carboxylic acid 2

[0114] The same method and conditions as in Example 37 were used to prepare cis-hydrobenzofuran 3 with different structures, only the type of carboxylic acid compound 2 in the reaction was changed to obtain cis-hydrobenzofuran 3ac, 3ad, 3ae, and 3af, respectively.

[0115] Example 42 Palladium-catalyzed tandem cyclization of alkynylcyclohexadienone 1a and acetylsalicylic acid 2g

[0116] Under nitrogen protection, palladium acetate Pd(OAc)2 (0.016 mmol), benzoxazole-pyridine ligand L1 (0.0176 mmol) and acetylsalicylic acid 2 g (1.0 mmol) were added to a 10 mL sealed tube, and then toluene (2.0 mL) was added. After stirring and reacting at room temperature for 120 minutes, alkynyl cyclohexadienone 1a (0.2 mmol) and cuprous iodide (0.02 mmol) were added under nitrogen. After stirring and reacting at 80° C., the solvent was dried and separated by column chromatography to obtain pure cis-hydrobenzofuran 3ag in a yield of 63%.

[0117] Example 43 Palladium-catalyzed tandem cyclization of alkynylcyclohexadienone 1a and carboxylic acid 2h

[0118] The same method and conditions as in Example 37 were used to prepare cis-hydrobenzofuran 3 with different structures, and only the type of carboxylic acid compound 2 in the reaction was changed to obtain cis-hydrobenzofuran 3ah.

[0119] The structure of the cis-hydrobenzofuran compound prepared in the above example is as follows:

[0120]

[0121]

[0122] Compound 3aa was subjected to a monochromatic Mo-Kα radiation After X-ray single crystal diffraction test (test condition: 213K) on BRUKER D8VENTURE diffractometer, the structure was analyzed by Olex21.2. The structure was confirmed by single crystal. Figure 1 As shown; the compound 3aa crystal belongs to the monoclinic system, the space group is P 21 / c, and the unit cell parameters are β=105.8040(10)°, Z=4.

[0123] The characterization data of the compounds in the above examples are as follows:

[0124]

[0125]

[0126]

[0127]

[0128]

[0129]

[0130]

[0131]

[0132]

Claims

1. A novel cis-hydrobenzofuran compound, characterized in that: Its structure is shown in Formula I; Where: R is selected from benzyl, phenyl or C1-C 20 One of alkyl and tert-butyldimethylsilyloxy; R ’ is selected from cyclohexyl, phenyl, substituted phenyl Ph1, heteroaryl or substituted heteroaryl; the heteroaryl is a five-membered heterocyclic group containing a heteroatom S in the skeleton; the substituents of the substituted phenyl Ph1 and the substituted heteroaryl are independently selected from at least one of methyl, methoxy, acetyl, fluorine, chlorine and bromine; the heteroaryl is preferably thienyl; R" is selected from C1-C 20 Alkyl, phenyl or substituted phenyl Ph2; the substituent of substituted phenyl Ph2 is selected from methyl, methoxy and acetoxy; X is oxygen or p-toluenesulfonylamide.

2. The cis-hydrobenzofuran compound according to claim 1, characterized in that The novel cis-hydrobenzofuran compound is selected from any one of the structures shown below:

3. A method for preparing a novel cis-hydrobenzofuran according to claim 1 or 2, characterized in that: Using palladium benzoxazole-pyridine complex as catalyst, alkynyl cyclohexadienone compounds and carboxylic acid compounds as substrates, a novel cis-hydrobenzofuran is synthesized through a tandem cyclization reaction. The reaction formula is as follows: Where: R is selected from benzyl, phenyl or C1-C 20 One of alkyl and tert-butyldimethylsilyloxy; R ’ is selected from cyclohexyl, phenyl, substituted phenyl Ph1, heteroaryl or substituted heteroaryl; the heteroaryl is a five-membered heterocyclic group containing a heteroatom S in the skeleton; the substituents of the substituted phenyl Ph1 and the substituted heteroaryl are independently selected from at least one of methyl, methoxy, acetyl, fluorine, chlorine and bromine; R" is selected from C1-C 20 Alkyl, phenyl or substituted phenyl Ph2; the substituent of substituted phenyl Ph2 is selected from methyl, methoxy and acetoxy; X is oxygen or p-toluenesulfonylamide.

4. The preparation method according to claim 3, characterized in that: An additive is added to the reaction, and the additive is a monovalent copper salt or N-iodosuccinimide; the monovalent copper salt includes cuprous chloride, cuprous bromide, cuprous iodide, and cuprous acetate.

5. The preparation method according to claim 4, characterized in that: The molar ratio of the alkynyl cyclohexadienone compound to the carboxylic acid compound is 1:5 to 1:17, the molar ratio of the additive to the alkynyl cyclohexadienone compound is 0.05 to 0.2:1, the molar ratio of the palladium metal precursor to the alkynyl cyclohexadienone compound is 0.01 to 0.1:1, and the molar ratio of the benzoxazole-pyridine ligand to the palladium metal precursor is 1 to 1.2:

1.

6. The preparation method according to claim 3, characterized in that: The solvent of the reaction is selected from at least one of 1,2-dichloroethane, ethyl acetate, toluene and methyl tert-butyl ether.

7. The preparation method according to claim 3, characterized in that: The reaction temperature is 60 to 100° C., and the reaction time is 1 to 96 hours.

8. The preparation method according to any one of claims 3 to 7, characterized in that: The method comprises the following steps: under nitrogen protection, adding a palladium metal precursor, a benzoxazole-pyridine ligand and a carboxylic acid compound into a sealed tube, then adding a solvent, stirring and reacting at room temperature for 30 to 150 minutes, adding an alkynyl cyclohexadienone compound and an additive under nitrogen protection, continuing to stir and react at 60 to 100° C. in a nitrogen atmosphere for 1 to 96 hours, spinning off the solvent, and separating by column chromatography to obtain pure cis-hydrobenzofuran.

9. The preparation method according to claim 3, characterized in that: The alkynyl cyclohexadienone compounds include the following structures:

10. The preparation method according to claim 3, characterized in that: The benzoxazole-pyridine comprises the following structure:

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