Method for organic catalytic synthesis of beta-alkyl azole compound

Abstract

The invention relates to the technical field of synthesis of alkylazole compounds, and discloses a method for synthesizing beta-alkylazole compounds through organic catalysis, which comprises the following steps: by taking a copper salt synergistic nitrogen-containing ligand as a catalyst, a trimethylsilyl-substituted azole compound as a heteroaryl source and diacyl peroxide as an alkyl free radical precursor, carrying out a reaction at the temperature of 60-80 DEG C to obtain the beta-alkylazole compounds. And carrying out a three-component alkyl-azolyl bifunctionalization reaction of olefin in an aprotic solvent to obtain the beta-alkyl substituted azole compound. According to the present invention, the reaction conditions of the system are simplified, the product yield is excellent, the good functional group compatibility and the good substrate universality are provided, and the method is suitable for olefin containing different substituent groups, thiazole, benzothiazole, benzoxazole and other azole substrates.

Description

Technical Field

[0001] The present invention relates to the field of synthesis of alkylazole compounds, and in particular to a method for synthesizing beta-alkylazole compounds through organic catalysis. Background Art

[0002] The 1,2-difunctionalization of alkenes is an important method for simultaneously constructing multifunctional compounds and achieving efficient synthesis of complex molecules. For example, alkenes can be combined with nitrogen-containing heterocyclic compounds such as oxazoles, thiazoles, and pyridines. The simultaneous introduction of two functional groups, azole and alkyl, into organic molecules through the 1,2-difunctionalization of alkenes is a convenient and efficient strategy for synthesizing alkylazole-containing compounds.

[0003] In 2020, Zhu Chen's group successfully achieved the photoinduced alkyl-oxazolyl difunctionalization of alkenes based on the free radical polarity inversion strategy (see Photoinduced alkyl-oxazolyl difunctionalization of alkenes). Figure 8 This study innovatively utilizes a bifunctional alkylating reagent with a sulfonyl group to convert a nucleophilic alkyl radical into an electrophilic intermediate through polarity reversal, thereby overcoming the polarity mismatch problem. However, this strategy is not applicable to simple alkyl reagents and relies on the intramolecular migration mechanism of the functional group of the pre-functionalized substrate, which limits its substrate applicability.

[0004] In 2021, Zhang Guodong's group reported copper-catalyzed highly enantioselective olefin alkylation and aryl / oxazolylation reactions. By using chiral carbazolyl bisoxazoline ligands, they successfully achieved a three-component coupling reaction of olefins (see Copper-catalyzed Asymmetric Alkyl / Aryl-Oxazolyl Bifunctionalization of Olefins). Figure 9 However, there are still certain limitations. For example, the use of ester-containing halogenated hydrocarbons with specific structures as alkylating agents limits substrate diversity. In addition, when diaryliodonium salts are used as aryl groups, the atom economy is low and some aryl substrates are not suitable.

[0005] In 2022, Wang Shaowu's research group successfully synthesized and characterized a new binuclear copper (I) complex, which is supported by a 1,3-disubstituted-2-indolyl NCO tridentate ligand. Using the binuclear copper metal complex as a catalyst, a three-component intermolecular trifluoromethyl oxazolidinylation reaction of olefins was developed (see Trifluoromethyl-oxazolidinylation of olefin molecules catalyzed by binuclear copper metal complexes). Figure 9 ), but the scope of application of alkyl substrates is narrow, and it is only applicable to trifluoromethyl substrates, and the applicable alkylating reagent is a high-valent iodine reagent.

[0006] Therefore, the difunctionalization of alkenes still needs to address issues such as limited substrate applicability and the need for photocatalysis or other additional catalytic conditions. Furthermore, efficient and regioselective difunctionalization still faces significant challenges. Therefore, there is a need to develop more affordable and versatile multifunctional alkylating agents based on simpler and more applicable catalytic systems, in order to achieve efficient alkyl azole conversion of alkenes under mild reaction conditions to yield various azole compounds. Summary of the Invention

[0007] The object of the present invention is to provide a method for synthesizing β-alkylazole compounds by organic catalysis, so as to solve the technical problem of how to realize alkyl azole formation of olefins and construct β-azole compounds by simple catalysis in the prior art.

[0008] In order to solve the above technical problems, the present invention specifically provides the following technical solutions:

[0009] The present invention provides a method for organically catalyzing the synthesis of β-alkyl azole compounds, wherein a copper salt and a nitrogen-containing ligand are used as catalysts, a trimethylsilyl-substituted azole compound is used as a heteroaryl source, and a diacyl peroxide is used as an alkyl radical precursor. A three-component alkyl-azole difunctionalization reaction of an olefin is carried out in an aprotic solvent to obtain a β-alkyl-substituted azole compound.

[0010] The general reaction formula of the three-component alkyl-oxazolyl difunctionalization reaction is as follows:

[0011]

[0012] Wherein, the structural formula of the olefin is:

[0013]

[0014] The general structural formula of the trimethylsilyl-substituted azole compound is:

[0015]

[0016] The general structural formula of the diacyl peroxide is:

[0017]

[0018] As a preferred embodiment of the present invention, the olefin has a structure shown in any one of Formulas 2-1a to 2-1aa:

[0019]

[0020] As a preferred embodiment of the present invention, the trimethylsilyl-substituted azole compound has a structure shown in any one of Formulas 2-2a to 2-2c;

[0021]

[0022] As a preferred embodiment of the present invention, the diacyl peroxide has a structure shown in any one of Formulas 2-3a to 2-3m;

[0023]

[0024] As a preferred embodiment of the present invention, the preparation method of the β-alkylazole compound comprises the following steps:

[0025] In a glove box under argon atmosphere, copper salt and nitrogen-containing ligand were weighed and added to an aprotic solvent. The first stirring was performed at room temperature, and the color of the system gradually changed from colorless to red.

