A method for preparing a beta-sulfonyl acrylate compound

Abstract

The present application relates to a kind of preparation of β-sulfonyl methacrylate compound method. Specifically under the condition of oxidation, end alkyne, sodium organic sulfinic acid under carbon monoxide atmosphere one-pot method is prepared. The present application is widely from substrate, commercially available end alkyne and sodium organic sulfinic acid, under oxidation and without transition metal catalysis, by radical process, obtains a series of β-sulfonyl methacrylate compound.

Description

Technical Field

[0001] This invention relates to a method for synthesizing methyl β-sulfonyl acrylate compounds. Background Technology

[0002] β-Sulfoacrylate methyl esters are a very important chemical structural segment because they are widely found in various natural products and modern pharmaceuticals and possess excellent biological activity. Furthermore, they are a crucial and valuable segment in organic synthesis. Previously, the synthesis of β-sulfonylacrylate methyl esters generally involved multiple steps and required the use of air-labile butyllithium reagents. In recent years, bifunctional carbonylation reactions have emerged as a promising method for preparing multifunctional carbonyl-containing compounds.

[0003] Compared to previous methods for synthesizing methyl β-sulfonyl acrylates, we have developed a one-step synthesis of methyl β-sulfonyl acrylates via a bifunctional carbonylation reaction of alkynes. Using readily available terminal alkynes and sodium organic sulfinates, we can synthesize methyl β-sulfonyl acrylates with a wide range of substrates in one step.

[0004] In summary, this paper describes a method for obtaining a series of β-sulfonyl acrylate compounds via a free radical process under oxidizing conditions without the need for transition metal catalysis. Summary of the Invention

[0005] The purpose of this invention is to provide a method for synthesizing methyl β-sulfonyl acrylate derivatives.

[0006]

[0007] Reaction Equation 1: Synthesis of β-sulfonyl acrylate derivatives, where wavy lines represent the connection of trans or cis structures;

[0008] The specific operating steps are as follows (reaction equation 1):

[0009] The reaction was carried out in a high-pressure reactor. Oxidizing agent, iodized salt, terminal alkyne 1, and organic sodium sulfinate 2 were weighed. The reaction was carried out in a carbon monoxide atmosphere at a pressure of 10-60 atmospheres at 90-150°C, preferably 130°C. The reaction time was 10.0-24.0 hours, preferably 20.0 hours. After the reaction was completed, β-sulfonyl acrylate compound 3 was separated.

[0010] The molar ratio of terminal alkyne 1 to organic sodium sulfinate 2 is 1:1.0-3.0, preferably 1:1.5-2.5, and more preferably 1:2.0.

[0011] The pressure of carbon monoxide is 10-60 atmospheres, preferably 40-45 atmospheres.

[0012] The solvent is one or more of 1,2-dichloroethane, tetrahydrofuran, dimethyl sulfoxide, 1,4-dioxane, acetonitrile, methanol, and a methanol-water mixture, preferably a methanol-water mixture (methanol to water volume ratio of 0.5-5:1, preferably 3-5:1, more preferably 3.5-4:1); the amount of solvent used is 1.0-5.0 mL per 0.2 mmol terminal yne, preferably 2.0 mL.

[0013] The oxidant is potassium persulfate, sodium persulfate, ammonium persulfate, potassium peroxymonosulfonate, preferably one or more of sodium persulfate; the amount of oxidant is 2-4 times the molar number of terminal alkyne 1, preferably 2.2-2.5 times.

[0014] The iodized salt is potassium iodide, sodium iodide, lithium iodide, calcium iodide, tetrabutylammonium iodide, elemental iodine, preferably one or more of potassium iodide; the amount of iodized salt is 1-3 times the molar number of terminal alkyne 1, preferably 1.1-1.5 times.

[0015] This invention starts with widely available, commercially available terminal alkynes and organic sodium sulfinates, and obtains a series of β-sulfonyl acrylate compounds via a free radical process under oxidative conditions without the need for transition metal catalysis.

