A method for the directed synthesis of tri (tetra) substituted alkenes

Abstract

A method for the directed synthesis of tri (tetra) substituted alkenes comprising the reaction of a compound of formula (I) in the presence of a nickel catalyst, a ligand, a base, a hydrogen source and a solvent. Formula (I) wherein R 1 is selected from any one of substituted or unsubstituted C1-C8 alkyl, phenyl, naphthyl, said substituents including nitrogen containing groups, oxygen containing groups, aryl groups, halogens, R 2 is selected from any one of hydrogen, alkyl groups, R 3 is selected from C1-C8 substituted or unsubstituted alkyl groups, said substituents including C1-C4 alkyl groups substituted with a nitrogen atom or an oxygen atom; the nickel catalyst is a divalent nickel salt or a divalent nickel salt complex; the ligand is a bisoxazoline ligand; the hydrogen source is a silane based compound; the base is a metal salt containing fluoride ions, carbonate ions, bicarbonate ions, alkoxide ions.

Description

Technical Field

[0001] This application belongs to the field of organic synthesis methodology, specifically relating to a method for the directed synthesis of tri(tetra)substituted alkenes. Background Technology

[0002] Tri-(quadri-substituted) alkenes are common structural units in natural products, drugs and bioactive molecules, and have important application value in materials science and drug development.

[0003] Among the many strategies studied for the synthesis of olefins, transition metal-catalyzed allene hydroalkylation is a highly efficient approach. Allenes, due to their unique structure—containing pairwise orthogonal π bonds occupying three carbon atom centers—can undergo 2,1-, 1,2-, 2,3-, and 3,2-hydroalkylation reactions. However, structurally simple terminal allenes can only be converted to tri(tetra)-substituted alkenes via 3,2-hydroalkylation.

[0004] However, the 3,2-hydroalkylation of terminal allenes by transition metal catalysis still faces significant challenges in terms of reaction conditions and substrate scope, and synergistic improvement of these two aspects has always been an important research goal in this field.

[0005] Takai et al. previously reported palladium-catalyzed C(sp) reactions of allenes and enamines. 2 )–C (sp 3 The coupling reaction provided an important foundation for the 3,2-hydroalkylation of allenes. This reaction requires a temperature of 135 °C and mainly uses alkyl allenes as substrates (Synlett. 2009, 18, 3027–3031). More than a decade later, Meng Fanke's team achieved the cobalt-catalyzed 3,2-hydrohydroxyalkylation of 1,1-disubstituted allenes with aldehydes at room temperature, providing a new approach for the hydroalkylation of allenes under mild conditions. Related research mainly focuses on 1,1-disubstituted allene substrates, and has not yet systematically investigated monosubstituted allenes (Angew. Chem. Int. Ed. 2023, 62, e202219257). In 2024, Doye et al. developed a titanium-triphenylmethyltetra(pentafluorophenyl)borate system, which successfully achieved the 3,2-hydroaminomethylation of allenes by activating the C–H bond of trimethylamine and coupling it to the C (β) position of the allene. Currently, the number of allene substrates applicable to this system is limited, including two examples of alkyl allenes and one example of a 1,1-disubstituted allene (Synlett. 2024, 35, 957–962).

[0006] In recent years, related research has made continuous progress. In 2025, Meng Fanke's team achieved the reductive coupling of allenes with succinimide and cyclobutene using a photo / cobalt synergistic catalytic system, enriching the types of alkylating agents. The study did not involve monosubstituted allene substrates, and the synthesis steps of the alkylating agents were relatively numerous (Angew. Chem. Int. Ed. 2025, 64, e202416524). Park's group, using N-sulfonyl groups as directing groups and combining a three-membered ring strain-driven strategy, established for the first time a palladium-catalyzed 3,2-hydroalkylation system of allene sulfonamides and cyclopropanol. The regioselectivity of this system is closely related to the participation of the directing group (Org. Lett. 2025, 27, 1706–1713). Recently, Cho's team developed a nickel-silicon hydrogen catalytic system at 50 °C to achieve the 3,2-hydroallylation reaction of allenes with vinylcyclopropane. Among them, 1,1-diaryl allenes showed good coupling efficiency, and there is still room for further expansion of the applicability of other allene substrates (Org. Lett. 2025,27, 12880–12885).

