A method for preparing polysubstituted olefins

Abstract

This patent application discloses a method for preparing polysubstituted olefins. This method, for the first time, develops a strategy where an alkyne halide first forms an alkenyl metal species, followed by C-H bond activation under the promotion of an amide to form a polysubstituted olefin. This achieves site-selective and stereoselective introduction of alkenyl segments into the amide molecule to form polysubstituted olefins. Under inert solvent conditions, and with the combined action of a transition metal catalyst and an oxidant, the alkyne halide first forms an allenone, then generates an alkenyl metal species under the action of a metal, followed by C-H bond activation to form a polysubstituted olefin. Considering that amides and olefins are ubiquitous functional groups in natural products, drugs, and materials, this reaction is expected to provide new ideas for the development and application of related new drugs and novel functional materials.

Description

Technical Field

[0001] This patent application relates to the field of organic compound synthesis technology, and more specifically, to a method for preparing polysubstituted olefins. Background Technology

[0002] Polysubstituted alkenes are widely found synthetic intermediates or products with broad applications in organic chemistry. Numerous methods exist for their synthesis, including Wittig-type reactions of carbonyl compounds, Heck reactions, alkyne carbon-metallization, olefin isomerization, and olefin metathesis reactions. However, these methods typically suffer from drawbacks such as poor procedural economy, low yields, the need for pre-prepared substrates, poor regio or stereoselectivity, and poor functional group tolerance, thus limiting the versatility of the substrates and the reaction selectivity. Therefore, regio- and stereoselective synthetic methods for polysubstituted alkenes remain worthy of further exploration.

[0003] It is particularly noteworthy that introducing electron-rich alkyl (such as β-H-containing alkyl) alkene skeletons is often extremely challenging. This is mainly because metal-catalyzed cross-coupling reactions with β-H-containing alkenyl metal reagents or alkenyl halides often produce non-target isomers during the reaction, thereby reducing the overall reaction efficiency and stereoselectivity. In summary, the regio- and stereoselective introduction of alkenyl segments into molecules, especially polyalkyl-substituted alkenes containing β-H, is both highly challenging and promising.

[0004] Based on our research interests in weakly coordinated C-H bond alkynylation, we have achieved Csp-H bond alkynylation promoted by weakly coordinated and easily convertible functional groups such as esters, ketones, sulfonamides, amides, alcohols, and amine derivatives. 2 -H and Csp 3 -H alkyneation (Angew. Chem. Int. Ed. 2014, 53, 14485-144895. Org. Chem. Front., 2021, 8, 6484-6490. (Front Cover); Chem. Commun., 2020, 56, 11255-11258. Chin. J. Chem., 2020, 38, 929-934. Org. Chem. Front., 2019, 6, 284-289. (Front Cover, Hot Paper); J. Org. Chem., 2017, 82, 13003-13011.) provides a new approach for the simplified synthesis of polyfunctional alkynes.

[0005] On the other hand, as readily available and multifunctional synthons, acetylene halides have recently provided a simple route for the highly selective synthesis of various functional molecules in transition metal catalysis. The applicant summarizes several reaction modes of acetylene halides: First, under basic conditions, acetylene halides break the CX bond through metal-halogen atom exchange to obtain acetyl anions; second, acetylene halides react with nucleophiles as electrophilic acetyl reagents; third, acetylene halides dissociate into halide cations under the action of organolithium reagents, which then act as electrophilic halogenating reagents in the reaction; fourth, acetylene halides react simultaneously as both electrophilic halogenating reagents and nucleophilic acetyl reagents. In general, further development of more reactivity of acetylene halides remains highly anticipated.

[0006] Classical directed-coordination strategies for metal-catalyzed C-H bond activation reactions utilize the coordination between the directing group and the metal catalyst to guide the in-situ formation of cyclometalation intermediates, thereby achieving site selectivity. However, this also leads to competitive coordination with substrates containing multiple functional groups, often resulting in metal catalyst deactivation or non-target site selectivity.

[0007] In summary, developing novel reactivity of acetylene halides to overcome certain shortcomings in existing Heck reactions and oxidation Heck reactions is both highly challenging and promising.

[0008] Patent application content

[0009] To overcome at least one problem existing in the prior art, this patent application provides a method for preparing polysubstituted olefins. This method utilizes the carbon-hydrogen bond activation promoted by the natural functional group amide to achieve site-selective and stereoselective introduction of alkenyl segments to construct polysubstituted olefins.

[0010] This patent application provides a method for preparing polysubstituted olefins, comprising the following steps: under inert solvent conditions, an amide compound and an alkyne bromide compound, under the combined action of a catalyst and an oxidant, first form an alkyne halide into an alkenyl metal species, and finally, under the promotion of the amide, undergo C-H bond activation to form a polysubstituted olefin. This method is highly efficient and economical (no prior metallization of the raw materials is required) and has a wide range of applicable substrates. This preparation method features readily available and easily convertible raw materials and high efficiency.

[0011] The possible reaction mechanism in the preparation method of this patent application is as follows:

[0012]

[0013] The specific mechanism is as follows: under the promotion of a base, the alkynyl halide leaves a sterically hindered group to generate an alkynyl carbocation A. It may undergo a Meyer-Schuster rearrangement to rearrange into an allene carbocation B. Subsequently, under the affinity attack of water, it generates C. Finally, it loses a hydrogen bromide to generate an allene ketone. The allene ketone loses carbon monoxide under the action of a metal to generate an alkenyl metal species E. Subsequently, under the promotion of an amide, it undergoes C-H bond activation to achieve the synthesis of polysubstituted alkenes.

