Aryl sulfonate-based Catellai type methylation method

Abstract

The invention aims to provide a method for preparing the polysubstituted methyl aromatic hydrocarbon compound by taking methyl 2-trifluoromethanesulfonyloxybenzoate, methyl p-toluenesulfonate and an olefin compound as raw materials under the promotion action of alkali, a palladium catalytic system and norbornene. The method has the advantages of cheap and easily available raw materials, simple reaction operation, mild conditions, high efficiency, economy and the like; the problem of excessive dependence on an iodine leaving group in a reaction for synthesizing the polysubstituted methyl aromatic hydrocarbon compound by using 2-trifluoromethanesulfonyloxy methyl benzoate is solved.

Description

[Technical field]

[0001] The invention belongs to the field of organic synthesis, and in particular relates to a new Catellani-type methylation method based on aryl sulfonate compounds. [Background technology]

[0002] The methyl group is the smallest alkyl structural unit and is widely present in small molecule drugs and bioactive molecules. Among the top 200 drugs in terms of sales in 2018, more than half of the drug molecules contain at least one methyl group. Methylation modification of drug molecules can change their molecular conformation, improve solubility, enhance metabolic stability and biological activity, which is called the "magic methyl effect". Therefore, methylation has become an efficient modification strategy in the field of medicinal chemistry, and it is particularly necessary to develop efficient methylation methods.

[0003] In the 1990s, Catellani (Angew. Chem., Int. Ed. 1997, 36, 119.) et al. reported a domino reaction promoted by palladium and norbornene, which attracted the attention of organic chemists. Compared with the traditional multi-step synthesis method, the cleverly designed domino reaction can greatly improve the reaction efficiency and atom utilization. On this basis, a "dual-task methylation" can be developed by combining ortho-CH activation methylation and different in situ cross-coupling termination reactions. Such a method will have great synthetic potential to obtain more diverse methylations and more diverse multi-substituted methylated aromatics, thereby meeting the growing needs of medicinal chemists.

[0004] The typical Catellani reaction usually uses aryl iodides as substrates, which greatly limits the application of this reaction in modern organic synthesis. The carbon-iodine bond in aryl iodides is relatively active, and the compatibility with other active groups during the introduction process is poor, the synthesis is relatively difficult, and it will cause environmental pollution during the preparation process, making it difficult to apply industrially. Commercially available aryl iodides are expensive and have less selectivity, which is not conducive to the research and development of this reaction. Therefore, it is meaningful to use other readily available raw materials and environmentally friendly aromatic sulfonate compounds as substrates to achieve Catellani-type methylation reactions. [Summary of the invention]

[0005] The object of the present invention is to provide a method for preparing a polysubstituted methyl aromatic compound by using methyl 2-trifluoromethanesulfonyloxybenzoate, methyl p-toluenesulfonate and olefin compounds as raw materials under the promotion of a base, a palladium catalyst system and norbornene.

[0006] In order to achieve the above-mentioned object of the invention, the present invention proposes the following technical solutions:

[0007] A method for synthesizing a polysubstituted methylated aromatic compound based on the Catellani reaction, wherein the structure of the polysubstituted methyl compound is as shown in Formula I:

[0008]

[0009] Wherein R is one of fluorophenyl, chlorophenyl, bromophenyl, methylphenyl, methoxyphenyl, nitrophenyl, phenyl, amide, carboxylic acid, and naphthyl. The synthesis method of compound I is characterized in that the raw materials methyl 2-trifluoromethanesulfonyloxybenzoate, methyl p-toluenesulfonate, olefin compounds, and bases, ligands, norbornene, catalysts, and organic solvents are placed in a reaction container and mixed, and stirred at 80-120° C. for 5-12 hours under an inert gas environment; after the reaction is completed, the organic solvent is removed by vacuum distillation and concentration, and the crude product is separated by column chromatography to obtain a polysubstituted methylated aromatic compound as shown in formula I.

[0010] In the synthesis method, the structures of the raw materials methyl 2-trifluoromethanesulfonyloxybenzoate, methyl morpholinebenzoate and olefin compounds are shown in Formula II, Formula III and Formula IV respectively:

[0011]

[0012] Wherein R is one of fluorophenyl, chlorophenyl, bromophenyl, methylphenyl, methoxyphenyl, nitrophenyl, phenyl, amide, carboxylic acid, and naphthyl.