[0007] In general, the reported strategies each have their own characteristics in terms of reaction conditions, availability of alkylating reagents, substrate range of allenes, requirement for directing groups, and catalyst cost, and there is still room for further optimization and improvement. Against this backdrop, developing a new method with mild conditions, readily available alkylating reagents, broad substrate scope, no need for directing groups, and inexpensive and readily available catalysts to achieve efficient 3,2-hydroalkylation of terminal allenes is of significant scientific importance for enriching the synthetic strategies of tri(tetra)substituted alkenes and promoting the continued development of the field of 3,2-hydrofunctionalization of allenes. Summary of the Invention

[0008] In view of this, in order to solve at least one technical problem in related technologies and other aspects, this application proposes a method for the directed synthesis of tri(tetra)substituted alkenes, comprising: mixing allene, alkyl iodine, nickel catalyst, ligand and base uniformly, then adding hydrogen source and solvent to undergo 3,2-hydroalkylation reaction to obtain tri(tetra)substituted alkenes; wherein, in the presence of hydrogen source, base and ligand, the nickel catalyst is converted into a nickel hydride species to initiate catalysis, the nickel hydride species undergoes directed migration insertion into the allene to obtain an alkenyl nickel species, and the alkenyl nickel species undergoes oxidative addition and reductive elimination reactions with alkyl iodine to obtain tri(tetra)substituted alkenes.

[0009] According to embodiments of this application, the allene is a terminal allene having the structure of formula (1).

[0010] Equation (1);

[0011] Alkyl iodine is the non-activated alkyl iodine shown in formula (2) below.

[0012] Equation (2);

[0013] Among them, R 1 It is selected from any one of substituted or unsubstituted C1-C8 alkyl, phenyl, and naphthyl groups, and the substituents include nitrogen-containing groups, oxygen-containing groups, aryl groups, and halogens;

[0014] R 2 Selected from hydrogen and alkyl groups;

[0015] R 3 Selected from C1 to C8 substituted or unsubstituted alkyl groups, the substituents including nitrogen-containing groups and oxygen-containing groups.

[0016] According to embodiments of this application, the molar ratio of allene to alkyl iodine is 1:2 or 2:1.

[0017] According to embodiments of this application, the ligands are as shown in formulas (3-1) to (3-3):

[0018] ;

[0019] Among them, R 1 Selected from hydrogen, C1-C3 alkyl, cycloalkyl, and aryl;

[0020] R 2 Selected from any one of C1-C3 alkyl, cycloalkyl, and aryl groups;

[0021] R 3 Selected from hydrogen and C1-C3 alkyl groups;

[0022] R 4 Selected from aryl;

[0023] R 5 Selected from aryl;

[0024] R 6 Selected from hydrogen, C1-C3 alkyl, and aryl;

[0025] R 7 Selected from aryl;

[0026] R 8 Selected from aryl compounds.

[0027] According to embodiments of this application, the amount of ligand used is 15% of the molar amount of the lesser component in the allene or alkyl iodine.

[0028] According to embodiments of this application, the alkali includes one of lithium tert-butoxide, lithium methoxide, sodium tert-butoxide, sodium carbonate, potassium fluoride, potassium tert-butoxide, potassium carbonate, potassium bicarbonate, rubidium fluoride, cesium fluoride, and cesium carbonate.

[0029] The amount of base used is three times the molar amount of the lesser component in allene or alkyl iodine.

[0030] According to embodiments of this application, the nickel catalyst includes one of nickel bromide diethylene glycol dimethyl ether, nickel chloride, nickel iodide, and nickel trifluoromethanesulfonate;

[0031] The amount of nickel catalyst is 10% of the molar amount of the lesser component in allene or alkyl iodine.

[0032] According to embodiments of this application, the hydrogen source includes at least one of phenylsilane, diphenylsilane, triethoxysilane, methyldimethoxysilane, methyldiethoxysilane, and polymethylhydrosiloxane.

[0033] The amount of hydrogen source used is twice the molar amount of the lesser component in allene or alkyl iodine.

[0034] According to embodiments of this application, the solvent includes at least one selected from ethylene glycol dimethyl ether, tetrahydrofuran, 1,4-dioxane, 1,3-dioxolane, 2-methyltetrahydrofuran, methyl tert-butyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, N,N-dimethylpropenylurea, trifluorotoluene, ethyl acetate, 1,2-dichloroethane, acetonitrile, and acetone.

[0035] According to the embodiments of this application, in the 3,2-hydroalkylation reaction, the reaction temperature is -20°C to 25°C, and the reaction time is 8 to 12 hours.

[0036] This application provides a method for the directional, simple, and efficient synthesis of tri(tetra)substituted alkenes under mild conditions using readily available alkylating reagents via nickel-catalyzed 3,2-hydroalkylation of terminal allenes. Attached Figure Description

[0037] Figure 1 This is the 1H NMR spectrum of compound 1 prepared in Example 1 of this application;

[0038] Figure 2 The proton NMR spectrum of compound 11 prepared in Example 11 of this application;

[0039] Figure 3 Compound 11 prepared in Example 11 of this application 1 H- 1 H NOESY spectrum;

[0040] Figure 4 The proton NMR spectrum of compound 16 prepared in Example 16 of this application. Detailed Implementation

[0041] To make the objectives, technical solutions, and advantages of this application clearer, the following detailed description is provided in conjunction with specific embodiments and the accompanying drawings.

[0042] The endpoints and any values ​​of the ranges disclosed in this application are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this application.