[0014] To solve the above-mentioned technical problems, the technical solution adopted in this patent application is:

[0015] A method for preparing a polysubstituted olefin includes the following steps: Under inert solvent conditions, an amide compound (Formula II) and an alkyne bromide compound (Formula III) react in the presence of a catalyst and an oxidant. The alkyne halide first forms an alkenyl metal species, and then, with the amide promoting carbon-hydrogen bond activation, a polysubstituted olefin (Formula I) is formed. The reaction equation is as follows:

[0016]

[0017] Where Ar represents a benzene ring, fused ring, heterocycle, or biaromatic ring containing different substituents, and R represents an alkyl group. 1 R 2 Both are alkyl or aryl, and n is 0 or 1.

[0018] Preferably, the amount of catalyst used is 2 mol% of the amount of the amide compound (Formula II).

[0019] Preferably, the catalyst is any one or a combination of pentamethylcyclopentadienyl rhodium chloride dimer, pentamethylcyclopentadienyl iridium chloride dimer, palladium acetate, dichloro(p-methylisopropylphenyl)ruthenium dimer, cobalt acetylacetonate, and manganese pentacarbonyl bromide.

[0020] Preferably, the oxidant is any one or more of silver acetate, silver carbonate, silver oxide, and potassium persulfate.

[0021] Preferably, the additive is any one or a combination of silver hexafluoroantimonate, silver bis(trifluoromethanesulfonyl)imide, sodium bicarbonate, lithium acetate, and dipotassium hydrogen phosphate.

[0022] Preferably, the inert solvent is any one or more of 1,2-dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, N,N'-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, and ethanol.

[0023] Preferably, the reaction is carried out at 80–120°C for 6–24 hours.

[0024] More preferably, the method for preparing the polysubstituted olefin includes the following specific steps:

[0025] S1: In the reactor, in air, add 22.7 mg N-tert-butylnaphthalene-1-carboxamide, 49.5 mg ((1-(bromoethynyl)cycloheptyl)oxy)(tert-butyl)dimethylsilane, 1.2 mg pentamethylcyclopentadiene rhodium dichloride dimer, 1.9 mg silver trifluoromethanesulfonyl imide, 14.8 mg lithium carbonate, 33.4 mg silver acetate, and 1.0 mL 1,2-dichloroethane;

[0026] S2: React the reaction solution at 100℃ for 12 hours;

[0027] S3: After the reaction is complete, the above mixture is separated by column chromatography to obtain the target compound.

[0028] More preferably, the developing agent or eluent selected in the column chromatography separation technique is petroleum ether: ethyl acetate.

[0029] More preferably, the developing agent or eluent is petroleum ether:ethyl acetate in a ratio of 20:1.

[0030] Compared with the prior art, the beneficial effects of this patent application are:

[0031] The method for preparing polysubstituted olefins provided in this patent application involves the formation of alkyne halides into alkenyl metal species in an inert solvent under the action of a metal catalyst, followed by C-H bond activation promoted by an amide to form polysubstituted olefins. This method is highly efficient and economical (no prior metallization of the raw materials is required) and has a wide range of applicable substrates. This preparation method features readily available and easily convertible raw materials and high efficiency; furthermore, it utilizes the naturally occurring functional group amide to promote C-H bond activation, achieving site-selectivity and stereoselectivity in introducing alkenyl fragments to construct polysubstituted olefins. Attached Figure Description

[0032] Figure 1 The proton NMR spectrum of compound 1a prepared in Example 1 of this patent application;

[0033] Figure 2 The carbon NMR spectrum of compound 1a prepared in Example 1 of this patent application;

[0034] Figure 3 The proton NMR spectrum of compound 1b prepared in Example 2 of this patent application;

[0035] Figure 4 The carbon NMR spectrum of compound 1b prepared in Example 2 of this patent application;

[0036] Figure 5The proton NMR spectrum of compound 1c prepared in Example 3 of this patent application;

[0037] Figure 6 The carbon NMR spectrum of compound 1c prepared in Example 3 of this patent application;

[0038] Figure 7 The proton NMR spectrum of compound 1d prepared in Example 4 of this patent application;

[0039] Figure 8 The carbon NMR spectrum of compound 1d prepared in Example 4 of this patent application;

[0040] Figure 9 The proton NMR spectrum of compound 1e prepared in Example 5 of this patent application;

[0041] Figure 10 The carbon NMR spectrum of compound 1e prepared in Example 5 of this patent application;

[0042] Figure 11 The proton NMR spectrum of compound 1f prepared in Example 6 of this patent application;

[0043] Figure 12 The carbon NMR spectrum of compound 1f prepared in Example 6 of this patent application;

[0044] Figure 13 The proton NMR spectrum of 1g of the compound prepared in Example 7 of this patent application;

[0045] Figure 14 The carbon NMR spectrum of 1 g of the compound prepared in Example 7 of this patent application. Detailed Implementation

[0046] The embodiments of this patent application will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be construed as limiting the scope of this patent application. Where specific conditions are not specified in the examples, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0047] It should be noted that:

[0048] Unless otherwise specified, all embodiments and preferred embodiments mentioned herein can be combined to form new technical solutions.

[0049] In this patent application, unless otherwise stated, the various reactions or operation steps may be performed sequentially or in a particular order. Preferably, the reaction methods described herein are performed sequentially.

[0050] Unless otherwise stated, the technical and scientific terms used herein have the same meanings as those familiar to a person skilled in the art. Furthermore, any methods or materials similar to or equivalent to those described herein may also be used in this patent application.

[0051] This patent application is the first to develop a method for the initial generation of alkyne halide alkenyl metal species, followed by site- and stereoselective introduction of polysubstituted alkenes into the amide molecule via aromatic ring C-H bond activation with the assistance of the natural functional group amide. This transformation has the following characteristics: 1) The amide, as a natural functional group, serves as a directing group and reactant in this application, achieving high site- and stereoselective synthesis of polysubstituted alkenes; 2) The alkenyl-containing product obtained in this application exhibits excellent stereoselectivity, and the alkene contains β-H alkyl substitution, which is difficult to achieve with classical metal-catalyzed cross-coupling reactions.

