Allene compound synthesized by coupling of three electrophilic reagents, and preparation method and application thereof

Abstract

The invention discloses an allene compound synthesized by coupling three electrophilic reagents and a preparation method and application thereof. The method comprises the following steps: under the protection of gas, reacting simple and easily available aryl iodide, propargyl alcohol derivative, alkyl bromide or aryl bromide in an organic solvent at 110-120 DEG C under the synergistic catalysis of a palladium catalyst and C5-site amide substituted norbornene or C2-site ethyl ester substituted norbornene to obtain a series of allene compounds. The method has the advantages of cheap and easily available raw materials, mild reaction conditions, good substrate universality, high yield and simple preparation process, and can be used for rapidly obtaining a high-value chiral skeleton.

Description

Technical Field

[0001] The present invention relates to a method for synthesizing allene compounds by coupling three electrophilic reagents, and its preparation method and application, belonging to the technical field of organic synthesis and preparation of chemical drug raw materials. Background Art

[0002] Since the discovery of the palladium / norbornene co-catalysis (i.e., the Catellani reaction), it has been developed for more than twenty years. As an efficient strategy for synthesizing polysubstituted aromatic hydrocarbons, it provides a new synthetic approach and design method for the field of synthetic chemistry, and this strategy has also achieved significant results in the fields of total synthesis of natural products, drug synthesis and design, and multi-functional materials in synthetic chemistry. ([1] Q. Li, L. Green, N. Venkataraman, I. Shiyanovskaya, A. Khan, A. Urbas, J. W. Doane, J. Am. Chem. Soc. 2007, 129, 12908; [2] J. E. Smyth, N. M. Butler, P. A. Keller, Nat. Prod. Rep. 2015, 32, 1562; [3] J. Clayden, W. J. Moran, P. J. Edwards, S. R. LaPlante, Angew. Chem. Int. Ed. 2009, 48, 6398).

[0003] In the past twenty years, the connotation of this reaction has been greatly developed. Through the unremitting efforts of chemists in this field, various initiation methods of palladium with different valence states, various novel electrophilic reagents and termination reagents have been developed, greatly enriching the research content in this field.

[0004] However, at present, the research on electrophilic termination reagents in this field is still very lacking, with only a few reports. This greatly limits the scope of application of this reaction. Therefore, it is particularly important to develop efficient and concise new synthesis methods. Summary of the Invention

[0005] To address the deficiencies in the prior art, the present invention uses three different electrophilic reagents for direct coupling through palladium / norbornene co-catalysis to achieve the ortho-alkylation / arylation in-situ allenylation reaction of aryl iodides. The raw materials used in this method are inexpensive and easily available, the reaction conditions are mild, the substrate generality is good, the yield is high, and the preparation process is simple. The present invention uses easily available aryl iodides, propargyl alcohol derivatives, alkyl bromides or aryl bromides as starting materials, and reacts in an organic solvent at 110-120 °C under the co-catalysis of a palladium catalyst and norbornene substituted at the C5 position with an amide or norbornene substituted at the C2 position with an ethyl ester to obtain a series of allene compounds. Moreover, the obtained products can be simply transformed subsequently to obtain more valuable compounds with high regioselectivity. Additionally, a styrene axial chiral skeleton can be constructed. In particular, the challenging asymmetric XEC is also achieved by the present invention. This catalysis uses sterically hindered 2,6-disubstituted aryl bromides as arylating reagents to prepare allenes with axial chirality.

[0006] In a first aspect, the present invention provides a method for synthesizing allene compounds by coupling three electrophilic reagents and its preparation method, including:

[0007] Under gas protection, aryl iodide A, bromide B, and propargyl alcohol ester C react in an organic solvent under the action of a palladium catalyst, norbornene derivative, ligand, and base to obtain allene compound I;

[0008] Among them, the structural formula of the aryl iodide A is R 1 including hydrogen, halogen, C1-C6 alkyl, -COOR 1a one or more of; R 1a including C1-C6 alkyl; R 2 selected from one of C1-C6 alkyl, C2-C8 ω-ester alkyl, and siloxy; L ring is a five-membered or six-membered ring, and L includes one or two of C, O, S, or N; 1 ≤ m ≤ 3;

[0009] The structural formula of the bromide B is Br-R 6 ; R 6 including R 6a substituted or unsubstituted C1-C6 alkyl, R 6’ substituted or unsubstituted benzene ring, naphthalene ring, phenanthrene ring, pyrene ring, pyridine ring, indole ring, dibenzofuran ring, benzothiophene ring, quinoline ring; R 6a including -CONHR 6b cyano, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, -COOR 6c one or more of C6-C12 aryl and substituted aryl; R 6bSelected from one of hydrogen, C1-C6 alkyl, C6-C12 aryl, and C5-C11 heteroaryl; R 6c Selected from one of C1-C6 alkyl, C6-C12 aryl, and C5-C11 heteroaryl; R 6’ Selected from one of C1-C6 alkyl, -COOR 6d , aldehyde group, carboxyl group, hydroxyl group, amino group, cyano group, nitro group, Cl, F, Br; R 6d Selected from C1-C6 alkyl;

[0010] The structural formula of the propargyl ester C is R 4 Selected from one of hydrogen, C1-C4 alkyl, and C1-C4 alkoxy; R 5 Selected from one of hydrogen, C1-C4 alkyl, and C1-C4 alkoxy; R 7 Selected from R 7a Substituted or unsubstituted C1-C6 alkyl, R 7b Substituted or unsubstituted phenyl, C1-C6 alkoxy; R 7a Selected from one or several of C1-C4 alkyl, C1-C4 alkoxy, TBSO-, phenyl, benzyl, and benzyloxy; R 7b Selected from one or several of C1-C4 alkyl and C1-C4 alkoxy; R 8 Selected from phenyl, benzyl, -Bz, C1-C4 alkyl, or -CO2R 8a ; R 8a Selected from one of hydrogen and C1-C4 alkyl;

[0011] The structural formula of the allene compound I is

[0012] In a possible implementation manner, the said R 4 and R 5 either form a ring or do not form a ring.

[0013] In a possible implementation manner, the structural formula of the aryl iodide A further includes:

[0014]

[0015] ; one of

[0016] R4, R4a, R4b, and R4c are each independently selected from one of hydrogen, C6-C12 aryl, C1-C6 alkyl, aldehyde group, carboxyl group, hydroxyl group, amino group, cyano group, nitro group, benzyloxy group, alkenyl group, alkynyl group, Cl, and F;

[0017] m1 represents the number of R4, where 1 ≤ m1 ≤ 2; when m1 ≥ 2, the multiple R4 groups are the same or different;

[0018] m2 represents the number of R4a, where 1 ≤ m2 ≤ 3; when m2 ≥ 2, the multiple R4a groups are the same or different;

[0019] m3 represents the number of R4b, where 1 ≤ m3 ≤ 3; when m3 ≥ 2, the multiple R4b groups are the same or different;

[0020] m4 represents the number of R4c, where 1 ≤ m4 ≤ 3; when m4 ≥ 2, the multiple R4c groups are the same or different.

[0021] In a possible implementation manner, the R 6a in, the heteroatoms of the C3-C6 heterocycloalkyl include N and O; the substituents of the C6-C12 aryl and substituted aryl include C1-C6 alkyl groups.

[0022] In a possible implementation manner, the R 6b in the C5-C11 heteroaryl includes N and O as heteroatoms.

[0023] In a possible implementation manner, the R 6c in the C5-C11 heteroaryl includes N and O as heteroatoms.

[0024] In a possible implementation manner, the structural formula of the norbornene derivative is:

[0025]

[0026] Wherein:

[0027] i) R9 is the substituent on the double bond, r represents the number of substituents, 1 ≤ r ≤ 2; R10 is the substituent on the left five-membered ring, q represents the number of substituents, 1 ≤ q ≤ 8;

[0028] ii) R9 or R10 is selected from any one or more of hydrogen, C6-C12 aryl, C5-C11 heteroaryl, C1-C6 alkyl, aldehyde group, carboxyl group, hydroxyl group, amino group, cyano group, nitro group, C1-C4 ether alkyl group, alkenyl group, alkynyl group, halogen;

[0029] iii) When the number of substituents on the left five-membered ring is 2 or more, the substituents on the left five-membered ring are the same or different; when the number of substituents on the double bond is 2, the double bonds are the same or different;

[0030] iv) The types of the R9 and R10 substituents are the same or the same.

[0031] In a possible implementation manner, the palladium catalyst includes one or more of Pd(OAc)2, Pd(MeCN)2Cl2, Pd(PPh3)2Cl2, Pd(dppf)Cl2, Pd(TFA)2, PdCl2, Pd(acac)2, Pd(PPh3)4.

[0032] In a possible implementation manner, the base includes any one or more of sodium carbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, cesium acetate, tripotassium phosphate, potassium acetate, potassium tert-butoxide.

[0033] In a possible implementation manner, the ligand includes any one or more of PPh3, P(p-OMe-Ph)3, P(m-F-Ph)3, P(o-Me-Ph)3, TFP, PCy3, XPhos, DavePhos, SPhos, BrettPhos, JohnPhos, DPPE, AsPh3.

[0034] In a possible implementation manner, the organic solvent includes any one or more of acetonitrile, benzonitrile, tetrahydrofuran, dimethoxyethane, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, 1,4-dioxane, N-methylpyrrolidone.

[0035] In a possible implementation manner, the reaction temperature of the preparation method is 110 - 120 °C.

[0036] In a possible implementation manner, taking the dosage of aryl iodide A as 1 equivalent, the dosage equivalents of bromide B, propargyl ester C, palladium catalyst, norbornene derivative, ligand and base are (1.0 - 4.0) equivalents, (0.5 - 2.0) equivalents, (0.1 - 0.5) equivalents, (0.5 - 1.0) equivalents, (0.1 - 0.2) equivalents and (2.0 - 4.0) equivalents in sequence.

[0037] In the second aspect, an allene compound is provided, which is prepared by the method described in the first aspect.

[0038] In the third aspect, the application of the allene compound described in the second aspect in the hydrogen conversion synthesis of a styrene axially chiral skeleton is provided.

[0039] The present invention has the following beneficial effects:

[0040] 1. The main raw materials involved in the present invention are aryl iodides, alkyl bromides, aryl bromides, and propargyl alcohol derivatives. Most of these raw materials can be commercial reagents, do not require special treatment, and are inexpensive and diverse in variety.

[0041] 2. The method of the present invention has very good enantioselectivity and diastereoselectivity, and the ee value of the obtained product is as high as 99%.

[0042] 3. The catalyst used in the reaction involved in the method of the present invention is a relatively inexpensive metal palladium salt, which is an important supplement compared to other catalysts or complexes, etc.

[0043] 4. The catalytic amount of norbornene derivative used in the reaction involved in the method of the present invention is easy to prepare and the raw material price is low.

[0044] 5. The reaction involved in the method of the present invention has good tolerance and generality for functional groups, and the substituents can be alkyl, alkoxy, ester group, nitro, halogen atom (F, Cl, Br), etc.

[0045] 6. The method of the present invention can efficiently and in large quantities (gram scale) prepare allene compounds, laying a good foundation for industrial production.