[0016] The present invention has the following advantages:

[0017] First, this reaction eliminates the need for metallic reagents such as n-butyllithium to synthesize methyl β-sulfonyl acrylate derivatives, significantly expanding the substrate range. Second, aryl-terminated alkynes, alkyl-terminated alkynes, sodium arylsulfinates, and sodium alkylsulfinates can all be converted in this reaction, broadening its applicability. Third, the one-pot, one-step preparation of methyl β-sulfonyl acrylate reduces the number of reaction steps. Detailed Implementation

[0018] To better understand the present invention, the following examples are provided. The reaction materials and results of Examples 1-14 are shown in Table 1.

[0019] Table 1. Reaction results of different substituted terminal alkynes 1 and organic sodium sulfinate 2

[0020]

[0021]

[0022]

[0023]

[0024] Example 1

[0025] The reaction was carried out in a high-pressure reactor. First, 0.2 mmol of phenylacetylene 1a, 0.4 mmol of sodium phenylsulfinate 2a, 0.44 mmol of sodium persulfate, and 0.22 mmol of potassium iodide were added to a 4 mL glass vial. A magnetic stir bar was added, followed by 2.0 mL of a methanol / water mixture (4:1 volume ratio). The vial was then sealed tightly with a rubber cap. A syringe needle was inserted through the cap into the vial, allowing it to communicate with the outside environment. The vial was then placed in the high-pressure reactor. The reactor head was connected to the outside environment. Carbon monoxide was replaced in the high-pressure reactor, and 40 atmospheres of carbon monoxide were introduced to raise the internal pressure of the high-pressure reactor to 40 atmospheres. At this time, the carbon monoxide in the reactor was connected to the inside of the vial through a needle. The reaction was stirred at 130°C for 20.0 hours. After the reaction was completed, β-sulfonyl acrylate compound 3a was obtained by column chromatography with a yield of 68%. The ratio of trans structure to cis structure (molar ratio, the same below) was 3:1. The structure of the compound was identified by nuclear magnetic resonance (H1N and C1N) and high-resolution mass spectrometry.

[0026] The test data is as follows:

[0027] 3a: Yellow oily substance (41 mg, 68%). 1 H NMR(700MHz,Chloroform-d)δ7.98–7.92(m,0.65H),7.51(s,1.00H),7.48(dd,J=8.4,1.5Hz,2.31H),7.46–7.44(m,1.02H),7.36–7.31(m,1. 60H),7.29(tt,J=7.4,1.6Hz,2.96H),7.22(dd,J=8.5,7.0Hz,1.96H), 7.08–7.03(m,1.95H),6.55(s,0.34H)3.94(s,1.01H),3.69(s,3.00H). 13 C NMR (176MHz, CDCl3) δ166.5,165.5,146.1,143.1,140.5,140.2,139.7,133.9,133.7,132.1,131.3,130.8,1 29.4,129.4,129.3,129.2,129.0,128.0,127.8,127.0,126.5,53.4,53.2.HRMS(ESI-TOF)m / z:[M+H]+Calcd for C 16 H 14 O4S 303.0686; Found:303.0685.

[0028] Example 2

[0029] The operation process and conditions were the same as in Example 1, except that the yield of raw materials 1 and / or 2 in Table 1 was 55%, with the trans structure / cis structure ratio being 10:3. The structure of the compound was identified by NMR (H1N and C1N) and high-resolution mass spectrometry.

[0030] Example 3

[0031] The operation process and conditions are the same as in Example 1, except that the raw materials 1 and / or 2 are shown in Table 1. The yield of 3c is 50%, and the ratio of trans structure to cis structure is 15:1. The structure of the compound is identified by NMR (H1N and C1N) and high-resolution mass spectrometry.

[0032] Example 4

[0033] The operation process and conditions were the same as in Example 1, except that the raw materials 1 and / or 2 were as shown in Table 1. The yield was 49% in 3 days, and the ratio of trans structure to cis structure was greater than 20:1. The structure of the compound was identified by NMR (H1N and C1N) and high-resolution mass spectrometry.

[0034] Example 5

[0035] The operation process and conditions were the same as in Example 1, except that the yield of raw materials 1 and / or 2 in Table 1 was 55%, and the ratio of trans structure to cis structure was 10:3. The structure of the compound was identified by NMR (H1N and C1N) and high-resolution mass spectrometry.