[0052] This patent application provides a method for preparing a polysubstituted olefin. The method includes the following steps: under inert solvent conditions, an amide compound (Formula II) and an alkyne bromide compound (Formula III) react in the presence of a catalyst and an oxidant. The alkyne halide first forms an alkenyl metal species, and then, with the amide promoting C-H bond activation, a polysubstituted olefin (Formula I) is formed. The reaction equation is as follows:

[0053]

[0054] Where Ar represents a benzene ring, fused ring, heterocycle, or biaromatic ring containing different substituents, and R represents an alkyl group. 1 R 2 Both are alkyl or aryl, and n is 0 or 1.

[0055] This patent application utilizes the ubiquitous amide functional group in human production and daily life. A strategy is employed to first form an alkenyl metal species from an alkyne halide, followed by C-H bond activation under the promotion of the amide to form a polysubstituted olefin. This reaction exhibits excellent regio and stereoselectivity, and can introduce a polysubstituted alkenyl skeleton into the amide molecule via transcyclic C-H bond activation, while also being compatible with β-H-containing alkenyl segments. This transformation not only overcomes the limitations of the classical Heck reaction and the oxidative Heck reaction in incorporating polysubstituted, β-H-containing alkyl segments, but also offers potential for the novel synthesis and application of drugs and materials, considering the practicality of amides and polysubstituted alkenes.

[0056] The possible specific reaction mechanism flow in the preparation method of this patent application is as follows:

[0057] Under inert solvent conditions, alkynyl halides, with the aid of a base, leave sterically hindered groups to generate an alkynyl carbocation A. This carbocation A may undergo a Meyer-Schuster rearrangement to form an allene carbocation B, which then undergoes affinity attack with water to generate C. Finally, it loses a hydrogen bromide ion to form an allene ketone. The allene ketone, under the influence of a metal, loses carbon monoxide to generate an alkenyl metal species E. Subsequently, C-H bond activation occurs with the aid of an amide, achieving the synthesis of polysubstituted alkenes. This method features readily available and convertible directing groups, good procedural economy, and rapid construction of various polysubstituted alkenes, achieving regio- and stereoselective synthesis of polysubstituted alkenes. The specific reaction mechanism is as follows:

[0058]

[0059] The preparation method in this patent application involves a strategy of first forming alkenyl metal species from alkyne halides through carbon-hydrogen bond activation promoted by natural functional group amides, and finally forming polysubstituted olefins through carbon-hydrogen bond activation promoted by amides.

[0060] In some preferred embodiments, the amount of catalyst used is 2 mol% of the amount of the amide compound (Formula II).

[0061] In some preferred embodiments, the catalyst is any one or a combination of pentamethylcyclopentadienyl rhodium chloride dimer, pentamethylcyclopentadienyl iridium chloride dimer, palladium acetate, dichloro(p-methylisopropylphenyl)ruthenium dimer, cobalt acetylacetonate, and manganese pentacarbonyl bromide.

[0062] In some preferred embodiments, the oxidant is any one or more of silver acetate, silver carbonate, silver oxide, and potassium persulfate.

[0063] In some preferred embodiments, the additive is any one or a combination of silver hexafluoroantimonate, silver bis(trifluoromethanesulfonyl)imide, sodium bicarbonate, lithium acetate, and dipotassium hydrogen phosphate.

[0064] In some preferred embodiments, the inert solvent is any one or more of 1,2-dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, N,N'-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, and ethanol.

[0065] In some preferred embodiments, the reaction is carried out at 80–120°C for 6–24 hours.

[0066] In some preferred embodiments, the developing agent or eluent is petroleum ether:ethyl acetate in a ratio of 20:1.

[0067] The preparation method of the polysubstituted olefins of this patent application will be described in detail below with specific embodiments.

[0068] 1. Preparation Example

[0069] Example 1: Preparation of N-tert-butyl-2-cycloheptane-1-naphthamide (1a)

[0070] Under an atmospheric pressure, N-tert-butylnaphthalene-1-carboxamide 2a (22.7 mg, 0.10 mmol), ((1-(bromoethynyl)cycloheptyl)oxy)(tert-butyl)dimethylsilane 3a (49.5 mg, 0.15 mmol), pentamethylcyclopentadiene rhodium dichloride dimer [Cp*RhCl2]2 (1.2 mg, 0.002 mmol), silver trifluoromethanesulfonylimide (1.9 mg, 0.005 mmol), lithium carbonate (14.8 mg, 0.20 mmol), silver oxide (46.2 mg, 0.20 mmol), and 1,2-dichloroethane (DCE, 1.0 mL) were added sequentially to a 15 mL Schlenk tube, and the reaction was carried out at 100 °C for 12 hours. The crude product was separated by silica gel chromatography using a petroleum ether (PE):ethyl acetate (EA) ratio of 20:1 as the developing or eluent, yielding N-tert-butyl-2-cycloheptane-1-naphthamide (1a) in 69% yield. The corresponding chemical reaction equation for this example is as follows:

[0071]

[0072] The 1H and 1C NMR spectra of the compound prepared in Example 1 are shown below. Figure 1 and Figure 2 As shown. From Figure 1 It can be seen that: 1 ¹H NMR (400MHz, CDCl₃) δ 7.95 (d, J = 8.0Hz, 1H), 7.78 (t, J = 10.0Hz, 2H), 7.52–7.43 (m, 2H), 7.37 (d, J = 8.4Hz, 1H), 6.50 (s, 1H), 5.56 (s, 1H), 2.46–2.40 (m, 4H), 1.73–1.68 (m, 2H), 1.65–1.59 (m, 6H), 1.51 (s, 9H). The molecular ¹H NMR peak energies correspond one-to-one with the target product, and the number is reasonable. Figure 2 It can be seen that: 13C10 NMR (100MHz, CDCl3) δ 169.0, 147.1, 134.7, 132.9, 132.0, 130.2, 128.2, 127.9, 127.7, 126.9, 125.8, 125.2, 123.4, 100.1, 52.2, 43.1, 38.2, 31.4, 29.9, 29.3, 29.2, 29.1, 27.4, 22.2. The molecular carbon spectrum peaks correspond one-to-one with the target product, and the number is reasonable. Combining the above 1H and 1C NMR results, it can be concluded that the product obtained in Example 1 is N-tert-butyl-2-cycloheptane-1-naphthamide (1a).

