Allylation coupling reaction of aromatic ketoxime and vinyl pyridine alkane

Abstract

The invention provides an allylation coupling reaction of ortho-position selectivity of aromatic ketoxime and vinyl pyridine alkane, and relates to simple and efficient synthesis of an aromatic allylamine product under a catalytic system of [Ru (COD) Cl2] n, a ligand PPh3 and an additive KF through coordination guiding of a ketoxime group and a ruthenium center. Compared with other synthesis methods in the prior art, the method has the advantages of mild process conditions, easily available raw materials, low cost, high product yield and environmental friendliness, and can be popularized to industrial production; the process disclosed by the invention can also be widely applied to pharmaceutical synthesis and total synthesis of natural products in industrial and academic industries.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to an allylation coupling reaction of aromatic ketoxime and vinylpyrrolidine. Background Art

[0002] There are various amines in nature. Due to the important applications of amine compounds, the development of methods for synthesizing amines has attracted much attention. In addition to traditional methods, transition metal-catalyzed C-N bond construction methods developed in recent years have made the synthesis methods of amines more diverse. At the same time, due to the wide sources of amines, amines are often used as starting materials for synthesizing other useful molecules, including constructing new chemical bonds through catalytic activation of C-H bonds and C-N bonds.

[0003] The research group of Zhongxia Wang developed a method for Ru-catalyzed C-H activation of vinylpyrrolidine and pyridyl-directed aryls, realizing allylation of aromatic hydrocarbons. The reaction can obtain aromatic allylamine products in ideal yields (https: / / doi.org / 10.1002 / ajoc.202300384).

[0004]

[0005] The research group of Clavier also developed a Co-catalyzed C-H allylation reaction of pyridine-directed and activated cyclic allylamines in 2018, preparing various aromatic allylamine products in good yields (https: / / doi:10.1039 / c8qo00173a).

[0006]

[0007] At present, the transformation reaction combining C-H bond activation of aromatic hydrocarbons or olefins with C-N bond activation of amines (or pre-activated amines) has great potential and is attracting more and more attention from researchers. If the nitrogen-containing group is left in the product molecule after C-H / C-N catalytic transformation to obtain aromatic allylamine products, the synthesis of multi-functional group molecules can be achieved in one step, with high atom economy. However, the existing synthesis methods of aromatic allylamine products are all pyridine-directed, and there is a lack of catalytic methods for the C-H allylation reaction of vinylpyrrolidine. The synthesis strategy still faces problems such as harsh reaction conditions and poor generality. Summary of the Invention

[0008] Based on the above technical problems, the present invention provides an allylation coupling reaction of aromatic ketoxime and vinylpyrrolidine, making the C-H allylation reaction of vinylpyrrolidine possible. It is not only simple in process, safe in operation, but also high in yield, good in functional group tolerance, and easy to be popularized in industrial production.

[0009] An allylation coupling reaction of an aromatic ketoxime and vinylpyridine alkane proposed by the present invention includes: performing an allylation coupling reaction on the aromatic ketoxime shown in Structural Formula I and the vinylpyridine alkane shown in Structural Formula II to obtain an aromatic allylamine product shown in Structural Formula III;

[0010]

[0011] Wherein, R1 is hydrogen, alkyl, alkoxy, alkylthio, alkenyl, aryl, heteroaryl, cyano, halogen, nitro, ester carbonyl, amide group or azide group; R2, R3, and R4 are each independently hydrogen, alkyl, cycloalkyl, aryl or heteroaryl.

[0012] Preferably, R2 and R3 are each independently C1-C4 alkyl, preferably methyl or ethyl, and R4 is aryl, preferably phenyl.

[0013] Preferably, R1 is hydrogen, C1-C4 alkyl, halogen or nitro.

[0014] Preferably, the allylation coupling reaction is carried out under the reaction conditions of a ruthenium catalyst, a phosphorus ligand, and a basic additive.