[0026] Then, the reaction substrates diacyl peroxide, olefin, and azole reagent are added to the system in sequence, and stirred for a second time at room temperature to obtain a reaction mixture;

[0027] After the reaction substrate disappears, the reaction mixture is filtered through diatomaceous earth and rinsed with ethyl acetate. The obtained filtrate is concentrated and separated by column chromatography using petroleum ether / ethyl acetate as eluent to obtain the β-alkylazole compound.

[0028] As a preferred embodiment of the present invention, the copper salt is any one of cuprous halide, copper tetraacetonitrile hexafluorophosphate, copper acetate, cuprous sulfide, cuprous acetate, and cuprous thiophene 2-carboxylate;

[0029] The nitrogen-containing ligand has a structure shown in any one of formulas L1-L16:

[0030]

[0031] The aprotic solvent is any one of dichloroethane, toluene, tetrahydrofuran, chlorine, acetonitrile and N,N-dimethylformamide.

[0032] As a preferred embodiment of the present invention, the copper salt is cuprous thiophene-2-carboxylate;

[0033] The nitrogen-containing ligand is a phenanthroline ligand;

[0034] The aprotic solvent is N,N-dimethylformamide

[0035] As a preferred embodiment of the present invention, the phenanthroline ligand has a structure shown in formula L3;

[0036] The name of L3 is 5,6-dimethyl-1,10-phenanthroline.

[0037] As a preferred embodiment of the present invention, based on the amount of the olefin, the equivalent of the cuprous thiophene carboxylate is 2-10 mol%; the equivalent of the 5,6-dimethyl-1,10-phenanthroline is 2-10 mol%.

[0038] As a preferred embodiment of the present invention, the olefin includes a compound with the structural formula shown in the figure;

[0039] The azole substrate includes a compound with the structural formula shown in the figure;

[0040] The diacyl peroxides include compounds with the structural formula shown in the figure.

[0041] As a preferred embodiment of the present invention, the first stirring time is 0.5h;

[0042] The second stirring time is 3-12h.

[0043] As a preferred embodiment of the present invention, the second stirring time is 3 hours.

[0044] Compared with the prior art, the present invention has the following beneficial effects:

[0045] The present invention provides a copper-catalyzed intermolecular alkyl-azole reaction of olefins. By screening the reaction conditions, the optimal reaction conditions were determined and substrate expansion was carried out under these conditions to synthesize a variety of β-alkyl-substituted azole compounds, thus developing a simple, direct and efficient new method for synthesizing alkyl-containing heterocyclic compounds.

[0046] The method proposed in the present invention has good substrate universality and broad functional group tolerance. It has good compatibility with alkenes containing various functional groups and different azole heterocyclic substrates. The yield of some products is as high as 93%;

[0047] The present invention proposes for the first time the reaction mechanism of copper-catalyzed intermolecular alkyl-oxazolidinylation of olefins, discloses the copper-catalyzed single electron transfer process, and provides a new preparation idea for other types of copper-catalyzed intermolecular reactions of olefins. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] To more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for the embodiments or the description of the prior art. Obviously, the drawings described below are merely exemplary, and those skilled in the art can derive other implementation drawings based on the provided drawings without inventive effort.

[0049] Figure 1 The present invention provides the reaction formula of Example 1;

[0050] Figure 2 A reaction formula for a gram-scale reaction is provided for the present invention;

[0051] Figure 3 The present invention provides 2-(1-phenyltridecyl)thiazole 1 H NMR (400 MHz, CDCl 3 ) spectrum;

[0052] Figure 4 The present invention provides 2-(1-phenyltridecyl)thiazole 13 C NMR (100 MHz, CDCl3) spectrum;

[0053] Figure 5 Provides a reaction formula for a free radical capture experiment for the present invention;

[0054] Figure 6 The present invention provides a reaction formula for a free radical clock experiment;

[0055] Figure 7 The present invention provides a schematic diagram of the catalytic reaction principle for the organic catalytic synthesis of β-alkylazole compounds;

[0056] Figure 8 The reaction formula for the photoinduced alkyl-oxazolyl difunctionalization of olefins is:

[0057] Figure 9 It is a copper-catalyzed highly enantioselective olefin alkylation and aryl / oxazolylation reaction;

[0058] Figure 10 The three-component intermolecular trifluoromethyl oxazolidation reaction formula of olefins is:

[0059] Figure 11 The present invention provides nitrogen-containing ligands of structural formulas L1 to L16 and their corresponding yields using styrene, dodecyl peroxide, and 2-trimethylsilylthiazole as substrates. DETAILED DESCRIPTION

[0060] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0061] The present invention provides a method for synthesizing β-alkylazole compounds by organic catalysis. The method comprises the following steps: using a copper salt in coordination with a phenanthroline ligand as a catalyst, a trimethylsilyl-substituted azole compound as a heteroaryl source, and a diacyl peroxide as an alkyl radical precursor; and carrying out a three-component alkyl-azole difunctionalization reaction of an olefin in an aprotic solvent to synthesize the β-alkyl-substituted azole compound.

