Method for synthesizing alkenyl boronate compound by palladium-catalyzed cross-coupling and iron-catalyzed hydroboration in series reaction

Abstract

The application discloses a method for synthesizing alkenyl borate ester compounds through a series reaction of palladium-catalyzed cross-coupling and iron-catalyzed borohydration, and belongs to the field of organic synthesis. The method inserts multiple methylene units into the carbon-carbon sigma-bond of the alkenyl borate ester through a series reaction of palladium-catalyzed cross-coupling and iron-catalyzed borohydration, and meanwhile, a valuable C(sp 2 )‑B functional group is reserved. The method utilizes the universality of the alkenyl borate ester in the cross-coupling reaction, provides an efficient approach for modular and iterative synthesis of C(sp3) homologues of bioactive molecules containing olefin structures, and is expected to accelerate the drug discovery process, applied to efficient preparation of drug molecule homologues and complex organic compounds, and provides a powerful tool for realizing rapid structural derivatization of drug lead compounds.

Description

Technical Field

[0001] This invention relates to an efficient and highly selective synthetic method for carbon chain homogenization of alkenyl borate ester compounds via a tandem catalytic reaction, belonging to the field of organic synthetic chemistry. Background Technology

[0002] In organic synthesis, drug development, and materials science, systematic structural modification of the core skeleton of lead compounds or functional molecules is a key strategy for optimizing their performance. Homogenization reactions, which involve inserting one or more methylene (-CH2) units into the molecular skeleton, can systematically alter the physicochemical properties of the molecule, thereby finely controlling its biological activity (such as binding affinity to the target) or material function. Therefore, developing synthetic methods that can efficiently and modularly extend the carbon chain directly from an important intermediate is of great significance.

[0003] Organoboron compounds, especially alkenylboronic esters, are indispensable building blocks in modern synthetic chemistry due to their efficient construction of C-C bonds via cross-coupling reactions such as the Suzuki-Miyaura reaction. Currently, homologation methods based on organoboron compounds have been developed to some extent, with strategies mainly focusing on the modification of carbon-boron (CB) bonds. For example, the classic Matteson homologation reaction inserts a methylene unit into the carbon-boron (CB) bond via a carbene or carbene-like intermediate, achieving precise and efficient insertion of carbon units into the CB bond. However, homologation of alkenylboronic esters via the Matteson reaction generates alkylboron species with extended carbon chains, leading to the loss of the C(sp²)-B portion, a multifunctional structure, in metal-catalyzed cross-coupling reactions.

[0004] Meanwhile, current technologies still cannot achieve the more prevalent and inert carbon-carbon σ-bond direct carbon insertion homogenization reaction in alkenylboron. If the C(sp²)-B functional groups can be retained while directly extending the C-C bonds on the alkenylboronate backbone, it will provide a powerful tool for the rapid structural derivatization of drug lead compounds.

[0005] From a retrosynthetic perspective, the coupling of alkenyl borate esters with vinyl halides (Suzuki-Miyaura) can generate conjugated dienes, which can then be hydrobored. Theoretically, this allows for the insertion of two methylene units into the original C-C bonds. However, this strategy faces two insurmountable obstacles in practice: (1) The hydroboration reaction of conjugated dienes has multiple reaction sites, making precise control of chemoselectivity, regioselectivity, and stereoselectivity extremely difficult. It typically produces a complex mixture of allyl boron, high-allyl boron, and various isomeric alkenyl borons, making it difficult to obtain the target straight-chain alkenyl borate ester in high yield and with high selectivity; (2) It is difficult to efficiently and efficiently integrate the palladium-catalyzed coupling step with the subsequent metal-catalyzed hydroboration step into a "one-pot" process. This tandem process presents significant challenges in terms of catalyst system and reaction compatibility.

[0006] Therefore, developing a novel catalytic system and method to overcome the aforementioned selectivity and compatibility challenges, and to achieve a highly efficient, selective, and modular synthesis of alkenylboronic homologues with extended carbon chains from alkenylboronic esters, is a major technical problem that urgently needs to be solved in this field. Summary of the Invention

[0007] The purpose of this invention is to overcome the shortcomings of existing technologies and provide a simple, selective, and highly compatible method for the homologation of alkenylboronic esters with high modularity. This method, through ingenious reaction design, links palladium-catalyzed Suzuki-Miyaura coupling with iron-catalyzed hydroboration, enabling the insertion of two methylene units into the original C-C bond of the alkenylboronic ester in a single step. Furthermore, iterative multi-step extension can be achieved, allowing for the further synthesis of homologues with four or six methylene groups while retaining their multifunctional C(sp²)-B functional groups.