[0015] Preferably, the ruthenium catalyst is at least one of [Ru(COD)Cl2], n [Ru(p-cymene)2Cl2]2 or RuCl2(PPh3)3, preferably [Ru(COD)Cl2]; n ;

[0016] The phosphorus ligand is at least one of PPh3, PCy3, Dppp or Xantphos, preferably PPh3;

[0017] The basic additive is at least one of KF, KPF6, K2CO3, Cs2CO3 or CsF, preferably KF.

[0018] Preferably, the solvent for the allylation coupling reaction is at least one of toluene, tetrahydrofuran, N,N-dimethylformamide, 1,4-dioxane or dichloroethane, preferably toluene.

[0019] Preferably, the temperature of the allylation coupling reaction is 80-110°C and the time is 6-24 h.

[0020] The present invention also proposes an aromatic allylamine product synthesized by the above allylation coupling reaction.

[0021] Preferably, the aromatic allylamine product has the structure shown as follows:

[0022]

[0023] An allylation coupling reaction of an aromatic ketoxime with vinylpyridine selectively at the ortho position proposed by the present invention involves coordination guidance through the ketoxime group with a ruthenium center and, under a catalytic system of [Ru(COD)Cl2] n and ligand PPh3 and additive KF, simply and efficiently synthesizes an aromatic allylamine product. Compared with other synthesis methods in the prior art, the process conditions of the present invention are mild, raw materials are easily available, the cost is low, the product yield is high, and it is environmentally friendly, and can be extended to industrial production; the process of the present invention can also be widely applied to drug synthesis in industry and academia and total synthesis of natural products. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 1H NMR spectrum of the target product described in Example 1. DETAILED DESCRIPTION OF THE INVENTION

[0025] Next, the present invention details the technical solution through specific examples, but it should be clearly stated that these examples are for illustrative purposes only and are not construed as limiting the scope of the present invention.

[0026] In the present invention, all raw materials used are commercially available, and each reagent is synthesized and purified by means well known in the art when necessary before use.

[0027] In the present invention, 1 1H NMR was measured using a Bruker Avance 400 spectrometer. The test temperature was room temperature, the solvent was deuterated chloroform (CDCl3), and the reference was selected as: 1 1H NMR: CDCl3 was 7.26 ppm.

[0028] In the present invention, the synthesis conditions of the aryl ortho-allylation reaction of cyclic allylamine are first optimized to determine the optimal catalytic reaction system. Specifically, taking the synthesis process of acetophenone oxime and 1-phenyl-2-vinylpyridine as an example, the synthesis route is as follows:

[0029]

[0030] As shown in the above reaction formula, in a glove box filled with argon, reactant 1a (0.20 mmol), reactant 1b (0.20 mmol), [Ru(COD)Cl2] n(0.01 mmol), PPh3 (0.01 mmol), KF (0.02 mmol), and toluene (1.00 mL) were added to a dried Schlenk flask. After sealing, it was taken out of the glove box. After stirring and reacting at 80 °C for 12 h, it was diluted with toluene, filtered through diatomaceous earth and silica gel, and the filtrate was concentrated. The crude product was separated and purified by silica gel column chromatography to obtain the target product 1c.

[0031] According to the above method, 22 groups of parallel test groups were set up, using different catalysts, ligands, additives, solvents, reaction temperatures, and times respectively to obtain the target product 1c, and its yield was calculated. The results are shown in Table 1 below:

[0032] Table 1 Comparison of yields of target product 1c under different reaction conditions

[0033]

[0034]

[0035] In the above table: The yield is the isolated yield of the target product 1c; PPh3 = triphenylphosphine; PCy3 = tricyclohexylphosphine; Dppp = bis(diphenylphosphino)propane; Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; toluene = toluene; THF = tetrahydrofuran; DMF = N,N-dimethylformamide; dioxane = 1,4-dioxane; DCE = dichloroethane.