[0062] The general reaction formula for the three-component alkyl-oxazolyl difunctionalization reaction is as follows:

[0063]

[0064] Wherein, the structural formula of the olefin is:

[0065]

[0066] The general structural formula of the trimethylsilyl-substituted azole compound is:

[0067]

[0068] The general structural formula of the diacyl peroxide is:

[0069]

[0070] Furthermore, the olefin has a structure represented by any one of Formulas 2-1a to 2-1aa:

[0071]

[0072] The trimethylsilyl-substituted azole compound has a structure shown in any one of Formulas 2-2a to 2-2c;

[0073]

[0074] The diacyl peroxide has a structure shown in any one of Formulas 2-3a to 2-3m;

[0075]

[0076] The copper salt is any one of cuprous halide, tetraacetonitrile copper hexafluorophosphate, copper acetate, cuprous sulfide, cuprous acetate, and cuprous thiophene 2-carboxylate; the nitrogen-containing ligand is such as Figure 11 Any one of the compounds of the structural formulae L1-L16 shown; the reaction solution is an aprotic solvent, and the aprotic solvent can be dichloroethane (DCE), toluene (Tol), tetrahydrofuran (THF), chlorine (PhCl), acetonitrile (MeCN) and N,N-dimethylformamide (DMF).

[0077] Under room temperature conditions, the above reaction undergoes a copper-catalyzed single-electron transfer process. The alkyl radical (I) generated by the diacyl peroxide through homolysis and decarboxylation adds to the olefin to obtain the benzyl radical (II). The benzyl radical (II) then reacts with the divalent copper species of the azole to generate a trivalent copper intermediate. Finally, the trivalent copper intermediate is reduced and eliminated to obtain the target product.

[0078] The system has mild reaction conditions and excellent product yields. It does not require photocatalysis or the addition of additional oxidants. It has good functional group compatibility and substrate universality. It is applicable to olefins containing different substituents and azole-based substrates such as thiazole, benzothiazole, and benzoxazole.

[0079] Specifically, the preparation method of this β-alkylazole compound is as follows:

[0080] In a glove box under argon atmosphere, copper salt and nitrogen-containing ligand were weighed and added to an aprotic solvent. The first stirring was performed at room temperature, and the color of the system gradually changed from colorless to red.

[0081] Then, the reaction substrates diacyl peroxide, olefin, and azole reagent were added to the system in sequence, and stirred for a second time at room temperature to obtain a reaction mixture;

[0082] After the reaction substrate disappears, the reaction mixture is filtered through diatomaceous earth and rinsed with ethyl acetate. The obtained filtrate is concentrated and separated by column chromatography using petroleum ether / ethyl acetate as eluent to obtain β-alkylazole compounds.

[0083] Depending on the type of azole compound, diacyl peroxide, and olefin, a series of β-alkyl substituted azole compounds can be obtained. The types of azole compound, diacyl peroxide, and olefin can be selected within a wide range. This reaction has broad functional group tolerance, high chemical and regioselectivity, and the highest yield can reach 93%. It has outstanding advantages in constructing multifunctional compounds of olefins and realizing the industrial quantification of efficient synthesis of complex molecules.

[0084] In the present invention, the ligand has a structure shown in any one of formulas L1-L16:

[0085]

[0086] Preferably, the nitrogen-containing ligand is L3, named 5,6-dimethyl-1,10-phenanthroline.

[0087] In the present invention, the aprotic solvent can be selected from a wide range. Preferably, the aprotic solvent is DCE.

[0088] In the present invention, the copper salt used as the catalyst can be selected from the wide range mentioned above. Preferably, the copper salt is cuprous thiophene 2-carboxylate (CuTc).

[0089] In the present invention, selecting 5,6-dimethyl-1,10-phenanthroline (L3 in the figure) as the ligand, DCE as the solvent, and cuprous thiophene-2-carboxylate as the copper salt can maximize the yield of the product.

[0090] In addition to the specific types of solvents and catalysts in the reaction conditions, their reaction amounts and reaction times are also key factors in the production process. Based on the amount of olefin, the equivalent weight of the copper salt catalyst can be selected within a wide range, such as 2-10 mol%, preferably 10 mol% when the copper salt is cuprous thiophene-2-carboxylate. The equivalent weight of the nitrogen-containing ligand can also be selected within a wide range, such as 2-10 mol%, preferably 10 mol% when the nitrogen-containing ligand is 5,6-dimethyl-1,10-phenanthroline.

[0091] Furthermore, under normal circumstances, the entire reaction is carried out at room temperature.

[0092] In the present invention, the first stirring time is determined by the color of the system gradually changing from colorless to red, which is 0.5 h after quantification (the specific time may vary slightly with the stirring rate, the volume of the reactant system or the container, mainly based on the color change). The second stirring time is 3-12 h. Preferably, the second stirring time is 3 hours.

[0093] It can be seen that this reaction does not require photocatalysis and can occur at room temperature. It is a mild reaction condition, which simplifies the construction conditions of β-azole compounds and can be better applied to the field of industrial production.