[0046] 7. The allene compound prepared by the present invention can be hydrogenated into a framework containing styrene axial chirality through the reaction with the allene of ortho-axially chiral biaryl. Detailed implementation mode

[0047] The technical solution of the present invention will be further described below through examples. It should be noted that the technical solution of the present invention is not limited to the following examples.

[0048] The present invention first examines the reaction conditions of ortho-alkylation, and screens important factors such as the termination reagent, reactant dosage, reaction temperature, solvent, norbornene cocatalyst, reaction time, ligand, palladium catalyst, norbornene equivalent, base and base dosage, and reaction concentration. The results are as follows:

[0049] 1. Investigation of the termination reagent

[0050]

[0051] As shown in formula ①, under argon protection, 1.0 equivalent of aryl iodide 1a, 3.0 equivalents of alkyl bromide 2a, and 1.5 equivalents of different electrophiles 3 react in acetonitrile (0.1 M, calculated as adding 1 mL of acetonitrile per 0.1 mmol of asymmetric aryl iodide 1a) at 110 °C under the action of 10 mol% palladium catalyst Pd(OAc)2, 20 mol% phosphine ligand PPh3, 1.0 equivalent of norbornene derivative (±)-N 1 and 4.0 equivalents of K2CO3 to obtain an allene compound with the structure shown in 4a; the relationship between the termination reagent, reaction temperature and yield is shown in Table 1.

[0052] Table 1 Investigation of the termination reagent

[0053]

[0054] a It indicates that the addition amount of iodide 1a in all reactions is 0.1 mmol. b It indicates that the yield is determined by gas chromatography using biphenyl as an internal standard.

[0055] Table 1 Experimental results show that when R is methyl and the leaving groups LG are benzoyl, acetyl, and carbonate respectively, the target product can be obtained in a yield of 16–34% (Entries 1–3). When propargyl alcohol derivatives 3d–e are used as the terminating reagent, no target product is formed (Entries 4–5). In summary, in this example, propargyl benzoate 3a is selected as the terminating reagent, and other reaction conditions are further optimized.

[0056] 2. Investigation of the amounts of reactants and reaction temperature

[0057]

[0058] As shown in formula ②, under argon protection, 1.0 equivalent of aryl iodide 1a, 3.0 equivalents of alkyl bromide 2a, and different equivalents of electrophile 3a react in acetonitrile (0.1 M, calculated as 1 mL of acetonitrile added per 0.1 mmol of asymmetric aryl iodide 1a) at different temperatures in the presence of 10 mol% palladium catalyst Pd(OAc)2, 20 mol% phosphine ligand PPh3, and 1.0 equivalent of norbornene derivative (±)-N 1 , 4.0 equivalents of K2CO3 to obtain an allene compound with the structure shown in 4a; the relationship between the amounts of reactants, reaction temperature, and yield is shown in Table 2.

[0059] Table 2 Investigation of the amounts of reactants and reaction temperature

[0060]

[0061] a It indicates that the addition amount of iodide 1a in all reactions is 0.1 mmol. b It indicates that the yield is determined by gas chromatography using biphenyl as an internal standard.

[0062] The experimental results in Table 2 show that when the equivalent of 3a exceeds 1.5 equivalents or is less than 1.5 equivalents, the yield of the target product will decrease (Entries 1-5). Therefore, in this example, the amount of the terminating reagent 3a is set at 1.5 equivalents. When the temperature is higher or lower than 110 °C, only the yield will decrease. Therefore, 110 °C is selected as the optimal reaction temperature for subsequent experiments.

[0063] 3. Investigation of the solvent

[0064]

[0065]

[0066] As shown in Formula ③, under argon protection, 1.0 equivalent of aryl iodide 1a, 3.0 equivalents of alkyl bromide 2a, and 1.5 equivalents of electrophile 3a react in 10 mol% palladium catalyst Pd(OAc)2, 20 mol% phosphine ligand PPh3, and 1.0 equivalent of norbornene derivative (±)-N 1 、in the presence of 4.0 equivalents of K2CO3 in different solvents (0.1 M, calculated as 1 mL of solvent added per 0.1 mmol of asymmetric aryl iodide 1a) at 110 °C to obtain an allene compound with the structure shown in 4a; the relationship between the solvent and the yield is shown in Table 3.

[0067] Table 3 Investigation of solvents

[0068]

[0069] a It indicates that the addition amount of iodide 1a in all reactions is 0.1 mmol. b It indicates that the yield was determined by gas chromatography using biphenyl as an internal standard.

[0070] The experimental results in Table 3 show that among nitrile solvents, acetonitrile gives the highest yield as the reaction solvent (Entry 1), while only a trace amount of the target product can be obtained when benzonitrile is used as the solvent (Entry 2). In non-polar solvents, for example, only a trace amount or no target product is formed in dichloroethane (DCE) and toluene (Entries 3 - 4). In polar amide solvents, for example, in N-methylpyrrolidone (NMP), N,N-dimethylacetamide (DMA), and N,N-dimethylformamide (DMF), the yield of the target product is low, only 9 - 18% (Entries 5 - 7). When using ether solvents, such as in ethylene glycol dimethyl ether (DME), 1,4-dioxane, and tetrahydrofuran (THF), the yield of the target product is also low (Entries 8 - 9). Therefore, acetonitrile was selected as the best reaction solvent for subsequent experiments.

[0071] 4. Investigation of norbornene cocatalyst

[0072]

[0073] As shown in Formula ④, under argon protection, 1.0 equivalent of aryl iodide 1a, 3.0 equivalents of alkyl bromide 2a, and 1.5 equivalents of electrophile 3a react in acetonitrile (0.1 M, calculated as adding 1 mL of acetonitrile for every 0.1 mmol of asymmetric aryl iodide 1a) at 110 °C in the presence of 10 mol% palladium catalyst Pd(OAc)2, 20 mol% phosphine ligand PPh3, 1.0 equivalent of different norbornene derivatives (±)-N x , and 4.0 equivalents of K2CO3 to obtain an allene compound with the structure shown in 4a; the relationship between the norbornene cocatalyst and the yield is shown in Table 4.

[0074] Table 4 Investigation of Norbornene Cocatalysts

[0075]

[0076] a It indicates that the addition amount of iodide 1a in all reactions is 0.1 mmol. b It indicates that the yield is determined by gas chromatography using biphenyl as an internal standard.

[0077] The experimental results in Table 4 show that when N 2 is selected as the norbornene cocatalyst, the yield of the target product 4a is the highest. Therefore, N 2 is used as the norbornene cocatalyst in subsequent experiments.

[0078] 5. Investigation of Reaction Time

[0079]

[0080] As shown in Formula ⑤, under argon protection, 1.0 equivalent of aryl iodide 1a, 3.0 equivalents of alkyl bromide 2a, and 1.5 equivalents of electrophile 3a react in acetonitrile (0.1 M, calculated as adding 1 mL of acetonitrile for every 0.1 mmol of asymmetric aryl iodide 1a) at 110 °C in the presence of 10 mol% palladium catalyst Pd(OAc)2, 20 mol% phosphine ligand PPh3, 1.0 equivalent of the norbornene derivative (±)-N 2 , and 4.0 equivalents of K2CO3 to obtain an allene compound with the structure shown in 4a; the relationship between the reaction time and the yield is shown in Table 5.

[0081] Table 5 Investigation of Reaction Time

[0082]

[0083] a It indicates that the addition amount of iodide 1a in all reactions is 0.1 mmol. b It indicates that the yield is determined by gas chromatography using biphenyl as an internal standard.

[0084] The experimental results in Table 5 show that when 24 h is selected as the reaction time, the yield of the target product 4a has reached the highest. When the reaction time exceeds 24 h, the reaction yield has basically no change, while when it is less than 24 h, the yield of the target product still shows an increasing trend. Therefore, 24 h is used as the reaction time in subsequent experiments.

[0085] 6. Investigation of ligands

[0086]

[0087] As shown in formula ⑥, under argon protection, 1.0 equivalent of aryl iodide 1a, 3.0 equivalents of alkyl bromide 2a, and 1.5 equivalents of electrophilic reagent 3a react in acetonitrile (0.1 M, calculated as 1 mL of acetonitrile is added per 0.1 mmol of asymmetric aryl iodide 1a) at 110 °C in the presence of 10 mol% palladium catalyst Pd(OAc)2, 1.0 equivalent of norbornene derivative (±)-N 2 , 20 mol% of different types of ligands, and 4.0 equivalents of K2CO3 to obtain an allene compound with the structure shown in 4a; the relationship between the ligand and the yield is shown in Table 6.

[0088] Table 6 Investigation of ligands

[0089]

[0090]

[0091] a It indicates that the addition amount of iodide 1a in all reactions is 0.1 mmol. b It indicates that the yield is determined by gas chromatography using biphenyl as an internal standard.

[0092] The experimental results in Table 6 show that when PPh3 is selected as the ligand, the yield of the target product 4a is the highest. Therefore, PPh3 is used as the ligand in subsequent experiments.

[0093] 7. Investigation of palladium catalysts

[0094]

[0095] As shown in formula ⑦, under argon protection, 1.0 equivalent of aryl iodide 1a, 3.0 equivalents of alkyl bromide 2a, and 1.5 equivalents of electrophilic reagent 3a react in the presence of 10 mol% of different types of palladium catalysts, 1.0 equivalent of norbornene derivative (±)-N 2, in the presence of 20 mol% phosphine ligand PPh3 and 4.0 equivalents of K2CO3, reacted in acetonitrile (0.1 M, calculated as adding 1 mL of acetonitrile per 0.1 mmol of the asymmetric aryl iodide 1a) at 110 °C to obtain an allene compound with the structure shown in 4a; the relationship between the palladium catalyst and the yield is shown in Table 7.

[0096] Table 7 Investigation of Palladium Catalysts

[0097]

[0098] a It indicates that the addition amount of iodide 1a in all reactions is 0.1 mmol. b It indicates that the yield was determined by gas chromatography using biphenyl as an internal standard.

[0099] The experimental results in Table 7 show that when Pd(PPh3)2Cl2 was selected as the palladium catalyst, the yield of the target product 4a was the highest. Therefore, Pd(PPh3)2Cl2 was used as the palladium catalyst in subsequent experiments.

[0100] 8. Investigation of the Equivalent Amount of Norbornene Derivatives

[0101]

[0102] As shown in Equation ⑧, under argon protection, 1.0 equivalent of aryl iodide 1a, 3.0 equivalents of alkyl bromide 2a, and 1.5 equivalents of electrophile 3a were reacted in acetonitrile (0.1 M, calculated as adding 1 mL of acetonitrile per 0.1 mmol of the asymmetric aryl iodide 1a) at 110 °C in the presence of 10 mol% palladium catalyst Pd(OAc)2, different equivalent amounts of norbornene derivatives (±)-N 2 , 20 mol% phosphine ligand PPh3, and 4.0 equivalents of K2CO3 to obtain an allene compound with the structure shown in 4a; the relationship between the palladium catalyst and the yield is shown in Table 8.

[0103] Table 8 Investigation of Norbornene Equivalent Amounts

[0104]

[0105]

[0106] a It indicates that the addition amount of iodide 1a in all reactions is 0.1 mmol. b It indicates that the yield was determined by gas chromatography using biphenyl as an internal standard.

[0107] The experimental results in Table 8 show that when the equivalent amount of the norbornene derivative is 1.0, the yield of the target product 4a is the highest. Therefore, 1.0 equivalent of the norbornene derivative was used in subsequent experiments.

