Synthetic method of butylenolide dimer

Abstract

The invention discloses a synthesis method of a butenolactone dimer, which comprises the following steps: adding an acrylic acid compound, ethyl glyoxylate, dichlorobis (4-methyl isopropyl phenyl) ruthenium (II), cesium acetate and silver sulfate into an organic solvent, heating under an air condition to react, and after the reaction is completed, performing post-treatment to obtain the butenolactone dimer. According to the method, the butene lactone dimer is synthesized from simple and easily available raw materials through a one-pot method, the conversion efficiency is high, and the step economy is good; meanwhile, the synthesis method is simple to operate, high in reaction yield and wide in substrate universality.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing a butene lactone dimer. Background Art

[0002] Transition metal-catalyzed chelation-assisted CH addition / cyclization reaction with aldehyde compounds has become an effective strategy for synthesizing heterocyclic molecules with atom and step economy. With the help of various nitrogen (oxygen) directing groups, structurally diverse N(O)-heterocyclic skeletons can be constructed by redox-neutral or oxidative cyclization. The research groups of Takai, Ellman, Ki and Wang Congyang at home and abroad have made important progress in the field of CH addition / cyclization construction of heterocycles.

[0003] Butenolides are ubiquitous building blocks in a large number of natural products and drugs. In addition, they are also used as universal synthetic building blocks for the synthesis of various bioactive analogs. For example: Benjamin J. Huffman et al. reported that a butenolide dimer acts as a cGAS / STING pathway antagonist (Nature Chemistry, volume 12, pages 310–317 (2020) Electronic complementarity permits hindered butenolide heterodimerization and discovery of novel cGAS / STING pathway antagonists).

[0004]

[0005] Accordingly, many strategies for synthesizing this skeleton have been extensively investigated. To the best of our knowledge, the preparation of butenolides using chelation-assisted C-H functionalization / cyclization is rare and mainly relies on the oxidative cyclization of acrylic acid with alkenes or allenes. For example, Miura and Zhong Guofu's groups achieved the synthesis of butenolides by adding stoichiometric oxidants through Rh-catalyzed oxidative cyclization of acrylic acid with acrylates, respectively. Cheng and Cramer also explored allenes as coupling agents to participate in the oxidative cyclization of acrylic acid to construct γ-butenolides. Compared with alkenes and allenes, the application examples of aldehydes in the C-H functionalization of carboxylic acids are quite limited. Recently, our group achieved the first cobalt-catalyzed alkenyl C-H addition / cyclization of acrylic acid with polyformaldehyde to efficiently synthesize butenolides under redox-neutral conditions. However, the reaction of acrylic acid with ethyl glyoxylate has not been explored. In addition, butenolide dimers are special skeletons and key intermediates of natural products. However, the synthetic protocols are very rare and usually involve multiple synthetic steps, resulting in increased waste. There is no report on a method for efficiently synthesizing butenolide dimers via C-H cyclization in one step.

[0006] Inspired by previous pioneering work and our continued interest in the research of CH cyclization to synthesize heterocyclic reactions, this invention is based on the CH bond activation reaction methodology directed by the weakly coordinated directing functional group-acrylic acid, and has developed a method for efficiently synthesizing complex butenolide dimer compounds through CH activation / ring closure / radical coupling reactions using cheap and readily available ethyl glyoxylate and acrylic acid as synthons in the presence of a metal ruthenium catalyst. This transformation can be further scaled up to prepare gram-scale dimer products using a strategy combining CH activation reactions with free radical coupling. Summary of the invention

[0007] The invention provides a method for synthesizing a butene lactone dimer. The method has cheap and readily available substrates, wide universality, high functional group compatibility and high reaction yield.