[0013] In the synthesis method, the base is selected from at least one of potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, sodium tert-butoxide, and potassium tert-butoxide.

[0014] In the synthesis method, the catalyst is selected from Pd(OAc) 2 、Pd(PPh 3 ) 4 , PdCl 2 (MeCN) 2 , PdCl 2 、Pd(acac) 2 、Pd(1.3-dppp)Cl 2 、Pd(cod) 2 Cl 2 、Pd(PPh 3 ) 2 Cl 2 At least one of .

[0015] In the synthesis method, the ligand is selected from at least one of CyJohnphos, Mephos, Davephos, Ruphos, S-phos, X-phos, tBuXphos, dpephos, dppbenz, dppe, dppm, dppp, dppb, dppe, and dpph.

[0016] In the synthesis method, the molar ratio of methyl 2-trifluoromethanesulfonyloxybenzoate, methyl p-toluenesulfonate, olefin compound, base, ligand, norbornene and catalyst is 1:1:[1.0-1.5]:[1.0-4.0]:[0.05-1.5]:[1.0-4.0]:[0.05-1.5].

[0017] In the synthesis method, the organic solvent is selected from at least one of toluene, p-xylene, anisole, cyclohexane, dioxane, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide.

[0018] In the synthesis method, the inert gas is selected from at least one of nitrogen, argon and helium.

[0019] According to the experimental results, the present invention provides a method for synthesizing multi-substituted methylated aromatic compounds by promoting methyl 2-trifluoromethanesulfonyloxybenzoate, methyl p-toluenesulfonate and olefin compounds through a base, a palladium catalyst system and norbornene. The method reduces waste discharge and eliminates the need for separation of intermediate products, and therefore has great significance for environmental protection.

Brief Description of the Drawings

[0020] Attached Figure 1 Shown is a synthetic route diagram of the multi-substituted methylated aromatic compounds provided by the present invention.

[0021] Attached Figure 2 Shown is the H NMR spectrum of methyl (E)-2-(3-methoxy-3-oxopropyl-1-enyl)-3-methylbenzoate.

[0022] Attached Figure 3 Shown is the H NMR spectrum of dimethyl (E)-5-methyl-4-(2-(naphthalen-2-yl)vinyl)isophthalate.

[0023] Attached Figure 4 Shown is the H NMR spectrum of methyl (E)-2-(3-ethoxy-3-oxopropyl-1-enyl)-3-methylbenzoate.

[0024] Attached Figure 5 Shown is the hydrogen nuclear magnetic resonance spectrum of methyl (E)-2-(3-(tert-butoxy)-3-oxopropyl-1-enyl)-3-methylbenzoate.

[0025] Attached Figure 6 Shown is the H NMR spectrum of (E)-2-(3-methoxy-3-oxopropyl-1-enyl)-3-methyl-1-naphthoate.

[0026] Attached Figure 7 Shown is the H NMR spectrum of methyl (E)-2-(3-methoxy-3-oxopropyl-1-enyl)-3,5-dimethylbenzoate.

[0027] Attached Figure 8 Shown is the H NMR spectrum of methyl (E)-3-(2-methylnaphthalen-1-yl)acrylate.

[0028] Attached Fig. 9 Shown is the H NMR spectrum of methyl (E)-5-methoxy-2-(3-methoxy-3-oxopropyl-1-enyl)-3-methylbenzoate.