[0036] As can be seen from Table 1 above, under the catalytic system of 5.0 mol% [Ru(COD)Cl2] n and ligand PPh3 and 10.0 mol% additive KF, the isolated yield of the target product can be as high as 94% (Table 1, entry 1); however, when the ligand PPh3 is not added, the yield of the target product decreases significantly (Table 1, entry 2). When using Ru catalysts such as [Ru(p-cymene)2Cl2]2 or RuCl2(PPh3)3, the yield of the target product also decreases a lot (Table 1, entries 3 - 4); when using other alternative transition metals, including PdCl2(PPh3)2, RhCl(PPh3)3, or [RhCp*Cl2]2, basically no or only trace amounts of products are formed, which confirms that [Ru(COD)Cl2] nSuperiority of the catalyst (Table 1, Entries 5 - 7); When other phosphine ligands PCy3, Dppp, Xantphos are used instead of PPh3, the yields of the target products all decrease to varying degrees, confirming the superiority of the PPh3 ligand (Table 1, Entries 8 - 10); When KPF6, K2CO3, Li2CO3, Cs2CO3, Et3N, CsF are used instead of KF as additives, the yields of the target products will all decrease to varying degrees (Table 1, Entries 11 - 16); When DMF, dioxane, THF, DCE are used to replace toluene as the solvent respectively, the yields of the target products also decrease significantly, thus determining toluene as the optimal solvent system (Table 1, No. 17 - 20); Lowering the reaction temperature will reduce the product yield (Table 1, Entries 21 - 22).

[0037] When optimizing the synthesis conditions, when using a pyridine-directed aromatic compound (i.e., 2-(o-tolyl)pyridine) as the substrate, in the case of using [Ru(p-cymene)Cl2]2 as the catalyst, AgOAc as the additive, and CF3CH2OH as the reaction solvent, even when the temperature is raised to over 80 °C, it still cannot undergo an allylation coupling reaction with 1-phenyl-2-vinylpyrrolidine.

[0038] Based on the above-determined optimal catalytic reaction system, the present invention expands the scope of the reaction substrates adapted thereto, as specifically shown below:

[0039] Example 1

[0040] Synthesis of the target product 1c

[0041] Inside a glove box filled with argon, the reactants 1a (0.20 mmol), 1b (0.20 mmol), [Ru(COD)Cl2] n (0.01 mmol), PPh3 (0.01 mmol), KF (0.02 mmol) and toluene (1.00 mL) were added to a dried schlenk flask, sealed and taken out of the glove box. After stirring and reacting at 120 °C for 12 h, it was diluted with toluene, filtered through diatomaceous earth and silica gel, and the filtrate was concentrated. The crude product was separated and purified by silica gel column chromatography, and the eluent was petroleum ether and ethyl acetate = 5:1, to obtain the purified target product 1c with a yield of 94%.

[0042] Characterization data of the target product 1c: 11H NMR (500 MHz, CDCl3) δ 7.72–7.68 (m, 1H), 7.38–7.35 (m, 1H), 7.23–7.08 (m, 3H), 6.70–6.63 (m, 1H), 6.58–6.50 (m, 2H), 5.56–5.19 (m, 2H), 4.03 (s, 3H), 3.81–3.30 (m, 3H), 3.04 (q, J = 7.3 Hz, 2H), 2.40–2.33 (m, 6H), 2.11–1.96 (m, 2H), 1.64–1.57 (m, 4H).

[0043] Example 2

[0044] Synthesis of target product 2c

[0045] Referring to the method described in Example 1, except that reactant 2a was used to replace reactant 1a, the purified target product 2c was obtained with a yield of 87%.

[0046] Characterization data of target product 2c: 1 1H NMR (500 MHz, CDCl3) δ 7.73–7.70 (m, 1H), 7.35–7.20 (m, 5H), 6.95–6.78 (m, 2H), 6.64–6.53 (m, 1H), 5.69–5.23 (m, 2H), 4.03 (s, 1H), 3.92 (s, 3H), 3.37–3.22 (m, 4H), 2.82 (s, 3H), 2.18 (m, 2H), 1.43–1.29 (m, 4H).

[0047] Example 3

[0048] Referring to the method described in Example 1, except that reactant 3a was used to replace reactant 1a, the purified target product 3c was obtained with a yield of 81%.

