Method for synthesizing sulfonamide compounds through photocatalytic [2 +2] cycloaddition

Abstract

The invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing sulfonamide compounds through photocatalytic [2 + 2] cycloaddition. The supramolecular TXO-BSA photocatalyst is designed and synthesized by reacting thioxanthone TXO with free amino groups on the surface of bovine serum albumin. And carrying out [2 + 2] cycloaddition reaction on the compound I, styrene and a derivative thereof under the action of a supramolecular photocatalyst TXO-BSA to prepare the sulfonamide compound II. Compared with the traditional photocatalytic [2 + 2] cycloaddition reaction, the photocatalyst used in the invention has the advantages of low production cost, easy preparation, mild reaction conditions and environmental protection.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for synthesizing sulfonamide compounds by photocatalytic [2+2] cycloaddition. Background Technology

[0002] Traditional catalytic [2+2] cycloaddition requires metals, such as iridium, which can achieve highly efficient cycloaddition reactions. (J.Am.Chem.Soc.,2017,139(29):9807-9810.) Rhodium has excellent stability and selectivity, and also exhibits excellent catalytic performance. (J.Am.Chem.Soc.,2017,139(27):9120-9123) However, such processes require metal catalysts, which are complex and expensive. Thioxanone (TXO) is an excellent photosensitizer with unique photophysical and photochemical properties; however, its ACQ effect has hindered its application in photocatalytic synthesis. The ACQ effect refers to the phenomenon that luminescent molecules emit light efficiently in dilute solutions, but their luminescence is weakened or even completely disappears in concentrated solutions or in aggregated states. The planar structure of thioxanone leads to weakened fluorescence intensity or even direct quenching under high concentration or aggregated conditions, limiting its application in photocatalysis. Summary of the Invention

[0003] The technical problem to be solved by the present invention is to provide a method for synthesizing sulfonamide compounds by photocatalytic [2+2] cycloaddition, thereby providing an efficient and environmentally friendly photocatalytic pathway, which addresses the shortcomings of the prior art.

[0004] To solve the above-mentioned technical problems, the present invention has the following approach:

[0005] Using only thioxanthone (TXO) as a photocatalyst fails to yield the target product, while bovine serum albumin (BSA) contains abundant amino acid residues, making it an excellent carrier. Inserting thioxanthone into BSA via the EDC-NHC pathway forms a stable supramolecular TXO-BSA photocatalyst. This photocatalyst combines the photosensitivity of thioxanthone with the biocompatibility of BSA, effectively addressing the ACQ effect inherent in traditional single thioxanthone (TXO) photocatalysts.

[0006] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is as follows:

[0007] A method for synthesizing sulfonamide compounds by photocatalytic [2+2] cycloaddition involves using compound I and styrene and its derivatives as raw materials, adding the photocatalyst TXO-BSA, dissolving them in a mixed solvent of organic solvent and water, and reacting them under blue light irradiation to prepare sulfonamide compound II;

[0008]

[0009] R1 is selected from methyl or hydrogen;

[0010] R2 is selected from methyl formate or phenyl;

[0011] R3 is selected from methoxy, chlorine, methanol, hydrogen, or phenyl.

[0012] The photocatalyst TXO-BSA was prepared according to the following steps:

[0013]

[0014] (1) Sodium phenylsulfate and dimethyl dinitroterephthalate were dissolved in N,N-dimethylformamide and reacted at 80°C. After the reaction was completed, a white precipitate was obtained. Then, chlorosulfonic acid solution was added, and the reaction was carried out at 5-10°C to obtain thioxanone TXO.

[0015] (2) Thioxanone TXO reacts with the free amino groups on the surface of bovine serum albumin (BSA) via NHS ester-amide coupling to obtain the photocatalyst TXO-BSA.

[0016] In some embodiments, the molar ratio of compound I to styrene and its derivatives is 1:1.5 to 6 (preferably 1:2).

[0017] In some embodiments, the molar ratio of compound I to the photocatalyst is 1:0.05 to 0.6 (preferably 1:0.1).

[0018] In some embodiments, the organic solvent is any one or a combination of several of tetrahydrofuran, dimethyl sulfoxide, and acetonitrile (preferably acetonitrile).