[0029] Attached Fig.10 This is the hydrogen nuclear magnetic resonance spectrum of methyl (E)-3-(10-methyl-9-phenanthrene)acrylate. [Specific implementation method]

[0030] The synthesis method of the present invention is further described below in conjunction with the synthesis examples of the present invention:

[0031] like Figure 1 As shown, the synthesis steps of a polysubstituted methylated aromatic hydrocarbon provided by the present invention are: methyl 2-trifluoromethanesulfonyloxybenzoate, methyl p-toluenesulfonate, olefin compound (molar ratio of 100%-200% based on methyl 2-trifluoromethanesulfonyloxybenzoate), base (molar ratio of 10%-400% based on methyl 2-trifluoromethanesulfonyloxybenzoate), ligand (molar ratio of 5%-150% based on methyl 2-trifluoromethanesulfonyloxybenzoate), norbornene (molar ratio of 10%-400% based on methyl 2-trifluoromethanesulfonyloxybenzoate), metal palladium catalyst (molar ratio of 1%-150% based on methyl 2-trifluoromethanesulfonyloxybenzoate), and organic solvent are placed in a reaction container and mixed, and stirred at 80-160° C. for 5-15 hours under a nitrogen environment; after the reaction is completed, the organic solvent is removed by vacuum distillation and concentration, and the crude product is separated by column chromatography to obtain the target product.

[0032] The present invention will be further described below in conjunction with specific preparation examples:

[0033] Synthesis example 1

[0034] Synthesis of Methyl (E)-2-(3-methoxy-3-oxopropyl-1-enyl)-3-methylbenzoate

[0035] In the reactor, 0.20 mmol of methyl 2-trifluoromethanesulfonyloxybenzoate, 0.40 mmol of methyl p-toluenesulfonate, 0.40 mmol of methyl acrylate, 2.5 mmol of potassium carbonate, 0.01 mmol of dpephos, 0.3 mmol of NBE-CN, and Pd(OAc) were added. 2 0.01mmol, acetonitrile solvent 0.8mL. Stir the reaction at 100℃ under nitrogen environment for 12 hours; after the reaction, distill and concentrate under reduced pressure to remove the organic solvent, and separate the crude product by column chromatography to obtain the target product with a yield of 98%.

[0036] 1 H NMR (400 MHz, CDCl 3 )δ8.06(d,J=16.4Hz,1H,E),7.81(d,J=8.0Hz,1H,Z),7.70(d,J=7.6Hz,1H,E),7.37(d,J=7.6Hz,1H,E),7.27(t,J=7.6Hz,1H,E),6.10(d, J=12.0Hz,1H,Z),5.92(d,J=16.4Hz,1H,E),3.85(s,3H,E),3.82(s,3H,Z),3.80(s,3H,E),3.53(s,3H,Z),2.35(s,3H,E),2.24(s,3H,Z).

[0037] Synthesis example 2

[0038] Synthesis of dimethyl (E)-5-methyl-4-(2-(naphthalen-2-yl)vinyl)isophthalate

[0039] Add 0.20mmol of methyl 2-trifluoromethanesulfonyloxybenzoate, 0.40mmol of methyl p-toluenesulfonate, 0.40mmol of 2-vinylnaphthalene, 2.5mmol of potassium carbonate, 0.01mmol of dpephos, 0.3mmol of NBE-CN, 0.01mmol of Pd(OAc)2, and 0.8mL of an organic solvent into a reactor. Stir and react at 100°C under a nitrogen atmosphere for 12 hours. After the reaction is completed, distill and concentrate under reduced pressure to remove the organic solvent, and separate the crude product by column chromatography to obtain the target product with a yield of 90%.

[0040] 1H NMR (400MHz, CDCl 3)δ7.85-7.77(m,4H),7.74(d,J=8.8Hz,1H),7.63(d,J=8.0Hz,1H),7.52(d,J=16.8Hz,1H),7.49–7.38(m, 2H),7.35(d,J=7.2Hz,1H),7.22(dd,J=7.6,2.8Hz,1H),6.66(d,J=16.4Hz,1H),3.80(s,3H),2.43(s,3H).

[0041] Synthesis example 3

[0042] Synthesis of Methyl (E)-2-(3-ethoxy-3-oxopropyl-1-enyl)-3-methylbenzoate

[0043] Add 0.20mmol of methyl 2-trifluoromethanesulfonyloxybenzoate, 0.40mmol of methyl p-toluenesulfonate, 0.40mmol of ethyl acrylate, 2.5mmol of potassium carbonate, 0.01mmol of dpephos, 0.3mmol of NBE-CN, 0.01mmol of Pd(OAc)2, and 0.8mL of acetonitrile solvent into the reactor. Stir and react at 100°C under nitrogen atmosphere for 12 hours. After the reaction is completed, the organic solvent is removed by vacuum distillation and concentration. The crude product is separated by column chromatography to obtain the target product with a yield of 78%.

