Synthesis method of sulfone oxoindole compound

Abstract

The invention belongs to the technical field of synthesis of organic compounds, and provides a novel synthesis method of a sulfone oxoindole compound. According to the method, under the conditions of an iridium catalyst and illumination of 460-465 nm, sulfonyl acrylamide and N-hydroxyphthalimide ester (NHPI ester) are utilized, and direct synthesis preparation of the sulfone oxoindole compound is realized through a controllable Smiles rearrangement reaction. The invention relates to a novel method for constructing a sulfone compound by adopting a collaborative strategy of free radical SO2 in-situ capture and Trice-Smiles rearrangement. The reaction is simple and convenient to operate, a stoichiometric oxidizing agent or gaseous SO2 is not needed, atom economical construction of double C-S bonds can be efficiently realized at room temperature, sulfone derivatives with various structures can be obtained with high step economy, and the method has a relatively high economic prospect.

Description

Technical Field

[0001] The invention belongs to the technical field of organic compound synthesis and relates to a method for synthesizing a sulfone oxidized indole compound. Background Art

[0002] Sulfones are an important class of sulfur-containing molecules, widely found in natural products, pharmaceuticals, pesticides, and materials. Consequently, their synthesis has historically garnered significant attention from chemists. Traditional methods for synthesizing sulfone compounds primarily involve the oxidation of low-valent sulfides or sulfoxides and the cross-coupling of sulfonyl derivatives with electrophilic reagents. However, these approaches often face challenges, such as the need for stoichiometric amounts of oxidants, multiple steps, and poor functional group compatibility. Unlike these approaches, direct insertion of sulfur dioxide (SO2) is a more modular strategy, utilizing SO2 gas as a sulfonyl source to simultaneously construct two C-S bonds. However, SO2's toxicity, gaseous properties, and irritation significantly limit its synthetic applications. In recent years, chemists have increasingly utilized safe and readily available solid sulfur dioxide sources, such as DABCO·(SO2)2 and persulfates, and significant progress has been made. While solid sulfur dioxide sources address the safety and practical challenges of gaseous sulfur dioxide, they still face challenges such as poor solubility and low atom economy. In order to comply with the trend of sustainable development, this method utilizes the SO2 group within the molecule to realize the photoinduced self-circulating Truce–Smiles rearrangement reaction of sulfur dioxide. It does not require the participation of additional oxidants, has mild reaction conditions, good functional group compatibility and atom economy, is simple to operate, is conducive to industrial production, and has significant economic prospects. Summary of the Invention

[0003] The present invention utilizes the SO2 group in the molecule to realize the light-induced sulfur dioxide self-circulating Truce–Smiles rearrangement reaction, directly constructs a double CS bond, and provides a novel synthetic method for the preparation of sulfone oxidized indole compounds.

[0004] To achieve the above purpose, the method utilizes light to illuminate an excited iridium catalyst to activate N-hydroxyphthalimide carboxylate, generate alkyl radicals, and then initiate a Smiles rearrangement reaction to synthesize sulfone oxidized indole compounds.

[0005] As a preferred embodiment of the present invention, the reaction equation for synthesizing the sulfone oxidized indole compound is:

[0006]

[0007] In formula (1), R 1 is a methyl, oxymethyl, or chlorine substituent, R 2 is a n-butyl or cyclohexyl substituent, in formula (2), R 3is cyclohexyl, propyl, n-hexyl, butenyl;

[0008] The synthesis process of the compound represented by formula (3) is as follows: dissolving the compound represented by formula (1) (2) and Ir(ppy)3 in a solvent, reacting under light conditions to generate the compound represented by formula (3);

[0009] The solvent is an aprotic solvent and does not include an ether solvent;

[0010] In the reaction system, the molar ratio of the compound represented by formula (1), the compound represented by formula (2), and Ir(ppy)3 is 1:1.5:0.01;

[0011] The reaction temperature was 25°C and the reaction time was 12 h.

[0012] More preferably, in formulas (1) and (2), R 1 Selected from phenyl, R 2 , R 3 Selected from alkyl groups.

[0013] Further preferably, the illumination wavelength range is 460-465 nm.

[0014] More preferably, the solvent is any one of dimethyl sulfoxide, acetonitrile, and ethyl acetate.

[0015] The present invention synthesizes sulfone oxidized indole compounds, which has the following advantages:

[0016] (1) The present invention utilizes SO2 released within the molecule to construct a double C-S bond, providing a green method for the synthesis of sulfone-type oxidized indole compounds, effectively reducing the environmental pollution of the traditional synthesis of sulfone-type oxidized indole compounds.