[0108] 9. Investigation of bases, base dosages, and reaction concentrations

[0109]

[0110] As shown in Equation ⑨, under argon protection, 1.0 equivalent of aryl iodide 1a, 3.0 equivalents of alkyl bromide 2a, and 1.5 equivalents of electrophile 3a react in acetonitrile (x M, calculated as adding x mL of acetonitrile per 0.1 mmol of asymmetric aryl iodide 1a) at 110 °C in the presence of 10 mol% palladium catalyst Pd(OAc)2, 1.0 equivalent of norbornene derivative (±)-N 2 , 20 mol% phosphine ligand PPh3, and different equivalents of different bases to obtain an allene compound with the structure shown in 4a; the relationship between bases, base dosages, reaction concentrations, and the yield is shown in Table 9.

[0111] Table 9. Investigation of bases, base dosages, and reaction solution concentrations

[0112]

[0113] a It means that the addition amount of iodide 1a in all reactions is 0.1 mmol. b It means that the yield is determined by gas chromatography using biphenyl as the internal standard.

[0114] The experimental results in Table 9 show that when K2CO3 is selected as the base, at 4.0 equivalents and a concentration of 0.2 M, the yield is the highest. Therefore, 4.0 equivalents of K2CO3 are used as the base in subsequent experiments, and the concentration is adjusted to 0.2 M.

[0115] Secondly, the present invention investigates the reaction conditions of ortho-arylation and screens important factors such as palladium catalysts, reaction temperature, reaction time, terminating reagents, and their dosages. The results are as follows:

[0116]

[0117] As shown in Equation ⑩, under argon protection, 2.0 equivalents of aryl iodide 1a, 1.0 equivalent of aryl bromide 5a, and different equivalents of different electrophiles 3a or 3b react in acetonitrile (0.2 M, calculated as adding 0.5 mL of acetonitrile per 0.1 mmol of asymmetric aryl iodide 1a) at different temperatures in the presence of 10 mol% different types of palladium catalysts, 0.5 equivalent of norbornene derivative (±)-N 8 , and 4.0 equivalents of potassium carbonate to obtain an allene compound with the structure shown in 6a; the relationship between different reaction conditions and the yield is shown in Table 10.

[0118] Table 10. Screening of ortho-arylation reaction conditions

[0119]

[0120] a It is indicated that the addition amount of iodide 1a in all reactions is 0.1 mmol. b It is indicated that the yield is determined by gas chromatography using biphenyl as an internal standard. c Isolated yield.

[0121] Based on the results of screening all the above reaction conditions, the optimal conditions for the ortho-arylation reaction in this example can be determined as follows: the equivalent ratio of substrates 1a:2a:3b is 2.0:1.0:1.5, Pd(OAc)2 (10 mol%) is used as a catalyst, N 8 (0.5 equiv) is used as a cocatalyst, potassium carbonate (4.0 equiv) is used as a base, ultra-dry acetonitrile is used as a reaction solvent, the reaction temperature is 120 °C, the reaction concentration is 0.2 M, and the reaction is carried out under an argon atmosphere.

[0122] Finally, the present invention does not investigate the reaction conditions for the ortho-arylation without enantioselectivity, and screens important factors such as reaction temperature, reaction time, termination reagent and its dosage. The results are as follows:

[0123]

[0124]

[0125] As shown in the formula Under argon protection, 2.0 equivalents of aryl iodide 1a, 1.0 equivalent of aryl bromide 5e, different equivalents of different electrophilic reagents 3b or 3c react in acetonitrile (0.2 M, calculated as adding 0.5 mL of acetonitrile per 0.1 mmol of asymmetric aryl iodide 1a) at different temperatures under the action of 10 mol% palladium acetate, 0.5 equivalent of norbornene derivative-3 (>99% e.e.), and 4.0 equivalents of potassium carbonate to obtain an allene compound with the structure shown in 6s; the relationship between different reaction conditions and yields is shown in Table 11.

[0126] Table 11 Screening of reaction conditions for asymmetric ortho-arylation

[0127]

[0128] a It is indicated that the addition amount of iodide 1a in all reactions is 0.1 mmol. b It is indicated that the yield is determined by gas chromatography using biphenyl as an internal standard. c Isolated yield. c It is indicated that the e.e. value is determined by chiral HPLC analysis. d It is indicated that no measurement is made. f Isolated yield.

[0129] Based on the results of screening all the above reaction conditions, the optimal conditions for the asymmetric ortho-arylation reaction can be determined as follows: the equivalent ratio of substrate 1a:5e:3c is 2.0:1.0:3.0, Pd(OAc)2 (10 mol%) is used as the catalyst, N 3 (0.5 equiv, >99% e.e.) is used as the cocatalyst, potassium carbonate (4.0 equiv) is used as the base, ultra-dry acetonitrile is used as the reaction solvent, the reaction temperature is 130 °C, the reaction concentration is 0.2 M, the reaction time is 48 hours, and the reaction is carried out under an argon atmosphere.

[0130] The technical solutions of the present application will be described below with more specific examples.

[0131] Example 1: Preparation of Compound 4a

[0132]

[0133] Under argon protection, Pd(PPh3)2Cl2 (7.1 mg, 0.01 mmol, 10 mol%), potassium carbonate (55.2 mg, 0.4 mmol, 4.0 equiv), (1S,2S,4S)-2-norbornene-5-phenylamide (22.4 mg, 1.0 mmol, 1.0 equiv), 2-iodo-5-fluorotoluene (0.1 mmol, 1.0 equiv), ethyl 4-bromobutyrate (0.3 mmol, 3.0 equiv), (2-methylpent-3-yn-2-yl benzoate) (0.15 mmol, 1.5 equiv) and dry acetonitrile (0.5 mL) were added to a dry reaction tube equipped with a magnetic stir bar. The reaction tube was sealed and then taken out of the glove box and stirred at 110 °C. After the mixture was cooled to room temperature, it was filtered through a short silica gel column and eluted with pure ethyl acetate solvent. The filtrate was combined and concentrated in vacuo. The residue was purified by silica gel column chromatography or directly purified by preparative thin layer chromatography (PTLC) to obtain the desired product 4a (colorless oily liquid, yield = 66%). 1 1H NMR (400 MHz, CDCl3): δ 6.76 (s, 1H), 6.74 (s, 1H), 4.13 (q, J = 7.1 Hz, 2H), 2.67 (t, J = 8.0 Hz 2H), 2.37 (t, J = 7.5 Hz, 2H), 2.32 (s, 3H), 1.95 - 1.87 (m, 2H), 1.83 (s, 3H), 1.68 (s, 6H), 1.26 (t, J = 7.2 Hz, 3H); 1313C NMR (100 MHz, CDCl3): δ 200.4, 173.5, 161.6 (d, J = 243.8 Hz), 141.3 (d, J = 7.4 Hz), 138.2 (d, J = 7.9 Hz), 135.3 (d, J = 2.9 Hz), 114.5 (d, J = 20.7 Hz), 113.0 (d, J = 20.7 Hz), 95.1, 93.8, 60.5, 34.4, 33.0 (d, J = 1.8 Hz), 26.8, 21.5, 20.5, 20.3 (d, J = 1.8 Hz), 14.4; 19 19F NMR (376 MHz, CDCl3): δ -117.3 (t, J = 9.6 Hz); HRMS (ESI-TOF): Calculated for C 19 H 26 FO2 + [M + H] + 305.1911, found 305.1905.

[0134] It should be noted that Pd(PPh3)2Cl2 has the dual functions of a palladium catalyst and a ligand, so there is no need to add an additional ligand.

[0135] Example 2: Preparation of Compound 4b

[0136]

[0137] Under argon protection, Pd(PPh3)2Cl2 (7.1 mg, 0.01 mmol, 10 mol%), potassium carbonate (55.2 mg, 0.4 mmol, 4.0 equiv), (1S,2S,4S)-2-norbornene-5-phenylamide (22.4 mg, 1.0 mmol, 1.0 equiv), 2-iodo-5-fluorotoluene (0.1 mmol, 1.0 equiv), N-bromobutylphthalimide (0.3 mmol, 3.0 equiv), 2-methylpent-3-yn-2-yl benzoate (0.15 mmol, 1.5 equiv) and dry acetonitrile (0.5 mL) were added to a dry reaction tube equipped with a magnetic stir bar. The reaction tube was sealed and then taken out of the glove box and stirred at 110 °C. After cooling the mixture to room temperature, it was filtered through a short silica gel column and eluted with pure ethyl acetate solvent. The filtrate was combined and concentrated in vacuo. The residue was purified by silica gel column chromatography or directly by preparative thin layer chromatography (PTLC) to obtain the desired product 4b (white solid, yield = 82%). 11H NMR (400 MHz, CDCl3): δ 7.86 - 7.81 (m, 2H), 7.74 - 7.67 (m, 2H), 6.74 (s, 1H), 6.71 (s, 1H), 3.72 (t, J = 7.2 Hz, 2H), 2.67 (t, J = 8.0 Hz, 2H), 2.31 (s, 3H), 1.81 (s, 3H), 1.80 - 1.74 (m, 2H), 1.66 (s, 6H), 1.64 - 1.58 (m, 2H); 13 13C NMR (100 MHz, CDCl3): δ 200.4, 168.6, 161.5 (d, J = 243.7 Hz), 141.8 (d, J = 7.4 Hz), 138.1 (d, J = 7.9 Hz), 135.1 (d, J = 3.0 Hz), 134.1, 132.3, 123.4, 114.3 (d, J = 20.8 Hz), 112.9 (d, J = 20.6 Hz), 95.1, 93.7, 38.0, 33.3 (d, J = 1.8 Hz), 28.9, 21.5, 20.5, 20.3 (d, J = 1.7 Hz); 19 19F NMR (376 MHz, CDCl3): δ -117.3 (t, J = 9.6 Hz); HRMS (ESI-TOF): Calculated for C 25 H 27 FNO2 + [M + H] + 392.2020, found 392.2018.

[0138] Example 3: Preparation of Compound 4c

[0139]

[0140]

[0141] Under argon protection, Pd(PPh3)2Cl2 (7.1 mg, 0.01 mmol, 10 mol%), potassium carbonate (55.2 mg, 0.4 mmol, 4.0 equiv), (1S,2S,4S)-2-norbornene-5-phenylamide (22.4 mg, 1.0 mmol, 1.0 equiv), 6-chloro-2-iodotoluene (0.1 mmol, 1.0 equiv), 4-bromobutyronitrile (0.3 mmol, 3.0 equiv), 2-methylpent-3-yn-2-yl benzoate (0.15 mmol, 1.5 equiv) and dry acetonitrile (0.5 mL) were added to a dried reaction tube equipped with a magnetic stir bar. The reaction tube was sealed, then taken out of the glove box and stirred at 110 °C. After the mixture was cooled to room temperature, it was filtered through a short silica gel column, eluted with pure ethyl acetate solvent, and the filtrate was combined and concentrated in vacuo. The residue was purified by silica gel column chromatography or directly purified by preparative thin layer chromatography (PTLC) to obtain the desired product 4c (colorless oily liquid, yield = 62%). 1 1H NMR (400 MHz, CDCl3): δ 7.21 (d, J = 8.2 Hz, 1H), 6.97 (d, J = 8.3 Hz, 1H), 2.78 (t, J = 8.0 Hz, 2H), 2.40 (s, 3H), 2.37 (t, J = 7.2 Hz, 2H), 1.97 - 1.91 (m, 2H), 1.86 (s, 3H), 1.70 (s, 6H); 13 13C NMR (100 MHz, CDCl3): δ 200.1, 141.4, 136.1, 134.3, 133.2, 127.7, 127.5, 119.6, 95.8, 94.7, 32.4, 27.2, 21.6, 20.5, 17.5, 17.1; HRMS (ESI-TOF): calculated value: [M+H] + 274.1357, found value: 274.1355.