[0043] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of this application. The terms “comprising,” “including,” etc., as used herein indicate the presence of the stated features, steps, operations, and / or components, but do not exclude the presence or addition of one or more other features, steps, operations, or components.

[0044] All terms used herein (including technical and scientific terms) have the meanings commonly understood by those skilled in the art, unless otherwise defined. It should be noted that the terms used herein are to be interpreted in a manner consistent with the context of this specification, and not in an idealized or overly rigid way.

[0045] Throughout the accompanying drawings, identical elements are represented by the same or similar reference numerals. Conventional structures or configurations will be omitted where they may cause confusion in understanding this application. Furthermore, the shapes, dimensions, and positional relationships of the components in the drawings do not reflect their actual size, scale, or actual positional relationships. Additionally, any reference symbols placed within parentheses in this application should not be construed as limiting the scope of this application.

[0046] Similarly, to simplify this application and aid in understanding one or more of the various disclosed aspects, in the above description of exemplary embodiments of this application, various features of this application are sometimes grouped together into a single embodiment, figure, or description thereof. The use of terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicates that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of this application. In this specification, illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples.

[0047] Furthermore, the technical solutions of the various embodiments can be combined with each other, but only if they are based on the ability of those skilled in the art to implement them. When the combination of technical solutions is contradictory or cannot be implemented, it should be considered that such combination of technical solutions does not exist and is not within the scope of protection claimed in this application.

[0048] In the process of developing this application, it was found that existing methods for synthesizing tri(tetra)substituted alkenes suffer from problems such as harsh reaction conditions, lengthy synthesis steps of alkylating reagents, expensive catalysts, the need for directing groups to control regioselectivity, and limited substrate applicability. In particular, in the 3,2-hydroalkylation reaction of terminal allenes, related technologies are mostly focused on specific alkylating reagents, such as enamines, aldehydes, or vinylcyclopropanes, which are difficult to be compatible with monosubstituted allenes, and the applicability of non-activated alkyl iodides as alkylating reagents is lacking.

[0049] Therefore, the purpose of this application is to provide a method for the efficient synthesis of tri(tetra)substituted alkenes via a terminal allene 3,2-hydroalkylation reaction under mild conditions, using a simple and inexpensive nickel salt and readily available alkyl iodine as the alkylating agent.

[0050] This application proposes a method for the directed synthesis of tri(tetra)substituted alkenes, comprising: uniformly mixing allene, alkyl iodine, nickel catalyst, ligand and base, then adding hydrogen source and solvent to undergo a 3,2-hydroalkylation reaction to obtain tri(tetra)substituted alkenes; wherein, in the presence of hydrogen source, base and ligand, the nickel catalyst is converted into a nickel hydride species to initiate catalysis, the nickel hydride species undergoes directed migration and insertion into the allene to obtain an alkenyl nickel species, and the alkenyl nickel species undergoes oxidative addition and reductive elimination reactions with the alkyl iodine to obtain tri(tetra)substituted alkenes.

[0051] Specifically, its reaction formula is shown in equation (I) below:

[0052] , formula (I).

[0053] According to embodiments of this application, a nickel catalyst is used instead of the noble metal catalyst commonly used in related technologies, reducing the cost of the catalytic system. Through the synergistic effect of the ligand and the base, the nickel catalyst generates nickel-hydrogen active species in the presence of a hydrogen source, and performs directional 3,2-migration insertion into allenes, achieving effective control over the regioselectivity of the reaction. The alkyl iodine, as an alkylating agent, directly participates in the subsequent oxidative addition and reductive elimination processes, avoiding additional steps such as the pre-preparation of organometallic reagents. The entire reaction process is initiated after the addition of a hydrogen source, linking the triggering of the catalytic cycle with the reaction progress, enabling each step to proceed in an orderly manner. The method for the directional synthesis of tri(tetra)substituted alkenes claimed in this application can construct tri(tetra)substituted alkenes through a single multi-component reaction, which is relatively simple to operate, has relatively mild reaction conditions, and can obtain moderate to good yields.

[0054] According to embodiments of this application, the allene is a terminal allene having the structure of formula (1).

[0055] Equation (1);

[0056] Alkyl iodine is the non-activated alkyl iodine shown in formula (2) below.

[0057] Equation (2);

[0058] Among them, R 1 It is selected from any one of substituted or unsubstituted C1-C8 alkyl, phenyl, and naphthyl groups, and the substituents include nitrogen-containing groups, oxygen-containing groups, aryl groups, and halogens;

[0059] R 2 Selected from hydrogen and alkyl groups;

[0060] R 3 Selected from C1 to C8 substituted or unsubstituted alkyl groups, the substituents including nitrogen-containing groups and oxygen-containing groups.