[0017] (2) The raw material carboxylic acid used in the present invention is cheap and readily available, and the operation is simple, and no heating is required, which effectively reduces the synthesis cost and is conducive to industrial production;

[0018] (3) The present invention does not require the addition of exogenous SO2, realizes the construction of sulfone-type oxidized indole compounds, effectively reduces costs, and has broad economic prospects. DETAILED DESCRIPTION

[0019] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0020] Example 1: In this example, N-butyl-N-sulfonylacrylamide was reacted with 1,3-dioxoisoindoline-2-cyclohexanecarboxylate to synthesize sulfone oxidized indole compound (3a):

[0021] The reaction equation is:

[0022]

[0023] The synthesis steps and process are as follows: N-butyl-N-sulfonylacrylamide (0.1 mmol, 29.5 mg), 1,3-dioxoisoindoline-2-cyclohexanecarboxylate (0.15 mmol, 41.0 mg), Ir(ppy)3 (0.001 mmol, 0.6 mg), and 1.0 mL of dimethyl sulfoxide are added to a 10 mL reaction tube equipped with a magnetic stirrer; under inert gas protection, the reaction tube is fixed on a magnetic stirrer, and the reaction is carried out under 460 nm light irradiation for 6 hours, 5 mL of sodium hydroxide aqueous solution (1 M) is added, and extraction with methyl tert-butyl ether (3×5 mL) is carried out, and the solvent is removed by rotary evaporation under reduced pressure. The crude product is separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain the target product (3a) in a yield of 82%.

[0024] The NMR data of compound (3a) are:

[0025] 1 H NMR (600MHz, CDCl3) δ7.27 (d, J=3.6Hz, 1H), 6.89 (dd, J=7.6, 0.5Hz, 1H), 6.71 (s, 1 H),3.71(td,J=7.2,1.6Hz,2H),3.57(d,J=14.1Hz,1H),3.43(d,J=14.1Hz,1H),2.5 9(tt,J=12.1,3.4Hz,1H),2.38(s,3H),2.11–2.04(m,2H),1.87(d,J=12.2Hz,2H), 1.68(t,J=7.5Hz,3H),1.48–1.37(m,7H),1.23–1.13(m,3H),0.97(t,J=7.4Hz,3H);

[0026] 13 C NMR (151MHz, CDCl3) δ178.4,142.8,138.8,127.8,123.7,122.8,109.8,62 .9,55.0,45.0,40.1,29.2,25.6,25.1,25.0,24.9,24.7,22.0,20.2,13.8.

[0027] Example 2: In this example, N-butyl-N-((4-methoxyphenyl)sulfonyl)methacrylamide was reacted with 1,3-dioxoisoindoline-2-cyclohexanecarboxylate to synthesize sulfone oxidized indole compound (3b):

[0028] The reaction equation is:

[0029]

[0030] The synthesis steps and process are as follows: N-butyl-N-((4-methoxyphenyl)sulfonyl)methacrylamide (0.1 mmol, 31.1 mg), 1,3-dioxoisoindoline-2-cyclohexanecarboxylate (0.15 mmol, 41.0 mg), Ir(ppy)3 (0.001 mmol, 0.6 mg), and 1.0 mL of dimethyl sulfoxide are added to a 10 mL reaction tube equipped with a magnetic stirrer; under inert gas protection, the reaction tube is fixed on a magnetic stirrer and reacted under 460 nm light irradiation for 12 hours, 5 mL of sodium hydroxide aqueous solution (1 M) is added, and extraction with methyl tert-butyl ether (3×5 mL) is performed. The solvent is then removed by rotary evaporation under reduced pressure, and the crude product is separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain the target product (3b) in a yield of 79%.

[0031] The NMR data of compound (3b) are:

[0032] 1 H NMR(600MHz, CDCl3) δ7.31(d,J=8.2Hz,1H),6.58(dd,J=8.2,2.2Hz,1H),6.47(d,J=2.1Hz ,1H),3.82(d,J=6.7Hz,3H),3.69(dd,J=8.3,6.8Hz,2H),3.55(d,J=14.1Hz,1H),3.42(d, J=14.1Hz,1H),2.60(tt,J=12.1,3.3Hz,1H),2.08(d,J=12.2Hz,2H),1.90–1.83(m,2H),1 .68(dq,J=15.0,7.6Hz,3H),1.48–1.36(m,7H),1.24–1.13(m,3H),0.96(t,J=7.4Hz,3H);

[0033] 13 C NMR (151MHz, CDCl3) δ178.7,160.5,144.0,124.7,122.6,105.8,97.1,62. 9,55.5,55.0,44.8,40.2,29.2,25.6,25.0,25.0,24.9,24.8,20.2,13.8.