[0073] In this embodiment, N-tert-butylnaphthalene-1-carboxamide 2a contains an amide functional group ubiquitous in human production and daily life. Promoted by this amide functional group, and through activation of the aromatic ring C-H bonds and the C-C triple bond in the acetylide ((1-(bromoethynyl)cycloheptyl)oxy)(tert-butyl)dimethylsilane 3a), a multi-substituted alkenyl segment was introduced into the C-H bonds of the arylformamide N-tert-butylnaphthalene-1-carboxamide 2a. This reaction exhibits excellent regio and stereoselectivity, and can introduce a multi-substituted alkenyl skeleton into the amide molecule via transcyclic C-H bond activation, while also being compatible with alkenyl segments containing β-H. In this embodiment, the reaction only requires atmospheric pressure and an air atmosphere at 100°C for 12 hours, followed by simple post-treatment, to obtain the final target product N-tert-butyl-2-cycloheptemethylene-1-naphthamide (1a) in a good yield (69%).

[0074] The chemical transformation in this embodiment can rapidly construct fused-ring polysubstituted olefins, which can be applied to organic optoelectronic materials.

[0075] Example 2 Preparation of N-tert-butyl-2-cycloheptane-6-methylbenzamide (1b)

[0076] Under an atmospheric pressure, N-tert-butyl-2-methylbenzamide 2b (19.1 mg, 0.10 mmol), ((1-(bromoethynyl)cycloheptyl)oxy)(tert-butyl)dimethylsilane 3b (49.5 mg, 0.15 mmol), pentamethylcyclopentadiene rhodium dichloride dimer [Cp*RhCl2]2 (1.2 mg, 0.002 mmol), silver trifluoromethanesulfonylimide (1.9 mg, 0.005 mmol), lithium carbonate (14.8 mg, 0.20 mmol), silver acetate (33.4 mg, 0.20 mmol), and 1,2-dichloroethane (DCE, 1.0 mL) were added sequentially to a 15 mL Schlenk tube, and the reaction was carried out at 100 °C for 12 hours. The crude product was separated by silica gel chromatography using a petroleum ether (PE):ethyl acetate (EA) ratio of 20:1 as the developing solvent or eluent, yielding N-tert-butyl-2-cycloheptane-6-methylbenzamide (1b) in 62% yield. The corresponding chemical reaction equation for this example is as follows:

[0077]

[0078] The 1H and 1C NMR spectra of the compounds prepared in Example 2 are shown below. Figure 3 and Figure 4 As shown. From Figure 3 It can be seen that: 1 ¹H NMR (400MHz, CDCl₃) δ 7.17 (t, J = 7.6Hz, 1H), 7.03 (t, J = 6.8Hz, 2H), 6.31 (s, 1H), 5.36 (s, 1H), 2.37 (t, J = 5.6Hz, 4H), 2.34 (s, 3H), 1.67–1.65 (m, 2H), 1.61–1.54 (m, 6H), 1.43 (s, 9H). The molecular ¹H NMR peak energies correspond one-to-one with the target product, and the number is reasonable. Figure 4 It can be seen that: 13 C10 NMR (100MHz, CDCl3) δ 169.4, 146.2, 138.0, 135.3, 134.5, 128.1, 128.0, 126.9, 123.2, 51.8, 38.1, 31.3, 29.9, 29.3, 29.0, 27.4, 19.1. The molecular carbon spectrum peaks correspond one-to-one with the target product, and the number is reasonable. Combining the above 1H and 1C NMR results, it can be concluded that the product obtained in Example 2 is N-tert-butyl-2-cycloheptane-6-methylbenzamide (1b).

[0079] In this embodiment, N-tert-butyl-2-methylbenzamide 2b contains an amide functional group ubiquitous in human production and daily life. Promoted by this amide functional group, and through activation of the aromatic ring C-H bonds and the C-C triple bond in the acetylide ((1-(bromoethynyl)cycloheptyl)oxy)(tert-butyl)dimethylsilane 3b), a process was developed to introduce a polysubstituted alkenyl segment into the C-H bonds of the arylformamide N-tert-butyl-2-methylbenzamide 2b. This reaction exhibits excellent regio and stereoselectivity, and can introduce a polysubstituted alkenyl skeleton into the amide molecule via transcyclic C-H bond activation, while also being compatible with alkenyl segments containing β-H. In this embodiment, the reaction only requires atmospheric pressure and an air atmosphere at 100°C for 12 hours, followed by simple post-processing, to obtain the final target product N-tert-butyl-2-cycloheptemethylene-6-methylbenzamide (1b) in a good yield (62%).

[0080] The chemical transformation described in this example can be applied to benzamide substrates, thus providing a platform for the construction of more complex polysubstituted olefin molecules.