[0049] Characterization data of target product 3c: 1 1H NMR (500 MHz, CDCl3) δ 7.62–7.60 (m, 1H), 7.26–7.20 (m, 4H), 6.78–6.59 (m, 3H), 5.89–5.32 (m, 2H), 4.09 (s, 3H), 3.91 (s, 1H), 3.31–3.18 (m, 4H), 2.85 (s, 3H), 2.15 (m, 2H), 1.49–1.29 (m, 4H).

[0050] Example 4

[0051] Referring to the method described in Example 1, except that reactant 4a was used to replace reactant 1a, the purified target product 4c was obtained with a yield of 76%.

[0052] Characterization data of the target product 4c: 1 H NMR(500MHz,CDCl3)δ7.60–7.57(m,1H),7.43–7.23(m,4H),6.82–6.61(m,3H),5.91–5.44(m,2H),4.05(s,1H),3.87(s,3H),3.35–3.21(m,4H),2.86(s,3H),2.18(m,2H),1.52–1.33(m,4H).

[0053] Example 5

[0054] Referring to the method described in Example 1, except that reactant 5a was used to replace reactant 1a, the purified target product 5c was obtained with a yield of 84%.

[0055] Characterization data of the target product 5c: 1 H NMR(500MHz,CDCl3)δ7.58–7.53(m,1H),7.17–7.14(m,4H),6.63–6.49(m,3H),5.87–5.35(m,2H),4.15(s,3H),3.83(s,1H),3.29–3.17(m,4H),2.84(s,3H),2.17(m,2H),1.48–1.27(m,4H).

[0056] Example 6

[0057] Referring to the method described in Example 1, except that reactant 6a was used to replace reactant 1a, the purified target product 6c was obtained with a yield of 70%.

[0058] Characterization data of the target product 6c: 1 H NMR(500MHz,CDCl3)δ8.21–8.14(m,2H),7.96–7.92(m,1H),7.26–7.20(m,2H),6.73–6.59(m,3H),5.95–5.41(m,2H),4.23(s,3H),3.95(s,1H),3.36–3.21(m,4H),2.92(s,3H),2.25(m,2H),1.51–1.33(m,4H).

[0059] Example 7

[0060] Referring to the method described in Example 1, except that reactant 7a was used to replace reactant 1a, the purified target product 7c was obtained with a yield of 78%.

[0061] Characterization data of the target product 7c:1 1H NMR (500 MHz, CDCl3) δ 7.80–7.77 (m, 1H), 7.41–7.26 (m, 3H), 7.11–6.96 (m, 2H), 6.74–6.58 (m, 2H), 5.91–5.37 (m, 2H), 4.05 (s, 1H), 3.91 (s, 3H), 3.82 (s, 3H), 3.35–3.21 (m, 4H), 2.84 (s, 3H), 2.19 (m, 2H), 1.50–1.31 (m, 4H).

[0062] Example 8

[0063] Referring to the method described in Reference Example 1, except that reactant 2a was used to replace reactant 1a, the purified target product 8c was obtained with a yield of 87%.

[0064] Characterization data of the target product 8c: 1 1H NMR (500 MHz, CDCl3) δ 7.66–7.60 (m, 1H), 7.33–7.30 (m, 2H), 7.17–6.58 (m, 4H), 5.68–5.21 (m, 2H), 4.09 (s, 1H), 3.93 (s, 3H), 3.34–3.19 (m, 4H), 2.85 (s, 3H), 2.36 (s, 6H), 2.19 (m, 2H), 1.51–1.26 (m, 4H).

[0065] Example 9

[0066] Referring to the method described in Reference Example 1, except that reactant 2a was used to replace reactant 1a, the purified target product 9c was obtained with a yield of 90%.

[0067] Characterization data of the target product 2c: 1 1H NMR (500 MHz, CDCl3) δ 7.48–7.45 (m, 1H), 7.23–7.20 (m, 2H), 6.80–6.58 (m, 4H), 6.02–5.40 (m, 2H), 4.05 (s, 1H), 3.88 (s, 3H), 3.35–3.21 (m, 4H), 2.87 (s, 3H), 2.21 (m, 2H), 1.54–1.32 (m, 4H).