[0034] Example 3: In this example, N-butyl-N-((4-chlorophenyl)sulfonyl)methacrylamide was reacted with 1,3-dioxoisoindoline-2-cyclohexanecarboxylate to synthesize a sulfone oxidized indole compound (3c):

[0035] The reaction equation is:

[0036]

[0037] The synthesis steps and process are as follows: N-butyl-N-((4-chlorophenyl)sulfonyl)methacrylamide (0.1 mmol, 31.5 mg), 1,3-dioxoisoindoline-2-cyclohexanecarboxylate (0.15 mmol, 41.0 mg), Ir(ppy)3 (0.001 mmol, 0.6 mg), and 1.0 mL of acetonitrile are added to a 10 mL reaction tube equipped with a magnetic stirrer. Under inert gas protection, the reaction tube is fixed on a magnetic stirrer and reacted under 460 nm light for 12 hours. Then, 5 mL of 1 M sodium hydroxide aqueous solution is added, and extraction with methyl tert-butyl ether (3×5 mL) is performed. The solvent is then removed by vacuum rotation. The crude product is separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain the target product (3c) in a yield of 81%.

[0038] The NMR data of compound (3c) are:

[0039] 1 H NMR (600MHz, CDCl3) δ7.32 (d, J=8.0Hz, 1H), 7.05 (dd, J=7.9, 1.8Hz, 1H), 6.88 (d ,J=1.7Hz,1H),3.73–3.66(m,2H),3.61(d,J=14.0Hz,1H),3.42(d,J=14.0Hz,1H ),2.66(tt,J=12.1,3.4Hz,1H),2.09(d,J=12.8Hz,2H),1.89(d,J=13.0Hz,2H), 1.71–1.64(m,3H),1.48–1.38(m,7H),1.26–1.13(m,3H),0.97(t,J=7.4Hz,3H);

[0040] 13 C NMR (151MHz, CDCl3) δ178.1,143.9,134.5,129.1,125.0,122.2,109.5,63 .1,54.7,45.0,40.3,29.1,25.5,25.1,25.0,25.0,25.0,24.6,20.2,13.7.

[0041] Example 4: In this example, N-cyclohexyl-N-p-methylbenzenesulfonylmethyl acrylamide was reacted with 1,3-dioxoisoindoline-2-cyclohexanecarboxylate to synthesize sulfone oxidized indole compound (3d):

[0042] The reaction equation is:

[0043]

[0044] The synthesis steps and process are as follows: N-cyclohexyl-N-p-methylphenylsulfonylmethyl acrylamide (0.1 mmol, 32.1 mg), 1,3-dioxoisoindoline-2-cyclohexanecarboxylate (0.15 mmol, 41.0 mg), Ir(ppy)3 (0.001 mmol, 0.6 mg), and 1.0 mL of dimethyl sulfoxide are added to a 10 mL reaction tube equipped with a magnetic stirrer. Under inert gas protection, the reaction tube is fixed on a magnetic stirrer and reacted under 460 nm light for 12 hours. Then, 5 mL of 1 M sodium hydroxide aqueous solution is added, and extraction with methyl tert-butyl ether (3×5 mL) is performed. The solvent is then removed by vacuum rotation. The crude product is separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain the target product (3d) in a yield of 83%.

[0045] The NMR data of compound (3d) are:

[0046] 1 H NMR(600MHz, CDCl3)δ7.17(d,J=7.5Hz,1H),6.85–6.77(m,2H),4.06(t,J=11.7H z,1H),3.51(d,J=14.0Hz,1H),3.34(d,J=14.0Hz,1H),2.48(tt,J=12.1,3.4Hz,1 H),2.31(s,3H),2.13–2.04(m,2H),2.02–1.97(m,2H),1.85–1.73(m,6H),1.63( dd,J=33.1,8.8Hz,2H),1.40–1.30(m,7H),1.25–1.19(m,1H),1.14–1.04(m,3H);

[0047] 13 C NMR (151MHz, CDCl3) δ177.3,141.5,137.5,126.9,122.7,121.4,110.3,61.8,54 .1,51.5,43.7,28.1,27.6,25.0,25.0,24.8,24.5,24.0,23.9,23.8,23.7,21.1.

