Preparation method of 2-(4-toluenemethyl)-3-toluenesulfonyl benzofuran derivative

Abstract

The invention provides a preparation method of a 2-(4-toluene methyl)-3-toluene sulfonyl benzofuran derivative, and belongs to the technical field of heterocyclic compounds. Lewis acid, o-hydroxyphenyl propargyl amine and sodium sulfinate are added into an organic solvent, a reaction is carried out for 14 hours at the temperature of 80 DEG C, and the 2-(4-toluene methyl)-3-toluene sulfonyl benzofuran derivative is obtained through aftertreatment. The preparation method is simple and convenient to operate, the initial raw materials are cheap and easy to obtain, the reaction efficiency is high, the substrate compatibility is good, and the 2-(4-toluenemethyl)-3-toluenesulfonyl benzofuran derivative can be efficiently and rapidly synthesized in one step.

Description

Technical Field

[0001] The present application relates to a method for preparing a 2-(4-methylphenylmethyl)-3-toluenesulfonylbenzofuran derivative, and belongs to the technical field of heterocyclic compounds. Background Art

[0002] Benzofurans are an important class of structural skeletons, widely found in natural products and pharmaceutical molecules, and possess diverse biological activities (J. Nat. Prod. 1998, 61, 351-353; Bioorg. Med. Chem. 2018, 28, 947-951). For example, compound I exhibits antibacterial activity, compound II exhibits anti-inflammatory, antipyretic, and analgesic activities; compound (III) is an acetylcholinesterase (AChE) inhibitor and a potential drug for the treatment of Alzheimer's disease (AD); compound IV is an angiotensin II antagonist and a potential drug for the treatment of hypertension; SeBZF1 can inhibit depression and memory impairment caused by SD; and compound VI can inhibit human chondrosarcoma.

[0003]

[0004] Lewis acid-catalyzed 5-exo-dig cyclization of propargylamine with sodium sulfinate provides an important method for directly and efficiently constructing 3-sulfonylbenzofuran skeletons (Med. Res. Rev. 2000, 20, 304-322), such as: One-Pot Transformation Strategy of o-Hydroxyphenyl Propargylamines for Modular Accessto 3-Functionalized Benzofurans (Mengdi Wu, et.al., Volume 367, Issue 2 January 21, 2025) in HCl (aq) and Ar 1 In the presence of SO2Na, the 5-exo-dig cyclization of o-hydroxyphenylpropargylamine (o-HPPA) gives C3-functionalized phenylated benzofuran, but the reaction is incompatible with some acid-sensitive groups, the reaction compatibility is not ideal, the reaction conditions are harsh, and the yield is low.

[0005] However, there have been no reports on the synthesis of 2-(4-methylphenylmethyl)-3-toluenesulfonylbenzofuran derivatives containing a 3-sulfonylbenzofuran skeleton based on the Lewis acid-catalyzed 5-exo-dig cyclization reaction, which poses a great limitation to the expansion and application potential of benzofuran derivatives. Summary of the Invention

[0006] In view of this, the present application provides a method for preparing 2-(4-methylphenylmethyl)-3-toluenesulfonylbenzofuran derivatives. The preparation steps are simple, and the resulting product, 2-(4-methylphenylmethyl)-3-toluenesulfonylbenzofuran derivatives, can simultaneously be compatible with multiple functional groups, have good reaction substrate compatibility, and have good applicability.

[0007] Specifically, this application is implemented through the following solutions:

[0008] A method for preparing a 2-(4-methylphenyl)-3-toluenesulfonylbenzofuran derivative comprises adding Lewis acid, o-hydroxyphenylpropargylamine and sodium sulfinate to an organic solvent, reacting at 80° C. for 14 to 22 hours, and after the reaction is complete, post-processing to obtain a 2-(4-methylphenyl)-3-toluenesulfonylbenzofuran derivative.

[0009] The structural formula of the o-hydroxyphenylpropargylamine (II) is:

[0010]

[0011] The structural formula of the sodium sulfite is:

[0012]

[0013] The structural formula of the 2-(4-methylphenylmethyl)-3-toluenesulfonylbenzofuran derivative (I) is:

[0014]

[0015] R 1 is any one of C1-C6 alkyl, C1-C6 alkoxy, nitro, and halogen; R is a substituted phenyl or an unsubstituted phenyl, wherein the corresponding substituent on the substituted phenyl is selected from any one of C1-C6 alkyl, C1-C6 alkoxy, and halogen;

[0016] The reaction equation of the above process is as follows:

[0017]

[0018] The above scheme uses o-hydroxyphenylpropargylamine and sodium sulfinate as starting materials. Under the action of Lewis acid, o-hydroxyphenylpropargylamine (o-HPPAs) generates o-acetylene benzoquinone (o-AQM) in situ; o-AQM then undergoes sulfur-Michael addition and 5-exo-dig cyclization with the sulfinate ion, and finally isomerizes under acidic conditions to obtain 2-(4-methylphenylmethyl)-3-toluenesulfonylbenzofuran derivatives.