[0008] Another object of the present invention is to provide a highly selective and highly compatible iron catalyst that plays a key role in the method.

[0009] Another object of the present invention is to provide an iterative application strategy for the method and its practical application in the derivatization of bioactive molecules.

[0010] To achieve the above objectives, the present invention adopts the following technical solution: , in, It is selected from aryl, heteroaryl, alkyl, heteroalkyl, cycloalkyl, alkenyl, alkynyl and organic groups containing at least one of O, N, S, halogen, carbonyl and ester groups; Bpin represents pinacol borate ester.

[0011] In a first aspect, the present invention provides a method for the homogenization of alkenyl borate ester compounds, wherein the method is a one-pot, two-step tandem reaction that does not require separation of intermediates, and includes the following steps performed in sequence: Step S1: Aryl olefin borate 1 reacts with a vinyl halide in the presence of a palladium catalyst, a base, and an organic solvent to generate a conjugated diene intermediate 2; Step S2: Cool the reaction system of conjugated diene intermediate 2 to room temperature, without separating the intermediate, add iron catalyst and pinacolborane to react and obtain alkenylboronic acid ester compound 3.

[0012] Furthermore, in the above technical solution, the palladium catalyst in the first step is preferably tetra(triphenylphosphine)palladium; the vinyl halide is selected from vinyl bromide or vinyl chloride.

[0013] Furthermore, in the above technical solution, the molar ratio of aryl olefin boronic acid ester 1, vinyl halide, palladium catalyst and base in the first step is 1:1-1.2:0.01-0.02:1-1.5.

[0014] Furthermore, in the above technical solution, the organic solvent in the first step is an aromatic solvent, preferably toluene; the alkali is selected from potassium methoxide, sodium methoxide, sodium tert-butoxide, or potassium tert-butoxide.

[0015] Furthermore, in the above technical solution, the reaction temperature in the first step needs to be controlled between 80-120 ℃, preferably 100-120 ℃. Studies have found that higher temperatures not only promote complete coupling reactions, but more importantly, they help eliminate trace amounts of vinyl halides that may remain in the system after the reaction in the presence of a base, preventing them from poisoning or interfering with subsequent iron-catalyzed steps. This is key to achieving high-yield tandem reactions.

[0016] Secondly, the present invention provides an iron catalyst for the second step of the above method, which is a zero-valent iron-bisphosphine complex with the following structure: .

[0017] Furthermore, the iron catalyst is preferably [Fe(dppe)] ([Fe]-1, where dppe is 1,2-bis(diphenylphosphine)ethane) or [Fe(dppbz)] ([Fe]-2, where dppbz is 1,2-bis(diphenylphosphine)benzene), with [Fe]-1 being the most preferred. This catalyst exhibits near-perfect chemoselectivity, regioselectivity, and stereoselectivity for the hydroboration reaction of conjugated dienes with HBpin.

[0018] Furthermore, in the above technical solution, the molar ratio of the conjugated diene intermediate 2, pinacol borane, and iron catalyst in the second step is 1:1-1.2:0.01-0.05.

[0019] Thirdly, the present invention provides an iterative application of the method. Using the homologous product 3 obtained by the above method as a new starting material, the one-pot tandem reaction can be repeated to sequentially insert two, four, six or even more methylene units, thereby achieving modular and controllable extension of the carbon chain.

[0020] Fourthly, this invention provides the application of the described method in the preparation of homologues of pharmaceutically active molecules. Using the method of this invention, a library of homologues of pharmaceutically active molecules with different chain lengths can be rapidly constructed for structure-activity relationship studies of specific drugs. For example: A. A method for synthesizing the pharmaceutical intermediate Piperdardine, comprising the following steps: , Compound 3ad was synthesized using the aforementioned two-step continuous reaction method. Then, compound 3ad and compound 6b were reacted with each other in the presence of tetrakis(triphenylphosphine)palladium, potassium carbonate, and toluene / water at a temperature of 80-100°C to obtain the pharmaceutical intermediate Piperdardine.