[0081] Example 3: Preparation of N-tert-butyl-2-chloro-6-cycloheptanemethylenebenzamide (1c)

[0082] Under an atmospheric pressure, N-tert-butyl-2-chlorobenzamide 2c (21.1 mg, 0.10 mmol), ((1-(bromoethynyl)cycloheptyl)oxy)(tert-butyl)dimethylsilane 3c (49.5 mg, 0.15 mmol), pentamethylcyclopentadiene rhodium dichloride dimer [Cp*RhCl2]2 (1.2 mg, 0.002 mmol), silver trifluoromethanesulfonylimide (1.9 mg, 0.005 mmol), lithium carbonate (14.8 mg, 0.20 mmol), silver acetate (33.4 mg, 0.20 mmol), and 1,2-dichloroethane (DCE, 1.0 mL) were added sequentially to a 15 mL Schlenk tube, and the reaction was carried out at 100 °C for 12 hours. The crude product was separated by silica gel chromatography using a petroleum ether (PE):ethyl acetate (EA) ratio of 20:1 as the developing solvent or eluent, yielding N-tert-butyl-2-chloro-6-cycloheptanemethylbenzamide (1c) in 62% yield. The corresponding chemical reaction equation for this example is as follows:

[0083]

[0084] The 1H and 1C NMR spectra of the compounds prepared in Example 3 are shown below. Figure 5 and Figure 6 As shown. From Figure 5 It can be seen that: 1¹H NMR (400MHz, CDCl₃) δ 7.20 (d, J = 4.4Hz, 2H), 7.12 (t, J = 4.4Hz, 1H), 6.32 (s, 1H), 5.23 (s, 1H), 2.39–2.34 (m, 4H), 2.10 (s, 9H), 1.67–1.64 (m, 2H), 1.60–1.52 (m, 6H). The molecular ¹H NMR peak energies correspond one-to-one with the target product, and the number is reasonable. Figure 6 It can be seen that: 13 C10 NMR (100MHz, CDCl3) δ 166.0, 147.7, 137.7, 137.2, 130.7, 129.1, 127.9, 127.1, 122.2, 52.9, 41.7, 38.1, 36.5, 31.3, 29.8, 29.6, 29.2, 27.4. The molecular carbon spectrum peaks correspond one-to-one with the target product, and the number is reasonable. Combining the above 1H and 1C NMR results, it can be concluded that the product obtained in Example 3 is N-tert-butyl-2-chloro-6-cycloheptanemethylbenzamide (1c).

[0085] In this embodiment, N-tert-butyl-2-chlorobenzamide 2c contains an amide functional group ubiquitous in human production and daily life. Promoted by this amide functional group, and through activation of the aromatic ring C-H bonds and the C-C triple bond in the acetylene halide ((1-(bromoethynyl)cycloheptyl)oxy)(tert-butyl)dimethylsilane 3c), a process was developed to introduce a polysubstituted alkenyl segment into the C-H bonds of N-tert-butyl-2-chlorobenzamide 2c. This reaction exhibits excellent regio and stereoselectivity, and can introduce a polysubstituted alkenyl skeleton into the amide molecule via transcyclic C-H bond activation, while also being compatible with alkenyl segments containing β-H. In this embodiment, the reaction only requires atmospheric pressure and an air atmosphere at 100°C for 12 hours, followed by simple post-processing, to obtain the final target product N-tert-butyl-2-chloro-6-cycloheptanemethylbenzamide (1c) in a good yield (62%).

[0086] This embodiment is compatible with halogenated chlorine functional groups to facilitate subsequent transformations such as metal-catalyzed coupling reactions, including the Suziki reaction, Buchwald-Hartwig coupling, etc., to construct complex molecules.

[0087] Example 4: Preparation of N-tert-butyl-2,2-diphenylvinyl-[1,1'-biphenyl]-2-carboxamide (1d)

[0088] Under an atmospheric pressure atmosphere, N-tert-butyl-[1,1'-biphenyl]-2-carboxamide 2d (25.3 mg, 0.10 mmol), ((3-bromo-1,1-diphenylprop-2-yn-1-yl)oxy)(tert-butyl)dimethylsilane 3d (60.4 mg, 0.15 mmol), pentamethylcyclopentadiene rhodium dichloride dimer [Cp*RhCl2]2 (1.2 mg, 0.002 mmol), silver trifluoromethanesulfonylimide (1.9 mg, 0.005 mmol), lithium carbonate (14.8 mg, 0.20 mmol), silver acetate (33.4 mg, 0.20 mmol), and N,N'-dimethylformamide (DMF, 1.0 mL) were added sequentially to a 15 mL Schlenk tube, and the reaction was carried out at 100 °C for 12 hours. The crude product was separated by silica gel chromatography using a petroleum ether (PE):ethyl acetate (EA) ratio of 20:1 as the developing or eluent, yielding N-tert-butyl-2,2-diphenylvinyl-[1,1'-biphenyl]-2-carboxamide (1d) in 65% yield. The corresponding chemical reaction equation for this example is as follows:

[0089]

[0090] The 1H and 1C NMR spectra of the compound prepared in Example 4 are shown below. Figure 7 and Figure 8 As shown. From Figure 7 It can be seen that: 1 ¹H NMR (400MHz, CDCl₃) δ 7.47 (d, J = 6.8Hz, 2H), 7.40–7.28 (m, 11H), 7.24–7.22 (m, 2H), 7.17 (s, 1H), 7.11 (d, J = 7.6Hz, 1H), 7.03 (t, J = 7.6Hz, 1H), 6.85 (d, J = 8.0Hz, 1H), 5.10 (s, 1H), 1.09 (s, 9H). The molecular ¹H NMR peak energies correspond one-to-one with the target product, and the number is reasonable. Figure 8 It can be seen that: 13 C10 NMR (100MHz, CDCl3) δ 168.6, 144.1, 143.2, 140.5, 140.3, 139.1, 138.1, 135.6, 130.7, 129.0, 128.9, 128.5, 128.4, 128.3, 128.2, 128.0, 127.9, 127.7, 127.5, 125.6, 51.6, 28.4. The molecular carbon spectrum peaks correspond one-to-one with the target product, and the number is reasonable. Combining the above 1H and 1C NMR results, it can be seen that the product obtained in Example 4 is N-tert-butyl-2,2-diphenylvinyl-[1,1'-biphenyl]-2-carboxamide (1d).