[0142] Example 4: Preparation of compound 4d

[0143]

[0144] Under argon protection, Pd(PPh3)2Cl2 (7.1 mg, 0.01 mmol, 10 mol%), potassium carbonate (55.2 mg, 0.4 mmol, 4.0 equiv), (1S,2S,4S)-2-norbornene-5-phenylamide (22.4 mg, 1.0 mmol, 1.0 equiv), 2-iodo-5-fluorotoluene (0.1 mmol, 1.0 equiv), 2-(2-bromoethyl)-1,3-dioxolane (0.3 mmol, 3.0 equiv), 2-methylpent-3-yn-2-yl benzoate (0.15 mmol, 1.5 equiv) and dry acetonitrile (0.5 mL) were added to a dry reaction tube equipped with a magnetic stir bar. The reaction tube was sealed, then taken out of the glove box and stirred at 110 °C. After cooling the mixture to room temperature, it was filtered through a short silica gel column, eluted with pure ethyl acetate solvent, and the combined filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography or directly by preparative thin layer chromatography (PTLC) to give the desired product 4d (colorless oily liquid, yield = 66%). 1 1H NMR (400 MHz, CDCl3): δ 6.79 - 6.76 (m, 1H), 6.75 - 6.73 (m, 1H), 4.93 (t, J = 4.7 Hz, 1H), 4.03 - 3.94 (m, 2H), 3.92 - 3.85 (m, 2H), 2.78 (t, J = 8.0 Hz, 2H), 2.32 (s, 3H), 1.96 - 1.90 (m, 2H), 1.84 (s, 3H), 1.70 (s, 6H); 13 13C NMR (100 MHz, CDCl3): δ 200.4, 161.6 (d, J = 243.6 Hz), 141.4 (d, J = 7.5 Hz), 138.2 (d, J = 7.9 Hz), 135.3 (d, J = 2.9 Hz), 114.4 (d, J = 20.7 Hz), 113.0 (d, J = 20.7 Hz), 104.2, 95.0, 93.9, 65.2, 35.7, 27.9 (d, J = 1.8 Hz), 21.5, 20.5, 20.3 (d, J = 1.7 Hz); 19 19F NMR (376 MHz, CDCl3): δ -117.2 (t, J = 9.6 Hz); HRMS (ESI-TOF): calculated value: C 18 H 24 FO2 + [M + H] + 291.1754, found: 291.1753.

[0145] Example 5: Preparation of compound 4e

[0146]

[0147]

[0148] Under argon protection, Pd(PPh3)2Cl2 (7.1 mg, 0.01 mmol, 10 mol%), potassium carbonate (55.2 mg, 0.4 mmol, 4.0 equiv), (1S,2S,4S)-2-norbornene-5-phenylamide (22.4 mg, 1.0 mmol, 1.0 equiv), 6-chloro-2-iodotoluene (0.1 mmol, 1.0 equiv), 3-bromopropyl quinoline-2-carboxylate (0.3 mmol, 3.0 equiv), benzoic acid 2-methylpent-3-yn-2-yl ester (0.15 mmol, 1.5 equiv) and dry acetonitrile (0.5 mL) were added to a dry reaction tube equipped with a magnetic stir bar. The reaction tube was sealed, then taken out of the glove box and stirred at 110 °C. After the mixture was cooled to room temperature, it was filtered through a short silica gel column, eluted with pure ethyl acetate solvent, and the combined filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography or directly by preparative thin layer chromatography (PTLC) to give the desired product 4e (colorless oily liquid, yield = 50%). 1 1H NMR (400 MHz, CDCl3): δ 8.33 - 8.29 (m, 2H), 8.13 (d, J = 8.6 Hz, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.82 - 7.78 (m, 1H), 7.68 - 7.64 (m, 1H), 7.20 (d, J = 8.2 Hz, 1H), 7.05 (d, J = 8.3 Hz, 1H), 4.55 (t, J = 6.6 Hz, 2H), 2.84 (t, J = 8.0 Hz, 2H), 2.39 (s, 3H), 2.17 - 2.11 (m, 2H), 1.87 (s, 3H), 1.68 (s, 6H); 13 13C NMR (100 MHz, CDCl3): δ 200.1, 165.5, 148.3, 147.9, 141.3, 137.39, 137.36, 133.9, 132.7, 131.0, 130.4, 129.5, 128.8, 127.7, 127.6, 127.5, 121.1, 95.9, 94.6, 66.0, 30.6, 30.0, 21.6, 20.5, 17.6; HRMS (ESI-TOF): Theoretical calcd for C 26 H 27 ClNO2 + [M + H] + 420.1724, found 420.1721.

[0149] Example 6: Preparation of Compound 4f

[0150]

[0151] Under argon protection, Pd(PPh3)2Cl2 (7.1 mg, 0.01 mmol, 10 mol%), potassium carbonate (55.2 mg, 0.4 mmol, 4.0 equiv), (1S,2S,4S)-2-norbornene-5-phenylamide (22.4 mg, 1.0 mmol, 1.0 equiv), 6-chloro-2-iodotoluene (0.1 mmol, 1.0 equiv), bromobutane (0.3 mmol, 3.0 equiv), 2-methylpent-3-yn-2-yl benzoate (0.15 mmol, 1.5 equiv) and dry acetonitrile (0.5 mL) were added to a dry reaction tube equipped with a magnetic stir bar. The reaction tube was sealed, then taken out of the glove box and stirred at 110 °C. After cooling the mixture to room temperature, it was filtered through a short silica gel column and eluted with pure ethyl acetate solvent. The filtrate was combined and concentrated in vacuo. The residue was purified by silica gel column chromatography or directly purified by preparative thin layer chromatography (PTLC) to obtain the desired product 4f (colorless oily liquid, yield = 53%). 1 1H NMR (400 MHz, CDCl3): δ 7.17 (d, J = 8.3 Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H), 2.60 (t, J = 8.0 Hz, 2H), 2.39 (s, 3H), 1.85 (s, 3H), 1.69 (s, 6H), 1.58 - 1.49 (m, 2H), 1.45 - 1.35 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H); 13 13C NMR (100 MHz, CDCl3): δ 200.1, 141.1, 139.1, 133.6, 132.2, 127.6, 127.4, 96.0, 94.3, 34.3, 33.4, 23.2, 21.6, 20.5, 17.5, 14.2; HRMS (ESI-TOF): Theoretical calculated value: C 17 H 24 Cl1 + [M + H] + 263.1561, found: 263.1563.

[0152] Example 7: Preparation of Compound 4g

[0153]

[0154] Under argon protection, Pd(PPh3)2Cl2 (7.1 mg, 0.01 mmol, 10 mol%), potassium carbonate (55.2 mg, 0.4 mmol, 4.0 equiv), (1S,2S,4S)-2-norbornene-5-phenylamide (22.4 mg, 1.0 mmol, 1.0 equiv), o-iodotoluene (0.1 mmol, 1.0 equiv), N-bromobutylphthalimide (0.3 mmol, 3.0 equiv), 2-methylpent-3-yn-2-yl benzoate (0.15 mmol, 1.5 equiv) and dry acetonitrile (0.5 mL) were added to a dry reaction tube equipped with a magnetic stir bar. The reaction tube was sealed, then taken out of the glove box and stirred at 110 °C. After the mixture was cooled to room temperature, it was filtered through a short silica gel column, eluted with pure ethyl acetate solvent, and the filtrate was combined and concentrated in vacuo. The residue was purified by silica gel column chromatography or directly purified by preparative thin layer chromatography (PTLC) to obtain the desired product 4 g (white solid, yield = 75%). 1 1H NMR (400 MHz, CDCl3): δ 7.86 - 7.81 (m, 2H), 7.73 - 7.68 (m, 2H), 7.09 - 7.01 (m, 3H), 3.72 (t, J = 7.2 Hz, 2H), 2.69 (t, J = 8.0 Hz, 2H), 2.33 (s, 3H), 1.85 (s, 3H), 1.81 - 1.76 (m, 2H), 1.66 (s, 6H), 1.64 - 1.59 (m, 2H); 13 13C NMR (100 MHz, CDCl3): δ 200.0, 168.6, 139.6, 139.3, 135.8, 134.0, 132.3, 127.8, 126.8, 126.6, 123.3, 95.7, 93.6, 38.1, 33.3, 29.3, 29.0, 21.5, 20.5, 20.2; HRMS (ESI-TOF): Theoretical calculated value: C 25 H 28 NO2 + [M + H] + 374.2114, found: 374.2109.

[0155] Example 8: Preparation of Compound 4h

[0156]

[0157] Under argon protection, Pd(PPh3)2Cl2 (7.1 mg, 0.01 mmol, 10 mol%), potassium carbonate (55.2 mg, 0.4 mmol, 4.0 equiv), (1S,2S,4S)-2-norbornene-5-phenylamide (22.4 mg, 1.0 mmol, 1.0 equiv), methyl 2-(2-iodophenyl)acetate (0.1 mmol, 1.0 equiv), N-bromobutylphthalimide (0.3 mmol, 3.0 equiv), 2-methylpent-3-yn-2-yl benzoate (0.15 mmol, 1.5 equiv) and dry acetonitrile (0.5 mL) were added to a dry reaction tube equipped with a magnetic stir bar. The reaction tube was sealed, then taken out of the glove box and stirred at 110 °C. After the mixture was cooled to room temperature, it was filtered through a short silica gel column and eluted with pure ethyl acetate solvent. The filtrate was combined and concentrated in vacuo. The residue was purified by silica gel column chromatography or directly purified by preparative thin layer chromatography (PTLC) to obtain the desired product 4h (colorless oily liquid, yield = 51%). 1 1H NMR (400 MHz, CDCl3): δ 7.86 - 7.81 (m, 2H), 7.73 - 7.68 (m, 2H), 7.17 - 7.11 (m, 3H), 3.72 (t, J = 7.2 Hz, 4H), 3.68 (s, 3H), 2.69 (t, J = 8.0 Hz, 2H), 1.84 (s, 3H), 1.80 - 1.75 (m, 2H), 1.65 (s, 6H), 1.63 - 1.57 (m, 2H); 13 13C NMR (100 MHz, CDCl3): δ 200.4, 172.7, 168.6, 140.1, 139.5, 134.1, 132.3, 132.1, 128.2, 127.9, 127.1, 123.4, 95.2, 94.1, 52.1, 39.0, 38.1, 33.3, 29.2, 29.0, 22.1, 20.4; HRMS (ESI-TOF): Theoretical calcd for C 27 H 30 NO4 + [M + H] + 432.2169, found 432.2168.