[0021] B. A method for synthesizing a Src kinase inhibitor, comprising the following steps: , Compound 3ae was synthesized using the aforementioned two-step continuous reaction method. Then, compound 3ae and compound 7b were reacted with each other in the presence of tetrakis(triphenylphosphine)palladium, potassium carbonate, and toluene / water at a temperature of 80-100°C to obtain the Src kinase inhibitor.

[0022] Compared with the prior art, the beneficial effects of the present invention are as follows: 1. Originality: For the first time, the "homogenization reaction from alkenylboron to alkenylboron" was realized, that is, the formal carbon insertion reaction of the unactivated CC σ bond in alkenylboronic ester was realized, breaking through the limitation of traditional methods that are limited to carbon unit insertion into the CB bond of boron-containing compounds.

[0023] 2. High selectivity: By using a specific iron catalyst [Fe]-1, the world-class problem of the special selectivity of the conjugated diene hydroboration reaction was solved, and the efficient synthesis of single isomer products was achieved.

[0024] 3. Step economy: A highly efficient "one-pot" series process has been developed, which eliminates the need to separate unstable diene intermediates, is simple to operate, and has high atom economy.

[0025] 4. Good functional group compatibility: The reaction conditions are mild and it is tolerant to many common functional groups, making it suitable for the later-stage modification of complex molecules.

[0026] 5. Iterable and modular: The product is still an alkenyl borate ester, which can be repeatedly added to the reaction cycle to achieve precise and modular growth of carbon chain length, providing a powerful tool for organic synthesis and drug research.

[0027] 6. Huge application potential: It can be directly used to efficiently derivatize known bioactive molecules in a "turning lead into gold" manner, accelerate the optimization process of drug lead compounds, and speed up the innovative development of drugs. Detailed Implementation

[0028] To make the objectives, technical solutions, and advantages of the present invention clearer, the embodiments of the present invention will be described in further detail below with reference to the examples. However, this does not limit the present invention to the scope of the described embodiments. Example 1

[0029] Condition optimization experiment (step S1) In a glove box, [Pd] catalyst (0.001 mmol, 1 mol%) and base (0.12 mmol, 1.2 eq) were added to a dried, pressure-resistant reaction tube, followed by the addition of an organic solvent (1 mL toluene). Subsequently, compound 1a (23.0 mg, 0.1 mmol, 1.0 eq) and ethylene bromide (110 μL, 0.11 mmol, 1.1 eq, 1.0 M THF solution) were added sequentially, and the mixture was stirred at a given temperature for a certain time. The reaction mixture was analyzed by GC using dodecane as an internal standard.

[0030] , Reaction conditions: 2a (13.1 mg, 0.1 mmol, 1.0 equivalent), HBpin (12.8 mg, 0.1 mmol, 1.0 equivalent), [Fe]-1 (1.3 mg, 0.002 mmol, 2 mol%), organic solvent (0.5 mL toluene), reaction at room temperature for 2 hours. Conversion and yield were determined by gas chromatography (GC) with dodecane as an internal standard.

[0031] The optimal conditions for the first step were finally determined to be: tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) / potassium methoxide (KOMe) / toluene solvent / reaction at 120 °C.

[0032] Condition optimization experiment (step S2) Iron catalyst (0.002 mmol, 2 mol%) was added to a dried, pressure-resistant reaction tube, followed by toluene (0.5 mL), then conjugated diene 2a (13.1 mg, 0.1 mmol, 1.0 eq) and HBpin (12.8 mg, 0.1 mmol, 1.0 eq), and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was analyzed by gas chromatography (GC) using dodecane as an internal standard.

[0033] , Reaction conditions: 2a (13.1 mg, 0.1 mmol, 1.0 equivalent), HBpin (12.8 mg, 0.1 mmol, 1.0 equivalent), [Fe]-1 (1.3 mg, 0.002 mmol, 2 mol%), organic solvent (0.5 mL toluene), reaction at room temperature for 2 hours. Conversion and yield were determined by gas chromatography (GC) with dodecane as an internal standard.

