Preparation method of sulfone-containing 1, 3-eneyne derivative

Abstract

The invention provides a preparation method of a sulfone-containing 1, 3-eneyne derivative, and belongs to the technical field of organic synthesis. The preparation method comprises the following steps: adding a palladium catalyst, a ligand, alkali, alkyne and paratoluensulfonyl iodide into an organic solvent, reacting at 40 DEG C for 4-8 hours, and performing post-treatment to obtain the sulfone-containing 1, 3-enyne derivative. The preparation method is easy to operate, and post-treatment is simple and convenient; the method has the advantages of cheap and easily available reaction starting raw materials, wide tolerance range of substrate functional groups, high reaction efficiency, one-step efficient and rapid synthesis of the sulfone-containing 1, 3-eneyne derivative, and strong practicality.

Description

Technical Field

[0001] The present application relates to a method for preparing a sulfone-containing 1,3-enyne derivative, and belongs to the technical field of organic synthesis. Background Art

[0002] Sulfone and 1,3-eneyne are important structural units, widely present in natural products and drug molecules, and have various biological activities such as anti-migraine, anti-inflammatory, and antibacterial (Fixation of sulfur dioxide into small molecules.Org.Biomol.

[0003] Chem., 2015, 13, 1592-1599; Sulfur containing scaffolds in drugs: synthesis and application in medicinal chemistry. Curr. Top. Med. Chem., 2016, 16, 1200-1216; New acetogenin peroxides from the indian sponge acarnusbicladotylota.J.Nat.Prod.,2001,64,131-133;Identification of a reactivemetabolite of terbinafine: insights into terbinafine-inducedhepatotoxicity.Chem.

[0004] Res. Toxicol.,2001,14,175-181).

[0005]

[0006] Tandem reactions provide an important method for the direct and efficient synthesis of multifunctional molecules (Dominoreactions inorganic synthesis. Chem. Rev., 1996, 96, 115-136). However, there are few reports on the synthesis of sulfone-containing 1,3-enyne derivatives based on tandem reactions, and their application is not widespread at present, but they have great application potential and need to be further studied. Summary of the invention

[0007] In view of this, the present application provides a method for preparing sulfone-containing 1,3-enyne derivatives. The preparation process is simple, and the obtained product, sulfone-containing 1,3-enyne derivatives, can be compatible with multiple functional groups at the same time and have good reaction applicability.

[0008] Specifically, the present application is implemented through the following scheme:

[0009] A method for preparing a sulfone-containing 1,3-enyne derivative, characterized in that: a palladium catalyst, a ligand, a base, an alkyne, and p-toluenesulfonyl iodide (TsI) are added to an organic solvent, reacted at 40° C., and post-treated to obtain a sulfone-containing 1,3-enyne derivative.

[0010] The structural formula of the alkyne is:

[0011] The structural formula of the sulfone-containing 1,3-enyne derivative is:

[0012] R is a substituted or unsubstituted phenyl group, and the substituent on the substituted phenyl group is selected from C1-C6 alkyl or halogen.

[0013] The reaction equation of the above process is as follows:

[0014]

[0015] The above scheme uses alkynes and p-toluenesulfonyl iodide as starting materials. In the reaction, palladium (0) first induces sulfonyl iodide to generate sulfonyl radicals and palladium (I) species. The sulfonyl radicals add to the carbon-carbon triple bond of the alkyne to generate alkenyl radical intermediates, which then react with palladium (I) species to generate alkenyl palladium (II) intermediates. Finally, the alkynes react with the alkenyl palladium (II) intermediates to obtain sulfone-containing 1,3-enyne derivatives by reduction elimination. This process efficiently and quickly synthesizes sulfone-containing 1,3-enyne derivatives through palladium-catalyzed tandem reactions.

[0016] Further, as a preference:

[0017] The molar ratio of the alkyne, p-toluenesulfonyl iodide, palladium catalyst, ligand and base is 3.0:1.0:0.02:0.03:1.5.

[0018] The organic solvent is any one of dioxane and tetrahydrofuran, and dioxane has the best effect. At this time, various raw materials can be converted into products with a high conversion rate. In the process of material preparation, the amount of organic solvent used can be sufficient to dissolve the raw materials well. Therefore, the amount of organic solvent used corresponding to 0.2 mmol of p-toluenesulfonyl iodide is preferably controlled to be around 2.0 mL.

[0019] The palladium catalyst is palladium acetate.

[0020] The ligand is bis(2-diphenylphosphinophenyl) ether.

[0021] The base is any one of potassium carbonate, cesium carbonate and potassium phosphate.

[0022] The reaction time is 4 to 8 hours to ensure complete reaction.