[0008] A method for synthesizing a butenolide dimer comprises the following steps: adding an acrylic acid compound, ethyl glyoxylate, a ruthenium catalyst, an additive and an oxidant to an organic solvent, heating under air conditions to react, and after the reaction is complete, post-treating to obtain the butenolide dimer;

[0009] The structure of the acrylic acid compound is shown in formula (II):

[0010]

[0011] The structure of ethyl glyoxylate is shown in formula (III):

[0012]

[0013] The structure of the butenolide dimer is shown in formula (I):

[0014]

[0015] In formula (I) to (II), R 1 The phenyl group is selected from substituted or unsubstituted phenyl, wherein the substituent on the phenyl group is selected from one or more of halogen, C1-C4 alkyl or phenyl; preferably, the phenyl group is selected from one or more of F, Cl, Br, methyl, tert-butyl or phenyl.

[0016] Preferably, the butenolide dimer is one of the compounds represented by formula (I-1) to formula (I-12):

[0017]

[0018]

[0019]

[0020] Preferably, the organic solvent is hexafluoroisopropanol (HFIP).

[0021] Preferably, the organic solvent is hexafluoroisopropanol (HFIP).

[0022] Preferably, the reaction temperature is 90-110° C., and the reaction time is 3-10 hours. More preferably, the reaction temperature is 100° C., and the reaction time is 5 hours.

[0023] Preferably, the additive for the reaction is cesium acetate.

[0024] Preferably, the oxidizing agent in the reaction is silver sulfate.

[0025] Preferably, the ruthenium catalyst is dichlorobis(4-methylisopropylphenyl)ruthenium(II).

[0026] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0027] (1) The present invention synthesizes butene lactone dimer in high yield through a one-pot method using very simple and readily available raw materials, with high conversion efficiency and good step economy;

[0028] (2) The synthesis method of the present invention is simple to operate, has a high reaction yield, and has good substrate universality and functional group compatibility. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 The hydrogen and carbon spectra of the compound obtained in Example 1;

[0030] Figure 2 The hydrogen and carbon spectra of the compound obtained in Example 2;

[0031] Figure 3 The hydrogen and carbon spectra of the compound obtained in Example 3;

[0032] Figure 4 The hydrogen and carbon spectra of the compound obtained in Example 4;

[0033] Figure 5 The hydrogen and carbon spectra of the compound obtained in Example 5;

[0034] Figure 6 The hydrogen and carbon spectra of the compound obtained in Example 6;

[0035] Figure 7 The hydrogen and carbon spectra of the compound obtained in Example 7;

[0036] Figure 8 The hydrogen and carbon spectra of the compound obtained in Example 8;

[0037] Fig. 9 The hydrogen and carbon spectra of the compound obtained in Example 9;

[0038] Fig.10 The hydrogen and carbon spectra of the compound obtained in Example 10;

[0039] Fig.11 The hydrogen and carbon spectra of the compound obtained in Example 11;

[0040] Fig.12 The hydrogen and carbon spectra of the compound obtained in Example 12;

[0041] The hydrogen spectrum was tested on a 400MHz nuclear magnetic resonance instrument. The carbon spectrum was tested on a 100MHz nuclear magnetic resonance instrument. The test conditions were all room temperature with tetramethylsilane as the internal standard and the samples were dissolved in deuterated chloroform. DETAILED DESCRIPTION

[0042] The present invention is further described below in conjunction with specific embodiments, and the following specific embodiments are all optimal implementation modes of the present invention.

[0043] Examples 1 to 12

[0044] According to the raw material ratio in Table 1, acrylic acid compound (0.2 mmol), ethyl glyoxylate (0.5 mmol), dichlorobis(4-methylisopropylphenyl)ruthenium (II) (0.05 mmol), cesium acetate (0.6 mmol), silver sulfate (0.6 mmol) and 1.5 mL of organic solvent were added into a test tube, mixed and stirred evenly, and after the reaction was completed according to the reaction conditions in Table 2, the mixture was cooled, filtered, mixed with silica gel, and purified by column chromatography to obtain the corresponding butene lactone dimer (I). The reaction process is shown in the following formula:

[0045]

[0046] Table 1 Raw material ratios of Examples 1 to 10

[0047]

[0048] Table 2 Reaction conditions and reaction results of Examples 1 to 10

[0049]

[0050] In Table 1 and Table 2, T is the reaction temperature, t is the reaction time, and 3,4-Cl is a 3,4-disubstituted chlorine atom. t Bu is 4-substituted tert-butyl.