[0036] Example 6

[0037] The operation process and conditions are the same as in Example 1, except that the raw materials 1 and / or 2 are shown in Table 1. The yield of 3f is 60%, and the ratio of trans structure to cis structure is 20:3. The structure of the compound is identified by NMR (H1N and C1N) and high-resolution mass spectrometry.

[0038] Example 7

[0039] The operation process and conditions are the same as in Example 1, except that the raw materials 1 and / or 2 in Table 1 yielded 67% of the 3g, with a trans-to-cis structure ratio of 10:1. The structure of the compound was identified by NMR (1H and 1C) and high-resolution mass spectrometry.

[0040] Example 8

[0041] The operation process and conditions are the same as in Example 1, except that the raw materials 1 and / or 2 are shown in Table 1. The yield is 82% after 3 hours, and the ratio of trans structure to cis structure is 5:1. The structure of the compound is identified by NMR (H1N and C1N) and high-resolution mass spectrometry.

[0042] Example 9

[0043] The operation process and conditions were the same as in Example 1, except that the yield of raw materials 1 and / or 2 and 3i was 58% in Table 1, with a trans structure / cis structure ratio of 5:1. The structure of the compound was identified by NMR (H1N and C1N) and high-resolution mass spectrometry.

[0044] Example 10

[0045] The operation process and conditions are the same as in Example 1, except that the yield of raw materials 1 and / or 2 and 3j in Table 1 is 45%, wherein the ratio of trans structure to cis structure is 4:1. The structure of the compound is identified by NMR (H1N and C1N) and high-resolution mass spectrometry.

[0046] Example 11

[0047] The operation process and conditions were the same as in Example 1, except that the raw materials 1 and / or 2 were as shown in Table 1. The yield of 3k was 67%, with a trans structure / cis structure ratio of 5:1. The structure of the compound was identified by NMR (1H NMR and 1C NMR) and high-resolution mass spectrometry.

[0048] Example 12

[0049] The operation process and conditions are the same as in Example 1, except that the yield of raw materials 1 and / or 2 and 3 is 43% as shown in Table 1, wherein the ratio of trans structure to cis structure is greater than 20:1. The structure of the compound is identified by NMR (H1N and C1N) and high-resolution mass spectrometry.

[0050] Example 13

[0051] The operation process and conditions are the same as in Example 1, except that the raw materials 1 and / or 2, 3m yielded 50%, wherein the trans structure / cis structure ratio was greater than 20:1. The structure of the compound was identified by NMR (H1N and C1N) and high-resolution mass spectrometry.

[0052] Example 14

[0053] The operation process and conditions are the same as in Example 1, except that the yield of raw materials 1 and / or 2 and 3n is 31% as shown in Table 1, wherein the ratio of trans structure to cis structure is greater than 20:1. The structure of the compound is identified by NMR (H1N and C1N) and high-resolution mass spectrometry.

[0054] Application Example 1:

[0055]

[0056] Reaction Equation 2: Synthesis of Methyl β-sulfonyl acrylate

[0057] Product 3a can be synthesized in one step through this reaction. 3a is a relatively important building block in organic chemistry (a known compound; in the literature, it requires a multi-step synthesis and involves the use of n-butyllithium; see reference: S. Paul and J. Guin, Green Chem., 2017, 19, 2530–2534, 1w compound in that literature). The specific procedures are as follows:

[0058] The reaction was carried out in a high-pressure reactor. First, 0.2 mmol of phenylacetylene 1a, 0.4 mmol of sodium phenylsulfinate 2a, 0.44 mmol of sodium persulfate, and 0.22 mmol of potassium iodide were added to a 4 mL glass vial. A magnetic stir bar was added, followed by 2.0 mL of a methanol / water mixture (4:1 volume ratio). The vial was then sealed tightly with a rubber cap. A syringe needle was inserted through the cap into the vial, allowing it to communicate with the outside environment. The vial was then placed in the high-pressure reactor. The reactor was connected to the outside environment via a needle. Carbon monoxide was purged from the high-pressure reactor, and 40 atmospheres of carbon monoxide were introduced to raise the internal pressure to 40 atmospheres. At this point, the carbon monoxide inside the reactor was connected to the inside of a vial via the needle. The reaction was carried out at 130°C with stirring for 20.0 hours. After the reaction, methyl β-sulfonyl acrylate compound 3a was obtained by column chromatography with a yield of 68%. The trans structure / cis structure ratio was 3:1. The structure of the compound was identified by NMR (1H and 1C) and high-resolution mass spectrometry.