[0034] The optimal conditions for the second step were finally determined to be: [Fe]-1 catalyst / reaction at room temperature for 2 h.

[0035] Synthesis of [Fe]-1: In an argon glove box, [Fe(acac)3] (176 mg, 0.5 mmol, 1.0 eq), (dppe, 200 mg, 0.535 mmol, 1.07 eq) and (dvtms, 279 mg, 1.5 mmol, 3.0 eq) was suspended in diethyl ether (10 mL). Then, diethylethoxyaluminum (0.50 mL, 3.50 mmol, 7.0 equiv) was added dropwise at room temperature. After stirring for 5 minutes, the solution turned dark green, and the reaction was continued overnight with stirring. After removing the diethyl ether under reduced pressure, a green oily substance was obtained. Extraction with n-pentane yielded a bright green solid, which was then washed three times with n-pentane (3 × 3 mL). After drying under reduced pressure, the [Fe]-1 catalyst (275.8 mg, 0.43 mmol, 86%) was obtained. [Fe]-1 catalyst 1H NMR spectrum; 1 HNMR (400 MHz, C6D6): δ12.78–11.05 (m, br, 6H), 9.86 (s, br, 4H), 8.14 (s, br,2H), 6.34–4.80 (s, br, 6H), 1.18–0.07 (m, br, 6H), -1.75 – -4.25 (m, br,14H), -8.44 (s, br, 2H), -12.43 (s, br, 2H).

[0036] Synthesis of [Fe]-2: In an argon glove box, [Fe(acac)3] (356.1 mg, 1.0 mmol, 1.0 eq), (dppbz, 477.7 mg, 1.07 mmol, 1.07 eq) and dvtms (558 mg, 3.0 mmol, 3.0 eq) were suspended in diethyl ether (20 mL). Then, diethylethoxyaluminum (1.0 mL, 7.0 mmol, 7.0 eq) was added dropwise at room temperature. After stirring for 5 minutes, the solution turned green, and stirring continued overnight. After removing the diethyl ether under reduced pressure, a green oily substance was obtained. Extraction with n-pentane yielded a bright green solid, which was then washed three times with n-pentane (3 × 5 mL) and dried under reduced pressure to obtain the [Fe]-2 catalyst (518.1 mg, 0.75 mmol, 75%). [Fe]-2 catalyst 1H NMR spectrum; 1 H NMR (400 MHz, C6D6): δ 13.66 (s, br, 1H), 12.34 (s, br, 4H), 11.04 (s, br, 4H), 8.57 (s, br,1H), 5.55 (s, br, 4H), 4.14 (s, br, 2H), 3.42–2.78 (m, br, 2H), 1.55–0.70 (m,br, 4H), -1.73 – -5.51 (m, br, 17H), -7.27 (s, br, 2H), -8.18 (s, br, 1H). Example 2

[0037] Step S1: In a glove box, tetra(triphenylphosphine)palladium (1.1 mg, 0.001 mmol, 1 mol%) and potassium methoxide (8.4 mg, 0.12 mmol, 1.2 eq) were added to a dried pressure-resistant reaction tube, followed by the addition of solvent (1 mL toluene), then compound 1a (23.0 mg, 0.1 mmol, 1.0 eq) and vinyl bromide (110 μL, 0.11 mmol, 1.1 eq, 1.0 MTHF solution), and the mixture was stirred at 120 °C for 2 hours.

[0038] Step S2: After cooling the reaction system from Step S1 to room temperature, without separating the intermediates, [Fe]-1 (1.3 mg, 0.002 mmol, 2 mol%) and HBpin (12.8 mg, 0.1 mmol, 1.0 eq) were directly added to the reaction system from Step S1 to initiate a hydroboration reaction. After the reaction was complete, the solvent was removed under reduced pressure. The resulting residue was purified by silica gel chromatography to obtain the corresponding product.

[0039] Using the same reaction conditions as described above, but changing only the reaction substrate, various substituted compounds were obtained. Using the homologous product 3 obtained by the above method as a new starting material, the reaction was repeated, allowing for the sequential insertion of four and six methylene units. The reaction results are as follows: , Wherein, a is the 5 mol% [Fe]-1 catalyst used in the hydroboration reaction (step S2); b is the Suzuki-Miyaura coupling in step S1, in which Zweifel alkenylation replaces Pd catalysis.

