Synthesis method of dihydrofuran derivative

Abstract

The invention relates to a synthesis method of a dihydrofuran derivative, and belongs to the technical field of chemical synthesis. The method comprises the following specific steps: taking beta-nitro aryl ethylene as shown in a formula I and acyl acetate as shown in a formula II as raw materials, taking Cs2CO3 / SiO2 as a catalyst, taking DMF (Dimethyl Formamide) as a reaction solvent, and synthesizing the dihydrofuran derivative as shown in a formula III through [3 + 2] cycloaddition reaction, the reaction time is 6-12 hours, and the reaction temperature is 110 DEG C. The invention has the following technical effects: the invention provides an efficient synthesis method, and the substituted 4, 5-dihydrofuran-3-carboxylic ester is prepared from substituted beta-nitrostyrene and acyl acetate in the presence of solid alkali Cs2CO3 / SiO2. The reaction is carried out in a DMF medium at 110 DEG C under mild reaction conditions, and a pure product is obtained at a relatively high yield. Thus, the method represents an attractive alternative for obtaining dihydrofuran derivatives.

Description

Technical Field

[0001] The invention relates to a method for synthesizing dihydrofuran derivatives, and belongs to the technical field of chemical synthesis. Background Art

[0002] Dihydrofuran is a unique structural unit found in many natural products, such as ascorbic acid, murranofuran A and higginsianins D. Dihydrofuran derivatives show significant pharmacological activity. For example, rofecoxib is widely used clinically as an anti-inflammatory drug, and amiodarone is used to treat heart disease and breast cancer. In addition, these functionalized dihydrofurans are widely studied as glucosidase inhibitors, anti-HIV, anticancer, anti-inflammatory, antibacterial and antifungal activities, antiviral, anti-candida, anticonvulsant and analgesic, and anti-Alzheimer's drugs. Dihydrofuran is also considered a special structural unit in agrochemicals, such as the selective herbicide furochloridone, the antifungal macrolide ketone and the antibiotic ronone.

[0003] In addition, dihydrofuran is used as an important oxygen heterocyclic compound intermediate in organic synthesis. Due to the importance of dihydrofuran derivatives in biology and medicine, many methods for the synthesis of dihydrofuran have been developed. In particular, the synthesis methods via [3+2] cycloaddition reactions have attracted widespread attention, including the reaction of classical olefins with oxygen-containing 1,3-dipoles, and the reaction of aldehydes or ketones with common 1,3-dipoles. Among them, there are many effective strategies for the synthesis of substituted dihydrofurans based on β-ketoester or β-ketosulfone substrates with various nitroolefins. β-Nitrostyrene, as a two-carbon building block, has been widely used in various [3+2] cycloaddition reactions to synthesize various compounds. In previous reports, many different carbocyclic and heterocyclic compounds were synthesized using β-nitrostyrene as an important raw material. In particular, in the synthesis of oxygen-containing heterocyclic compounds, β-nitrostyrene is an efficient building block for the domino reaction between β-nitrostyrene, naphthol, substituted benzaldehydes and ammonium acetate. Recently, β-nitroolefins have also been applied to the synthesis of polysubstituted dihydrofuran derivatives. Even based on the application of polysubstituted dihydrofuran derivatives in medicine, it is still necessary to develop a simpler and innovative method to synthesize functionalized dihydrofuran using readily available β-nitroolefins. From the perspective of sustainable development, [3+2] cycloaddition reaction, especially non-metal-catalyzed cycloaddition reaction, is an environmentally friendly reaction process and has great significance.

[0004] Existing synthesis methods of dihydrofuran derivatives mainly include the following:

[0005] 1) In 2001, the Evans research group of Harvard University used the scandium-bisoxazoline system to effectively catalyze the [3+2]-cycloaddition reaction of ethyl glyoxylate and silicon-based allene compounds, and constructed dihydrofuran compounds with a separation yield of up to 98% and an enantioselectivity of 89%. In the reaction, the use of trivalent scandium as a Lewis acid can complex with the carbonyl group of glyoxylate, enhance the electrophilicity of its receptor, and thus react more easily with allene (Evans, DA; Sweeney, ZK; Rovis, T.; Tedrow, JS, Highly Enantioselective Syntheses of Homopropargylic Alcohols and Dihydrofurans Catalyzed by a Bis(oxazolinyl)pyridine-scandium Triflate Complex, J. Am. Chem. Soc., 2001, 123, 12095-12096.). The specific reaction route is as follows:

[0006]

[0007] This method has the following disadvantages: the reaction needs to be carried out at -45°C and a trivalent scandium catalyst which is difficult to obtain is required, making it difficult to achieve industrial production.