[0023] The post-treatment process is as follows: the reaction product is filtered, the sample is mixed with silica gel, and finally the corresponding sulfone-containing 1,3-enyne derivative is purified by column chromatography. Column chromatography purification is a commonly used technical means in the art.

[0024] The sulfone-containing 1,3-enyne derivative is any one of the following structural formulas:

[0025]

[0026] In the above preparation method, alkyne, palladium acetate, bis(2-diphenylphosphinophenyl) ether and potassium carbonate are generally commercially available products, which can be easily obtained from the market; p-toluenesulfonyl iodide can be quickly synthesized from sodium p-toluenesulfinate and iodine.

[0027] Compared with the prior art, the beneficial effects of the present invention are embodied in that: the preparation method is easy to operate and the post-processing is simple; the reaction starting materials are cheap and easy to obtain, the substrate functional group tolerance range is wide, the reaction efficiency is high, and the sulfone-containing 1,3-enyne derivatives can be synthesized efficiently and quickly in one step, and the practicability is strong. DETAILED DESCRIPTION

[0028] In order to make the technical problems, technical solutions and beneficial effects to be solved by this application clearer, the technical solutions of this application will be further described in detail below in combination with the specific cases in the embodiments of this application. It should be understood that the specific embodiments described herein are only used to explain this application and are not used to limit the technical solutions of this application. Based on the embodiments in this application, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of this application.

[0029] Example 1

[0030] According to the raw material ratio in Table 1, palladium acetate, bis(2-diphenylphosphinophenyl) ether, potassium carbonate, p-toluenesulfonyl iodide, alkyne (II) and 2.0 mL of organic solvent were added to a 15 mL Schlenk tube, mixed and stirred evenly, and reacted at 40° C. for 6 hours, as shown in Table 1. After the reaction was complete, the mixture was filtered, mixed with silica gel, and purified by column chromatography to obtain the corresponding sulfone-containing 1,3-enyne derivative (I).

[0031] The reaction equation of the above process is as follows:

[0032]

[0033] Table 1: Raw material addition and effect comparison of different implementation schemes

[0034]

[0035]

[0036] In Table 1, T is the reaction temperature, t is the reaction time, Me is a methyl group, Et is an ethyl group, OMe is a methoxy group, Ph is a phenyl group, n Pr is n-propyl, n Bu is n-butyl.

[0037] At the same time, the applicant also confirmed the structure of the product prepared by the above reaction, and tested the products represented by numbers 1-1 to 1-5 in Table 1.

[0038] The structural formula of the sulfone-containing 1,3-enyne derivative corresponding to the serial number (I-1) is:

[0039]

[0040] Its nuclear magnetic resonance ( 1 H NMR, 13 C NMR) and high resolution (HRMS) detection data are: 1 H NMR (400MHz, CDCl3) δ7.60(d,J=8.3Hz,2H),7.51(d,J=8.8Hz,2H),7.36(d,J=8.8Hz,2H),7.21(d,J=8.1H z,2H),6.88(d,J=8.8Hz,2H),6.84(d,J=8.8Hz,2H),6.81(s,1H),3.84(s,3H),3.80(s,3H),2.39(s,3H); 13 C NMR (100MHz, CDCl3) δ160.9,160.7,144.2,138.5,136.9,133.7,133.0,131.1,129.6, 127.7,126.8,114.2,113.8,113.4,97.4,88.0,55.4,21.7; HRMS(ESI-TOF)m / z:[M+Na] + Calcd.for C 25 H 22 NaO4S + :441.1131; found:441.1138.

[0041] The structural formula of the sulfone-containing 1,3-enyne derivative corresponding to sequence number (I-2) is:

[0042]

[0043] Its nuclear magnetic resonance ( 1 H NMR, 13C NMR) and high resolution (HRMS) detection data are: 1 H NMR (400MHz, CDCl3) δ7.57(d,J=8.3Hz,2H),7.50-7.45(m,4H),7.35-7.32(m,2H),7.25(t,J=8.4Hz,4H),6.93(s,1H),2.41(s,3H); 13 C NMR (100MHz, CDCl3) δ144.8,137.9,136.2,135.1,133.4,133.0,132.0,131.3,130. 8,129.8,127.9,124.4,124.3,120.4,96.5,89.0,21.7; HRMS(ESI-TOF)m / z:[M+Na] + Calcd.for C 23 H 16 Br2NaO2S + :536.9130; found:536.9138.