[0091] In this embodiment, N-tert-butyl-[1,1'-biphenyl]-2-carboxamide 2d contains an amide functional group ubiquitous in human production and daily life. Promoted by this amide functional group, and through activation of the aromatic ring C-H bonds and the C-C triple bond in the alkynyl halide ((3-bromo-1,1-diphenylprop-2-yn-1-yl)oxy)(tert-butyl)dimethylsilane 3d, a process was developed to introduce polysubstituted alkenyl segments into the C-H bonds of N-tert-butyl-[1,1'-biphenyl]-2-carboxamide 2d. This reaction exhibits excellent regio and stereoselectivity, and can introduce polysubstituted alkenyl skeletons into amide molecules via transcyclic C-H bond activation, while also being compatible with alkenyl segments containing β-H. In this embodiment, the reaction only needs to be carried out in an atmospheric pressure air atmosphere at 100°C for 12 hours, followed by simple post-processing, to obtain the final target product N-tert-butyl-2,2-diphenylvinyl-[1,1'-biphenyl]-2-carboxamide (1d) in a good yield (65%).

[0092] This embodiment is compatible with sterically hindered alkyneation reagents, providing a framework for the rapid construction of polycyclic aromatic compounds and sterically hindered alkenes. Furthermore, this transformation involves a macrocyclic metallization intermediate, achieving a transcyclic C-H bond oxidative alkylation reaction.

[0093] Example 5 Preparation of N-tert-butyl-2'-cycloheptane-[1,1'-biphenyl]-2-carboxamide (1e)

[0094] Under an atmospheric pressure, N-tert-butyl-[1,1'-biphenyl]-2-carboxamide 2e (25.3 mg, 0.10 mmol), ((1-(bromoethynyl)cycloheptyl)oxy)(tert-butyl)dimethylsilane 3e (49.5 mg, 0.15 mmol), pentamethylcyclopentadiene rhodium dichloride dimer [Cp*RhCl2]2 (1.2 mg, 0.002 mmol), silver trifluoromethanesulfonylimide (1.9 mg, 0.005 mmol), lithium carbonate (14.8 mg, 0.20 mmol), silver acetate (33.4 mg, 0.20 mmol), and 1,2-dichloroethane (DCE, 1.0 mL) were added sequentially to a 15 mL Schlenk tube, and the reaction was carried out at 100 °C for 12 hours. The crude product was separated by silica gel chromatography using a petroleum ether (PE):ethyl acetate (EA) ratio of 20:1, yielding N-tert-butyl-2'-cycloheptane-[1,1'-biphenyl]-2-carboxamide (1e) in 68% yield. The corresponding chemical reaction equation for this example is as follows:

[0095]

[0096] The 1H and 1C NMR spectra of the compound prepared in Example 5 are shown below. Figure 9 and Figure 10 As shown. From Figure 9 It can be seen that: ¹H NMR (400MHz, CDCl₃) δ 7.49-7.46 (m, 2H), 7.39-7.32 (m, 4H), 7.24-7.19 (m, 2H), 6.45 (s, 1H), 5.05 (s, 1H), 2.42-2.37 (m, 4H), 1.68-1.62 (m, 4H), 1.59-1.52 (m, 4H), 1.12 (s, 9H). The molecular proton NMR peak energies correspond one-to-one with the target product, and the number is reasonable. From Figure 10 It can be seen that the 13C NMR (100MHz, CDCl3) δ 168.6, 146.4, 140.7, 139.2, 137.3, 136.4, 129.0, 128.7, 128.2, 128.2, 127.6, 127.4, 123.3, 51.5, 44.6, 38.1, 31.3, 29.9, 29.4, 29.2, 28.5, 27.5. The molecular carbon spectrum peaks correspond one-to-one with the target product, and the number is reasonable. Combining the above 1H and 1C NMR results, it can be concluded that the product obtained in Example 5 is N-tert-butyl-2'-cycloheptane-[1,1'-biphenyl]-2-carboxamide (1e).

[0097] In this embodiment, N-tert-butyl-[1,1'-biphenyl]-2-carboxamide 2e contains an amide functional group ubiquitous in human production and daily life. Promoted by this amide functional group, and through activation of the aromatic ring C-H bonds and the C-C triple bond in the alkynyl halide ((1-(bromoethynyl)cycloheptyl)oxy)(tert-butyl)dimethylsilane 3e), a process was developed to introduce a polysubstituted alkenyl segment into the C-H bonds of N-tert-butyl-[1,1'-biphenyl]-2-carboxamide 2e. This reaction exhibits excellent regio and stereoselectivity, and can introduce a polysubstituted alkenyl skeleton into the amide molecule via transcyclic C-H bond activation, while also being compatible with alkenyl segments containing β-H. In this embodiment, the reaction only requires atmospheric pressure and an air atmosphere at 100°C for 12 hours, followed by simple post-processing, to obtain the final target product N-tert-butyl-2'-cycloheptemethylene-[1,1'-biphenyl]-2-carboxamide (1e) in a good yield (68%).

[0098] This embodiment can modify different sites of orthophenyl to achieve transcyclic C-H bond activation reactions, thereby providing a platform for the construction of more complex polysubstituted olefin molecules.

[0099] Example 6 Preparation of N-tert-butyl-2-(3-(cycloheptanemethyl)thiophen-2-yl)acetamide (1f)

[0100] Under an atmospheric pressure atmosphere, N-tert-butyl-2-thiophene-2-ylacetamide 2f (19.7 mg, 0.10 mmol), ((1-(bromoethynyl)cycloheptyl)oxy)(tert-butyl)dimethylsilane 3f (49.5 mg, 0.15 mmol), pentamethylcyclopentadiene rhodium dichloride dimer [Cp*RhCl2]2 (3.0 mg, 0.005 mmol), silver trifluoromethanesulfonylimide (3.8 mg, 0.010 mmol), lithium carbonate (14.8 mg, 0.20 mmol), silver acetate (33.4 mg, 0.25 mmol), and 1,2-dichloroethane (DCE, 1.0 mL) were added sequentially to a 15 mL Schlenk tube, and the reaction was carried out at 100 °C for 12 hours. The crude product was separated by silica gel chromatography using a petroleum ether (PE):ethyl acetate (EA) ratio of 20:1, yielding N-tert-butyl-2-(3-(cycloheptamethyl)thiophen-2-yl)acetamide (1f) in 56% yield. The corresponding chemical reaction equation for this example is as follows:

[0101]

[0102] The 1H and 1C NMR spectra of the compound prepared in Example 6 are shown below. Figure 11 and Figure 12 As shown. From Figure 11 It can be seen that: 1 ¹H NMR (400MHz, CDCl₃) δ 7.17 (d, J = 5.2Hz, 1H), 7.03 (d, J = 5.2Hz, 1H), 6.03 (s, 1H), 5.33 (s, 1H), 3.60 (s, 2H), 2.40–2.37 (m, 4H), 1.67–1.63 (m, 6H), 1.56–1.55 (m, 2H), 1.25 (s, 9H). The molecular proton NMR peak energies correspond one-to-one with the target product, and the number is reasonable. Figure 12 It can be seen that: 13 C10 NMR (100MHz, CDCl3) δ 169.1, 146.8, 137.6, 131.5, 129.2, 123.4, 117.7, 51.3, 38.4, 37.2, 31.9, 29.7, 29.6, 29.2, 28.7, 27.3. The molecular carbon spectrum peaks correspond one-to-one with the target product, and the number is reasonable. Combining the above 1H and 1C NMR results, it can be seen that the product obtained in Example 6 is N-tert-butyl-2-(3-(cycloheptamethylene)thiophen-2-yl)acetamide (1f).

[0103] In this embodiment, N-tert-butyl-2-thiophene-2-ylacetamide 2f contains an amide functional group ubiquitous in human production and daily life. Promoted by this amide functional group, and through activation of the aromatic ring C-H bonds and the C-C triple bond in the alkynyl halide ((1-(bromoethynyl)cycloheptyl)oxy)(tert-butyl)dimethylsilane 3f), a multi-substituted alkenyl segment was introduced into the C-H bonds of N-tert-butyl-2-thiophene-2-ylacetamide 2f. This reaction exhibits excellent regio and stereoselectivity, and can introduce multi-substituted alkenyl skeletons into amide molecules via transcyclic C-H bond activation, while being compatible with alkenyl segments containing β-H. In this embodiment, the reaction only requires atmospheric pressure and an air atmosphere at 100°C for 12 hours, followed by simple post-treatment, to obtain the final target product N-tert-butyl-2-(3-(cycloheptemethylene)thiophene-2-yl)acetamide (1f) in a good yield (56%).

[0104] The chemical transformations in this embodiment are compatible with heterocyclic acetamide substrates, exhibiting extremely broad substrate applicability, thus providing a platform for the construction of more complex polysubstituted olefin molecules.

[0105] Example 7 Preparation of N-adamantane-1-yl-2'-cycloheptanemethylene-[1,1'-biphenyl]-2-carboxamide (1 g)

[0106] Under an atmospheric pressure, 2 g (33.1 mg, 0.10 mmol) of N-adamantane-1-yl-1-adamantane-[1,1'-biphenyl]-2-carboxamide, 3 g (49.5 mg, 0.15 mmol) of ((1-(bromoethynyl)cycloheptyl)oxy)(tert-butyl)dimethylsilane, 3.0 mg (0.005 mmol) of pentamethylcyclopentadiene rhodium dichloride dimer [Cp*RhCl2]2, 3.8 mg (0.01 mmol) of silver trifluoromethanesulfonylimide, 14.8 mg (0.20 mmol) of lithium carbonate, 58.7 mg (0.25 mmol) of silver oxide, and 1,2-dichloroethane (DCE, 1.0 mL) were added sequentially to a 15 mL Schlenk tube, and the reaction was carried out at 100 °C for 12 hours. The crude product was separated by silica gel chromatography using a petroleum ether (PE):ethyl acetate (EA) ratio of 20:1, yielding N-adamantane-1-yl-2'-cycloheptanemethylene-[1,1'-biphenyl]-2-carboxamide (1 g) in 66% yield. The corresponding chemical reaction equation for this example is as follows:

[0107]

[0108] The 1H and 1C NMR spectra of the compounds prepared in Example 7 are shown below. Figure 13 and Figure 14 As shown. From Figure 13 It can be seen that: 1 ¹H NMR (400MHz, CDCl₃) δ 7.49 (d, J = 6.8 Hz, 2H), 7.40–7.31 (m, 4H), 7.21 (dd, J = 12.8, 7.6 Hz, 2H), 6.46 (s, 1H), 4.93 (s, 1H), 2.43–2.39 (m, 4H), 1.97 (s, 3H), 1.76 (d, J = 2.0 Hz, 6H), 1.69–1.64 (m, 6H), 1.59 (s, 6H), 1.55 (d, J = 8.8 Hz, 2H). The molecular proton NMR peak energies correspond one-to-one with the target product, and the number is reasonable. Figure 14 It can be seen that: 13 C10 NMR (100MHz, CDCl3) δ 168.3, 146.3, 140.7, 139.1, 137.4, 136.3, 129.0, 128.6, 128.2, 128.1, 127.7, 127.4, 123.4, 52.2, 41.4, 38.1, 36.4, 31.3, 29.9, 29.5, 29.4, 29.2, 27.5. The molecular carbon spectrum peaks correspond one-to-one with the target product, and the number is reasonable. Combining the above 1H and 1C NMR results, it can be seen that the product obtained in Example 7 is N-adamantane-1-yl-2'-cycloheptanemethylene-[1,1'-biphenyl]-2-carboxamide (1g).