[0019] In some embodiments, the volume ratio of the organic solvent to water in the mixed solvent is 1-4:1-2 (preferably 2:1).

[0020] In some embodiments, the blue light irradiation is performed under the conditions of 390–450 nm and 5–35 W (preferably 450 nm and 20 W).

[0021] In some embodiments, the reaction is a [2+2] cycloaddition reaction, and the reaction temperature is 20-30°C (preferably 25°C).

[0022] In some embodiments, the reaction is a [2+2] cycloaddition reaction, and the reaction time is 12 to 36 hours (preferably 24 hours).

[0023] In some embodiments, the reaction is a [2+2] cycloaddition reaction, and the reaction conditions are either N2 or O2 (preferably N2).

[0024] Beneficial effects:

[0025] (1) Compared with the prior art, the present invention provides an innovative supramolecular photocatalytic system. By covalently binding planar TXOs on the surface of natural protein (bovine serum albumin, BSA), we can overcome strong π-π intermolecular interactions and avoid the quenching (ACQ) effect caused by aggregation compared with traditional organic catalysts or photocatalysts.

[0026] (2) This study provides a new strategy for promoting selective photochemical reactions in a sustainable manner by utilizing supramolecular interactions and offers valuable insights for designing supramolecular photocatalysts with improved photophysical properties.

[0027] (3) The unique supramolecular structure of TXO-BSA photocatalyst can effectively reduce the activation energy of the reaction and improve the catalytic efficiency, achieving a high reaction rate and yield under relatively mild conditions.

[0028] (4) Compared with traditional organic or metal catalysts, TXO-BSA photocatalyst uses bovine serum albumin as a carrier, which is green and environmentally friendly, has low production cost, and excellent product quality, reflecting the principles of green chemistry. Attached Figure Description

[0029] The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments, and the advantages of the present invention in the above and / or other aspects will become clearer.

[0030] Figure 1 Compound 3a in the embodiments of the present invention 1 H NMR spectrum.

[0031] Figure 2 Compound 3a in the embodiments of the present invention 13 C10 NMR spectrum.

[0032] Figure 3 Compound 3b in the embodiments of the present invention 1 H NMR spectrum.

[0033] Figure 4 Compound 3b in the embodiments of the present invention 13 C10 NMR spectrum.

[0034] Figure 5 Compound 3c in the embodiments of the present invention 1 H NMR spectrum.

[0035] Figure 6 Compound 3c in the embodiments of the present invention 13 C10 NMR spectrum.

[0036] Figure 7 Compound 3d in the embodiments of the present invention 1 H NMR spectrum.

[0037] Figure 8 Compound 3d in the embodiments of the present invention 13 C10 NMR spectrum.

[0038] Figure 9 Compound 3e in the embodiments of the present invention 1 H NMR spectrum.

[0039] Figure 10 Compound 3e in the embodiments of the present invention 13 C10 NMR spectrum. Detailed Implementation

[0040] Unless otherwise specified, the experimental methods described in the embodiments of this invention are all conventional methods; unless otherwise specified, the reagents and materials are all commercially available.

[0041] In this embodiment of the invention, the supramolecular photocatalyst TXO-BSA is prepared according to the following steps:

[0042] (1) Sodium phenylsulfate and dimethyl dinitroterephthalate were dissolved in N,N-dimethylformamide solution at a molar ratio of 1.5:1 and reacted at 80℃ for 4 h. After the reaction was completed, the mixture was filtered to obtain a precipitate. Then, 20 equivalents of 99% chlorosulfonic acid solution (15 mol / L) were added, and the mixture was reacted at 10℃ for another 1 h. After filtration, the precipitate was dried under vacuum to obtain a pale yellow powder, thioxanthone (TXO).

[0043] (2) Thioxanone TXO reacts with the free amino groups on the surface of bovine serum albumin (BSA) via NHS ester-amide coupling. Under nitrogen protection, thioxanone TXO, N-hydroxysuccinimide, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were dissolved in N,N-dimethylformamide at a molar ratio of 1:1:0.8 and stirred overnight at room temperature. 0.01 equivalents of bovine serum albumin (BSA) dissolved in phosphate buffer were added to the solution, and the mixture was stirred overnight at room temperature. The solvent was then removed by rotary evaporation to obtain the supramolecular TXO-BSA photocatalyst.