[0051] The structural confirmation data of some compounds prepared in Examples 1 to 12 are as follows:

[0052]

[0053] Diethyl 5,5'-dioxo-4,4'-diphenyl-[2,2'-bifuran]-2,2'(5H,5'H)-dicarboxylate (I-1): After column chromatography purification (petroleum ether:EtOAc=10:1), a mixture of diastereomers (78.6 mg, 85% yield, 1.3:1 dr) was obtained as a yellow oil. 1 H NMR (400MHz, CDCl3) δ7.89-7.86(m,4H),7.85(s,1H),7.68(s,1H),7.44-7.43(m,6H),4.40-4.26(m,4H),1.35-1.30(m,6H); 13C NMR (100MHz, CDCl3) δ169.2,168.8,165.4,165.2,141.9,140.4,134.7,133.7,130.6,130.3,128. 9,128.8,128.3,128.0,127.5(2C),87.2,86.3,63.8,63.7,14.0,13.9.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 26 H 22 O8Na:485.1207; measured value:485.1207.

[0054]

[0055] Diethyl 4,4'-bis(4-fluorophenyl)-5,5'-dioxo-[2,2'-bifuran]-2,2'(5H,5'H)-dicarboxylate (I-2): After column chromatography purification (petroleum ether:EtOAc=10:1), a mixture of diastereomers (78.8 mg, 79% yield, 1.2:1dr) was obtained as a colorless oil. 1 H NMR (400MHz, CDCl3) δ7.91-7.87(m,4H),7.82(s,0.92H),7.62(s,1.08H,major),7.14-7.09(m,4H),4.39-4.25(m,4H),1.34-1.29(m,6H). 13 C NMR (100MHz, CDCl3) δ169.1,168.7,165.2(2C),165.1(2C),162.8,162.6,141.5,139.8,133.6,132.5,129.7,129.6,129.5,124.5,124.4(d,J C-F =3.0Hz),124.2(d,J C-F =3.4Hz),116.1(d,J C-F =21.9Hz),116.0(d,J C-F =21.9Hz),87.1,86.2,63.9,63.8,13.9(2C). 19 F NMR(300MHz, CDCl3)δ-108.7,-109.3.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 26 H20 F2O8Na:521.1018; measured value:521.1020.

[0056]

[0057] Diethyl 4,4'-bis(3-fluorophenyl)-5,5'-dioxo-[2,2'-bifuran]-2,2'(5H,5'H)-dicarboxylate (I-3): After column chromatography purification (petroleum ether:EtOAc=10:1), a mixture of diastereomers (81.7 mg, 82% yield, 1.3:1dr) was obtained as a colorless oil. 1 H NMR(400MHz, CDCl3)δ7.91(s,0.86H,minor),7.70(s,1.12H,major),7.66-7.61(m ,4H),7.44-7.38(m,2H),7.16-7.12(m,2H),4.40-4.26(m,4H),1.35-1.30(m,6H). 13 C NMR (100MHz, CDCl3) δ168.7,168.3,165.2,164.9,164.0,161.6,143.0,141.3,133.6(d,J C-F =2.7Hz),132.5(d,J C-F =2.7Hz),130.6(d,J C-F =8.3Hz),130.5(d,J C-F =8.3Hz),130.1(d,J C-F =8.6Hz),129.8(d,J C-F =8.6Hz),123.2(d,J C-F =3.3Hz),123.2(d,J C-F =3.3Hz),117.6(d,J C-F =21.2Hz),117.3(d,J C-F =21.2Hz),114.6(d,J C-F =11.8Hz),114.5(d,J C-F =11.7Hz),87.2,86.2,64.0,63.9,13.9(2C). 19 FNMR(300MHz, CDCl3)δ-111.4,-111.7.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C26 H 20 F2O8Na:521.1018; measured value:521.1019.