[0158] Example 9: Preparation of Compound 4i

[0159]

[0160] Under argon protection, Pd(PPh3)2Cl2 (7.1 mg, 0.01 mmol, 10 mol%), potassium carbonate (55.2 mg, 0.4 mmol, 4.0 equiv), (1S,2S,4S)-2-norbornene-5-phenylamide (22.4 mg, 1.0 mmol, 1.0 equiv), tert-butyl ((2-iodobenzyl)oxy)dimethylsilane (0.1 mmol, 1.0 equiv), N-bromobutylphthalimide (0.3 mmol, 3.0 equiv), 2-methylpent-3-yn-2-yl benzoate (0.15 mmol, 1.5 equiv) and dry acetonitrile (0.5 mL) were added to a dry reaction tube equipped with a magnetic stir bar. The reaction tube was sealed, then taken out of the glove box and stirred at 110 °C. After cooling the mixture to room temperature, it was filtered through a short silica gel column, eluted with pure ethyl acetate solvent, and the combined filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography or directly purified by preparative thin layer chromatography (PTLC) to give the desired product 4i (colorless oily liquid, yield = 40%). 1 1H NMR (400 MHz, CDCl3): δ 7.85 - 7.81 (m, 2H), 7.72 - 7.69 (m, 2H), 7.39 (d, J = 7.6 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.09 (d, J = 9.0 Hz, 1H), 4.77 (s, 2H), 3.72 (t, J = 7.2 Hz, 2H), 2.68 (t, 2H), 1.8 (s, 3H), 1.80 - 1.74 (m, 2H), 1.65 (s, 6H), 1.63 - 1.61 (m, 2H), 0.96 (s, 9H), 0.11 (s, 6H); 13 13C NMR (100 MHz, CDCl3): δ 200.0, 168.6, 139.1, 138.8, 136.5, 134.0, 132.4, 127.5, 127.0, 123.8, 123.3, 94.5, 93.8, 63.1, 38.1, 32.8, 29.3, 29.0, 26.2, , 20.5, 18.6, -5.1; HRMS (ESI-TOF): Calculated value: C 21 H 42 NO3Si + [M + H] + 504.2928, found: 504.2922.

[0161] Example 10: Preparation of Compound 4j

[0162]

[0163] Under argon protection, Pd(PPh3)2Cl2 (7.1 mg, 0.01 mmol, 10 mol%), potassium carbonate (55.2 mg, 0.4 mmol, 4.0 equiv), (1S,2S,4S)-2-norbornene-5-phenylamide (22.4 mg, 1.0 mmol, 1.0 equiv), 6-chloro-3-iodo-2-methylpyridine (0.1 mmol, 1.0 equiv), N-bromobutylphthalimide (0.3 mmol, 3.0 equiv), 2-methylpent-3-yn-2-yl benzoate (0.15 mmol, 1.5 equiv) and dry acetonitrile (0.5 mL) were added to a dry reaction tube equipped with a magnetic stir bar. The reaction tube was sealed, then taken out of the glove box and stirred at 110 °C. After the mixture was cooled to room temperature, it was filtered through a short silica gel column, eluted with pure ethyl acetate solvent, and the filtrate was combined and concentrated in vacuo. The residue was purified by silica gel column chromatography or directly purified by preparative thin layer chromatography (PTLC) to give the desired product 4j (colorless oily liquid, yield = 39%). 1 1H NMR (400 MHz, CDCl3): δ 7.87 - 7.82 (m, 2H), 7.74 - 7.70 (m, 2H), 6.98 (s, 1H), 3.72 (t, J = 7.1 Hz, 2H), 2.64 (t, J = 8.0 Hz, 2H), 2.51 (s, 3H), 1.83 (s, 3H), 1.83 - 1.73 (m, 2H), 1.66 (s, 6H), 1.64 - 1.61 (m, 2H); 13 13C NMR (100 MHz, CDCl3): δ 200.6, 168.6, 157.1, 151.9, 148.5, 134.2, 133.5, 132.3, 123.4, 121.5, 95.1, 93.4, 37.8, 32.6, 28.8, 27.9, 22.7, 21.0, 20.3; HRMS (ESI-TOF): Calculated value: C 24 H 26 ClN2O2 + [M + H] + 409.1677, Found: 409.1672.

[0164] Example 11: Preparation of compound 4k

[0165]

[0166] Under argon protection, Pd(PPh3)2Cl2 (7.1 mg, 0.01 mmol, 10 mol%), potassium carbonate (55.2 mg, 0.4 mmol, 4.0 equiv), (1S,2S,4S)-2-norbornene-5-phenylamide (22.4 mg, 1.0 mmol, 1.0 equiv), 2-iodo-6-chlorotoluene (0.1 mmol, 1.0 equiv), N-bromobutylphthalimide (0.3 mmol, 3.0 equiv), (0.15 mmol, 1.5 equiv) and dry acetonitrile (0.5 mL) were added to a dry reaction tube equipped with a magnetic stir bar. The reaction tube was sealed, then taken out of the glove box and stirred at 110 °C. After cooling the mixture to room temperature, it was filtered through a short silica gel column, eluted with pure ethyl acetate solvent, and the combined filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography or directly purified by preparative thin layer chromatography (PTLC) to obtain the desired product 4k (white solid, yield = 72%). 1 1H NMR (400 MHz, CDCl3): δ 7.89 - 7.78 (m, 2H), 7.75 - 7.67 (m, 2H), 7.19 (d, J = 8.3 Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H), 3.92 (s, 2H), 3.70 (t, J = 7.2 Hz, 2H), 3.36 (s, 3H), 2.71 - 2.63 (m, 2H), 2.38 (s, 3H), 1.79 - 1.74 (m, 2H), 1.73 (s, 6H); 13 13C NMR (100 MHz, CDCl3): δ 200.0, 168.6, 139.3, 137.7, 134.7, 134.1, 132.5, 132.3, 128.1, 127.6, 123.4, 98.4, 97.0, 74.6, 58.8, 38.0, 33.2, 29.1, 28.9, 20.3, 17.9; HRMS (ESI-TOF): calculated value: C 26 H 29 ClNO3 + [M + H] + 438.1830, found: 438.1828.

[0167] Example 12: Preparation of Compound 4l

[0168]

[0169] Under argon protection, Pd(PPh3)2Cl2 (7.1 mg, 0.01 mmol, 10 mol%), potassium carbonate (55.2 mg, 0.4 mmol, 4.0 equiv), (1S,2S,4S)-2-norbornene-5-phenylamide (22.4 mg, 1.0 mmol, 1.0 equiv), 2-iodo-6-chlorotoluene (0.1 mmol, 1.0 equiv), N-bromobutylphthalimide (0.3 mmol, 3.0 equiv), (0.15 mmol, 1.5 equiv) and dry acetonitrile (0.5 mL) were added to a dry reaction tube equipped with a magnetic stir bar. The reaction tube was sealed, then taken out of the glove box and stirred at 110 °C. After cooling the mixture to room temperature, it was filtered through a short silica gel column, eluted with pure ethyl acetate solvent, and the combined filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography or directly purified by preparative thin layer chromatography (PTLC) to obtain the desired product 4l (colorless oily liquid, yield = 37%). 1 1H NMR (400 MHz, CDCl3): δ 7.86 - 7.81 (m, 2H), 7.73 - 7.68 (m, 2H), 7.34 - 7.32 (m, 2H), 7.32 - 7.29 (m, 2H), 7.25 - 7.21 (m, 1H), 7.17 (d, J = 8.2 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 4.50 (s, 2H), 3.68 (t, J = 7.2 Hz, 2H), 3.62 (t, J = 6.7 Hz, 2H), 2.73 - 2.55 (m, 2H), 2.39 - 2.37 (m, 2H), 2.36 (s, 3H), 1.75 - 1.69 (m, 2H), 1.68 (s, 3H), 1.66 (s, 3H), 1.59 - 1.51 (m, 2H); 13 13C NMR (100 MHz, CDCl3): δ 199.6, 168.5, 140.1, 138.7, 138.6, 134.08, 134.06, 132.5, 132.3, 128.5, 127.72, 127.69, 127.6, 123.5, 123.3, 97.8, 96.6, 73.2, 68.7, 38.0, 34.7, 33.1, 29.1, 28.9, 20.5, 20.3, 17.7; HRMS (ESI-TOF): Theoretical calculated value: C 33 H 35 ClNO3 + [M + H] + 528.2299, found: 528.2283.

[0170] Example 13: Preparation of Compound 4m

[0171]

[0172] Under argon protection, Pd(PPh3)2Cl2 (7.1 mg, 0.01 mmol, 10 mol%), potassium carbonate (55.2 mg, 0.4 mmol, 4.0 equiv), (1S,2S,4S)-2-norbornene-5-phenylamide (22.4 mg, 1.0 mmol, 1.0 equiv), 2-iodo-6-chlorotoluene (0.1 mmol, 1.0 equiv), N-bromobutylphthalimide (0.3 mmol, 3. equiv), (0.15 mmol, 1.5 equiv) and dry acetonitrile (0.5 mL) were added to a dry reaction tube equipped with a magnetic stir bar. The reaction tube was sealed, then taken out of the glove box and stirred at 110 °C. After cooling the mixture to room temperature, it was filtered through a short silica gel column, eluted with pure ethyl acetate solvent, and the combined filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography or directly purified by preparative thin layer chromatography (PTLC) to obtain the desired product 4m (colorless oily liquid, yield = 60%). 1 1H NMR (400 MHz, CDCl3): δ 7.84 - 7.81 (m, 2H), 7.73 - 7.68 (m, 2H), 7.16 (d, J = 8.2 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 3.70 (t, J = 7.2 Hz, 2H), 3.62 (t, J = 6.0 Hz, 2H), 2.68 - 2.54 (m, 2H), 2.34 (s, 3H), 2.00 (t, J = 8.0 Hz, 2H), 1.79 - 1.71 (m, 2H), 1.69 (s, 3H), 1.66 (s, 3H), 1.60 - 1.49 (m, 6H), 0.89 (s, 9H), 0.04 (s, 6H); 13 13C NMR (100 MHz, CDCl3): δ 199.3, 168.6, 140.8, 138.4, 134.1, 133.9, 132.5, 132.3, 127.54, 127.51, 123.3, 101.2, 96.6, 63.3, 38.0, 34.4, 33.2, 32.7, 29.2, 28.9, 26.1, 24.1, 20.5, 20.4, 18.6, 17.7, -5.1; HRMS (ESI-TOF): Theoretical calcd for C 34 H 47 ClNO3Si + [M + H] + 580.3008, found 580.2984.