[0044] In the embodiments of the present invention, the cyclic N-sulfonyl ketone amine raw materials, styrene and its derivative raw materials, and sulfonamide target compounds are shown in Tables 1, 2, and 3, respectively.

[0045] Table 1 Reactants: Cyclic N-sulfonyl ketone amine compounds

[0046]

[0047] Table 2 Reactants: Styrene and its derivatives raw materials

[0048]

[0049] Table 3. Structures of target products of sulfonamide compounds

[0050]

[0051] Example 1: Synthesis of compound 3a

[0052] Under nitrogen protection, 0.1 mmol of compound 1a and 0.2 mmol of 4-methoxystyrene (2a) were added to a 15 mL pressure-resistant tube, along with 0.01 mmol of supramolecular TXO-BSA photocatalyst. The mixture was dissolved in 3 mL of an acetonitrile-water mixed solvent (acetonitrile to water volume ratio 2:1). The pressure-resistant tube was placed under 450 nm, 20 W blue light irradiation for 24 h at room temperature (25 °C). The resulting reaction solution was collected, extracted, dried under reduced pressure, concentrated, and then separated by column chromatography to obtain the target product 3a in 46% yield.

[0053] The 1H NMR spectrum of compound 3a is shown below. Figure 1 As shown, the carbon NMR spectrum is as follows: Figure 2 As shown, the specific NMR data are 1 HNMR(400MHz, CDCl3) δ7.79(d,J=7.7Hz,1H),7.68–7.60(m,2H),7.54(ddd,J=8.1,6.8,1.5Hz,1H),7.32–7.28(m,2 H),7.16–7.10(m,4H),7.09–7.04(m,1H),6.75–6.70(m,2H),4.49(t,J=9.0Hz,1H),4.06–3.97(m,2H),3.73(s,3H). 13 CNMR(101MHz,CDCl3)δ159.05,145.86,138.65,134.49,134.19,130.28,129.94 ,128.18,127.25,125.73,124.45,122.76,113.97,82.05,56.44,55.33,47.81.

[0054] Example 2: Synthesis of compound 3b

[0055] The preparation method was the same as in Example 1, except that compound 2a was replaced with 4-chlorostyrene (2b), and product 3b was finally prepared with a yield of 50%.

[0056] The 1H NMR spectrum of product 3b is shown below. Figure 3 As shown, the carbon NMR spectrum is as follows: Figure 4The specific NMR data are as shown: 1 H NMR(400MHz, CDCl3)δ7.80(dt,J=7.7,0.9Hz,1H),7.69–7.62(m,2H),7.56(ddd,J=8.1,6.3,1.9Hz,1H),7.32–7.2 7(m,2H),7.17(p,J=2.3Hz,4H),7.15–7.11(m,2H),7.11–7.06(m,1H),4.48(t,J=10.6Hz,1H),4.04–3.97(m,2H). 13 C NMR (101MHz, CDCl3) δ145.41,138.27,136.94,134.43,134.28,133.57,130.48, 130.15,128.77,128.35,127.52,125.61,124.50,122.83,81.69,56.22,47.71.

[0057] Example 3: Synthesis of compound 3c

[0058] The preparation method was the same as in Example 1, except that compound 2a was replaced with 4-methanolstyrene (2c), and the final product 3c was obtained with a yield of 66%.

[0059] The 1H NMR spectrum of product 3C is shown below. Figure 5 As shown, the carbon NMR spectrum is as follows: Figure 6 The specific NMR data are as shown: 1 H NMR (400MHz, CDCl3) δ7.79(d,J=7.7Hz,1H),7.65(d,J=5.8Hz,2H),7.55(ddd,J=8.1,6.0,2.3Hz,1H),7.33–7.29(m,2H),7.24(d,J=8.2 Hz,2H),7.19(d,J=8.1Hz,2H),7.11(dd,J=8.1,6.6Hz,2H),7.07–7.02(m,1H),4.59(s,2H),4.49(t,J=10.5Hz,1H),4.07–4.01(m,2H). 13 C NMR (101MHz, CDCl3) δ145.70,140.36,138.52,137.66,134.42,134.24,130.04,129 .38,128.19,127.31,127.09,125.64,124.52,122.77,81.84,64.93,56.29,48.07.