[0044] 1 H NMR (400 MHz, CDCl 3 )δ8.05(d,J=16.0Hz,1H,E),7.80(d,J=7.6Hz,1H,Z),7.70(d,J=7.6Hz,1H,E),7.38( d,J=7.2Hz,1H,E),7.28(t,J=7.6Hz,1H,E),6.08(d,J=12.0Hz,1H,Z),5.91(d,J=16. 4Hz,1H,E),4.27(q,J=7.2Hz,2H,E),3.97-3.93(m,2H,Z),3.85(s,3H,E),3.83(s,3H ,Z),2.37(s,3H,E),2.25(s,3H,Z),1.34(t,J=7.2Hz,3H,E),1.03(t,J=7.2Hz,3H,Z).

[0045] Synthesis example 4

[0046] Synthesis of Methyl (E)-2-(3-(tert-Butoxy)-3-oxopropyl-1-enyl)-3-methylbenzoate

[0047] Add 0.20mmol of methyl 2-trifluoromethanesulfonyloxybenzoate, 0.40mmol of methyl p-toluenesulfonate, 0.40mmol of tert-butyl acrylate, 2.5mmol of potassium carbonate, 0.01mmol of dpephos, 0.3mmol of NBE-CN, 0.01mmol of Pd(OAc)2, and 0.8mL of acetonitrile solvent into the reactor. Stir and react at 100°C under nitrogen atmosphere for 12 hours; after the reaction is completed, distill and concentrate under reduced pressure to remove the organic solvent, and separate the crude product by column chromatography to obtain the target product with a yield of 78%.

[0048] 1 H NMR (400 MHz, CDCl 3 )δ7.94(d,J=16.4Hz,1H,E),7.78(d,J=8.0Hz,1H,Z),7.67(d,J=8.0Hz,1H,E),7.36(d,J=7.6Hz,1H,E),7.26(t,J=7.6Hz,1H,E), 5.98(d,J=12.4Hz,1H,Z),5.85(d,J=16.4Hz,1H,E),3.85(s,3H,E),3.83(s,3H,Z),2.36(s,3H,E),2.25(s,3H,Z),1.54(s,9H,E).

[0049] Synthesis example 5

[0050] Synthesis of (E)-2-(3-methoxy-3-oxopropyl-1-enyl)-3-methyl-1-naphthoate

[0051] Add 0.20mmol of methyl 2-((trifluoromethyl)sulfonyl)oxy)-1-naphthalenesulfonate, 0.40mmol of methyl p-toluenesulfonate, 0.40mmol of ethyl acrylate, 2.5mmol of potassium carbonate, 0.01mmol of dpephos, 0.3mmol of NBE-CN, 0.01mmol of Pd(OAc)2, and 0.8mL of acetonitrile solvent into the reactor. Stir and react at 100°C under nitrogen atmosphere for 12 hours. After the reaction, distill and concentrate under reduced pressure to remove the organic solvent, and separate the crude product by column chromatography to obtain the target product with a yield of 91%.

[0052] 1 H NMR (400 MHz, CDCl 3 )δ7.98(d,J=16.4Hz,1H),7.78(dd,J=6.0,5.6Hz,2H),7.72(s,1H),7.51–7 .48(m,2H),6.20(d,J=16.4Hz,1H),3.96(s,3H),3.82(s,3H),2.49(s,3H).

[0053] Synthesis example 6

[0054] Synthesis of Methyl (E)-2-(3-methoxy-3-oxopropyl-1-enyl)-3,5-dimethylbenzoate

[0055] Add 0.20mmol of methyl 5-methyl-2-((trifluoromethyl)sulfonyl)oxy)benzoate, 0.40mmol of methyl p-toluenesulfonate, 0.40mmol of ethyl acrylate, 2.5mmol of potassium carbonate, 0.01mmol of dpephos, 0.3mmol of NBE-CN, 0.01mmol of Pd(OAc)2, and 0.8mL of acetonitrile solvent into the reactor. Stir the reaction at 100°C under nitrogen atmosphere for 12 hours. After the reaction is completed, the organic solvent is removed by vacuum distillation and concentration. The crude product is separated by column chromatography to obtain the target product with a yield of 87%.