[0061] According to embodiments of this application, by limiting the substituent range of allenes and alkyl iodides, the reaction is compatible with substrates of various structural types. Specifically, R 1 Including alkyl, aryl, and heteroatom-containing substituents, R 2 It can be hydrogen or alkyl, R 3 The alkyl groups can be substituted or unsubstituted with different chain lengths, demonstrating that this method has good applicability to monosubstituted and 1,1-disubstituted allenes as well as various non-activated alkyl iodides.

[0062] In some specific embodiments, the alkyl iodine is a primary alkyl iodine.

[0063] In some specific embodiments, R 1 R 2 R 3 The options are shown in Table 1 below.

[0064] Table 1

[0065]

[0066] According to embodiments of this application, the molar ratio of allene to alkyl iodine is 1:2 or 2:1.

[0067] According to embodiments of this application, the ligands are as shown in formulas (3-1) to (3-3):

[0068] ;

[0069] Among them, R 1Selected from hydrogen, C1-C3 alkyl, cycloalkyl, and aryl;

[0070] R 2 Selected from any one of C1-C3 alkyl, cycloalkyl, and aryl groups;

[0071] R 3 Selected from hydrogen and C1-C3 alkyl groups;

[0072] R 4 Selected from aryl;

[0073] R 5 Selected from aryl;

[0074] R 6 Selected from hydrogen, C1-C3 alkyl, and aryl;

[0075] R 7 Selected from aryl;

[0076] R 8 Selected from aryl compounds.

[0077] According to embodiments of this application, the ligand controls the migration and insertion sites of nickel-hydrogen to allenes by coordinating and regulating the electronic properties and steric hindrance of the nickel center, thereby achieving regioselective hydridation of the 3,2-site.

[0078] In some specific embodiments, the structure of the ligand is shown in equations L1-L14 below:

[0079] .

[0080] There is no specific quantity limit for i and p.

[0081] According to embodiments of this application, the amount of ligand used is 15% of the molar amount of the lesser component in the allene or alkyl iodine.

[0082] According to embodiments of this application, the role of the ligand is to enhance the activation ability of nickel for alkyl electrodes after coordination with nickel, stabilize the active metal intermediate species of the reaction, and control the regioselectivity of the reaction.

[0083] According to embodiments of this application, the alkali includes one of lithium tert-butoxide (t-BuOLi), lithium methoxide (MeOLi), sodium tert-butoxide (t-BuONa), sodium carbonate (Na2CO3), potassium fluoride (KF), potassium tert-butoxide (t-BuOK), potassium carbonate (K2CO3), potassium bicarbonate (KHCO3), rubidium fluoride (RbF), cesium fluoride (CsF), and cesium carbonate (Cs2CO);

[0084] The amount of base used is three times the molar amount of the lesser component in allene or alkyl iodine.

[0085] According to embodiments of this application, the base can provide nucleophilic anions in the reaction system. Its role is to promote the negative hydrogen transfer process between the nickel catalyst and the hydrogen source, assisting in the generation of active nickel-hydrogen species and maintaining the normal operation of the catalytic cycle. Using three equivalents of base can provide sufficient nucleophilic anions for the catalytic cycle, ensuring the smooth progress of the reaction and improving the efficiency of nickel-hydrogen species generation.

[0086] According to embodiments of this application, the nickel catalyst includes one of nickel bromide (NiBr2(diglyme) or NiBr2), nickel chloride (NiCl2), nickel iodide (NiI2), and nickel trifluoromethanesulfonate (Ni(OTf)2);

[0087] The amount of nickel catalyst is 10% of the molar amount of the lesser component in allene or alkyl iodine.

[0088] According to the embodiments of this application, the nickel catalyst is a common divalent nickel salt, which is widely available and inexpensive. Using a small amount of the component, 10% of the molar amount, as the catalyst dosage can ensure that sufficient catalytic active sites participate in the reaction while avoiding excessive use, which is beneficial for controlling the balance between catalytic efficiency and reaction cost.

[0089] According to embodiments of this application, the hydrogen source includes at least one of phenylsilane (PhSiH3), diphenylsilane (Ph2SiH2), triethoxysilane ((EtO)3SiH), methyldimethoxysilane (DMMS), methyldiethoxysilane (DEMS), and polymethylhydrosiloxane (PMHS).

[0090] The amount of hydrogen source used is twice the molar amount of the lesser component in allene or alkyl iodine.

[0091] According to embodiments of this application, using silane compounds as a hydrogen source enables the reduction of divalent nickel to active monovalent nickel-hydrogen species under reaction conditions, thus initiating a catalytic cycle. Using twice the molar amount of a smaller component provides sufficient hydrogen for the reduction process while maintaining the concentration of active nickel-hydrogen species in the reaction system. Adding the hydrogen source last prevents it from reducing the catalyst in the initial stage, ensuring the catalytic cycle starts orderly after thorough substrate mixing, which is beneficial for controlling the reaction progress.