[0019] Furthermore, as a preference:

[0020] The molar ratio of o-hydroxyphenylpropargylamine, sodium sulfinate, and Lewis acid is 2:3:1. During the material preparation process, the amount of organic solvent used should be sufficient to dissolve the raw materials. Therefore, the amount of organic solvent used corresponding to 0.2 mmol of o-hydroxyphenylpropargylamine is preferably controlled at approximately 1.0 mL.

[0021] The organic solvent is dichloromethane. At this time, various raw materials can be converted into products with a higher conversion rate.

[0022] The Lewis acid is scandium trifluoromethanesulfonate, which has a higher reaction efficiency among many Lewis acids.

[0023] 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 the corresponding 2-(4-methylphenylmethyl)-3-toluenesulfonylbenzofuran derivative. The column chromatography purification parameters can be set using conventional settings.

[0024] The 2-(4-methylphenylmethyl)-3-toluenesulfonylbenzofuran derivative is any one of the following structural formulas:

[0025]

[0026] In the above preparation method, Lewis acid and organic solvent are generally commercially available products and can be easily obtained from the market; o-hydroxyphenylpropargylamine can be quickly synthesized from corresponding raw materials such as benzaldehyde, tetrahydropyrrole, and terminal alkyne; sodium sulfinate can be synthesized in one step from sulfonyl chloride through a hydration reaction.

[0027] Compared with the prior art, the beneficial effects of the present invention are reflected in: the preparation method is easy to operate and the post-processing is simple; the reaction starting materials are cheap and easily available, the substrate functional group tolerance range is wide, the reaction efficiency is high, and the 2-(4-methylphenylmethyl)-3-toluenesulfonylbenzofuran derivative is synthesized efficiently and quickly in one step, which has strong practicality. DETAILED DESCRIPTION

[0028] In order to make the technical problems, technical solutions and beneficial effects to be solved by this application more clearly understood, the technical solutions of this application will be further described in detail below in conjunction with 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 making creative efforts are within the scope of protection of this application.

[0029] Example 1

[0030] In a 15 mL Schlenk tube equipped with a magnetic stirrer, 0.2 mmol of o-hydroxyphenylpropargylamine (II), 0.3 mmol of sodium sulfinate, 0.1 mmol of scandium trifluoromethanesulfonate, and 1.0 mL of an organic solvent, dichloromethane, were added, mixed and stirred evenly, and reacted at 80° C. for 14 hours. After the reaction was complete, the mixture was filtered, mixed with silica gel, and purified by column chromatography to obtain the corresponding 2-(4-methylphenylmethyl)-3-toluenesulfonylbenzofuran derivative (I).

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

[0032]

[0033] R 1 The substituents corresponding to R and the corresponding yields are shown in Table 1.

[0034] Table 1: Raw material addition amounts for different implementation schemes

[0035]

[0036]

[0037] The products obtained in Examples 1, 5, 8, 11, and 14 were used as representatives to confirm the structures of the corresponding products. The test results are as follows:

[0038] The nuclear magnetic resonance (NMR) of the 3-sulfonylbenzofuran derivative (I-1) prepared in Example 1 1 H NMR, 13 C NMR) detection data are:

[0039]

[0040] 1 H NMR (500MHz, CDCl3) δ7.93-7.87(m,1H),7.81(d,J=7.4Hz,2H),7.41(dd,J=4.9,4.1Hz,1H),7.38-7.20(m,9H),4.60(s,2H),2.37(s,3H).

[0041] 13 C NMR (126MHz, CDCl3) δ161.5,153.6,144.4,139.4,135.9,129.9,129.2,12 8.8,127.1,127.0,125.6,124.5,124.3,120.7,118.4,111.6,33.3,29.8.

[0042] The nuclear magnetic resonance (NMR) of the 3-sulfonylbenzofuran derivative (I-5) prepared in Example 5 1 H NMR, 13 C NMR, 19 F NMR) detection data are:

[0043]

[0044] 1 H NMR(500MHz, CDCl3)δ7.91-7.87(m,1H),7.81(dd,J=8.3,1.7Hz,2H),7.45-7.39(m,1H),7 .35-7.29(m,4H),7.25(d,J=8.3Hz,2H),6.99(t,J=8.6Hz,2H),4.55(s,2H),2.37(s,3H).

[0045] 13 C NMR (126MHz, CDCl3) δ163.1,161.2,161.1,153.6,144.5,139.4,131.6,131.6,130.8,13 0.7,130.0,126.9,125.7,124.6,124.2,120.7,118.5,115.7,115.6,111.6,32.5,21.6.

[0046] 19 F NMR (471MHz, CDCl3) δ-115.57,-115.58,-115.59.

[0047] Example 8 Preparation of 3-sulfonylbenzofuran derivative (I-8) NMR ( 1 H NMR, 13 C NMR) detection data are:

[0048]

[0049] 1 H NMR(500MHz, CDCl3)δ7.90-7.85(m,1H),7.79(d,J=8.3Hz,2H),7.59(d,J=8.3Hz,2H), 7.48-7.39(m,3H),7.35-7.31(m,2H),7.25(d,J=8.0Hz,2H),4.63(s,2H),2.38(s,3H). 13C NMR (126MHz, CDCl3) δ159.5,153.7,144.8,141.3,139.1,132.6,130.0,13 0.0,126.9,126.0,124.8,124.0,120.8,118.8,111.6,111.2,33.3,21.7.