[0173] Example 14: Preparation of Compound 4n

[0174]

[0175] Under argon protection, Pd(PPh3)2Cl2 (7.1 mg, 0.01 mmol, 10 mol%), potassium carbonate (55.2 mg, 0.4 mmol, 4.0 equiv), (1S,2S,4S)-2-norbornene-5-phenylamide (22.4 mg, 1.0 mmol, 1.0 equiv), 2-iodo-6-chlorotoluene (0.1 mmol, 1.0 equiv), N-bromobutylphthalimide (0.3 mmol, 3.0 equiv), 1-(pent-1-yn-1-yl)cyclobutyl benzoate (0.15 mmol, 1.5 equiv) and dry acetonitrile (0.5 mL) were added to a dry reaction tube equipped with a magnetic stir bar. The reaction tube was sealed, then taken out of the glove box and stirred at 110 °C. After cooling the mixture to room temperature, it was filtered through a short silica gel column, eluted with pure ethyl acetate solvent, and the filtrate was combined and concentrated in vacuo. The residue was purified by silica gel column chromatography or directly purified by preparative thin layer chromatography (PTLC) to obtain the desired product 4n (colorless oily liquid, yield = 66%). 1 H NMR (400 MHz, CDCl3): δ 7.84 - 7.82 (m, 2H), 7.71 - 7.69 (m, 2H), 7.16 (d, J = 8.2 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 3.69 (t, J = 8.0 Hz, 2H), 2.94 - 2.86 (m, 2H), 2.83 - 2.73 (m, 2H), 2.64 - 2.50 (m, 2H), 2.31 (s, 3H), 2.01 (td, J = 7.3, 2.6 Hz, 2H), 1.96 - 1.80 (m, 2H), 1.75 - 1.67 (m, 2H), 1.62 - 1.54 (m, 2H), 1.54 - 1.48 (m, 2H), 0.97 (t, J = 7.3 Hz, 3H); 13 C NMR (100 MHz, CDCl3): δ 193.5, 168.6, 140.9, 138.4, 134.0, 133.8, 132.5, 132.3, 127.7, 127.5, 123.3, 105.3, 102.2, 38.0, 36.9, 33.3, 30.0, 29.8, 29.2, 28.8, 20.9, 17.7, 17.7, 14.1; HRMS (ESI-TOF): Theoretical calculated value: C 28 H 31 ClNO2 + [M + H] +448.2037, Measured value: 448.2021.

[0176] Example 15: Preparation of Compound 4o

[0177]

[0178] Under argon protection, Pd(PPh3)2Cl2 (7.1 mg, 0.01 mmol, 10 mol%), potassium carbonate (55.2 mg, 0.4 mmol, 4.0 equiv), (1S,2S,4S)-2-norbornene-5-phenylamide (22.4 mg, 1.0 mmol, 1.0 equiv), 2-iodo-6-chlorotoluene (0.1 mmol, 1.0 equiv), N-bromobutylphthalimide (0.3 mmol, 3.0 equiv), 3-(pent-1-yn-1-yl)oxetane-3-yl benzoate (0.15 mmol, 1.5 equiv) and dry acetonitrile (0.5 mL) were added to a dry reaction tube equipped with a magnetic stir bar. The reaction tube was sealed, then taken out of the glove box and stirred at 110 °C. After cooling the mixture to room temperature, it was filtered through a short silica gel column and eluted with pure ethyl acetate solvent. The filtrate was combined and concentrated in vacuo. The residue was purified by silica gel column chromatography or directly by preparative thin layer chromatography (PTLC) to obtain the desired product 4o (colorless oily liquid, yield = 66%). 1 H NMR (400 MHz, CDCl3): δ 7.86 - 7.82 (m, 2H), 7.74 - 7.69 (m, 2H), 7.20 (d, J = 8.2 Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H), 5.39 - 5.36 (m, 2H), 5.30 - 5.25 (m, 2H), 3.68 (t, J = 7.2 Hz, 2H), 2.54 (t, J = 7.8 Hz, 2H), 2.27 (s, 3H), 2.10 - 2.06 (m, 2H), 1.74 - 1.65 (m, 2H), 1.62 - 1.49 (m, 4H), 0.98 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, CDCl3): δ 188.9, 168.6, 139.4, 138.0, 134.1, 133.5, 132.7, 132.3, 128.1, 127.8, 123.4, 110.5, 98.9, 77.7, 77.6, 37.9, 36.8, 33.0, 29.0, 28.7, 20.8, 17.7, 14.0; HRMS (ESI-TOF): Theoretical calculated value: C 27 H 29 ClNO3 + [M + H] +450.1830, Measured value: 450.1818.

[0179] Example 16: Preparation of Compound 4p

[0180]

[0181] Under argon protection, Pd(PPh3)2Cl2 (7.1 mg, 0.01 mmol, 10 mol%), potassium carbonate (55.2 mg, 0.4 mmol, 4.0 equiv), (1S,2S,4S)-2-norbornene-5-phenylamide (22.4 mg, 1.0 mmol, 1.0 equiv), methyl 4-iodo-3-methylbenzoate (0.1 mmol, 1.0 equiv), N-bromobutylphthalimide (0.3 mmol, 3.0 equiv), 2-methylpent-3-yn-2-yl benzoate (0.15 mmol, 1.5 equiv) and dry acetonitrile (0.5 mL) were added to a dry reaction tube equipped with a magnetic stir bar. The reaction tube was sealed, then taken out of the glove box and stirred at 110 °C. After cooling the mixture to room temperature, it was filtered through a short silica gel column, eluted with pure ethyl acetate solvent, and the filtrate was combined and concentrated in vacuo. The residue was purified by silica gel column chromatography or directly purified by preparative thin layer chromatography (PTLC) to obtain the desired product 4p (colorless oily liquid, yield = 30%). 1 H NMR (400 MHz, CDCl3): δ 7.85 - 7.83 (m, 2H), 7.72 - 7.70 (m, 4H), 5.05 - 5.01 (m, 1H), 3.88 (s, 3H), 3.71 (t, J = 7.1 Hz, 2H), 2.70 (t, J = 8. .0 Hz, 2H), 2.34 (s, 3H), 1.87 (d, J = 3.0 Hz, 3H), 1.80 - 1.73 (m, 2H), 1.68 - 1.63 (m, 2H), 1.61 (d, J = 7.0 Hz, 3H); 13 C NMR (100 MHz, CDCl3): δ 202.5, 168.6, 167.5, 143.6, 140.1, 136.4, 134.1, 132.3, 129.0, 128.6, 128.0, 123.4, 97.0, 85.1, 52.2, 38.1, 33.4, 29.1, 28.9, 20.8, 20.1, 14.3; HRMS (ESI-TOF): Calculated value: C 26 H 28 NO4 + [M + H] + 418.2012, Measured value: 418.2015.

[0182] Example 17: Preparation of Compound 4q

[0183]

[0184] Under argon protection, Pd(PPh3)2Cl2 (7.1 mg, 0.01 mmol, 10 mol%), potassium carbonate (55.2 mg, 0.4 mmol, 4.0 equiv), (1S,2S,4S)-2-norbornene-5-phenylamide (22.4 mg, 1.0 mmol, 1.0 equiv), 2-iodo-6-chlorotoluene (0.1 mmol, 1.0 equiv), N-bromobutylphthalimide (0.3 mmol, 3.0 equiv), 3-methylhex-4-yn-3-yl benzoate (0.15 mmol, 1.5 equiv) and dry acetonitrile (0.5 mL) were added to a dry reaction tube equipped with a magnetic stir bar. The reaction tube was sealed, then taken out of the glove box and stirred at 110 °C. After the mixture was cooled to room temperature, it was filtered through a short silica gel column, eluted with pure ethyl acetate solvent, and the filtrate was combined and concentrated in vacuo. The residue was purified by silica gel column chromatography or directly by preparative thin layer chromatography (PTLC) to obtain the desired product 4q (white solid, yield = 75%). 1 1H NMR (400 MHz, CDCl3): δ 7.85 - 7.83 (m, 2H), 7.72 - 7.70 (m, 2H), 7.16 (d, J = 8.2 Hz, 1H), 6.97 (d, J = 8.3 Hz, 1H), 3.72 (t, J = 7.2 Hz, 2H), 2.67 (t, J = 8.0 Hz, 2H), 2.39 (s, 3H), 1.98 - 1.92 (m, 2H), 1.84 (s, 3H), 1.78 - 1.73 (m, 2H), 1.67 (s, 3H), 1.62 - 1.59 (m, 3H), 1.02 (t, J = 7.4 Hz, 3H); 13 13C NMR (100 MHz, CDCl3): δ 199.4, 168.6, 141.2, 138.2, 134.1, 133.7, 132.5, 132.3, 127.5, 123.4, 100.7, 97.7, 38.0, 33.1, 29.02, 28.97, 27.7, 22.0, 19.0, 17.8, 12.8; HRMS (ESI-TOF): calculated value: C 26 H 29 ClNO2 + [M + H] + 422.1881, found: 422.1870.

[0185] Example 18: Preparation of Compound 4r

[0186]

[0187] Under argon, to a dry reaction tube equipped with a magnetic stirrer was added Pd(PPh3)2Cl2 (7.1 mg, 0.01 mmol, 10 mol%), potassium carbonate (55.2 mg, 0.4 mmol, 4.0 equiv), (1S,2S,4S,)-2-norbornene-5-phenylamide (22.4 mg, 1.0 mmol, 1.0 equiv), iodonaphthalene (0.1 mmol, 1.0 equiv), N-bromobutylphthalimide (0.3 mmol, 3.0 equiv), 2-methylpent-3-yn-2-benzoate (0.15 mmol, 1.5 equiv), and dry acetonitrile (0.5 mL). The reaction tube was sealed, removed from the glove box, and stirred at 110°C. After cooling to room temperature, the mixture was filtered through a short silica gel column, eluting with pure ethyl acetate. The combined filtrates were concentrated in vacuo. The residue was purified by silica gel column chromatography or directly purified by preparative thin layer chromatography (PTLC) to give the desired product 4r (white oily liquid, yield = 64%). 1 H NMR (400MHz, CDCl3): δ8.07(d,J=9.2Hz,1H),7.86-7.81(m,2H),7.78(d,J=8.0Hz,1H),7.72-7.67(m,3H),7.49-7.45(m,1H),7.42-7.39 (m,1H),7.35(d,J=8.4Hz,1H),3.75(t,J=7.1Hz,2H),2.90-2.85(m,2H),1.99(s,3H),1.87-1.80(m,2H),1.75-1.73(m,2H),1.70(s,6H); 13 C NMR (100 MHz, CDCl3): δ 201.0, 168.6, 136.3, 136.1, 134.0, 132.5, 132.3, 131.8, 128.2, 127.8, 127.1, 126.0, 125.9, 125.0, 123.3, 94.8, 93.9, 38.1, 33.7, 29.3, 29.1, 22.4, 20.7; HRMS (ESI-TOF): theoretical calculated value: C 28 H 28 N1O2 + [M+H] + 410.2114, measured value: 410.2107.