[0092] According to embodiments of this application, the solvent includes at least one selected from ethylene glycol dimethyl ether (DME), tetrahydrofuran, 1,4-dioxane, 1,3-dioxolane, 2-methyltetrahydrofuran, methyl tert-butyl ether, N,N-dimethylformamide (DMF), dimethylacetamide (DMAc), N-methylpyrrolidone, N,N-dimethylpropenylurea, trifluorotoluene, ethyl acetate, 1,2-dichloroethane, acetonitrile, and acetone.

[0093] According to the embodiments of this application, the solvent can be selected from various types such as ethers, amides, halogenated hydrocarbons, nitriles, and ketones, which is beneficial for adapting to allenes and alkyl iodide substrates with different solubilities. This allows the reaction system to maintain a homogeneous state in a single solvent or mixed solvent, which is conducive to sufficient contact between the substrate and the catalytic active center and ensures the smooth progress of the reaction.

[0094] According to the embodiments of this application, in the 3,2-hydroalkylation reaction, the reaction temperature is -20°C to 25°C, and the reaction time is 8 to 12 hours.

[0095] According to embodiments of this application, the catalytic cycle is initiated under mild conditions of room temperature or low temperature, avoiding side reactions or catalyst deactivation that may be caused by high temperatures. The reaction time is controlled within 8 to 12 hours, which ensures sufficient substrate conversion while avoiding efficiency loss due to excessively long reaction times, making it suitable for the synthesis needs of different active substrates.

[0096] In some specific embodiments, the method for the directed synthesis of tri(tetra)substituted olefins is as follows: First, at room temperature and in air, allene, alkyl iodine, nickel catalyst, ligand, and base are added to a Shrek tube equipped with a magnetic stirrer. Second, in an inert gas atmosphere, a solvent and a hydrogen source are added to the reaction system to carry out a hydroalkylation reaction.

[0097] It should be noted that the described embodiments are merely some, not all, of the embodiments described in this application. Other embodiments obtained by those skilled in the art based on the embodiments described in this application without inventive effort are all within the scope of protection of this application.

[0098] Example 1:

[0099] Weigh allene 1 (0.4 mmol), 2-(3-iodopropoxy)naphthalene (0.2 mmol), ligand L8 (0.03 mmol), NiBr2 (diglyme) (0.02 mmol), CsF (0.6 mmol), DME (2.0 mL), and PMHS (0.4 mmol). React at 10 °C for 12 h, and separate by column chromatography to obtain compound 1.

[0100] Figure 1 The 1H NMR spectrum of compound 1 prepared in Example 1 of this application;

[0101] like Figure 1 As shown, the test results are as follows: 1 H NMR (400 MHz, chloroform-d) δ 7.68 – 7.59 (m, 3H), 7.33 (t, J = 7.5 Hz, 1H), 7.22 (t, J = 7.5 Hz, 1H), 7.06 (dd, J = 8.9, 2.5Hz, 1H), 7.01 (d, J = 2.6 Hz, 1H), 5.11 (t, J = 7.2 Hz, 1H), 3.94 (t, J = 6.5Hz, 2H), 2.10 (t, J = 7.5 Hz, 2H), 1.94 – 1.80 (m, 4H), 1.56 (s, 3H), 1.17(d, J = 9.4 Hz, 12H), 0.79 (t, J = 6.7 Hz, 3H).

[0102] It was determined to be a colorless liquid with a yield of 68%, rr > 20:1, and E / Z > 20:1.

[0103] Specifically, its reaction formula is shown in equation (1-1):

[0104] Equation (1-1).

[0105] Where n is not specifically limited.

[0106] Example 2:

[0107] Weigh allene 2 (0.2 mmol), 2-(3-iodopropoxy)naphthalene (0.4 mmol), ligand L8 (0.03 mmol), NiBr2 (diglyme) (0.02 mmol), CsF (0.6 mmol), DME (2.0 mL), and PMHS (0.4 mmol), react at 10 °C for 12 h, and separate by column chromatography to obtain compound 2.

[0108] It was determined to be a colorless liquid with a yield of 66%, rr > 20:1, and E / Z > 20:1.

[0109] Specifically, its reaction formula is shown in equation (1-2) below:

[0110] Equation (1-2).

[0111] Example 3:

[0112] Weigh allene 3 (0.2 mmol), 2-(3-iodopropoxy)naphthalene (0.4 mmol), ligand L8 (0.03 mmol), NiBr2 (diglyme) (0.02 mmol), CsF (0.6 mmol), DME (2.0 mL), and PMHS (0.4 mmol), react at 10 °C for 12 h, and separate by column chromatography to obtain compound 3.

[0113] It was determined to be a colorless liquid with a yield of 62%, rr > 20:1, and E / Z > 20:1.

[0114] Specifically, its reaction formula is shown in equation (1-3) below:

[0115] Equation (1-3).