[0059] 3a: Yellow oily substance (41 mg, 68%). 1 H NMR(700MHz,Chloroform-d)δ7.98–7.92(m,0.65H),7.51(s,1.00H),7.48(dd,J=8.4,1.5Hz,2.31H),7.46–7.44(m,1.02H),7.36–7.31(m,1. 60H),7.29(tt,J=7.4,1.6Hz,2.96H),7.22(dd,J=8.5,7.0Hz,1.96H), 7.08–7.03(m,1.95H),6.55(s,0.34H)3.94(s,1.01H),3.69(s,3.00H). 13C NMR (176MHz, CDCl3) δ166.5,165.5,146.1,143.1,140.5,140.2,139.7,133.9,133.7,132.1,131.3,130.8,1 29.4,129.4,129.3,129.2,129.0,128.0,127.8,127.0,126.5,53.4,53.2.HRMS(ESI-TOF)m / z:[M+H]+Calcd for C 16 H 14 O4S 303.0686; Found:303.0685.

[0060] Example 15

[0061] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the oxidant in the reaction is changed to an equimolar amount of potassium persulfate, and the yield of the target product methyl β-sulfonyl acrylate compound will be 61%.

[0062] Example 16

[0063] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the oxidant in the reaction is replaced with an equimolar amount of ammonium persulfate, and the yield of the target product methyl β-sulfonyl acrylate compound will be 41%.

[0064] Example 17

[0065] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the pressure of carbon monoxide in the reaction is reduced to 10 atmospheres, and the yield of the target product methyl β-sulfonyl acrylate compound is reduced to 23%.

[0066] Example 18

[0067] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the pressure of carbon monoxide in the reaction is reduced to 20 atmospheres, and the yield of the target product methyl β-sulfonyl acrylate compound is reduced to 52%.

[0068] Example 19

[0069] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the iodine salt in the reaction is replaced with an equimolar amount of calcium iodide, and the yield of the target product methyl β-sulfonyl acrylate compound will be 13%.

[0070] Example 20

[0071] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the iodine salt in the reaction is replaced with an equimolar amount of tetrabutylammonium iodide, and the yield of the target product methyl β-sulfonyl acrylate compound will be 33%.

[0072] Example 21

[0073] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the reaction solvent is changed to methanol / water = 1:1, and the yield of the target product methyl β-sulfonyl acrylate compound will be 25%.

[0074] Example 22

[0075] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the reaction solvent is methanol / water = 1:1, and the yield of the target product methyl β-sulfonyl acrylate compound will be 25%.

[0076] Example 23

[0077] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the solvent used is 4.0 mL, and the yield of the target product methyl β-sulfonyl acrylate compound is reduced to 40%.

[0078] Comparative Example 1

[0079] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the reaction temperature is reduced to 50 degrees Celsius, and the yield of the target product methyl β-sulfonyl acrylate compound is reduced to 1%.

[0080] Comparative Example 2

[0081] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the reaction time is reduced to 5 hours, the yield of the target product methyl β-sulfonyl acrylate compound is reduced to 10%, and the starting material is not fully converted.

[0082] Comparative Example 3

[0083] Keeping all other reaction conditions as described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the iodine-containing salt in the reaction is removed, and the yield of the target product methyl β-sulfonyl acrylate compound is reduced to 0%.

[0084] Comparative Example 4

[0085] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the oxidant is removed from the reaction, and the yield of the target product methyl β-sulfonyl acrylate compound is reduced to 0%.

[0086] Comparative Example 5

[0087] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the oxidant is replaced with an equimolar amount of 1,4-benzoquinone, and the yield of the target product methyl β-sulfonyl acrylate compound is reduced to 0%.

[0088] Comparative Example 6

[0089] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the oxidant is replaced with an equimolar amount of silver carbonate, and the yield of the target product methyl β-sulfonyl acrylate compound is reduced to 0%.