[0048] Example 5: In this example, N-butyl-N-sulfonylacrylamide was reacted with 1,3-dioxoisoindoline-2-butyrate to synthesize a sulfone oxidized indole compound (3e):

[0049] The reaction equation is:

[0050]

[0051] The synthesis steps and process are as follows: N-butyl-N-sulfonylacrylamide (0.1 mmol, 29.5 mg), 1,3-dioxoisoindoline-2-butyrate (0.15 mmol, 35.0 mg), Ir(ppy)3 (0.001 mmol, 0.6 mg), and 1.0 mL of dimethyl sulfoxide are added to a 10 mL reaction tube equipped with a magnetic stirrer; under inert gas protection, the reaction tube is fixed on a magnetic stirrer and reacted under 460 nm light irradiation for 12 hours, 5 mL of sodium hydroxide aqueous solution (1 M) is added, and extraction with methyl tert-butyl ether (3×5 mL) is performed. The solvent is then removed by rotary evaporation under reduced pressure, and the crude product is separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain the target product (3e) in a yield of 80%.

[0052] The NMR data of compound (3e) are:

[0053] 1 H NMR (600MHz, CDCl3) δ7.24(d,J=7.6Hz,1H),6.90(dd,J=7.5,0.5Hz,1H),6.72(s,1H),3.73–3.69(m,2H),3.60(d,J=14.5Hz,1H),3.49( d,J=14.5Hz,1H),2.74–2.65(m,2H),2.39(s,3H),1.78–1.74(m,2H),1.70–1.65(m,2H),1.45–1.38(m,5H),0.97(td,J=7.4,5.1Hz,6H);

[0054] 13 C NMR (151MHz, CDCl3) δ178.1,142.8,139.0,127.6,123.5,122.9,109.9,58.4,56.9,45.2,40.1,29.3,25.5,22.0,20.2,15.7,13.8,13.0.

[0055] Example 6: In this example, N-butyl-N-sulfonylacrylamide was reacted with 1,3-dioxoisoindoline-2-heptanoate to synthesize a sulfone oxidized indole compound (3f):

[0056] The reaction equation is:

[0057]

[0058] The synthesis steps and process are as follows: N-butyl-N-sulfonylacrylamide (0.1 mmol, 29.5 mg), 1,3-dioxoisoindoline-2-heptanoate (0.15 mmol, 41.2 mg), Ir(ppy)3 (0.001 mmol, 0.6 mg), and 1.0 mL of dimethyl sulfoxide are added to a 10 mL reaction tube equipped with a magnetic stirrer. Under inert gas protection, the reaction tube is fixed on a magnetic stirrer and reacted under 460 nm light for 12 hours. Then, 5 mL of 1 M sodium hydroxide aqueous solution is added, and extraction with methyl tert-butyl ether (3×5 mL) is performed. The solvent is then removed by vacuum rotation. The crude product is separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain the target product (3f) in a yield of 66%.

[0059] The NMR data of compound (3f) are:

[0060] 1 H NMR (600MHz, CDCl3) δ7.24(d,J=7.5Hz,1H),6.90(d,J=7.5Hz,1H),6.72(s,1H),3.73–3.69(m,2H),3.59(d,J=14.5Hz,1H),3.49(d,J=14.5Hz ,1H),2.74–2.65(m,2H),2.39(s,3H),1.74–1.66(m,4H),1.45–1.38(m ,5H),1.34–1.22(m,6H),0.97(t,J=7.4Hz,3H),0.87(t,J=7.1Hz,3H);

[0061] 13 C NMR (151MHz, CDCl3) δ178.1,142.8,139.0,127.6,123.5,122.9,109.9,58.4, 55.2,45.2,40.1,31.1,29.3,28.0,25.5,22.3,21.9,21.7,20.2,13.9,13.8.