[0068] Example 10

[0069] Referring to the method described in Reference Example 1, except that reactant 2a was used to replace reactant 1a, the purified target product 10c was obtained with a yield of 86%.

[0070] Characterization data of the target product 10c: 11H NMR (500 MHz, CDCl3) δ 7.69–7.66 (m, 1H), 7.33–7.29 (m, 1H), 7.19–7.04 (m, 2H), 6.61–6.57 (m, 1H), 6.49–6.43 (m, 3H), 5.58–5.21 (m, 2H), 4.07 (s, 1H), 3.59 (m, 2H), 3.36–3.23 (m, 4H), 2.86 (s, 3H), 2.36 (s, 3H), 2.19–2.21 (m, 2H), 1.48–1.27 (m, 4H), 1.12–1.07 (m, 3H).

[0071] The reaction substrates, target products and yields in Examples 1-10 are listed in a table as shown in Table 2 below:

[0072] Table 2 Comparison Table of Reaction Substrates, Target Products and Yields in Examples 1-10

[0073]

[0074]

[0075] As can be seen from Table 2 above, under the aforementioned optimized catalytic system, after reacting aromatic ketoxime with 1-aryl-2-vinylpyrrolidine, various target products can be efficiently synthesized.

[0076] The above is only a preferred specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention, according to the technical solution and inventive concept of the present invention, making equivalent substitutions or changes, shall be covered by the protection scope of the present invention.

Claims

1. An allylation coupling reaction of an aromatic ketoxime and vinylpyridine alkane, characterized in that, Comprising: Performing an allylation coupling reaction between the aromatic ketoxime shown in Structural Formula I and the vinylpyridine alkane shown in Structural Formula II to obtain an aromatic allylamine product shown in Structural Formula III; Wherein, R1 is hydrogen, alkyl, alkoxy, alkylthio, alkenyl, aryl, heteroaryl, cyano, halogen, nitro, ester carbonyl, amido or azide; R2, R3, R4 are each independently hydrogen, alkyl, cycloalkyl, aryl or heteroaryl.

2. The allylation coupling reaction of the aromatic ketoxime and vinylpyridine alkane according to claim 1, wherein R2 and R3 are each independently C1-C4 alkyl, and R4 is aryl.

3. The allylation coupling reaction of the aromatic ketoxime and vinylpyridine alkane according to claim 1, characterized in that, R1 is hydrogen, C1-C4 alkyl, halogen or nitro.

4. The allylation coupling reaction of the aromatic ketoxime and vinylpyridine alkane according to any one of claims 1-3, characterized in that, The allylation coupling reaction is carried out under the reaction conditions of a ruthenium catalyst, a phosphorus ligand and a basic additive.

5. The allylation coupling reaction of the aromatic ketoxime and vinylpyridine alkane according to claim 4, characterized in that, The ruthenium catalyst is [Ru(COD)Cl2] n , at least one of [Ru(p-cymene)2Cl2]2 or RuCl2(PPh3)3; The phosphorus ligand is at least one of PPh3, PCy3, Dppp or Xantphos; The basic additive is at least one of KF, KPF6, K2CO3, Cs2CO3 or CsF.

6. The allylation coupling reaction of the aromatic ketoxime and vinylpyridine alkane according to claim 4, characterized in that, The ruthenium catalyst is [Ru(COD)Cl2] n ; the phosphorus ligand is PPh3; the basic additive is KF.

7. The allylation coupling reaction of the aromatic ketoxime and vinylpyridine alkane according to any one of claims 1-3, characterized in that, The solvent for the allylation coupling reaction is at least one of toluene, tetrahydrofuran, N,N-dimethylformamide, 1,4-dioxane or dichloroethane.

8. The allylation coupling reaction of the aromatic ketoxime and vinylpyridine alkane according to any one of claims 1-3, characterized in that, The temperature of the allylation coupling reaction is 80-110 °C and the time is 6-24 h.

9. An aromatic allylamine product synthesized by the allylation coupling reaction according to any one of claims 1-8.

10. The aromatic allylamine product synthesized by the allylation coupling reaction according to claim 9, characterized in that, It is as shown in the following structural formula:

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