[0109] In this embodiment, N-adamantane-1-yl-1-akindane-[1,1'-biphenyl]-2-carboxamide 2g contains an amide functional group ubiquitous in human production and daily life. Promoted by this amide functional group, and through activation of the aromatic ring C-H bonds and the C-C triple bond in the alkynyl halide ((1-(bromoethynyl)cycloheptyl)oxy)(tert-butyl)dimethylsilane 3g), a process was developed to introduce a polysubstituted alkenyl segment into the C-H bonds of N-adamantane-1-yl-1-akindane-[1,1'-biphenyl]-2-carboxamide 2g. This reaction exhibits excellent regio and stereoselectivity, and can introduce a polysubstituted alkenyl skeleton into the amide molecule via transcyclic C-H bond activation, while also being compatible with alkenyl segments containing β-H. In this embodiment, the reaction only needs to be carried out in an atmospheric pressure air atmosphere at 100°C for 12 hours, followed by simple post-processing, to obtain the final target product N-adamantane-1-yl-2'-cycloheptanemethylene-[1,1'-biphenyl]-2-carboxamide (1g) in a good yield (66%).

[0110] The chemical transformation in this embodiment is compatible with sterically hindered adamantyl alkyl groups, thus providing a platform for the construction of more complex, sterically hindered, multi-substituted olefin molecules.

[0111] In summary, this patent application provides a method for preparing a polysubstituted olefin. The method includes the following steps: under inert solvent conditions, an amide compound (Formula II) and an alkynyl bromide compound (Formula III) react in the presence of a catalyst and an oxidant to form a polysubstituted olefin (Formula I) through the formation of a cyclic metal intermediate, the cleavage of the alkynyl carbon-carbon triple bond, and its role as an alkenyl synthon. The reaction equation is as follows:

[0112]

[0113] Where Ar represents a benzene ring, fused ring, heterocycle, or biaromatic ring containing different substituents, and R represents an alkyl group. 1 R 2 Both are alkyl or aryl, and n is 0 or 1.

[0114] This patent application is the first to develop a method for breaking the alkynyl carbon-carbon triple bond of an alkynyl halide and using it as an alkenyl synthon. With the assistance of the natural functional group amide, and through activation via the C-H bond of the aromatic ring, site-selective and stereoselective introduction of polysubstituted alkenes into amide molecules is achieved. This transformation has the following characteristics: 1) The amide, as a natural functional group, serves as a directing group and reactant in this application, enabling the synthesis of polysubstituted alkenes with high site- and stereoselectivity; 2) The product containing the alkenyl fragment obtained in this application exhibits excellent stereoselectivity, and the alkene contains β-H alkyl substitution, which is difficult to achieve with classical metal-catalyzed cross-coupling reactions.

[0115] This patent application utilizes the ubiquitous amide functional groups in human production and daily life to develop a method for introducing polysubstituted alkenyl segments into the C-H bonds of arylformamides and acetamides through activation of aromatic ring C-H bonds and alkynyl halide C-C triple bonds. This reaction exhibits excellent regio and stereoselectivity, and can introduce polysubstituted alkenyl skeletons into amide molecules via transcyclic C-H bond activation, while also being compatible with alkenyl segments containing β-H. This transformation not only overcomes the limitations of classical Heck reactions and oxidative Heck reactions in incorporating polysubstituted, β-H-containing alkyl segments, but also offers potential for the novel synthesis and application of pharmaceuticals and materials, considering the practicality of amides and polysubstituted alkenes.

[0116] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "illustrative embodiment," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with an embodiment or example is included in at least one embodiment or example of this patent application. In this specification, the 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.

[0117] Although several embodiments of this patent application have been shown and described, those skilled in the art will understand that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of this patent application, the scope of which is defined by the claims and their equivalents.

Claims

1. A method for preparing a polysubstituted olefin, characterized in that, Includes the following steps: Under inert solvent conditions, amide compound (Formula II) and alkynyl bromide compound (Formula III) react in the presence of a catalyst and an oxidant. The alkynyl halide first forms an alkenyl metal species, and then, with the amide promoting carbon-hydrogen bond activation, forms a polysubstituted alkene (Formula I). ​​The reaction equation is as follows: The amide compound of formula II is selected from one of the following structures: The bromine compound of formula III is selected from one of the following structural formulas: The polysubstituted olefin of Formula I is selected from one of the following structural formulas: The catalyst is pentamethylcyclopentadienyl rhodium chloride dimer, the oxidant is silver acetate or silver oxide, and the additive is trifluoromethanesulfonyl imide silver.

2. The method for preparing polysubstituted olefins according to claim 1, characterized in that: The amount of catalyst used is 2 mol% of the amount of the amide compound (Formula II).

3. The method for preparing polysubstituted olefins according to claim 1, characterized in that: The inert solvent is any one or more of 1,2-dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, N,N'-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, and ethanol.

4. The method for preparing polysubstituted olefins according to claim 1, characterized in that: The reaction is carried out at 80–120°C for 6–24 hours.

5. The method for preparing polysubstituted olefins according to claim 1, characterized in that, The specific steps include the following: S1: In the reactor, in air, add 22.7 mg N-tert-butylnaphthalene-1-carboxamide, 49.5 mg ((1-(bromoethynyl)cycloheptyl)oxy)(tert-butyl)dimethylsilane, 1.2 mg pentamethylcyclopentadiene rhodium dichloride dimer, 1.9 mg silver trifluoromethanesulfonyl imide, 14.8 mg lithium carbonate, 33.4 mg silver acetate, and 1.0 mL 1,2-dichloroethane; S2: React the reaction solution at 100℃ for 12 hours; S3: After the reaction is complete, the above mixture is separated by column chromatography to obtain the target compound.

6. The method for preparing polysubstituted olefins according to claim 5, characterized in that: The developing or eluent selected in the column chromatography separation technique is petroleum ether: ethyl acetate.

7. The method for preparing polysubstituted olefins according to claim 6, characterized in that: The developing agent or eluent is petroleum ether:ethyl acetate in a ratio of 20:1.

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