[0094] The following provides several examples and verification examples to illustrate the universality, high yield, and low reaction conditions of the reaction:

[0095] The following experimental operations involving anhydrous and oxygen-free conditions are all carried out in a Vigor glove box with an argon atmosphere or standard Schlenk technology. All reagents, drugs and reaction products that are sensitive to water and air are stored in a glove box with an argon atmosphere. All reagents, drugs and reaction products that need to be stored at low temperatures are stored in a glove box refrigerator or explosion-proof refrigerator with an argon atmosphere. Solvents required for the catalytic reaction (1,2-dichloroethane, chlorobenzene, DMSO, DMF, DMA, etc.) are added with CaH2 before use and heated to reflux, and then collected by distillation at normal pressure or reduced pressure before use. The deuterated reagent CDCl3 required for nuclear magnetic resonance testing is added before use. Molecular sieves were used for drying, and C6D6 was dried with Na-K alloy before use. NMR analysis of all compounds was performed using a 400 MHz Bruker-AV NMR spectrometer.

[0096] Example 1

[0097] In a glove box under argon atmosphere, CuTc (3.8 mg, 0.02 mmol, 0.1 equiv.) and L3 (4.1 mg, 0.02 mmol, 0.1 equiv.) were weighed and added to a 15 mL Schlenk glass reaction vial. 0.5 mL of DCE was then added and stirred at room temperature for 0.5 h, during which the color of the system gradually changed from colorless to red. Subsequently, the reaction substrate, acyl peroxide (111.470 mg, 0.28 mmol, 1.4 equiv.), olefin (0.2 mmol, 1.0 equiv.), and azole reagent (0.3 mmol, 1.5 equiv.) were added sequentially, and the reaction was stirred at room temperature for another 6 h.

[0098] The reaction was monitored by TLC. After the disappearance of the substrate, the reaction mixture was directly filtered through diatomaceous earth and eluted with ethyl acetate. The filtrate was concentrated and separated by column chromatography using petroleum ether / ethyl acetate (6:1) as the eluent to obtain a colorless oil: 2-(1-phenyltridecyl)thiazole. The yield was 66 mg, with a yield of 96%.

[0099] The reaction formula of Example 1 is shown in the figure. In Example 1, the olefin is styrene (2-1a), the azole reagent is 2-(trimethylsilyl)benzothiazole (2-3a), and the acyl peroxide is dodecanoyl peroxide (2-2a).

[0100] The following provides Examples 2 to 27, wherein in Example 2 and Example 27, other reaction conditions are consistent with Example 1, except that the structure of the olefin is different. The structural formulas of Examples 1 to 27 are shown in Formulas 2-4a to 2-4aa, respectively.

[0101]

[0102] The name of 2-4a is: 2-(1-phenyltridecyl)thiazole, and the yield is: 96%;

[0103] The name of 2-4b is: 2-(1-(p-tolyl)tridecyl)thiazole, and the yield is: 85%;

[0104] The name of 2-4c is: 2-(1-(4-tert-butylphenyl)tridecyl)thiazole, and the yield is: 89%;

[0105] The name of 2-4d is: 2-(1-(4-methoxyphenyl)tridecyl)thiazole, and the yield is: 94%;

[0106] 2-4e is named 2-(1-(4-(tert-butoxy)phenyl)tridecyl)thiazole, and the yield is: 93%;

[0107] 2-4f is named: 2-(1-(4-fluorophenyl)tridecyl)thiazole, and the yield is: 93%;

[0108] 2-4g name: 2-(1-(4-chlorophenyl)tridecyl)thiazole, yield: 93%;

[0109] 2-4h is named: 2-(1-(4-bromophenyl)tridecyl)thiazole, and the yield is: 94%;

[0110] The name of 2-4i is: 4-(1-(thiazol-2-yl)tridecyl)benzonitrile, and the yield is: 94%;

[0111] The name of 2-4j is: 2-(1-(4-(trifluoromethyl)phenyl)tridecyl)thiazole, and the yield is: 84%;

[0112] 2-4k is named as: methyl-4-(1-(thiazol-2-yl)tridecyl)benzoate, with a yield of 88%;

[0113] 2-41 is named: 4-(1-(thiazol-2-yl)tridecyl)phenyl acetate, and the yield is: 93%;

[0114] 2-4m is named: 2-(1-(m-methylphenyl)tridecyl)thiazole, and the yield is: 93%;

[0115] 2-4n is named: 2-(1-(4-methoxyphenyl)tridecyl)thiazole, and the yield is: 92%;

[0116] 2-4o is named: 2-(1-(3-fluorophenyl)tridecyl)thiazole, and the yield is: 78%;

[0117] The name of 2-4p is: 2-(1-(3-chlorophenyl)tridecyl)thiazole, and the yield is: 86%;

[0118] 2-4q is named: 2-(1-(3-bromophenyl)tridecyl)thiazole, and the yield is: 82%;

[0119] 2-4r is named: 2-(1-(2-methoxyphenyl)tridecyl)thiazole, and the yield is: 75%;

[0120] The name of 2-4s is: 2-(1-(2-bromophenyl)tridecyl)thiazole, and the yield is: 96%;

[0121] 2-4t is named: 2-(1-(2-(trifluoromethyl)phenyl)tridecyl)thiazole, and the yield is: 84%;

[0122] The name of 2-4u is: 2-(1-(2,5-dimethylphenyl)tridecyl)thiazole, and the yield is: 88%;

[0123] 2-4v is named: 2-(1-(3,4-dimethoxyphenyl)tridecyl)thiazole, and the yield is: 93%;

[0124] The name of 2-4w is: 2-(1-(perfluorophenyl)tridecyl)thiazole, and the yield is: 91%;

[0125] 2-4x is named: 2-(1-(thiophen-2-yl)tridecyl)thiazole, and the yield is: 85%;

[0126] The name of 2-4y is: 2-(1-(pyridin-4-yl)tridecyl)thiazole, and the yield is: 90%;

[0127] The name of 2-4z is: 2-(2-methyl-1-phenyltridecyl)thiazole, and the yield is: 35%;

[0128] The name of 2-4aa is: 2-(2-undecyl-1,2,3,4-tetrahydronaphthalen-1-yl)thiazole, and the yield is: 25%;

[0129] In Examples 28 to 35, other reaction conditions are the same as in Example 1, except that the azole substrates are different. The structural formulas of Examples 18 to 35 are shown in Formulas 2-5a to 2-5j, respectively.