[0116] Example 4:

[0117] Weigh allene 4 (0.2 mmol), 2-(3-iodopropoxy)naphthalene (0.4 mmol), ligand L8 (0.03 mmol), NiBr2 (diglyme) (0.02 mmol), CsF (0.6 mmol), DME (2.0 mL), and PMHS (0.4 mmol), react at 10 °C for 12 h, and separate by column chromatography to obtain compound 4.

[0118] Specifically, its reaction formula is shown in equation (1-4) below:

[0119] It was determined to be a colorless liquid with a yield of 63%, rr > 20:1, and E / Z > 20:1.

[0120] Equation (1-4).

[0121] Example 5:

[0122] Weigh allene 5 (0.2 mmol), 2-(3-iodopropoxy)naphthalene (0.4 mmol), ligand L8 (0.03 mmol), NiBr2 (diglyme) (0.02 mmol), CsF (0.6 mmol), DME (2.0 mL), and PMHS (0.4 mmol), react at 10 °C for 12 h, and separate by column chromatography to obtain compound 5.

[0123] It was determined to be a colorless liquid with a yield of 70%, rr > 20:1, and E / Z > 20:1.

[0124] Specifically, its reaction formula is shown in equation (1-5):

[0125] Equation (1-5).

[0126] Example 6:

[0127] Weigh allene 6 (0.2 mmol), 2-(3-iodopropoxy)naphthalene (0.4 mmol), ligand L8 (0.03 mmol), NiBr2 (diglyme) (0.02 mmol), CsF (0.6 mmol), DME (2.0 mL), and PMHS (0.4 mmol), react at 10 °C for 12 h, and separate by column chromatography to obtain compound 6.

[0128] It was determined to be a white solid with a yield of 40%, rr > 20:1, and E / Z > 20:1.

[0129] Specifically, its reaction formula is shown in equation (1-6) below:

[0130] Equation (1-6).

[0131] Example 7:

[0132] Weigh allene 7 (0.2 mmol), 2-(3-iodopropoxy)naphthalene (0.4 mmol), ligand L8 (0.03 mmol), NiBr2 (diglyme) (0.02 mmol), CsF (0.6 mmol), DME (2.0 mL), and PMHS (0.4 mmol), react at 10 °C for 12 h, and separate by column chromatography to obtain compound 7.

[0133] It was determined to be a white solid with a yield of 40%, rr > 20:1, and E / Z > 20:1.

[0134] Specifically, its reaction formula is shown in equation (1-7):

[0135] Equation (1-7).

[0136] Example 8:

[0137] Weigh allene 8 (0.2 mmol), 2-(3-iodopropoxy)naphthalene (0.4 mmol), ligand L8 (0.03 mmol), NiBr2 (diglyme) (0.02 mmol), CsF (0.6 mmol), DME (2.0 mL), and PMHS (0.4 mmol), react at 10 °C for 12 h, and separate by column chromatography to obtain compound 8.

[0138] It was determined to be a white solid with a yield of 73%, rr > 20:1, and E / Z > 20:1.

[0139] Specifically, its reaction formula is shown in equation (1-8) below:

[0140] Equation (1-8).

[0141] Example 9:

[0142] Weigh allene 9 (0.2 mmol), 2-(3-iodopropoxy)naphthalene (0.4 mmol), ligand L8 (0.03 mmol), NiBr2 (diglyme) (0.02 mmol), CsF (0.6 mmol), DME (2.0 mL), and PMHS (0.4 mmol), react at 10 °C for 12 h, and separate by column chromatography to obtain compound 9.

[0143] It was found to be a white solid with a yield of 72%, rr > 20:1, and E / Z > 20:1.

[0144] Specifically, its reaction formula is shown in equation (1-9) below:

[0145] Equation (1-9).

[0146] Example 10:

[0147] Weigh allene 10 (0.2 mmol), 2-(3-iodopropoxy)naphthalene (0.4 mmol), ligand L8 (0.03 mmol), NiBr2 (diglyme) (0.02 mmol), CsF (0.6 mmol), DME (2.0 mL), and PMHS (0.4 mmol). React at 10 °C for 12 h, and separate by column chromatography to obtain compound 10.

[0148] It was found to be a white solid with a yield of 69%, rr > 20:1, and E / Z > 20:1.

[0149] Specifically, its reaction formula is shown in equation (1-10) below:

[0150] Equation (1-10).

[0151] Example 11:

[0152] Weigh allene 11 (0.2 mmol), 2-(3-iodopropoxy)naphthalene (0.4 mmol), ligand L8 (0.03 mmol), NiBr2 (diglyme) (0.02 mmol), CsF (0.6 mmol), DME (2.0 mL), and PMHS (0.4 mmol). React at 10 °C for 12 h, and separate by column chromatography to obtain compound 11.

[0153] Figure 2 The 1H NMR spectrum of compound 11 prepared in Example 11 of this application; Figure 3 The compound 11 prepared in Example 11 of this application1 H- 1 H NOESY spectrum.