[0058]

[0059] Diethyl 4,4'-bis(2-fluorophenyl)-5,5'-dioxo-[2,2'-bifuran]-2,2'(5H,5'H)-dicarboxylate (I-4): After column chromatography purification (petroleum ether:EtOAc=10:1), a mixture of diastereomers (75.8 mg, 76% yield, 1.4:1dr) was obtained as a yellow oil. 1 H NMR (400MHz, CDCl3) δ8.25 (t, J=7.6Hz, 2H), 8.07 (s, 0.84H, minor), 7.90 (s, 1.15H, major), 7.4 4-7.39(m,2H),7.24(t,J=7.6Hz,2H),7.19-7.12(m,2H),4.40-4.30(m,4H),1.37-1.30(m,6H). 13 C NMR (100MHz, CDCl3) δ169.2,168.8,164.9(2C),162.4(d,J C-F =5.4Hz),159.9(d,J C-F =5.2Hz),146.1(d,J C-F =13.8Hz),144.7(d,J C-F =13.8Hz),131.9(d,J C-F =9.1Hz),131.7(d,J C-F =9.1Hz),129.7(d,J C-F =1.3Hz),129.6(d,J C-F =1.3Hz),128.2(d,J C-F =1.6Hz),127.3(d,J C-F =1.6Hz),124.6(d,J C-F =3.6Hz),124.5(d,J C-F =3.6Hz),116.7(d,J C-F =11.4Hz),116.4(d,J C-F =11.4Hz),115.9(d,J C-F=22.1Hz),87.5,86.7,63.8,63.7,13.9(2C). 19 F NMR(300MHz, CDCl3)δ-111.3,-111.6.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 26 H 20 F2O8Na:521.1018; measured value:521.1019.

[0060]

[0061] Diethyl 4,4'-bis(4-chlorophenyl)-5,5'-dioxo-[2,2'-bifuran]-2,2'(5H,5'H)-dicarboxylate (I-5): Purified by column chromatography (petroleum ether:EtOAc=10:1) to obtain a mixture of diastereomers (79.7 mg, 75% yield, 1.2:1dr) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ7.87 (s, 0.89H, minor), 7.83 (dd, J = 8.4, 5.6Hz, 4H), 7.66 (s, 1.08 H,major),7.41(dd,J=8.6,2.8Hz,4H),4.39-4.25(m,4H),1.32(dd,J=12.6,6.8Hz,6H). 13 C NMR (100MHz, CDCl3) δ168.9,168.5,165.2,164.9,142.2,140.4,136.9,136.5,133.6,132.5,129.2 ,129.1,128.8,128.7,126.7,126.3,87.2,86.3,63.9,63.8,13.9(2C).HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 26 H 20 Cl2O8Na:553.0427; measured value:553.0428.

[0062]

[0063] Diethyl 4,4'-bis(3,4-dichlorophenyl)-5,5'-dioxo-[2,2'-bifuran]-2,2'(5H,5'H)-dicarboxylate (I-6): Purified by column chromatography (petroleum ether:EtOAc=10:1) to give a mixture of diastereomers (85.2 mg, 71% yield, 1:1dr) as a white solid, mp163-164°C. 1 H NMR (400MHz, CDCl3) δ7.99 (d, J = 3.6Hz, 2H), 7.94 (s, 1H), 7.76-7.70 (m, 3H), 7.51-7.49 (m, 2H), 4.40-4.26 (m, 4H), 1.35-1.30 (m, 6H). 13 C NMR (100MHz, CDCl3) δ168.4,168.0,165.0,164.7,143.2,141.4,135.1,134.7,133.4,133.3,132.7,131.5,130 .9,130.8,129.2(2C),128.0,127.6,126.6(2C),87.2,86.2,64.1,64.0,13.9(2C).HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 26 H 18 Cl4O8Na:620.9648; measured value:620.9655.