[0090] Comparative Example 7

[0091] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the solvent is changed to pure water, and the yield of the target product methyl β-sulfonyl acrylate compound is 0%.

[0092] Comparative Example 8

[0093] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the solvent is changed to pure methanol, and the yield of the target product methyl β-sulfonyl acrylate compound is 0%.

Claims

1. A method for preparing methyl β-sulfonyl acrylate compounds, characterized in that: Using the terminal alkyne 1 and organic sodium sulfinate 2 as raw materials, β-sulfonyl acrylate derivative 3 is generated, and the reaction formula is as follows: ； R 1 It is one of 3-thienyl, n-hexyl, phenyl, or a substituted phenyl group, wherein the substituents on the benzene ring of the substituted phenyl group include one to five of the following: methyl, tert-butyl, fluorine atom, chlorine atom, bromine atom, methyl formate group, and trifluoromethoxy group, and the number of substituents is 1 to 5; R 2 It is one of phenyl, 4-methylphenyl, 4-fluorophenyl, 4-chlorophenyl, ethyl, or methyl; the specific operating steps are as follows: The reaction was carried out in a high-pressure reactor. Oxidizing agent, iodized salt, terminal alkyne 1, organic sodium sulfinate 2, and methanol-containing solvent were weighed and placed in the high-pressure reactor. The atmosphere in the reactor was replaced with a carbon monoxide atmosphere at a pressure of 10-60 atm. The reaction was carried out at 90-150°C for 10.0-24.0 hours. After the reaction was completed, β-sulfonyl acrylate compound 3 was obtained by separation. The oxidizing agent was one of potassium persulfate, sodium persulfate, ammonium persulfate, and potassium peroxymonosulfonate.

2. The method according to claim 1, characterized in that: The substituents on the benzene ring of the substituted phenyl group include 1-2 of the following: methyl, tert-butyl, fluorine atom, chlorine atom, bromine atom, methyl formate group, and trifluoromethoxy group. The number of substituents is 1-2. The atmosphere in the reactor is replaced with a carbon monoxide atmosphere at a pressure of 10-60 atmospheres, and the reaction is carried out at 130°C-140°C for 20.0-24.0 hours.

3. The method according to claim 1, characterized in that: The molar ratio of terminal alkyne 1 to organic sodium sulfite 2 is 1:1.0-3.

0.

4. The method according to claim 3, characterized in that: The molar ratio of terminal alkyne 1 to organic sodium sulfite 2 is 1:1.5-2.

5.

5. The method according to claim 3, characterized in that: The molar ratio of terminal alkyne 1 to organic sodium sulfite 2 is 1:2.

0.

6. The method according to claim 1, characterized in that: The methanol-containing solvent is a mixture of methanol and other solvents, which are one or more of 1,2-dichloroethane, tetrahydrofuran, dimethyl sulfoxide, 1,4-dioxane, acetonitrile, and water, wherein the volume ratio of methanol to other solvents is 0.5-5:1; the amount of methanol-containing solvent used is 1.0-5.0 mL per 0.2 mmol of terminal acetylene.

7. The method according to claim 6, characterized in that: The methanol-containing solvent is a mixture of methanol and other solvents, with water as the other solvent, wherein the volume ratio of methanol to water is 3-5:1; the amount of methanol-containing solvent used is 2.0 ml of solvent per 0.2 mmol of terminal acetylene.

8. The method according to claim 7, characterized in that: The volume ratio of methanol to water is 3.5-4:

1.

9. The method according to claim 1, characterized in that: The oxidant is sodium persulfate, and the amount of oxidant used is 2-4 times the molar number of terminal alkyne 1.

10. The method according to claim 9, characterized in that: The amount of oxidant used is 2.2-2.5 times the number of moles of terminal alkyne 1.

11. The method according to claim 1, characterized in that: The iodized salt is one of potassium iodide, sodium iodide, lithium iodide, calcium iodide, or tetrabutylammonium iodide; the amount of iodized salt used is 1-3 times the molar number of terminal alkyne 1.

12. The method according to claim 11, characterized in that: The iodized salt is potassium iodide, and the amount of iodized salt used is 1.1-1.5 times the molar number of terminal alkyne 1.

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