[0188] Example 19: Preparation of Compound 4s

[0189]

[0190] Under argon protection, Pd(PPh3)2Cl2 (7.1 mg, 0.01 mmol, 10 mol%), potassium carbonate (55.2 mg, 0.4 mmol, 4.0 equiv), (1S,2S,4S)-2-norbornene-5-phenylamide (22.4 mg, 1.0 mmol, 1.0 equiv), 2-iodo-6-chlorotoluene (0.1 mmol, 1.0 equiv), N-bromobutylphthalimide (0.3 mmol, 3.0 equiv), 1-(4-methoxyphenyl)-3-methylpent-1-yn-3-yl benzoate (0.15 mmol, 1.5 equiv) and dry acetonitrile (0.5 mL) were added to a dry reaction tube equipped with a magnetic stir bar. The reaction tube was sealed, then taken out of the glove box and stirred at 110 °C. After the mixture was cooled to room temperature, it was filtered through a short silica gel column, eluted with pure ethyl acetate solvent, and the filtrate was combined and concentrated in vacuo. The residue was purified by silica gel column chromatography or directly purified by preparative thin layer chromatography (PTLC) to give the desired product 4s (colorless oily liquid, yield = 63%). 1 1H NMR (400 MHz, CDCl3): δ 7.83 - 7.80 (m, 2H), 7.71 - 7.68 (m, 2H), 7.27 - 7.26 (m, 2H), 7.05 (dd, J = 8.3, 4.5 Hz, 1H), 7.00 - 6.98 (m, 2H), 6.78 - 6.76 (m, 2H), 3.76 (s, 3H), 3.62 - 3.56 (m, 2H), 2.65 - 2.54 (m, 2H), 2.30 (s, 1.3H), 2.25 (s, 1.7H), 2.14 - 2.09 (m, 2H), 1.80 (s, 3H), 1.65 - 1.57 (m, 3H), 1.54 - 1.41 (m, 2H), 1.10 (dt, J = 11.6, 7.4 Hz, 3H); 1HNMR(400MHz, DMSO): δ 7.87 - 7.80 (m, 4H), 7.34 (dd, J = 8.3, 1.6 Hz, 1H), 7.17 (dd, J = 8.4, 1.6 Hz, 1H), 6.90 - 6.88 (m, 2H), 6.84 - 6.80 (m, 2H), 3.68 (s, 1.3H), 3.68 (s, 1.7H), 3.53 - 3.43 (m, 2H), 2.60 - 2.42 (m, 2H), 2.20 (s, 1.3H), 2.15 (s, 1.7H), 2.11 - 1.99 (m, 2H), 1.76 (s, 1.3H), 1.72 (s, 1.7H), 1.58 - 1.45 (m, 2H), 1.45 - 1.38 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H); 1 H NMR(400MHz, DMSO, 80 °C): δ 7.82 (s, 4H), 7.32 (d, J = 8.3 Hz, 1H), 7.16 (d, J = 8.2 Hz, 1H), 6.92 (d, J = 8.7 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 3.71 (s, 3H), 3.49 (d, J = 7.3 Hz, 2H), 2.63 - 2.51 (m, 2H), 2.21 (s, 3H), 2.16 - 2.04 (m, 2H), 1.78 (s, 3H), 1.64 - 1.51 (m, 2H), 1.50 - 1.37 (m, 2H), 1.05 (t, J = 7.4 Hz, 3H); 13 C NMR(150MHz, CDCl3) δ 200.0, 199.9, 168.52, 168.51, 158.62, 158.59, 139.7, 139.6, 138.2, 138.1, 135.25, 135.21, 134.0, 132.7, 132.5, 132.3, 129.9, 128.12, 128.07, 127.8, 127.6, 127.2, 127.1, 123.3, 114.1, 105.2, 104.9, 104.6, 55.4, 38.0, 33.3, 33.1, 28.8, 28.5, 28.4, 27.94, 27.87, 18.7, 18.3, 18.0, 13.0, 12.9; HRMS(ESI - TOF): Theoretical calculated value: C 32 H 33 ClNO3 + [M + H] +514.2143, Measured value: 514.2145. HPLC conditions: Daicel Chiralpak AD-H chromatographic column, mobile phase is a mixture of isopropanol and n-hexane (v / v = 3:97), 1 mL / min, λ = 254 nm, t R (major) = 7.46 min, t R (minor) = 7.99 min.

[0191] Example 20: Preparation of Compound 4t

[0192]

[0193] Under argon protection, Pd(OAc)2 (2.2 mg, 0.01 mmol, 10 mol%), potassium carbonate (55.2 mg, 0.4 mmol, 4.0 equiv), (1S,4R)-ethyl bicyclo[2.2.1]hept-5-ene-2-carboxylate (e.e. > 99%, 8.3 mg, 0.05 mmol, 0.5 equiv), methyl 3-iodo-2-methylbenzoate (0.2 mmol, 2.0 equiv), methyl 2-bromo-3-methylbenzoate (0.1 mmol, 1.0 equiv), 2-methylpent-3-yn-2-yl benzoate (0.3 mmol, 3.0 equiv) and dry acetonitrile (0.5 mL) were added to a dry reaction tube equipped with a magnetic stir bar. The reaction tube was sealed and then taken out of the glove box and stirred at 120 °C. After the mixture was cooled to room temperature, it was filtered through a short silica gel column and eluted with pure ethyl acetate solvent. The filtrate was combined and concentrated in vacuo. The residue was purified by silica gel column chromatography or directly purified by preparative thin layer chromatography (PTLC) to obtain the desired product 4t (colorless oily liquid, yield = 69%, e.e. > 99%). 1 1H NMR (400 MHz, CDCl3): δ 7.87 (d, J = 7.8 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 7.5 Hz, 1H), 7.31 (t, J = 7.7 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 3.90 (s, 3H), 3.58 (s, 3H), 2.62 (s, 3H), 1.94 (s, 3H), 1.57 (s, 3H), 1.53 (s, 3H), 1.29 (s, 3H); 13CNMR (100 MHz, CDCl₃): δ 199.8, 169.0, 167.5, 143.7, 142.9, 139.1, 138.1, 137.8, 134.0, 129.7, 129.3, 128.5, 128.0, 127.2, 126.4, 96.0, 94.0, 52.0, 51.8, 21.1, 20.9, 20.2, 20.1, 18.3; HRMS (ESI-TOF): Calculated: C 24 H 26 NaO₄ [M+Na] + 401.1723 Found: 401.1722. HPLC conditions: Daicel Chiralpak AD-H column, mobile phase: isopropanol - n-hexane mixture (v / v = 2:98), 1 mL / min, λ = 254 nm, t R (major) = 4.71 min.

[0194] Example 21: Preparation of Compound 4u

[0195]

[0196] Under argon protection, Pd(OAc)₂ (2.2 mg, 0.01 mmol, 10 mol%), potassium carbonate (55.2 mg, 0.4 mmol, 4.0 equiv), (1S,4R)-ethyl bicyclo[2.2.1]hept-5-ene-2-carboxylate (e.e. >99%, 8.3 mg, 0.05 mmol, 0.5 equiv), 2-iodo-6-chlorotoluene (0.2 mmol, 2.0 equiv), methyl 2-bromo-3-methylbenzoate (0.1 mmol, 1.0 equiv), 2-methylpent-3-yn-2-yl benzoate (0.3 mmol, 3.0 equiv) and dry acetonitrile (0.5 mL) were added to a dry reaction tube equipped with a magnetic stir bar. The reaction tube was sealed and then taken out of the glove box and stirred at 120 °C. After cooling the mixture to room temperature, it was filtered through a short silica gel column and eluted with pure ethyl acetate solvent. The filtrate was combined and concentrated in vacuo. The residue was purified by silica gel column chromatography or directly by preparative thin layer chromatography (PTLC) to give the desired product 4u (colorless oily liquid, yield = 71%, e.e. >99%). 11H NMR (400 MHz, CDCl3): δ 7.85 (d, J = 6.4 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.32 - 7.28 (m, 2H), 6.84 (d, J = 8.2 Hz, 1H), 3.61 (s, 3H), 2.44 (s, 3H), 1.96 (s, 3H), 1.56 (s, 3H), 1.54 (s, 3H), 1.30 (s, 3H); 13 13C NMR (100 MHz, CDCl3): δ 199.8, 167.7, 142.7, 139.3, 138.5, 138.2, 134.0, 133.9, 133.8, 129.7, 128.0, 127.5, 127.3, 127.2, 96.3, 94.1, 51.9, 21.1, 20.8, 20.3, 20.2, 17.9; HRMS (ESI-TOF): Calculated: C 23 H 23 ClNaO2 [M + Na] + 377.1279, Found: 377.1277. HPLC conditions: Daicel Chiralpak AD-H column, mobile phase: isopropanol - n-hexane mixture (v / v = 1:99), 1 mL / min, λ = 210 nm, t R (major) = 7.91 min.

[0197] Example 22: Preparation of Compound 4v

[0198]

[0199] Under argon protection, Pd(OAc)2 (2.2 mg, 0.01 mmol, 10 mol%), potassium carbonate (55.2 mg, 0.4 mmol, 4.0 equiv), (1S,4R)-ethyl bicyclo[2.2.1]hept-5-ene-2-carboxylate (e.e. >99%, 8.3 mg, 0.05 mmol, 0.5 equiv), 2-iodo-5-bromotoluene (0.2 mmol, 2.0 equiv), methyl 2-bromo-3-methylbenzoate (0.1 mmol, 1.0 equiv), 2-methylpent-3-yn-2-yl benzoate (0.3 mmol, 3.0 equiv) and dry acetonitrile (0.5 mL) were added to a dry reaction tube equipped with a magnetic stir bar. The reaction tube was sealed, then taken out of the glove box and stirred at 120 °C. After the mixture was cooled to room temperature, it was filtered through a short silica gel column, eluted with pure ethyl acetate solvent, and the filtrate was combined and concentrated in vacuo. The residue was purified by silica gel column chromatography or directly purified by preparative thin layer chromatography (PTLC) to give the desired product 4v (colorless oily liquid, yield = 41%, e.e. >99%). 1 1H NMR (400 MHz, CDCl3): δ 7.86 (d, J = 7.8 Hz, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.35 (d, J = 2.2 Hz, 1H), 7.31 (t, J = 7.7 Hz, 1H), 7.05 (d, J = 2.1 Hz, 1H), 3.62 (s, 3H), 2.36 (s, 3H), 2.00 (s, 3H), 1.54 (s, 6H), 1.33 (s, 3H); 13 13C NMR (100 MHz, CDCl3): δ 199.9, 167.5, 142.0, 141.5, 138.3, 138.2, 136.6, 133.9, 131.8, 129.7, 129.3, 128.0, 127.3, 119.9, 95.4, 93.9, 51.9, 21.1, 20.5, 20.4, 20.3, 20.2; HRMS (ESI-TOF): calculated value: C 22 H 23 BrNaO2 [M + Na] + 421.0774 found: 421.0768. HPLC conditions: Daicel Chiralpak IA-H column, mobile phase is a mixture of isopropanol - n-hexane (v / v = 1:99), 1 mL / min, λ = 220 nm, t R (major) = 8.28 min.