[0154] like Figure 2 , Figure 3 As shown, the test results are as follows: 1 ¹H NMR (500 MHz, chloroform-d) δ 7.66 – 7.57 (m, 3H), 7.31 (ddd, J = 8.0, 6.7, 1.3 Hz, 1H), 7.23 – 7.17 (m, 3H), 7.12 (d, J = 7.3 Hz, 2H), 7.07 (ddd, J = 8.8, 6.3, 1.9 Hz, 2H), 7.02 (d, J = 2.5 Hz, 1H), 6.23 (s, 1H), 3.99 (t, J = 6.4 Hz, 2H), 2.27 (t, J = 7.6 Hz, 2H), 1.98 – 1.92 (m, 2H), 1.81 – 1.79 (m, 3H).

[0155] It was determined to be a white solid with a yield of 57%, rr > 20:1, and E / Z > 20:1.

[0156] Specifically, its reaction formula is shown in equation (1-11):

[0157] Equation (1-11).

[0158] Example 12:

[0159] Weigh allene 12 (0.2 mmol), 2-(3-iodopropoxy)naphthalene (0.4 mmol), ligand L8 (0.03 mmol), NiBr2 (diglyme) (0.02 mmol), CsF (0.6 mmol), DME (2.0 mL), and PMHS (0.4 mmol), react at 10 °C for 12 h, and separate by column chromatography to obtain compound 12.

[0160] It was determined to be a white solid with a yield of 40%, rr > 20:1, and E / Z > 20:1.

[0161] Specifically, its reaction formula is shown in equation (1-12):

[0162] Equation (1-12).

[0163] Example 13:

[0164] Weigh allene 13 (0.2 mmol), 2-(3-iodopropoxy)naphthalene (0.4 mmol), ligand L8 (0.03 mmol), NiBr2 (diglyme) (0.02 mmol), CsF (0.6 mmol), and DME (2.0 mL). React at 10 °C for 12 h, and separate by column chromatography to obtain compound 13.

[0165] It was determined to be a white solid with a yield of 61%, rr > 20:1, and E / Z > 20:1.

[0166] Specifically, its reaction formula is shown in equation (1-13):

[0167] Equation (1-13).

[0168] Example 14:

[0169] Weigh allene 11 (0.2 mmol), 2-(3-iodopropoxy)benzene (0.4 mmol), ligand L8 (0.03 mmol), NiBr2 (diglyme) (0.02 mmol), CsF (0.6 mmol), DME (2.0 mL), and PMHS (0.4 mmol). React at 10 °C for 12 h. Separate compound 14 by column chromatography.

[0170] It was determined to be a colorless liquid with a yield of 51%, rr > 20:1, and E / Z > 20:1.

[0171] Specifically, its reaction formula is shown in equation (1-14):

[0172] Equation (1-14).

[0173] Example 15:

[0174] Weigh allene 11 (0.2 mmol), n-iodohexane (0.4 mmol), ligand L8 (0.03 mmol), NiBr2 (diglyme) (0.02 mmol), CsF (0.6 mmol), DME (2.0 mL), and PMHS (0.4 mmol). React at 10 °C for 12 h. Separate compound 15 by column chromatography.

[0175] It was determined to be a colorless liquid with a yield of 47%, rr > 20:1, and E / Z > 20:1.

[0176] Specifically, its reaction formula is shown in equation (1-15):

[0177] Equation (1-15).

[0178] Example 16:

[0179] Weigh allene 11 (0.2 mmol), n-iodobutane (0.4 mmol), ligand L8 (0.03 mmol), NiBr2 (diglyme) (0.02 mmol), CsF (0.6 mmol), DME (2.0 mL), and PMHS (0.4 mmol). React at 10 °C for 12 h. Separate compound 16 by column chromatography.

[0180] Figure 4 The proton NMR spectrum of compound 16 prepared in Example 16 of this application.

[0181] like Figure 4 As shown, the test results are as follows: 1 ¹H NMR (400 MHz, chloroform-d) δ 7.34 – 7.28 (m, 2H), 7.25 – 7.14 (m, 3H), 6.26 (s, 1H), 2.19 – 2.12 (m, 2H), 1.85 (d, J = 1.4 Hz, 3H), 1.52 – 1.47 (m, 2H), 1.40 – 1.31 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H).

[0182] It was determined to be a colorless liquid with a yield of 43%, rr > 20:1, and E / Z > 20:1.

[0183] Specifically, its reaction formula is shown in equation (1-16):

[0184] Equation (1-16).

[0185] Example 17:

[0186] Weigh allene 14 (0.2 mmol), 2-(3-iodopropoxy)naphthalene (0.4 mmol), ligand L8 (0.03 mmol), NiBr2 (diglyme) (0.02 mmol), CsF (0.6 mmol), and DME (2.0 mL). React at 10 °C for 12 h. Separate compound 17 by column chromatography.

[0187] It was determined to be a white solid with a yield of 56%, rr > 20:1, and E / Z > 20:1.