[0130]

[0131] The name of 2-5a is: 2-(1-phenyltridecyl)benzo[d]thiazole, and the yield is: 76%;

[0132] The name of 2-5b is: 2-(1-(4-bromophenyl)tridecyl)benzo[d]thiazole, and the yield is: 58%;

[0133] The name of 2-5c is: 2-(1-(2,5-dimethylphenyl)tridecyl)benzo[d]thiazole, and the yield is: 77%;

[0134] The name of 2-5d is: 2-(1-phenyltridecyl)benzo[d]thiazole, and the yield is: 95%;

[0135] The name of 2-5e is: 2-(1-(4-methoxyphenyl)tridecyl)benzo[d]thiazole, and the yield is: 92%;

[0136] The name of 2-5f is: 2-(1-(4-bromophenyl)tridecyl)benzo[d]thiazole, and the yield is: 93%;

[0137] 2-5g name: 4-(1-(Benzo[d]thiazol-2-yl)tridecyl)benzonitrile, yield: 93%;

[0138] 2-5h is named: 2-(1-(3-fluorophenyl)tridecyl)benzo[d]thiazole, and the yield is: 95%;

[0139] The name of 2-5i is: 2-(1-(2-chlorophenyl)tridecyl)benzo[d]thiazole, and the yield is: 94%;

[0140] The name of 2-5j is: 4-bromo-2-(1-(4-chlorophenyl)tridecyl)thiazole, and the yield is: 74%.

[0141] In Examples 36 to 48, other reaction conditions are consistent with those in Example 1, except that the acyl peroxides are different. The structural formulas of Examples 36 to 48 are shown in Formulas 2-6a to 2-6m, respectively.

[0142]

[0143] The name of 2-6a is: 2-(1-phenylhexyl)thiazole, and the yield is: 76%;

[0144] The name of 2-6b is: 2-(1-phenylundecyl)thiazole, and the yield is: 92%;

[0145] The name of 2-6c is: 2-(4-methyl-1-phenylpentyl)thiazole, and the yield is: 93%;

[0146] The name of 2-6d is: 2-(5-methyl-1-phenylhexyl)thiazole, and the yield is: 94%;

[0147] The name of 2-6e is: 2-(1,4-diphenylbutyl)thiazole, and the yield is: 15%;

[0148] The name of 2-6f is: 2-(3-chloro-1-phenylpropyl)thiazole, and the yield is: 81%;

[0149] 2-6g name: 2-(7-bromo-1-phenylheptyl)thiazole, yield: 73%;

[0150] 2-6h is named: 7-phenyl-7-(thiazol-2-yl)heptan-2-one, and the yield is: 45%;

[0151] The name of 2-6i is: 2-(1-phenylundec-1-en-1-yl)thiazole, and the yield is: 95%;

[0152] The name of 2-6j is: 2-(1-phenylhept-6-en-1-yl)thiazole, and the yield is: 93%;

[0153] 2-6k is named: 2-(3-cyclohexyl-1-phenylpropyl)thiazole, and the yield is: 93%;

[0154] 2-61 is named: 2-(1-phenyl-5-(thiophen-2-yl)pentyl)thiazole, and the yield is: 93%;

[0155] 2-6m is named: 2-(3-adamantan-1-yl)-1-phenylpropyl)thiazole, and the yield is: 78%;

[0156] In fact, the present invention also provides three comparative examples, namely comparative examples 1-3. In comparative examples 1-3, other reaction conditions are consistent with those in Example 1, except that the acyl peroxide is a symmetrical peroxide that produces a tertiary carbon radical, and the target product is not obtained.

[0157] Analyzing the above embodiments, it can be seen from Examples 1 to 27 that:

[0158] (1) Styrene has excellent substrate universality; (2) When the para position of styrene is substituted by an electron-donating group, the reaction can proceed smoothly and the target product can be obtained in an excellent yield; (3) When the para position is substituted by a halogen, the reaction yield is also high; (4) When a strong electron-withdrawing group such as nitro, tert-butyl oxide, cyano, ester, trifluoromethyl, etc. is introduced into the para position, the reaction is not affected and the target product can still be obtained in a good yield; (5) When there are substituents at the ortho and meta positions of styrene, the reaction can also obtain the target product in a good yield; (6) When there are multiple substituents on the aromatic ring of styrene or the substrate steric hindrance is increased, the reaction The reaction can still proceed smoothly; (7) Cyclic olefins were obtained with a yield of 35% and 25% and a diastereoselectivity of 99:1 and 19:1, respectively, to obtain the target product with trans addition as the main product; (8) The yield of 1,1-disubstituted styrene substrates (such as а-methylstyrene) increased to 51% after the reaction temperature was raised to 80°C (the steric hindrance of the tertiary carbon radical is large, making the formation of the CC bond more difficult); (9) Heterocyclic olefins with 2-vinylthiophene (2-4x) and 2-vinylpyridine (2-4y) as substrates were obtained with a yield of 85% and 90%, respectively.