[0200] Example 23: Preparation of compound 4w

[0201]

[0202] Under argon protection, Pd(OAc)2 (2.2 mg, 0.01 mmol, 10 mol%), potassium carbonate (55.2 mg, 0.4 mmol, 4.0 equiv), ethyl (1S,4R)-2-norbornene-2-carboxylate (e.e. >99%, 8.3 mg, 0.05 mmol, 0.5 equiv), 2-iodo-5-fluorotoluene (0.2 mmol, 2.0 equiv), methyl 2-bromo-3-methylbenzoate (0.1 mmol, 1.0 equiv), 2-methylpent-3-yn-2-yl benzoate (0.3 mmol, 3.0 equiv) and dry acetonitrile (0.5 mL) were added to a dry reaction tube equipped with a magnetic stir bar. The reaction tube was sealed, then taken out of the glove box and stirred at 120 °C. After the mixture was cooled to room temperature, it was filtered through a short silica gel column and eluted with pure ethyl acetate solvent. The filtrate was combined and concentrated in vacuo. The residue was purified by silica gel column chromatography or directly purified by preparative thin layer chromatography (PTLC) to give the desired product 4w (colorless oily liquid, yield = 76%, e.e. = 98%). 1 1H NMR (400 MHz, CDCl3): δ 7.86 (d, J = 9.2 Hz, 1H), 7.39 (d, J = 7.5 Hz, 1H), 7.31 (t, J = 7.7 Hz, 1H), 6.91 (dd, J = 9.6, 2.8 Hz, 1H), 6.62 (dd, J = 9.2, 2.8 Hz, 1H), 3.61 (s, 3H), 2.38 (s, 3H), 2.00 (s, 3H), 1.55 (s, 3H), 1.53 (s, 3H), 1.34 (s, 3H); 13 13C NMR (100 MHz, CDCl3): δ 200.1, 167.6, 161.2 (d, J = 244.1 Hz), 142.3 (d, J = 2.1 Hz), 141.4 (d, J = 8.4 Hz), 138.3, 138.2 (d, J = 7.9 Hz), 133.9, 133.5 (d, J = 3.0 Hz), 129.7, 128.0, 127.3, 115.7 (d, J = 20.7 Hz), 113.2 (d, J = 21.1 Hz), 95.4, 93.5, 51.9, 21.0, 20.8 (d, J = 1.7 Hz), 20.7,20.3, 20.2; 19 19F NMR (376 MHz, CDCl3) δ -118.0 (t, J = 9.3 Hz); HRMS (ESI-TOF): calculated value: C 22 H 23 FNaO2 [M + Na] +Measured value of 361.1574: 361.1569. HPLC conditions: Daicel Chiralpak IC-H chromatographic column, mobile phase is a mixture of isopropanol - n-hexane (v / v = 2:98), 1 mL / min, λ = 280 nm, t R (major) = 3.95 min, t R (minor) = 3.18 min

[0203] Example 24: Preparation of Compound 4x

[0204]

[0205] Under argon protection, Pd(OAc)2 (2.2 mg, 0.01 mmol, 10 mol%), potassium carbonate (55.2 mg, 0.4 mmol, 4.0 equiv), (1S,4R)-ethyl bicyclo[2.2.1]hept-5-ene-2-carboxylate (e.e. >99%, 8.3 mg, 0.05 mmol, 0.5 equiv), 2-iodotoluene (0.2 mmol, 2.0 equiv), methyl 2-bromo-3-methylbenzoate (0.1 mmol, 1.0 equiv), 2-methylpent-3-yn-2-yl benzoate (0.3 mmol, 3.0 equiv) and dry acetonitrile (0.5 mL) were added to a dry reaction tube equipped with a magnetic stir bar. The reaction tube was sealed, then taken out of the glove box and stirred at 120 °C. After cooling the mixture to room temperature, it was filtered through a short silica gel column, eluted with pure ethyl acetate solvent, and the filtrate was combined and concentrated in vacuo. The residue was purified by silica gel column chromatography or directly purified by preparative thin layer chromatography (PTLC) to obtain the desired product 4x (colorless oily liquid, yield = 55%, e.e. >96%).

[0206] 1 1H NMR (600 MHz, CDCl3): δ 7.24 - 7.21 (m, 2H), 7.16 (d, J = 6.8 Hz, 1H), 7.11 (d, J = 7.5 Hz, 1H), 7.09 (t, J = 4.4 Hz, 1H), 6.82 (d, J = 7.5 Hz, 1H), 2.86 (s, 3H), 2.86 (s, 3H), 2.38 (s, 3H), 2.00 (s, 3H), 1.76 (s, 3H), 1.60 (s, 3H), 1.33 (s, 3H); 1313C NMR (150 MHz, CDCl3): δ 200.3, 171.0, 140.0, 138.8, 138.6, 137.8, 136.3, 135.8, 130.3, 129.8, 126.8, 126.5, 126.1, 123.8, 96.9, 93.3, 39.4, 34.7, 21.1, 21.0, 20.7, 20.4; HRMS (ESI-TOF): calculated: C 23 H 27 NaNO [M+Na] + 356.1985, found: 356.1991. HPLC conditions: Daicel Chiralpak IC column, mobile phase: isopropanol - n - hexane mixture (v / v = 10:90), 1 mL / min, λ = 210 nm, t R (major) = 13.0 min, t R (minor) = 9.9 min, HRMS (ESI-TOF): calculated: C 22 H 23 FNaO2 [M+Na] + 361.1574 found: 361.1572.

[0207] Example 25: Preparation of styrene axially chiral skeleton compound 5

[0208]

[0209] Add Pd / C (2.0 mg, 10 mol%) and compound 4x (20 mg) dissolved in methanol to a dry reaction tube equipped with a magnetic stir bar. Stir at room temperature for 10 h under a hydrogen atmosphere. Filter the mixture through a short silica gel column, elute with pure ethyl acetate, combine the filtrates and concentrate in vacuo. Purify the residue directly by preparative thin layer chromatography (PTLC) to obtain the desired product 5 (colorless oily liquid, yield = 86%, 7:1 d.r., 97% e.e.). This styrene axially chiral skeleton has potential applications in the preparation of chiral ligands for asymmetric catalysis.

[0210] The above are only the preferred specific embodiments of the present invention, but the scope of protection of the present invention is not limited thereto. Any modifications, equivalent substitutions, and improvements made by those skilled in the art within the technical scope disclosed by the present invention shall all be included within the scope of protection of the invention.

Claims

1. A preparation method for synthesizing allene compounds by coupling of a tri-electrophilic reagent, characterized in that, Comprising: Under gas protection, aryl iodide A, bromide B, and propargyl ester C react in an organic solvent under the action of a palladium catalyst, norbornene derivative, ligand, and base to obtain allene compound I; Among them, the structural formula of the aryl iodide A is R 1 including one or more of hydrogen, halogen, C1-C6 alkyl, -COOR 1a ; R 1a includes C1-C6 alkyl; R 2 is selected from one of C1-C6 alkyl, C2-C8 ω-ester alkyl, and siloxy; the L ring is a five-membered ring or a six-membered ring, and L includes one or two of C, O, S, or N; 1 ≤ m ≤ 3; The structural formula of the bromide B is Br-R 6 ; R 6 includes R 6a a substituted or unsubstituted C1-C6 alkyl group, R 6’ a substituted or unsubstituted benzene ring, naphthalene ring, phenanthrene ring, pyrene ring, pyridine ring, indole ring, dibenzofuran ring, benzothiophene ring, quinoline ring; R 6a includes -CONHR 6b a cyano group, a C3-C6 cycloalkyl group, a C3-C6 heterocycloalkyl group, -COOR 6c a C6-C12 aryl group and a substituted aryl group, one or more of them; R 6b includes hydrogen, a C1-C6 alkyl group, a C6-C12 aryl group, a C5-C11 heteroaryl group; R 6c includes a C1-C6 alkyl group, a C6-C12 aryl group, a C5-C11 heteroaryl group; R 6’ includes a C1-C6 alkyl group, -COOR 6d an aldehyde group, a carboxyl group, a hydroxyl group, an amino group, a cyano group, a nitro group, Cl, F, Br, one or more of them; R 6d includes a C1-C6 alkyl group; The structural formula of the propargyl ester C is R 4 is one of hydrogen, C1-C4 alkyl, and C1-C4 alkoxy; R 5 is one of hydrogen, C1-C4 alkyl, and C1-C4 alkoxy; R 7 includes R 7a substituted or unsubstituted C1-C6 alkyl, R 7b substituted or unsubstituted phenyl, and one of C1-C6 alkoxy; R 7a includes one or more of C1-C4 alkyl, C1-C4 alkoxy, TBSO-, phenyl, benzyl, and benzyloxy; R 7b includes one or more of C1-C4 alkyl and C1-C4 alkoxy; R 8 includes phenyl, benzyl, -Bz, C1-C4 alkyl, or -CO2R 8a and one of them; R 8a is one of hydrogen and C1-C4 alkyl; The structural formula of the allene compound I is 2. The method for preparing an allene compound according to claim 1, wherein The structural formula of the aryl iodide A further includes: one of; R4, R4a, R4b, and R4c are each independently selected from one of hydrogen, C6-C12 aryl, C1-C6 alkyl, aldehyde group, carboxyl group, hydroxyl group, amino group, cyano group, nitro group, benzyloxy group, alkenyl group, alkynyl group, Cl, and F; m1 represents the number of R4 groups, 1 ≤ m1 ≤ 2; when m1 ≥ 2, multiple R4 groups are the same or different; m2 represents the number of R4a groups, 1 ≤ m2 ≤ 3; when m2 ≥ 2, multiple R4a groups are the same or different; m3 represents the number of R4b groups, 1 ≤ m3 ≤ 3; when m3 ≥ 2, multiple R4b groups are the same or different; m4 represents the number of R4c groups, 1 ≤ m4 ≤ 3; when m4 ≥ 2, multiple R4c groups are the same or different.

3. The method for preparing an allene compound according to claim 1, wherein, The structural formula of the norbornene derivative is: Wherein: i) R9 is the substituent on the double bond, r represents the number of substituents, 1 ≤ r ≤ 2; R10 is the substituent on the left five-membered ring, q represents the number of substituents, 1 ≤ q ≤ 8; ii) R9 or R10 is selected from any one or more of hydrogen, C6-C12 aryl, C5-C11 heteroaryl, C1-C6 alkyl, aldehyde group, carboxyl group, hydroxyl group, amino group, cyano group, nitro group, C1-C4 ether alkyl, alkenyl group, alkynyl group, and halogen; iii) When the number of substituents on the left five-membered ring is 2 or more, the substituents on the left five-membered ring are the same or different; when the number of substituents on the double bond is 2, the double bonds are the same or different; iv) The types of R9 and R10 substituents are the same or different.

4. The method for preparing an allene compound according to claim 1, wherein The palladium catalyst includes one or more of Pd(OAc)2, Pd(MeCN)2Cl2, Pd(PPh3)2Cl2, Pd(dppf)Cl2, Pd(TFA)2, PdCl2, Pd(acac)2, and Pd(PPh3)4.

5. The preparation method of the allene compound according to claim 1, wherein The base includes any one or more of sodium carbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, cesium acetate, tripotassium phosphate, potassium acetate, and potassium tert-butoxide.

6. The preparation method of the allene compound according to claim 1, characterized in that, The ligand includes any one or more of PPh3, P(p-OMe-Ph)3, P(m-F-Ph)3, P(o-Me-Ph)3, TFP, PCy3, XPhos, DavePhos, SPhos, BrettPhos, JohnPhos, DPPE, and AsPh3.

7. The method for preparing an allene compound according to claim 1, wherein The organic solvent includes any one or more of acetonitrile, benzonitrile, tetrahydrofuran, dimethyl ethyl ether, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, 2-methyltetrahydrofuran, ether, methyl tert-butyl ether, 1,4-dioxane, and N-methylpyrrolidone.

8. The method for preparing an allene compound according to claim 1, wherein The reaction temperature of the preparation method is 110-120 °C.

9. A method for synthesizing allene compounds by coupling of a tri-electrophilic reagent, characterized in that, Prepared by the method according to any one of claims 1-9.

10. Use of the allene compound according to claim 9 in the synthesis of a framework containing a styrene axial chirality by hydrogen conversion.

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