[0064]

[0065] Diethyl 4,4'-bis(4-bromophenyl)-5,5'-dioxo-[2,2'-bifuran]-2,2'(5H,5'H)-dicarboxylate (I-7): Purified by column chromatography (petroleum ether:EtOAc=10:1) to give a mixture of diastereomers (91.8 mg, 74% yield, 1.6:1 dr) as a white solid, mp135-137°C. 1 H NMR (400MHz, CDCl3) δ7.88 (s, 0.76H, minor), 7.77-7.74 (m, 4H), 7.68 (s, 1.22H, major), 7.56 (dd, J = 8.6, 2.8Hz, 4H), 4.39-4.25 (m, 4H), 1.34-1.29 (m, 6H). 13C NMR (100MHz, CDCl3) δ168.8,168.4,165.2,164.9,142.3,140.6,133.7,132.6,132.2,132.1,129.0 ,128.9,127.1,126.8,125.3,124.9,87.2,86.3,63.9,63.8,13.9(2C).HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 26 H 20 Br2O8Na:640.9417; measured value:640.9416.

[0066]

[0067] Diethyl 4,4'-bis(3-bromophenyl)-5,5'-dioxo-[2,2'-bifuran]-2,2'(5H,5'H)-dicarboxylate (I-8): After column chromatography purification (petroleum ether:EtOAc=10:1), a mixture of diastereomers (86.8 mg, 70% yield, 1.2:1dr) was obtained as a colorless oil. NMR (400MHz, CDCl3) δ8.01-8.00(m,2H),7.91(s,0.89H,minor),7.84(t,J=6.8Hz,2H),7.70(s,1 .11H,major),7.56(d,J=7.6Hz,2H),7.34-7.26(m,2H),4.40-4.26(m,4H),1.35-1.30(m,6H).13C NMR (100 MHz, CDCl3) δ 168.6, 168.2, 165.1, 164.9, 143.1, 141.3, 133.6, 133.4, 133.3, 132.3, 130.5, 130.4, 130.3 (2C), 130.1, 129.8, 126.1, 126.0, 123.0, 122.9, 87.2, 86.3, 64.0, 63.9, 13.9 (2C). HRMS (ESI-TOF) m / z: [M+Na]+Calcd for C26H20Br2O8Na: 640.9417; Measured value: 640.9417.

[0068]

[0069] Diethyl 4,4'-bis(2-bromophenyl)-5,5'-dioxo-[2,2'-bifuran]-2,2'(5H,5'H)-dicarboxylate (I-9): After column chromatography purification (petroleum ether:EtOAc=10:1), a mixture of diastereomers (84.3 mg, 68% yield, 1:1dr) was obtained as a white solid, mp146-148°C. 1 H NMR (400MHz, CDCl3) δ7.97 (d, J = 7.2Hz, 2H), 7.65-7.63 (m, 2H), 7.58-7.56 (m, 2H) ,7.38(t,J=7.6Hz,2H),7.29-7.24(m,2H),4.39-4.32(m,4H),1.37-1.31(m,6H). 13 C NMR (100MHz, CDCl3) δ169.1,168.8,165.0,164.8,147.5,146.5,134.7,134.2,133.6,133.6,131.2,131.1,13 1.0,129.2,128.9,127.7,127.5,123.1,122.9,87.5,86.8,63.9,63.8,14.0(2C).HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 26 H 20 Br2O8Na:640.9417; measured value:640.9416.

[0070]

[0071] Diethyl 4,4'-di([1,1'-biphenyl]-4-yl)-5,5'-dioxo-[2,2'-bifuran]-2,2'(5H,5'H)-dicarboxylate (I-10): After column chromatography purification (petroleum ether:EtOAc=10:1), a mixture of diastereomers (89.7 mg, 73% yield, 2:1dr) was obtained as a colorless oil. 1H NMR(400MHz, CDCl3)δ8.00-7.98(m,4H),7.91(s,0.66H,minor),7.74(s,1.34H,major),7.6 9-7.61(m,8H),7.49-7.46(m,4H),7.41-7.38(m,2H),4.43-4.29(m,4H),1.38-1.32(m,6H); 13 C NMR (100MHz, CDCl3) δ169.3,168.9,165.4,165.3,143.4,143.1,141.6,140.1,140.0,134.3,133.3,129.0(2C) ,128.0(2C),127.9,127.5(2C),127.2,127.1,126.9,87.3,86.5,63.8,63.7,14.0.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 38 H 30 O8Na:637.1833; measured value:637.1835.