[0062] Example 7: In this example, a sulfone oxidized indole compound (3 g) was synthesized by reacting N-butyl-N-sulfonylacrylamide with 1,3-dioxoisoindoline-2-pentyl-4-enoate:

[0063] The reaction equation is:

[0064]

[0065] The synthesis steps and process are as follows: N-butyl-N-sulfonylacrylamide (0.1 mmol, 29.5 mg), 1,3-dioxoisoindolin-2-pentyl-4-enoate (0.15 mmol, 36.8 mg), and Ir(ppy)3 (0.001 mmol, 0.6 mg) were added to a 10 mL reaction tube equipped with a magnetic stirrer, followed by 1.0 mL of acetonitrile. Under inert gas, the reaction tube was fixed on a magnetic stirrer and irradiated with 460 nm light for 12 hours. Then, 5 mL of 1 M sodium hydroxide solution was added, and the mixture was extracted with methyl tert-butyl ether (3 × 5 mL). The solvent was removed by vacuum evaporation, and the crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain the desired product (3 g) in a 70% yield. The NMR data of compound (3 g) are as follows:

[0066] 1 H NMR (600MHz, CDCl3) δ7.24(d,J=7.5Hz,1H),6.90(d,J=7.5Hz,1H),6.72(s,1H),5. 77–5.67(m,1H),5.10–5.07(m,1H),5.06(t,J=1.3Hz,1H),3.72–3.68(m,2H),3.63( d,J=14.5Hz,1H),3.50(d,J=14.5Hz,1H),2.81(td,J=7.4,4.2Hz,2H),2.50–2.44(m ,2H),2.39(s,3H),1.68(t,J=5.7Hz,2H),1.45–1.38(m,5H),0.97(t,J=7.4Hz,3H);

[0067] 13 C NMR (151MHz, CDCl3) δ178.1,142.8,139.1,133.9,127.6,123.5,123.0,117.3,109.9,58.7,54.3,45.3,40.1,29.3,25.9,25.5,22.0,20.2,13.8.

[0068] The present invention utilizes the SO2 group within the molecule to achieve a light-induced self-circulating Truce–Smiles rearrangement reaction of sulfur dioxide, directly constructing a double C-S bond, providing a novel synthetic method for the preparation of sulfone-based oxidized indole compounds. The present invention has the following advantages:

[0069] (1) This invention pioneers a light-induced intramolecular SO2 self-circulation mechanism, triggering the Truce–Smiles rearrangement through visible light to simultaneously construct a double C-S bond without the need for exogenous SO2 or oxidants, effectively shortening the synthesis steps of sulfone oxidized indole compounds;

[0070] (2) The raw materials used in the present invention, methacrylamide and NHPI ester, are cheap and readily available, simple to operate, and do not require heating, which is conducive to industrial production;

[0071] (3) The present invention achieves a qualitative leap in added value by converting cheap carboxylic acid derivatives into sulfone oxidized indole compounds, and has broad economic prospects.

[0072] The above description is merely a preferred embodiment of the present application and is not intended to limit the present application. Various modifications and variations are possible for those skilled in the art. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present application shall be included within the scope of protection of the present application.

Claims

1. A synthetic method for preparing a sulfone oxidized indole compound, characterized in that: Sulfone oxidized indole compounds were synthesized by using Ir(ppy)3 catalyst and 460-465nm light conditions, by utilizing the in situ capture of free radical SO2 and the synergistic strategy of Truce–Smiles rearrangement.

2. The method for synthesizing the sulfone oxidized indole compound according to claim 1, wherein the reaction equation is: In formula (1), R 1 is a methyl, methoxy, or chlorine substituent, R 2 is a n-butyl or cyclohexyl substituent, in formula (2), R 3 is a cyclohexyl, propyl, n-hexyl, or butenyl substituent; The synthesis process of the compound represented by formula (3) is as follows: dissolving the compound represented by formula (1) (2) and Ir(ppy)3 in a solvent, reacting under light conditions to generate the compound represented by formula (3); The solvent is an aprotic solvent and does not include an ether solvent; In the reaction system, the molar ratio of the compound represented by formula (1), the compound represented by formula (2), and Ir(ppy)3 is 1:1.5:0.01; The reaction temperature was 25°C and the reaction time was 12 h.

3. The method for synthesizing the sulfone oxidized indole compound according to claim 2, wherein: In formulas (1) and (2), R 1 Selected from the phenyl para position, R 2 , R 3 Selected from alkyl groups.

4. The method for synthesizing a sulfone oxidized indole compound according to any one of claims 1 to 2, characterized in that: The illumination wavelength range is 460-465nm.

5. The method for synthesizing a sulfone oxidized indole compound according to any one of claims 1 to 2, characterized in that: The solvent is any one of dimethyl sulfoxide, acetonitrile and ethyl acetate.

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