[0040] The NMR spectra of representative products are as follows: , 1 H NMR (400 MHz, CDCl3): δ 7.30–7.25 (m, 2H), 7.20–7.16 (m, 3H), 6.71(dt, J = 17.9, 6.2 Hz, 1H), 5.50 (dt, J = 18.0, 1.6 Hz, 1H), 2.80–2.71 (m,2H), 2.48 (dtd, J = 9.7, 6.3, 1.6 Hz, 2H), 1.27 (s, 12H). 13 C{ 1 H NMR (101MHz, CDCl3): δ153.59, 141.90, 128.46, 125.98, 83.21, 37.65, 34.69, 24.91. 11 B{ 1 H} NMR (128 MHz, CDCl3): δ 29.3.。

[0041] , 1 H NMR (400 MHz, CDCl3): δ 7.15–7.09 (m, 4H), 6.74 (dt, J = 18.0, 6.3Hz, 1H), 5.52 (dt, J = 17.9, 1.6 Hz, 1H), 2.76–2.68 (m, 2H), 2.47–2.38 (m,2H), 2.29 (s, 3H), 1.28 (s, 12H). 13 C{ 1 H} NMR (101 MHz, CDCl3): δ 153.75,140.08, 136.02, 130.28, 128.68, 126.14, 126.12, 83.25, 36.34, 32.10, 24.93,19.39. 11 B{ 1 H} NMR (128 MHz, CDCl3): δ 29.8.。

[0042] , 1 HNMR (400 MHz, CDCl3): δ 7.25–7.21 (m, 2H), 7.17–7.12 (m, 3H), 6.60(dt, J = 18.2, 6.5 Hz, 1H), 5.40 (dt, J = 18.0, 1.4 Hz, 1H), 2.58 (t, J = 7.7Hz, 2H), 2.21–2.10 (m, 2H), 1.65–1.57 (m, 2H), 1.48–1.40 (m, 2H), 1.24 (s,12H). 13 C{ 1H} NMR (101 MHz, CDCl3): δ 154.39, 142.58, 128.42, 128.24, 125.63,83.01, 35.80, 35.67, 31.02, 27.85, 24.80. 11 B{ 1 H} NMR (128 MHz, CDCl3): δ 29.7.。

[0043] , 1 HNMR (400 MHz, CDCl3): δ 7.14–7.06 (m, 4H), 6.63 (dt, J = 17.9, 6.4Hz, 1H), 5.44 (dt, J = 18.0, 1.6 Hz, 1H), 2.58 (t, J = 7.7 Hz, 2H), 2.29 (s,3H), 2.23–2.16 (m, 2H), 1.66–1.57 (m, 2H), 1.56–1.48 (m, 2H), 1.27 (s, 12H). 13 C{ 1 H} NMR (101 MHz, CDCl3): δ 154.52, 140.91, 135.95, 130.22, 128.97,125.97, 125.90, 83.16, 35.86, 33.25, 29.92, 28.31, 24.92, 19.46. 11 B{ 1 H} NMR(128 MHz, CDCl3): δ 29.2.。

[0044] , 1 H NMR (400 MHz, CDCl3): δ 7.30–7.25 (m, 2H), 7.17 (m, 3H), 6.63 (dt, J = 17.9, 6.4 Hz, 1H), 5.42 (dt, J = 18.0, 1.6 Hz, 1H), 2.59 (t, J= 7.2 Hz, 2H), 2.18 - 2.10 (m, 2H), 1.65 - 1.58 (m, 2H), 1.45 - 1.39 (m, 2H), 1.33 (quint, J = 3.6 Hz, 4H), 1.26 (s, 12H). 13 C{ 1 H} NMR (101 MHz, CDCl3): δ 154.86, 143.00, 128.53, 128.36, 125.69, 83.14, 36.09, 35.93, 31.56, 29.29, 29.19, 28.28, 24.93. 11 B{ 1 H} NMR (128 MHz, CDCl3) δ 30.0.