[0188] Specifically, its reaction formula is shown in equation (1-17):

[0189] Equation (1-17).

[0190] Example 18:

[0191] Weigh allene 15 (0.2 mmol), 2-(3-iodopropoxy)naphthalene (0.4 mmol), ligand L8 (0.03 mmol), NiBr2 (diglyme) (0.02 mmol), CsF (0.6 mmol), and DME (2.0 mL). React at 10 °C for 12 h. Separate compound 18 by column chromatography.

[0192] It was determined to be a colorless liquid with a yield of 61%, rr > 20:1, and E / Z > 20:1.

[0193] Specifically, its reaction formula is shown in equation (1-18):

[0194] Equation (1-18).

[0195] The group R involved in Examples 1-18 above 1 It is 2-naphthoxy, R 2 It is a phenoxy group.

[0196] The specific embodiments described above further illustrate the purpose, technical solution, and beneficial effects of this application. It should be understood that the above descriptions are merely specific embodiments of this application and are not intended to limit this application. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this application should be included within the protection scope of this application.

Claims

1. A method for the directed synthesis of tri(tetra)substituted alkenes, comprising: Allene, alkyl iodine, nickel catalyst, ligand, and base are mixed uniformly, and then a hydrogen source and solvent are added to induce a 3,2-hydroalkylation reaction to obtain a tri(tetra)substituted olefin; wherein, the 3,2-hydroalkylation reaction includes: In the presence of the hydrogen source, the base, and the ligand, the nickel catalyst is converted into a nickel-hydrogen species and catalysis is initiated. The nickel-hydrogen species undergoes directional migration and insertion into the allene to obtain an alkenyl nickel species. The alkenyl nickel species undergoes oxidative addition and reductive elimination reactions with the alkyl iodine to obtain the tri(tetra) substituted olefin.

2. The method according to claim 1, wherein, The allene is a terminal allene having the structure of formula (1). Equation (1); The alkyl iodine is a non-activated alkyl iodine as shown in formula (2). Equation (2); Among them, R 1 The substituent is selected from any one of substituted or unsubstituted C1-C8 alkyl, phenyl, and naphthyl groups, wherein the substituent includes nitrogen-containing groups, oxygen-containing groups, aryl groups, and halogens; R 2 Selected from hydrogen and alkyl groups; R 3 The substituents are selected from C1 to C8 substituted or unsubstituted alkyl groups, and the substituents include nitrogen-containing groups and oxygen-containing groups.

3. The method according to claim 2, wherein, The molar ratio of the allene to the alkyl iodine is 1:2 or 2:

1.

4. The method according to claim 1, wherein, The ligands are shown in equations (3-1) to (3-3): ； Among them, R 1 Selected from hydrogen, C1-C3 alkyl, cycloalkyl, and aryl; R 2 Selected from any one of C1-C3 alkyl, cycloalkyl, and aryl groups; R 3 Selected from hydrogen and C1-C3 alkyl groups; R 4 Selected from aryl; R 5 Selected from aryl; R 6 Selected from hydrogen, C1-C3 alkyl, and aryl; R 7 Selected from aryl; R 8 Selected from aryl compounds.

5. The method according to claim 4, wherein, The amount of the ligand is 15% of the molar amount of the lesser component in the allene or the alkyl iodine.

6. The method according to claim 1, wherein, The alkali includes one of lithium tert-butoxide, lithium methoxide, sodium tert-butoxide, sodium carbonate, potassium fluoride, potassium tert-butoxide, potassium carbonate, potassium bicarbonate, rubidium fluoride, cesium fluoride, and cesium carbonate. The amount of base used is three times the molar amount of the lesser component in the allene or alkyl iodine.

7. The method according to claim 1, wherein, The nickel catalyst includes one of nickel bromide diethylene glycol dimethyl ether, nickel chloride, nickel iodide, and nickel trifluoromethanesulfonate; The amount of nickel catalyst used is 10% of the molar amount of the lesser component in the allene or alkyl iodine.

8. The method according to claim 1, wherein, The hydrogen source includes at least one of phenylsilane, diphenylsilane, triethoxysilane, methyldimethoxysilane, methyldiethoxysilane, and polymethylhydrosiloxane; The amount of hydrogen source used is twice the molar amount of the lesser component in the allene or alkyl iodine.

9. The method according to claim 1, wherein, The solvent includes at least one of ethylene glycol dimethyl ether, tetrahydrofuran, 1,4-dioxane, 1,3-dioxolane, 2-methyltetrahydrofuran, methyl tert-butyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, N,N-dimethylpropenylurea, trifluorotoluene, ethyl acetate, 1,2-dichloroethane, acetonitrile, and acetone.

10. The method according to claim 1, wherein, In the 3,2-hydroalkylation reaction, the reaction temperature is -20℃ to 25℃ and the reaction time is 8 to 12 h.

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