[0159] As shown in Examples 28 to 35, the yield decreases when reacting with alkenes bearing various electron-withdrawing groups. When bromine is attached to the benzene ring, the target product is obtained in a 58% yield. Using 4-bromo-2-trimethylsilylthiazole as a substrate, the product is obtained in a 74% yield. Compared to 2-(trimethylsilyl)thiazole, the electron-rich 2-(trimethylsilyl)benzothiazole is more reactive and can produce the target product in good to excellent yields when reacting with alkenes bearing various electron-withdrawing or electron-donating groups. This demonstrates that the reaction mechanism is highly dependent on electron transfer.

[0160] As shown in Examples 36 to 48, the butyl radical (2-6a) was obtained in a 76% yield, and the nonyl radical (2-6b) was obtained in a 92% yield. Aliphatic radicals substituted with isopropyl groups (2-6c-2-6d) were each obtained in a 94% yield. Aliphatic radicals substituted with alkynes (2-6k) and alkenes (2-6j) were obtained in 93% and 95% yields, respectively. Aliphatic radicals substituted with cyclohexane (2-6i) were obtained in a 93% yield.

[0161] The above examples show that under the catalytic conditions disclosed in the present invention, a variety of target products can be synthesized with good substrate universality and broad functional group tolerance. It has good compatibility with olefins containing various functional groups and different azole heterocyclic substrates, and the yield of some products is as high as 93%.

[0162] The following further provides verification examples to illustrate the catalytic reaction conditions disclosed in the present invention:

[0163] Verification Example 1 - Reaction amplification verification.

[0164] Many reactions have high yields in small amounts because they can fully react. Taking the reaction in Example 1 as an example, the present invention further verifies the applicability of the catalytic reaction by conducting gram-scale reactions (Scheme 3-5). The specific reaction steps are as follows:

[0165] In a glove box under argon atmosphere, CuTc (19 mg, 0.1 mmol, 0.05 equiv.) and L3 (25 mg, 0.12 mmol, 0.06 equiv.) were weighed and added to a 15 mL Schlenk glass reaction vial. 5 mL of DCE was then added and stirred at room temperature for 0.5 h, during which the color of the reaction gradually changed from colorless to red. Subsequently, the reaction substrates LPO (2790 mg, 7.0 mmol, 1.4 equiv.), styrene (360 mg, 5.0 mmol, 1.0 equiv.), and trimethylsilylthiazole (1177 mg, 7.5 mmol, 1.5 equiv.) were added sequentially, and the reaction was stirred at room temperature for another 6 h. The reaction was monitored by TLC. After the disappearance of the substrate, the reaction mixture was directly filtered through celite and washed with ethyl acetate. The filtrate was concentrated and separated by column chromatography using n-hexane / ethyl acetate as the eluent to obtain the purified white product, 2-(1-phenyltridecyl)thiazole.

[0166] In Verification Example 1, styrene was used as the substrate. The reaction was scaled up to 5 mmol, and 1.46 g of the target product was still obtained with a yield of 85%.

[0167] The reaction equation for the gram-scale reaction is as follows Figure 2 As shown, the target product 1 H NMR (400MHz, CDCl3) spectrum is shown in Figure 3 As shown, 13 C NMR (100MHz, CDCl3) spectrum is shown in Figure 4 shown.

[0168] Verification Example 2-Verification of reaction principle.

[0169] Based on Example 1, the reaction principle for the organic catalytic synthesis of β-alkylazole compounds is as follows:

[0170] (1) Free radical reaction

[0171] First, a free radical capture experiment was conducted, including the following steps:

[0172] In a glove box under argon atmosphere, CuTc (3.8 mg, 0.02 mmol, 0.1 equiv.) and L3 (4.1 mg, 0.02 mmol, 0.1 equiv.) were weighed and added to a 15 mL Schlenk glass reaction bottle. 0.5 mL of DCE was then added and the reaction was stirred at room temperature for 0.5 h. The color of the system gradually changed from colorless to red.

[0173] The reaction substrates LPO (111.470 mg, 0.28 mmol, 1.4 equiv.), styrene (20.8 mg, 0.2 mmol, 1.0 equiv.), 2-trimethylsilylthiazole (47.1 mg, 0.3 mmol, 1.5 equiv.), and the radical scavenger TEMPO (46.9 mg, 0.3 mmol, 1.5 equiv.) were then added sequentially to the system, and the reaction was stirred at room temperature for 6 hours. 1,3,5-Trimethoxybenzene (0.1 mmol) was then added as an internal standard, and the mixture was completely dissolved in 5 mL of ethyl acetate. Samples were then removed for 1H NMR and GC-MS analysis.

[0174] The reaction equation for the free radical capture experiment is as follows: Figure 5 shown.

[0175] In Verification Example 2, by adding 1.5 equivalents of the free radical inhibitor 2,2,6,6-tetramethylpiperidinyl oxide TEMPO (Scheme 2-6) to the standard reaction system, it was found that the standard reaction was almost completely inhibited, and TEMPO-C was detected in the system by GC-MS. 11 H 23 The product was generated with an NMR yield of 72%. These results suggest that the reaction may have undergone a free radical process, in which alkyl radical species were generated.