[0045] , 1 H NMR (400 MHz, CDCl3): δ 7.32–7.27 (m, 2H), 7.16–7.06 (m, 2H), 6.63 (dt, J = 18.0, 6.4 Hz, 1H), 5.42 (dt, J = 17.9, 1.6 Hz, 1H), 2.59 (t, J = 7.6 Hz, 2H), 2.20–2.09 (m, 2H), 1.60 (m, 2H), 1.42 (m, 2H), 1.36–1.32 (m, 4H), 1.31 (s, 9H), 1.26 (s, 12H). 13 C{ 1 H} NMR (101 MHz, CDCl3) δ 154.91, 148.44, 139.94, 128.15, 125.25, 83.14, 35.94, 35.53, 34.47, 31.57, 31.54, 29.40, 29.22, 28.30, 24.92. 11 B{ 1 H} NMR (128 MHz, CDCl3): δ 31.6. Example 3

[0046] , Synthesis of Piperdardine (6): Using alkenylboronic acid ester 1ad (61.2 mg, 0.2 mmol) as a substrate, homologation was performed according to the steps of Example 2 to obtain crude product 3ad. Without purification, compound 6b (43.0 mg, 0.2 mmol), Pd(PPh3)4 (2.3 mg, 1 mol%), and other compounds were added directly to the reaction flask. (55.2 mg, 0.4 mmol), toluene (2 mL), and water (0.2 mL) were stirred at 80 °C for 12 hours. After cooling, the mixture was extracted with ethyl acetate, and the organic phase was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5:1) to give a white solid product 6 (43.8 mg, total yield 63%). 1 H NMR (400 MHz, CDCl3): δ 7.21 (dd, J = 14.8, 10.8 Hz, 1H), 6.72 (d, J = 7.9 Hz, 1H), 6.66(d, J = 1.7 Hz, 1H), 6.61 (dd, J = 7.9, 1.7 Hz, 1H), 6.26 (d, J = 14.8 Hz, 1H), 6.18 (dd, J = 15.2, 10.7 Hz, 1H), 6.09–6.00 (m, 1H), 5.92 (s, 2H), 3.61 (s, 2H), 3.48 (s, 2H), 2.65 (t, J = 7.7 Hz, 2H), 2.42 (q, J = 7.3 Hz, 2H),1.69–1.61 (m, 2H), 1.59–1.52 (m, 4H). 13 C{ 1 ¹H NMR (101 MHz, CDCl₃): δ 165.71, 147.70, 145.85, 142.59, 141.00, 135.30, 129.61, 121.31, 119.24, 108.97, 108.29, 100.92, 47.01, 43.32, 35.15, 26.84, 25.76, 24.81.

[0047] The method of the present invention has shorter synthesis steps, simpler purification methods, and higher overall yield than the methods for synthesizing compound 6 in the literature. Example 4

[0048] , Synthesis of Src kinase inhibitor (7): Using alkenylboronic acid ester 1ae as a substrate, homogenization was performed according to the steps in Example 2 to obtain crude product 3ae. Without purification, the crude product was then processed according to the steps in Example 4 to directly obtain target product 7 (overall yield 60%). 1 H NMR (400 MHz, CDCl3): δ 8.76 (s, 1H), 7.93 (d, J = 1.3 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.57 (dd, J = 9.0, 1.9 Hz, 1H), 7.53 (d, J = 2.3Hz, 1H), 7.20 (dd, J = 8.6, 2.4 Hz, 1H), 6.98 (d, J = 8.7 Hz, 1H), 6.88 (s,1H), 6.60–6.47 (m, 2H), 3.73 (t, J = 4.7 Hz, 4H), 2.48–2.40 m, 4H), 2.41 (t, J = 5.3Hz, 2H), 2.34 (m, 2H), 1.76–1.69 (m, 2H). 13 C{ 1 ¹H NMR (101 MHz, CDCl₃): δ 152.14, 150.49, 149.67, 142.05, 136.02, 135.25, 131.11, 130.14, 129.15, 127.93, 127.92, 127.46, 125.18, 123.72, 122.59, 118.37, 116.27, 93.23, 67.11, 58.54, 53.89, 31.17, 26.09.