[0072]

[0073] Diethyl 4,4'-bis(4-(tert-butyl)phenyl)-5,5'-dioxo-[2,2'-bifuran]-2,2'(5H,5'H)-dicarboxylate(I-11): After column chromatography purification (petroleum ether:EtOAc=10:1), a mixture of diastereomers (91.9 mg, 80% yield, 3:1dr) was obtained as a colorless oil. 1 H NMR (400MHz, CDCl3) δ7.83-7.80(m,4H),7.76(s,0.5H,minor),7.62(s,1.5H,major),7.46-7.44(m,4H),4.39-4.26(m,4H),1.34-1.30(m,24H); 13C NMR (100MHz, CDCl3) δ169.4,169.0,165.5,165.4,154.1,153.7,140.9,139.4,134.4,133.6,127.3,127.2 ,125.8(2C),125.5,125.2,87.2,86.4,63.6,63.5,34.9(2C),31.2,31.1,13.9.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 34 H 38 O8Na:597.2459; measured value:597.2459.

[0074]

[0075] Diethyl 5,5'-dioxo-4,4'-di-p-tolyl-[2,2'-bifuran]-2,2'(5H,5'H)-dicarboxylate (I-12): After column chromatography purification (petroleum ether:EtOAc=10:1), a mixture of diastereomers (81.4 mg, 83% yield, 2:1dr) was obtained as a colorless oil. 1 H NMR (400MHz, CDCl3) δ7.78-7.76 (m, 4.66H), 7.61 (s, 1.32H), 7.23 (d, J = 8.0Hz, 4H), 4.38-4.25 (m, 4H), 2.38 (s, 6H), 1.34-1.28 (m, 6H); 13 CNMR (100MHz, CDCl3) δ169.4,169.0,165.5,165.3,141.0,140.8,140.6,139.3,134.4,

[0076] 133.6,129.6,129.5,127.4,127.3,125.5,125.2,87.2,86.4,63.7,63.6,21.5,13.9.HRMS

[0077] (ESI-TOF)m / z:[M+Na] + Calcd for C 28 H 26 O8Na:513.1520; measured value:513.1523.

Claims

1. A method for synthesizing a butenolide dimer, characterized in that: The method comprises the following steps: adding an acrylic acid compound, ethyl glyoxylate, a ruthenium catalyst, an additive and an oxidant into an organic solvent, heating under air conditions to react, and after the reaction is complete, post-treating to obtain the synthetic butene lactone dimer; The structure of the acrylic acid compound is shown in formula (II): The structure of ethyl glyoxylate is shown in formula (III): The structure of the butenolide dimer is shown in formula (I): In formula (I) to (II), R 1 The phenyl group is selected from substituted or unsubstituted phenyl groups, wherein the substituents on the phenyl group are selected from one or more of halogen, C1-C4 alkyl or phenyl.

2. The method for synthesizing butene lactone dimer according to claim 1, characterized in that: R 1 is selected from substituted or unsubstituted phenyl, wherein the substituent on the phenyl is selected from one or more of F, Cl, Br, methyl, tert-butyl or phenyl.

3. The method for synthesizing butenolide dimer according to claim 1, characterized in that: The organic solvent is hexafluoroisopropanol (HFIP).

4. The method for synthesizing butene lactone dimer according to claim 1, characterized in that: All additives were cesium acetate.

5. The method for synthesizing butenolide dimer according to claim 1, characterized in that: All oxidizing agents were silver sulfate.

6. The method for synthesizing butenolide dimer according to claim 1, characterized in that: The ruthenium catalyst is dichlorobis(4-methylisopropylphenyl)ruthenium(II).

7. The method for synthesizing butenolide dimer according to claim 1, characterized in that: The reaction temperature is 90 to 110° C., and the reaction time is 3 to 10 hours under air atmosphere.

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