[0176] Subsequently, a "free radical clock" experiment (Scheme 3-8) was conducted, which included the following steps:

[0177] In a glove box under argon atmosphere, CuTc (3.8 mg, 0.02 mmol, 0.05 equiv.) and L11 (4.1 mg, 0.02 mmol, 0.1 equiv.) were weighed and added to a 15 mL Schlenk glass reaction vial. 0.5 mL of DCE was then added and stirred at room temperature for 0.5 h, during which the color of the reaction gradually changed from colorless to red. Subsequently, the reaction substrates 2-3b (56.6 mg, 0.28 mmol, 1.5 equiv.), 2-1b (44.1 mg, 0.2 mmol, 1.0 equiv.), and 2-trimethylsilylthiazole (47.1 mg, 0.3 mmol, 1.4 equiv.) were added sequentially, and the reaction was stirred at room temperature for another 6 h. The reaction was monitored by TLC. After the substrate disappeared, the reaction mixture was directly filtered through celite and eluted with ethyl acetate. The filtrate was concentrated and separated by column chromatography using n-hexane / ethyl acetate as eluent to obtain 63 mg of a white purified product 3-6 with a yield of 80%.

[0178] The reaction equation of the free radical clock experiment is as follows Figure 6 shown.

[0179] In Verification Example 2, the three-membered ring substrate 2-1z underwent a three-membered ring opening reaction under standard conditions, yielding product 2-6 in 80% isolated yield. This experiment suggests that the reaction likely involves the addition of the generated alkyl radical species to the olefin, generating an alkyl radical intermediate.

[0180] (2) Catalytic reaction principle

[0181] Based on the above experimental results, it can be inferred that the LCu(I) catalyst initially reduces the alkyl peroxide via single electron transfer (SET) to generate an alkyl radical, a Cu(II) species A, and a carbon dioxide molecule. Subsequently, the alkyl radical reacts with the vinyl group to generate the more stable benzyl radical B. Simultaneously, the Cu(II) species can transfer with the TMS-protected nucleophile to generate the LCu(II)Nu species C through ligand exchange. Finally, the benzyl radical B combines with the LCu(II)Nu species C to generate the Cu(III) intermediate D, which undergoes reductive elimination to obtain the final product, and the LCu(I) catalyst can also be regenerated.

[0182] The catalytic reaction principle of organic catalytic synthesis of β-alkylazole compounds is as follows Figure 7 shown.

[0183] Verification Example 3-Screening of reaction conditions.

[0184] (1) Ligand screening

[0185] In the present invention, the ligand can be selected within a preferred range, such as Figure 11 The 16 ligands disclosed in Formulas L1 to L16 are shown. However, in order to obtain the largest target product, the present invention screened different bipyridine, biquinoline, bridged bipyridine, and phenanthroline ligands using styrene, lauroyl peroxide, and 2-trimethylsilylthiazole as substrates, 10 mol% cuprous thiophenedicarboxylate (CuTc) as a catalyst, dichloromethane (DCM) as a solvent, 1.0 equivalent (equiv) of alkyl diacyl peroxide (LPO), and 1.2 equiv of 2-trimethylsilylthiazole under an argon atmosphere at room temperature.

[0186] Depend on Figure 11 It can be seen that the target product obtained by the ligand containing phenanthroline is higher. The target product can be obtained with an NMR yield of 89% using L3 (5,6-dimethyl-1,10-phenanthroline). Therefore, 5,6-dimethyl-1,10-phenanthroline is the most preferred ligand provided by the present invention.

[0187] (2) Reaction solvent screening

[0188] The reaction solvent can be selected within a preferred range, such as dichloroethane (DCE), toluene (Tol), tetrahydrofuran (THF), chlorine (PhCl), acetonitrile (MeCN) and N,N-dimethylformamide (DMF). In order to obtain a higher yield of the target product, the above different reaction solvents were screened, and the results are shown in Table 1:

[0189] Table 1

[0190]

[0191]

[0192] From Table 1, we can see that DCE is the optimal solvent for the reaction.

[0193] (3) Copper salt screening

[0194] In the present invention, the copper catalyst can be selected from a wide range, and the screening results are shown in Table 2:

[0195] Table 2

[0196]

[0197] It can be seen from Table 2 that CuTc is the best copper salt catalyst for the reaction.

[0198] (4) Catalyst equivalent screening

[0199] In the present invention, the catalyst equivalent can be selected in a wide range, such as 2-10 mol%. The effect of the catalyst equivalent on the yield is shown in Table 3:

[0200] Table 3

[0201]

[0202] As shown in Table 3, when the CuTc loading is reduced to 5 mol%, the yield is reduced to 80%, and further reducing the catalyst equivalent to 2 mol%, the yield is reduced to 76%. Therefore, the catalyst equivalent is preferably CuTc (10 mol%) and L3 (10 mol%).

[0203] (5) Reactant ratio screening

[0204] In the present invention, the reaction substrates are alkyl diacyl peroxide (LPO) and trimethylsilyl substituted azole compounds. The equivalent weight of the two can be selected within a wide range, and the reaction time can also be selected within a wide range. The effects of the reaction substrate equivalent weight and reaction time on the yield are shown in Table 4:

[0205] Table 4

[0206]

[0207] Table 4 shows that reducing the amount of 2-2a and 2-3a to 1.4 and 1.5 equivalents, respectively, did not affect the reaction yield. Further reducing the amount of 4-2a to 1.2 equivalents decreased the yield to 90%. Shortening the reaction time to 6 h allowed the reaction to complete. Further shortening the reaction time to 3 h reduced the yield to 89%. Reducing the amount of reaction solvent to 0.5 mL did not affect the reaction.