[0049] This novel synthetic route avoids the use of organotin reagents compared to the routes described in the literature, making it more environmentally friendly and greener. Example 5

[0050] Synthesis of a series of bioactive olefin homologues (8-20) Synthesis of O-Me Tapinarof homologue (8): Using 1a as substrate, 3a was synthesized according to the steps of Example 2, and directly combined with... (43.4 mg, 0.2 mmol) Suzuki-Miyaura conjugation (Pd(PPh3)4, Toluene / water, 80 °C, 12 h). Column chromatography yielded a white solid 8 (58.3 mg, 76% yield). 1 H NMR (400 MHz, CDCl3): δ 7.28–7.21 (m, 2H), 7.20–7.11 (m,3H), 6.46 (s, 2H), 6.31 (dt, J = 15.7, 1.4 Hz, 1H), 6.16 (dt, J = 15.7, 6.7Hz, 1H), 3.74 (s, 6H), 3.50 (quint, J = 7.1 Hz, 1H), 2.76-2.72 (m, 2H), 2.52-2.41 (m, 2H), 1.21 (d, J = 7.1 Hz, 6H). 13 C{ 1 ¹H NMR (101 MHz, CDCl₃): δ 158.75, 141.93, 136.46, 130.73, 129.51, 128.59, 128.49, 126.02, 123.74, 102.60, 55.86, 36.09, 34.98, 24.22, 20.87.

[0051] Synthesis of IP6K inhibitor homologue (9): Using 1b as substrate, proceed as described above, but... A white solid 9 was obtained with a yield of 71%. The structure was confirmed by single-crystal X-ray diffraction. 1 H NMR (400 MHz, CDCl3): δ 11.03 (s, 1H), 8.19 (d, J = 2.1 Hz,1H), 8.06 (s, 1H), 7.79 (dd, J = 8.5, 2.1 Hz, 1H), 7.69 (d, J= 8.5 Hz, 1H),7.22–7.13 (m, 2H), 7.03–6.94 (m, 2H), 6.51 (d, J = 16.0 Hz, 1H), 6.40 (dt, J = 15.9, 6.6 Hz, 1H), 2.80 (t, J = 7.7 Hz, 2H), 2.57 (q, J = 7.2 Hz, 2H). 13 C{ 1 ¹H NMR (101 MHz, CDCl₃): δ 162.66 (d, J = 9.3 Hz), 160.28, 147.94, 142.78,137.20 (d, J = 14.2 Hz), 132.62, 132.27, 129.92 (d, J = 7.7 Hz), 129.40,128.15, 127.43, 123.38, 122.84, 115.30 (d, J = 21.1 Hz), 35.12, 34.95. 19 F{ 1 ¹H NMR (376 MHz, CDCl₃): δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ –117.5.

[0052] Synthesis of TEAD inhibitor homologue (10): using 1c as substrate, homologation was followed by coupling with the corresponding aryl bromide to obtain 10 (yield 71%).

[0053] Synthesis of homologue (11): using 1d as substrate, 11 was obtained (yield 68%).

[0054] Synthesis of IRAK4 inhibitor homologue (12): Using 1e as substrate, the procedure in Example 3 was followed to obtain 12 (yield 65%).

[0055] Synthesis of homologue (13): using 1f as substrate, 13 was obtained (yield 67%).

[0056] Synthesis of Istradefylline homologue (14): Using 1g as substrate, after homologation, it was combined with... Coupled, yielding 14 (yield 62%).

[0057] Synthesis of drug active molecule homologues 15–19: Using 1h–1l as substrates, the procedure was performed according to Example 3 to obtain target products 15–19 in yields between 61% and 70%. All compounds were confirmed by NMR and HRMS.

[0058] Synthesis of Officinine B homologue (20): Using 1m as the starting material, homologation was carried out according to Example 3, but [Fe]-1 (5 mol%) was used in the second stage, and the reaction was carried out for 12 hours. The resulting crude product 3am was directly reacted with... Coupling under photo-redox conditions yielded 20. The product precipitated as a hydrochloride salt, and its structure was confirmed by X-ray single-crystal diffraction. The reaction results are as follows: , Reaction conditions: Step S1: Alkenyl borate ester 1 (0.2 mmol), vinyl bromide (0.2 mmol), potassium methoxide (0.24 mmol), tetrakis(triphenylphosphine)palladium (1 mol%), and toluene (1 mL), 120 °C, 2 h. Step S2: Add pinacol borate ester (0.24 mmol) and [Fe]-1 (2 mol%) to the reaction mixture from Step S1, room temperature, 12 h. Step S3: The use of aryl bromide, palladium catalyst, base, and solvent varies depending on the target molecule. a In the first stage, the Zweifel olefination reaction was used instead of palladium-catalyzed SMC. b Use isolated 1,3-diene 2ah. c The yields in parentheses are based on the isolated two-carbon homologous alkenylboronic esters 3ak and 3al.