[0056] 1 H NMR (400 MHz, CDCl 3 )δ8.03(d,J=16.4Hz,1H,E),7.63(s,1H,Z),7.51(s,1H,E),7.35(d,J=12.0Hz,1H,Z),7.20(s,1H,E),6.08(d,J=12.0Hz,1H,Z) ,5.91(d,J=16Hz,1H,E),3.85(s,3H,E),3.82(s,3H,Z),3.80(s,3H,E),3.55(s,3H,Z),2.34(d,J=4.8Hz,6H,E),2.21(s,6H,Z).

[0057] Synthesis Example 7

[0058] Synthesis of Methyl (E)-3-(2-Methylnaphthyl-1-yl)acrylate

[0059] 0.20mmol of 1-naphthyl trifluoromethanesulfonate, 0.40mmol of methyl p-toluenesulfonate, 0.40mmol of ethyl acrylate, 2.5mmol of potassium carbonate, 0.01mmol of dpephos, 0.3mmol of NBE-CN, 0.01mmol of Pd(OAc)2, and 0.8mL of acetonitrile solvent were added to the reactor. The reaction was stirred at 100°C for 12 hours under nitrogen environment. After the reaction was completed, the organic solvent was removed by vacuum distillation and concentration, and the crude product was separated by column chromatography to obtain the target product with a yield of 87%.

[0060] 1 H NMR (400 MHz, CDCl 3)δ8.19(d,J=16.4Hz,1H,E),8.02(d,J=8.4Hz,1H,E),7.79(d,J=8.4Hz,1H,E),7.72(d,J=8.4Hz,1H,E),7.46-7.41(m,2H,E),7.32(d ,J=8.4Hz,1H,E),6.38(d,J=12.0Hz,1H,Z),6.23(d,J=16.4Hz,1H,E),3.86(s,3H,E),3.45(s,3H,Z),2.49(s,3H,E),2.38(s,3H,Z).

[0061] Synthesis example 8

[0062] Synthesis of Methyl (E)-5-Methoxy-2-(3-Methoxy-3-oxopropyl-1-enyl)-3-Methylbenzoate

[0063] In the reactor, 0.20 mmol of methyl 5-methoxy-2-((trifluoromethyl)sulfonyl)oxy)benzoate, 0.40 mmol of methyl p-toluenesulfonate, 0.40 mmol of ethyl acrylate, 2.5 mmol of potassium carbonate, 0.01 mmol of dpephos, 0.3 mmol of NBE-CN, and Pd(OAc) were added. 2 0.01mmol, acetonitrile solvent 0.8mL. Stir the reaction at 100°C under nitrogen environment for 12 hours; after the reaction, distill and concentrate under reduced pressure to remove the organic solvent, and separate the crude product by column chromatography to obtain the target product with a yield of 83%.

[0064] 1 H NMR (400 MHz, CDCl 3 )δ8.38(d,J=15.6Hz,1H,Z),8.00(d,J=16.0Hz,1H,E),7.33(d,J=2.8Hz,1H,Z ),7.19(d,J=2.4Hz,1H,E),6.91(d,J=1.6Hz,1H,E),6.08(d,J=12.0Hz,1H,Z), 5.90(d,J=0.4Hz,1H,E),3.86(d,J=0.4Hz,3H,E),3.83(d,J=1.2Hz,3H,E),3. 80(d,J=0.4Hz,3H,E),3.56(d,J=0.4Hz,3H,Z),2.36(s,3H,Z),2.22(s,3H,E).