[0208] To improve the atom economy and efficiency of the reaction, the most preferred reaction conditions are 1.4 equivalents of 2-2a, 1.5 equivalents of 2-3a, 0.5 mL of DCE solvent, and 6 h of reaction time.

[0209] The most preferred reaction conditions of the present invention are: 10 mol% CuTc as a catalyst, 10 mol% L3 as a ligand, DCE (0.2 M) as a reaction solvent, 1.4 equivalents of dodecanoyl peroxide 2-2a as an oxidant and an alkyl source, 1.5 equivalents of 2-(trimethylsilyl)thiazole 2-3a as an azole source, and the reaction is carried out at room temperature for 6 h to finally obtain the target product with an isolated yield of 96%.

[0210] The present invention uses a cuprous thiophenedicarboxylate catalyst, finds a suitable alkylating agent and azole source reagent, and adjusts the reaction conditions. The cuprous thiophenedicarboxylate triggers single electron transfer to generate an alkyl radical, which is captured by the olefin and added to form an alkyl radical. The alkyl radical then reacts with an azole nucleophile to achieve an amination-azole reaction between olefin molecules. This reaction does not require photocatalysis or the addition of other oxidants, has simple reaction conditions, is easy to implement, and can achieve a high yield.

[0211] The above reaction conditions are simple, belong to mild condition reactions, and have high chemical and regioselectivity, which can reduce the synthesis cost of β-alkylazole compounds. The present invention also provides specific reaction conditions for the specific synthesis of β-alkylazole compound products, which can be applied to the industrial production of β-alkylazole compounds, simplifying the industrial production process and reducing the difficulty of industrialization.

[0212] The above embodiments are merely exemplary embodiments of the present application and are not intended to limit the scope of the present application. The scope of protection of the present application is defined by the claims. Those skilled in the art may make various modifications or equivalent substitutions to the present application within the essence and scope of protection of the present application, and such modifications or equivalent substitutions shall also be deemed to fall within the scope of protection of the present application.

Claims

1. A method for organically catalyzing the synthesis of β-alkylazole compounds, characterized in that: The steps include: A three-component alkyl-azole difunctionalization reaction of olefins is carried out in an aprotic solvent using copper salts and nitrogen-containing ligands as catalysts, trimethylsilyl-substituted azole compounds as heteroaryl sources, and diacyl peroxides as alkyl radical precursors to obtain β-alkyl-substituted azole compounds. The general reaction formula of the three-component alkyl-oxazolyl difunctionalization reaction is as follows: Wherein, the structural formula of the olefin is: The general structural formula of the trimethylsilyl-substituted azole compound is: The general structural formula of the diacyl peroxide is:

2. The method for organically synthesizing β-alkylazole compounds according to claim 1, wherein: The olefin has a structure shown in any one of Formulas 2-1a to 2-1aa:

3. The method for organically synthesizing β-alkylazole compounds according to claim 1, wherein: The trimethylsilyl-substituted azole compound has a structure shown in any one of Formulas 2-2a to 2-2c; 4. The method for organically catalyzing the synthesis of β-alkylazole compounds according to claim 1, wherein: The diacyl peroxide has a structure shown in any one of Formulas 2-3a to 2-3m:

5. The method for organically catalyzing the synthesis of β-alkylazole compounds according to claim 1, wherein: The preparation method of the β-alkylazole compound comprises the following steps: In a glove box under argon atmosphere, copper salt and nitrogen-containing ligand were weighed and added to an aprotic solvent. The first stirring was performed at room temperature, and the color of the system gradually changed from colorless to red. Then, the reaction substrates diacyl peroxide, olefin, and azole reagent are added to the system in sequence, and stirred for a second time at room temperature to obtain a reaction mixture; After the reaction substrate disappears, the reaction mixture is filtered through diatomaceous earth and rinsed with ethyl acetate. The obtained filtrate is concentrated and separated by column chromatography using petroleum ether / ethyl acetate as eluent to obtain the β-alkylazole compound.

6. The method for organically catalyzing the synthesis of β-alkylazole compounds according to claim 5, characterized in that: The copper salt is any one of cuprous halide, tetraacetonitrile copper hexafluorophosphate, copper acetate, cuprous sulfide, cuprous acetate, and cuprous thiophene-2-carboxylate; The nitrogen-containing ligand has a structure shown in any one of formulas L1-L16: The aprotic solvent is any one of dichloroethane, toluene, tetrahydrofuran, chlorine, acetonitrile and N,N-dimethylformamide.

7. The method for organically catalyzing the synthesis of β-alkylazole compounds according to claim 6, characterized in that: The copper salt is cuprous thiophene 2-carboxylate; The aprotic solvent is N,N-dimethylformamide.

8. The method for organically catalyzing the synthesis of β-alkylazole compounds according to claim 7, wherein: The phenanthroline ligand has a structure shown in formula L3; The name of L3 is 5,6-dimethyl-1,10-phenanthroline.

9. The method for organically catalyzing the synthesis of β-alkylazole compounds according to claim 8, wherein: Based on the amount of the olefin, the equivalent of the cuprous thiophene 2-carboxylate is 2-10 mol%; the equivalent of the 5,6-dimethyl-1,10-phenanthroline is 2-10 mol%.

10. The method for organically catalyzing the synthesis of β-alkylazole compounds according to claim 5, characterized in that: The first stirring time is 0.5h; The second stirring time is 3-12h.

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