[0059] The above embodiments describe the basic steps, some applications, main features, and unique advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the specific embodiments described above. The embodiments and descriptions in the specification are merely illustrative of the principles of the present invention. Various changes and modifications can be made to the present invention without departing from its principles, and all such changes and modifications fall within the scope of protection of the present invention.

Claims

1. A method for synthesizing alkenyl borate compounds by a palladium-catalyzed cross-coupling and iron-catalyzed hydroboration tandem reaction, characterized in that, Includes the following steps: ， Step S1: Aryl olefin borate 1 reacts with a vinyl halide in the presence of a palladium catalyst, a base, and an organic solvent to generate a conjugated diene intermediate 2; Step S2: Cool the reaction system of conjugated diene intermediate 2 to room temperature, without separating the intermediate, add iron catalyst and pinacol borane to react and obtain alkenyl borate compound 3; in, It is selected from aryl, heteroaryl, alkyl, heteroalkyl, cycloalkyl, alkenyl, alkynyl and organic groups containing at least one of O, N, S, halogen, carbonyl and ester groups; Bpin represents pinacol borate ester.

2. The method for synthesizing alkenyl borate ester compounds by palladium-catalyzed cross-coupling and iron-catalyzed hydroboration tandem reaction according to claim 1, characterized in that: In the first step, the palladium catalyst is tetra-triphenylphosphine palladium; the vinyl halide is selected from vinyl bromide or vinyl chloride.

3. The method for synthesizing alkenyl borate ester compounds by palladium-catalyzed cross-coupling and iron-catalyzed hydroboration tandem reaction according to claim 1, characterized in that: In the first step, the reaction temperature is 80-120 ℃.

4. The method for synthesizing alkenyl borate ester compounds by palladium-catalyzed cross-coupling and iron-catalyzed hydroboration tandem reaction according to claim 1, characterized in that: In the first step, the alkali is selected from potassium methoxide, sodium methoxide, sodium tert-butoxide, or potassium tert-butoxide; the organic solvent is toluene.

5. The method for synthesizing alkenyl borate ester compounds by palladium-catalyzed cross-coupling and iron-catalyzed hydroboration tandem reaction according to claim 1, characterized in that: In the first step, the molar ratio of aryl olefin boronic acid ester 1, vinyl halide, palladium catalyst and base is 1:1-1.2:0.01-0.02:1-1.

5.

6. The method for synthesizing alkenyl borate ester compounds by palladium-catalyzed cross-coupling and iron-catalyzed hydroboration tandem reaction according to claim 1, characterized in that: In the second step, the iron catalyst is selected from... 。 7. The method for synthesizing alkenyl borate ester compounds by palladium-catalyzed cross-coupling and iron-catalyzed hydroboration tandem reaction according to claim 1, characterized in that: In the second step, the molar ratio of conjugated diene intermediate 2, pinacolborane, and iron catalyst is 1:1-1.2:0.01-0.

05.

8. A method for synthesizing the pharmaceutical intermediate Piperdardine, characterized in that, Includes the following steps: ， Compound 3ad was synthesized using any one of claims 1-7. Then, compound 3ad and compound 6b were reacted with each other in the presence of tetrakis(triphenylphosphine)palladium, potassium carbonate and toluene / water at a temperature of 80-100°C to obtain the pharmaceutical intermediate Piperdardine.

9. A method for synthesizing a Src kinase inhibitor, characterized in that, Includes the following steps: ， Compound 3ae was synthesized using any one of claims 1-7. Then, compound 3ae and compound 7b were reacted with each other in the presence of tetrakis(triphenylphosphine)palladium, potassium carbonate and toluene / water, and the temperature was raised to 80-100°C to obtain the Src kinase inhibitor.

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