[0060] Example 4: Synthesis of compound 3d

[0061] The preparation method is the same as in Example 1, except that compound 1a is replaced with compound 1b and compound 2a is replaced with styrene (2d), and finally product 3d is obtained with a yield of 70%.

[0062] The 3d NMR spectrum of the product is shown below. Figure 7 As shown, the carbon NMR spectrum is as follows: Figure 8 The specific NMR data are as shown: 1 HNMR(400MHz, CDCl3)δ7.64(d,J=8.0Hz,1H),7.57(s,1H),7.49–7.45(m,2H),7.41–7.32(m,3H),7.31–7.26( m,1H),4.30–4.24(m,1H),4.04(dd,J=9.7,4.1Hz,1H),3.74(dd,J=9.1,4.1Hz,1H),3.35(s,3H),2.46(s,3H). 13 C NMR (101MHz, CDCl3) δ167.45,145.56,138.99,137.33,133.12,132.22,12 9.07,128.58,128.07,125.85,122.33,79.32,55.22,52.92,47.56,22.01.

[0063] Example 5: Synthesis of compound 3e

[0064] The preparation method is the same as in Example 1, except that compound 1a is replaced with compound 1b and compound 2a is replaced with phenylstyrene (2e), and finally product 3e is obtained with a yield of 64%.

[0065] The 3d NMR spectrum of the product is shown below. Figure 9 As shown, the carbon NMR spectrum is as follows: Figure 10 The specific NMR data are as shown: 1 HNMR(400MHz, CDCl3)δ7.71(d,J=8.0Hz,1H),7.68–7.59(m,7H),7.49–7.43(m,3H),7.37(t,J=7.3Hz,1H), 4.35(t,J=9.4Hz,1H),4.12(dd,J=9.7,4.1Hz,1H),3.85(dd,J=9.1,4.0Hz,1H),3.44(s,3H),2.53(s,3H). 13C NMR (101MHz, CDCl3) δ167.43,145.54,141.26,140.28,138.92,136.32,133.10,132.21,12 8.96,128.51,127.71,127.58,127.09,125.86,122.27,79.29,55.21,52.91,47.22,21.95.

[0066] Example 6: Synthesis of compound 3a

[0067] The preparation method is the same as in Example 1, except that the blue light irradiation wavelength is 450nm and the W is 30, and the yield of the final target product 3a is 35%.

[0068] Example 7: Synthesis of compound 3a

[0069] The preparation method is the same as in Example 1, except that the blue light irradiation wavelength is 420nm and the W is 30W, and the yield of the final target product 3a is 31%.

[0070] Example 8: Synthesis of compound 3a

[0071] The preparation method is the same as in Example 1, except that the molar ratio of compound 1a to 4-methoxystyrene (2a) is 1:1.5, and the yield of the final target product 3a is 38%.

[0072] Example 9: Synthesis of compound 3a

[0073] The preparation method is the same as in Example 1, except that the molar ratio of compound 1a to 4-methoxystyrene (2a) is 1:3, and the yield of the final target product 3a is 29%.

[0074] Example 10: Synthesis of compound 3a

[0075] The preparation method is the same as in Example 1, except that the organic solvent used in the reaction is tetrahydrofuran, and the yield of the final target product 3a is 30%.

[0076] Example 11: Synthesis of compound 3a

[0077] The preparation method is the same as in Example 1, except that the reaction solvent is acetonitrile, and the yield of the final target product 3a is 22%.

[0078] Example 12: Synthesis of compound 3a

[0079] The preparation method is the same as in Example 1, except that the molar mass ratio of compound 1a to TXO-BSA photocatalyst is 1:0.05, and the yield of the final target product 3a is 28%.

[0080] Example 13: Synthesis of compound 3a

[0081] The preparation method is the same as in Example 1, except that the molar mass ratio of compound 1a to TXO-BSA photocatalyst is 1:0.6, and the yield of the final target product 2a is 36%.