[0044] The structural formula of the sulfone-containing 1,3-enyne derivative corresponding to sequence number (I-3) is:

[0045]

[0046] Its nuclear magnetic resonance ( 1 H NMR, 13 C NMR) and high resolution (HRMS) detection data are: 1 H NMR (400MHz, CDCl3) δ7.57 (d, J = 8.1Hz, 2H), 7.29-7.21 (m, 10H), 6.97 (s, 1H), 2.43 (s, 3H), 2.36 (d, J = 10.5Hz, 6H); 13 C NMR (100MHz, CDCl3) δ144.2,138.33,138.29,137.7,137.4,135.5,134.3,132.6,130.6,130.3,129.5 ,129.2,128.5,128.0,127.9,126.3,121.6,97.7,88.2,21.7,21.4,21.2; HRMS(ESI-TOF)m / z:[M+Na] + Calcd.for C 25 H 22 NaO2S + :409.1233; found:409.1230.

[0047] The structural formula of the sulfone-containing 1,3-enyne derivative corresponding to sequence number (I-4) is:

[0048]

[0049] Its nuclear magnetic resonance ( 1 H NMR, 13 C NMR) and high resolution (HRMS) detection data are:

[0050] 1 H NMR (400MHz, CDCl3) δ7.48 (d, J = 8.1Hz, 2H), 7.35 (s, 1H), 7.29 (t, J = 6.7Hz, 3H), 7.24-7.16 (m, 6H), 6.93 (s, 1H), 2.36 (s, 3H); 13 C NMR (100MHz, CDCl3) δ144.8,137.7,137.4,135.6,134.7,134.5,134.1,131.8,130.2,130.1,129. 9,129.8,129.7,129.5,128.6,128.0,127.5,123.1,96.2,88.6,21.7; HRMS(ESI-TOF)m / z:[M+Na] + Calcd.forC 23 H 16 Cl2NaO2S + :449.0140; found:449.0149.

[0051] The structural formula of the sulfone-containing 1,3-enyne derivative corresponding to sequence number (I-5) is:

[0052]

[0053] Its nuclear magnetic resonance ( 1 H NMR, 13 C NMR) and high resolution (HRMS) detection data are: 1 H NMR (400MHz, CDCl3) δ7.83-7.74(m,2H),7.40-7.22(m,2H),6.42(s,1H),2.65-2.62(m,2H),2. 43(s,3H),2.32(t,J=6.8Hz,2H),1.51-1.46(m,4H),1.40-1.33(m,4H),0.90(t,J=7.1Hz,6H); 13C NMR (100MHz, CDCl3) δ144.3,141.5,139.3,133.1,129.9,127.5,98.9,79.9,40 .0,31.7,30.5,30.4,22.5,22.0,19.3,14.0,13.6; HRMS(ESI-TOF)m / z:[M+Na] + Calcd.for C 19 H 26 NaO2S + :341.1546; found:341.1556.

[0054] The above-mentioned embodiments only express several feasible implementation methods of the present invention, and the description is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent of the present invention, and the embodiments are not used to limit the scope of protection in the claims 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, and all equivalent implementations or changes that do not depart from the present invention should be included in the technology of the present invention.

Claims

1. A method for preparing a sulfone-containing 1,3-enyne derivative, characterized in that: Add palladium catalyst, ligand, base, alkyne and p-toluenesulfonyl iodide to an organic solvent, react at 40°C, and then post-treat to obtain a sulfone-containing 1,3-enyne derivative. The structural formula of the alkyne is: The structural formula of the sulfone-containing 1,3-enyne derivative is: R is a substituted or unsubstituted phenyl group, and the substituent on the substituted phenyl group is selected from C1-C6 alkyl or halogen.

2. The method for preparing a sulfone-containing 1,3-enyne derivative according to claim 1, characterized in that: The molar ratio of alkyne, p-toluenesulfonyl iodide, palladium catalyst, ligand and base is 3.0:1.0:0.02:0.03:1.

5.

3. The method for preparing a sulfone-containing 1,3-enyne derivative according to claim 1, characterized in that: The organic solvent is dioxane or tetrahydrofuran.

4. The method for preparing a sulfone-containing 1,3-enyne derivative according to claim 1, characterized in that: The palladium catalyst is palladium acetate.

5. The method for preparing a sulfone-containing 1,3-enyne derivative according to claim 1, characterized in that: The ligand is bis(2-diphenylphosphinophenyl) ether.

6. The method for preparing a sulfone-containing 1,3-enyne derivative according to claim 1, characterized in that: The base is any one of potassium carbonate, cesium carbonate and potassium phosphate.

7. The method for preparing a sulfone-containing 1,3-enyne derivative according to claim 1, characterized in that: The reaction time is 4 to 8 hours.

8. The method for preparing a sulfone-containing 1,3-enyne derivative according to claim 1, characterized in that: The post-treatment process is as follows: the reaction product is filtered, the sample is mixed with silica gel, and finally purified by column chromatography to obtain a sulfone-containing 1,3-enyne derivative.

9. The method for preparing a sulfone-containing 1,3-enyne derivative according to any one of claims 1 to 8, characterized in that: The sulfone-containing 1,3-enyne derivative is any one of the following structural formulas:

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