[0065] Synthesis example 9

[0066] Synthesis of Methyl (E)-3-(10-Methyl-9-phenanthrene)acrylate

[0067] Add 0.20 mmol of 9-phenanthrenyl trifluoromethanesulfonate, 0.40 mmol of methyl p-toluenesulfonate, 0.40 mmol of ethyl acrylate, 2.5 mmol of potassium carbonate, 0.01 mmol of dpephos, 0.3 mmol of NBE-CN, and Pd(OAc) into the reactor. 2 0.01mmol, acetonitrile solvent 0.8mL. Stir the reaction at 100°C under nitrogen environment for 12 hours; after the reaction, distill and concentrate under reduced pressure to remove the organic solvent, and separate the crude product by column chromatography to obtain the target product with a yield of 83%.

[0068] 1 H NMR (400 MHz, CDCl 3 )δ8.69(t,J=6.4Hz,2H,E),8.27(d,J=16.4Hz,1H,E),8.13(d,J=11.6Hz,1H,E),7.97(d,J=4.8Hz,1H,E),7.85(d,J=10.0Hz,1H,Z),7. 68–7.56(m,4H,E),6.47(d,J=12.0Hz,1H,Z),6.19(d,J=16.4Hz,1H,E),3.89(s,3H,E),3.45(s,3H,Z),2.72(s,3H,E),2.64(s,3H,Z).

[0069] It should be noted that the above embodiments do not constitute a limitation on the protection scope of the present invention. For ordinary technicians in this field, several modifications and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention.

Claims

1. A Catellani-type methylation method based on aryl sulfonates, comprising the following steps: The raw materials methyl 2-trifluoromethanesulfonyloxybenzoate, methyl p-toluenesulfonate, olefin compounds, as well as base, ligand, norbornene, catalyst and organic solvent are placed in a reaction container and mixed, and stirred at 80-120° C. for 5-12 hours under an inert gas environment; after the reaction is completed, the organic solvent is removed by vacuum distillation and concentration, and the crude product is separated by column chromatography to obtain a polysubstituted aromatic methyl compound as shown in Formula I. Wherein R is one of fluorophenyl, chlorophenyl, bromophenyl, methylphenyl, methoxyphenyl, nitrophenyl, phenyl, amide, carboxylic acid, and naphthyl.

2. The Catellani-type methylation method of aryl sulfonate according to claim 1, characterized in that The structures of the raw materials 2-trifluoromethanesulfonyloxybenzoic acid methyl ester, p-toluenesulfonic acid methyl ester and olefin compounds are shown in Formula II, Formula III and Formula IV respectively. Wherein R is one of fluorophenyl, chlorophenyl, bromophenyl, methylphenyl, methoxyphenyl, nitrophenyl, phenyl, amide, carboxylic acid, and naphthyl. The Catellani-type methylation method of aryl sulfonate according to claim 1, characterized in that the base is selected from at least one of potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, sodium tert-butoxide, and potassium tert-butoxide.

3. The Catellani type methylation method of aryl sulfonate according to claim 1, characterized in that The catalyst is selected from at least one of Pd(OAc)2, Pd(PPh3)4, PdCl2(MeCN)2, PdCl2, Pd(acac)2, Pd(1.3-dppp)Cl2, Pd(cod)2Cl2, and Pd(PPh3)2Cl2.

4. The Catellani type methylation method of aryl sulfonate according to claim 1, characterized in that The ligand is selected from at least one of CyJohnphos, Mephos, Davephos, Ruphos, S-phos, X-phos, tBuXphos, dpephos, dppbenz, dppe, dppm, dppp, dppb, dppe, and dpph.

5. The Catellani type methylation method of aryl sulfonate according to claim 1, characterized in that In the synthesis method, the molar ratio of methyl 2-trifluoromethanesulfonyloxybenzoate, methyl p-toluenesulfonate, olefin compound, base, ligand, norbornene and catalyst is 1:1:[1.0-1.5]:[1.0-4.0]:[0.05-1.5]:[1.0-4.0]:[0.05-1.5].

6. The Catellani type methylation method of aryl sulfonate according to claim 1, characterized in that The organic solvent is selected from at least one of toluene, p-xylene, anisole, cyclohexane, dioxane, tetrahydrofuran, acetonitrile, N,N-dimethylformamide and dimethyl sulfoxide.

7. The Catellani type methylation method of aryl sulfonate according to claim 1, characterized in that The inert gas is selected from at least one of nitrogen, argon and helium.

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