[0050] The nuclear magnetic resonance (NMR) of the 3-sulfonylbenzofuran derivative (I-11) prepared in Example 11 1 H NMR, 13 CNMR) test data is:

[0051]

[0052] 1 H NMR (500MHz, CDCl3) δ7.92-7.85(m,3H),7.44-7.39(m,1H),7.35-7.27(m,2H),7.24(d,J=7.9 Hz,2H),7.12(d,J=7.8Hz,2H),6.90(d,J=8.9Hz,2H),4.56(s,2H),3.81(s,3H),2.34(s,3H).

[0053] 13 C NMR (126MHz, CDCl3) δ163.47,161.49,153.54,136.73,134.06,132.88,129.47,129.13, 129.05,125.48,124.39,124.31,120.59,118.58,114.44,111.55,55.69,32.86,21.14.

[0054] The nuclear magnetic resonance (NMR) of the 3-sulfonylbenzofuran derivative (I-14) prepared in Example 14 1 H NMR, 13 CNMR) test data is:

[0055]

[0056] 1 H NMR (500MHz, CDCl3) δ7.89-7.82(m,1H),7.74-7.66(m,2H),7.55-7.50(m,2H),7.46-7.41(m,1 H),7.35-7.29(m,2H),7.18(d,J=8.0Hz,2H),7.10(d,J=7.9Hz,2H),4.52(s,2H),2.33(s,3H).

[0057] 13 C NMR (126MHz, CDCl3) δ162.50,153.62,141.36,137.00,132.59,132.56,129.59,129.02, 128.55,128.43,125.80,124.72,124.16,120.49,117.52,111.77,32.96,29.85,21.21.

[0058] The above test results prove that the present invention achieves the preparation of 2-(4-methylphenylmethyl)-3-toluenesulfonylbenzofuran derivatives under mild conditions of 80°C. The different substituent compositions of the raw materials make the yield as low as 60% and as high as 98%, and more than half of the raw materials can guarantee a yield of more than 90%. The reaction conditions given in the present invention have high reaction efficiency, and the substrate functional group (R 1 , R) up to more than ten kinds, with a wide tolerance range, which effectively broadens the synthetic application of benzofuran derivatives.

[0059] The above-described embodiments merely represent several feasible implementation methods of the present invention. The description thereof is relatively specific and detailed, but it should not be understood as limiting the scope of the invention. The embodiments are not intended to limit the scope of protection in the claims of the present invention. For those skilled in the art, various modifications and improvements can be made without departing from the concept of the present invention. Any equivalent implementation or modification that does not depart from the scope of the present invention should be included in the technology of the present invention.

Claims

1. A method for preparing a 2-(4-methylphenyl)-3-toluenesulfonylbenzofuran derivative, characterized in that: Lewis acid, o-hydroxyphenylpropargylamine and sodium sulfinate are added to an organic solvent and reacted at 80°C to obtain a 2-(4-methylphenylmethyl)-3-toluenesulfonylbenzofuran derivative. The structural formula of the o-hydroxyphenyl propargylamine is: The structural formula of the sodium sulfite is: The structural formula of the 2-(4-methylphenylmethyl)-3-toluenesulfonylbenzofuran derivative is: R 1 Any one selected from C1~C6 alkyl, C1~C6 alkoxy, halogen, and nitro; R is a substituted phenyl group or an unsubstituted phenyl group, wherein the corresponding substituent on the substituted phenyl group is selected from any one selected from C1~C6 alkyl, C1~C6 alkoxy, and halogen.

2. The method for preparing a 2-(4-methylphenyl)-3-toluenesulfonylbenzofuran derivative according to claim 1, wherein: The molar ratio of o-hydroxyphenylpropargylamine, sodium sulfinate and Lewis acid is 2:3:

1.

3. The method for preparing a 2-(4-methylphenyl)-3-toluenesulfonylbenzofuran derivative according to claim 1, wherein: The organic solvent is dichloromethane.

4. A 2-(4-methylphenylmethyl)-3-toluenesulfonylbenzofuran derivative according to claim 1, characterized in that: The Lewis acid is scandium trifluoromethanesulfonate.

5. The method for preparing a 2-(4-methylphenyl)-3-toluenesulfonylbenzofuran derivative according to claim 1, wherein: The reaction time is 14 to 22 hours.

6. The method for preparing a 2-(4-methylphenylmethyl)-3-toluenesulfonylbenzofuran derivative according to claim 1, wherein: The product obtained by the reaction was filtered, mixed with silica gel, and purified by column chromatography to obtain a 2-(4-methylphenylmethyl)-3-toluenesulfonylbenzofuran derivative.

7. The method for preparing a 2-(4-methylphenylmethyl)-3-toluenesulfonylbenzofuran derivative according to any one of claims 1 to 6, characterized in that: The 2-(4-methylphenylmethyl)-3-toluenesulfonylbenzofuran derivative is any one of the following structural formulas:

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