[0082] Comparative Example 1: Reaction without supramolecular TXO-BSA photocatalyst

[0083] Under nitrogen protection, 0.1 mmol of compound 1a and 0.2 mmol of 4-methoxystyrene (2a) were added to a 15 mL pressure-resistant tube, and the mixture was dissolved in 3 mL of an acetonitrile-water mixed solvent. The volume ratio of acetonitrile to water was 2:1. The pressure-resistant tube was placed under 450 nm, 20 W blue light irradiation for 24 h at room temperature (25 °C). The reaction progress was monitored by HPLC at 1 h, 5 h, 12 h, 18 h, and 24 h after the start of the reaction. The experimental results showed that no reaction occurred in the reaction system, proving that the TXO-BSA photocatalyst was a necessary condition for the reaction.

[0084] Comparative Example 2: Reaction using thioxanthone catalyst

[0085] Under nitrogen protection, 0.1 mmol of compound 1a and 0.2 mmol of 4-methoxystyrene (2a) were added to a 15 mL pressure-resistant tube, along with 0.01 mmol of thioxanthone (TXO) catalyst. The mixture was dissolved in 3 mL of an acetonitrile-water mixture (acetonitrile to water volume ratio 2:1). The pressure-resistant tube was placed under 450 nm, 20 W blue light irradiation for 24 h at room temperature (25 °C). The reaction progress was monitored by HPLC at 1 h, 5 h, 12 h, 18 h, and 24 h. The experimental results showed that no reaction occurred in the reaction system, proving that the TXO-BSA photocatalyst was a necessary condition for the reaction.

[0086] This invention provides a method and approach for the photocatalytic [2+2] cycloaddition synthesis of sulfonamide compounds. Many methods and approaches exist for implementing this technical solution; the above description is merely a preferred embodiment of the invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of this invention, and these improvements and modifications should also be considered within the scope of protection of this invention. All components not explicitly stated in this embodiment can be implemented using existing technologies.

Claims

1. A method for synthesizing sulfonamide compounds by photocatalytic [2+2] cycloaddition, characterized in that, Using compound I and styrene and its derivatives as raw materials, the photocatalyst TXO-BSA was added, and the mixture was dissolved in a mixed solvent of organic solvent and water. The reaction was carried out under blue light irradiation to prepare sulfonamide compound II. R1 is selected from methyl or hydrogen; R2 is selected from methyl formate or phenyl; R3 is selected from methoxy, chlorine, methanol, hydrogen, or phenyl.

2. The method according to claim 1, characterized in that, The photocatalyst TXO-BSA was prepared according to the following steps: (1) Sodium phenylsulfate and dimethyl dinitroterephthalate were dissolved in N,N-dimethylformamide and reacted at 80°C. After the reaction was completed, a white precipitate was obtained. Then, chlorosulfonic acid solution was added, and the reaction was carried out at 5-10°C to obtain thioxanone TXO. (2) Thioxanone TXO reacts with the free amino groups on the surface of bovine serum albumin (BSA) via NHS ester-amide coupling to obtain the photocatalyst TXO-BSA.

3. The method according to claim 1, characterized in that, The molar ratio of compound I to styrene and its derivatives is 1:1.5 to 6.

4. The method according to claim 1 or 2, characterized in that, The molar ratio of compound I to the photocatalyst is 1:0.05 to 0.

6.

5. The method according to claim 1, characterized in that, The organic solvent is any one or a combination of tetrahydrofuran, dimethyl sulfoxide, and acetonitrile.

6. The method according to claim 1, characterized in that, The organic solvent and water mixture has a volume ratio of organic solvent to water of 1-4:1-2.

7. The method according to claim 1, characterized in that, The blue light irradiation conditions are 390–450 nm and 5–35 W.

8. The method according to claim 1, characterized in that, The reaction is a [2+2] cycloaddition reaction, and the reaction temperature is 20-30℃, preferably 25℃.

9. The method according to claim 1, characterized in that, The reaction is a [2+2] cycloaddition reaction, and the reaction time is 12-36 h.

10. The method according to claim 1, characterized in that, The reaction is a [2+2] cycloaddition reaction, and the reaction conditions are either N2 or O2.

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