[0008] 2) Huang Danfeng from Northwest Normal University used tin powder to promote the tandem allylation / oxa-Michael addition reaction of o-formyl chalcone and allyl bromide to synthesize 1,3-disubstituted-1,3-dihydroisobenzofuran with potential biological activity. This method has the advantages of short reaction time, simple operation and excellent yield (Tang Duoduo, Huang Danfeng, Wang Kehu, et al. Synthesis of 1,3-disubstituted-1,3-dihydroisobenzofuran compounds promoted by tin powder [J]. Organic Chemistry, 2023, 43(12): 4227-4238. DOI: 10.6023 / cjoc202304003.). The specific reaction route is as follows:

[0009]

[0010] This method has the following disadvantages: tin powder is used, wastewater is difficult to treat, and it has potential environmental hazards.

[0011] 3) Wang Yuanhua from the Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, used isopropylbenzene derivatives and β-dicarbonyl compounds as raw materials, sodium bicarbonate as base, rhodium catalyst and N-fluorobisbenzenesulfonamide catalytic system, and synthesized 12 dihydrofuran compounds through desaturation process and [3+2] cycloaddition process, with the yield up to 50%. (Liu Xinyu, Luo Like, Zhang Heqing, et al. Desaturation [3+2] cycloaddition reaction of isopropylbenzene and β-dicarbonyl compounds catalyzed by binuclear rhodium [J]. Synthetic Chemistry, 2024, 32(05): 400-405. DOI: 10.15952 / j.cnki.cjsc.1005-1511.23088.). The specific reaction route is as follows:

[0012]

[0013] This method has the following disadvantages: it requires the use of expensive rhodium catalysts, and the reaction yield is limited, making it unsuitable for industrial applications.

[0014] Based on the above problems, a new method for synthesizing dihydrofuran derivatives is provided. Summary of the invention

[0015] The purpose of the present invention is to overcome the deficiencies of the prior art and provide a method for synthesizing a dihydrofuran derivative.

[0016] Inspired by the discovery of β-nitroolefins in the prior art, the present invention proposes that the combination of β-nitroolefins and ketoesters under mild conditions can help to carry out [3+2] cyclization in an environmentally friendly manner. The present invention provides a Cs2CO3 / SiO2-catalyzed [3+2] cycloaddition reaction involving β-nitroarylethylene and β-acylacetate, thereby developing an efficient and diverse method for synthesizing functional dihydrofurans.

[0017] The invention discloses a method for synthesizing dihydrofuran compounds by [3+2] cycloaddition reaction catalyzed by Cs2CO3 / SiO2, and a series of dihydrofuran compounds are obtained by cycloaddition reaction of β-nitroarylethylene and β-acylacetic acid ester under non-metal catalytic conditions, mild reaction conditions and good product yield. The aromatic substituent groups include benzene, substituted benzene, furan, oxazole, thiophene, pyridine, 1,4-benzodioxane and the like.

[0018] The technical solution of the present invention is as follows:

[0019] The synthesis method of the dihydrofuran derivatives of the present invention has the following reaction scheme:

[0020]

[0021] The specific steps of the method are as follows: using β-nitroarylethylene as shown in formula I and acylacetate as shown in formula II as raw materials, using Cs2CO3 / SiO2 as a catalyst, and using DMF as a reaction solvent, synthesizing a dihydrofuran derivative as shown in formula III through a [3+2] cycloaddition reaction; the reaction time is 6-12 hours, and the reaction temperature is 110°C;

[0022] In formula I and formula III, Ar is selected from any one of the following groups:

[0023]

[0024] Ar in formula I and formula III is the same;

[0025] In formula II and formula III, R is methyl or phenyl; R in formula II and formula III is the same.

[0026] The solid line in the Ar group represents the actual chemical bond, and the dotted line represents the part of Formula III other than Ar, which is omitted.

[0027] Preferably,

[0028] In the method, the molar ratio of β-nitroarylethylene, acylacetic acid ester and catalyst is 1:1:0.2;

[0029] Preferably,

[0030] The acyl acetate shown in formula II is ethyl 3-oxobutyrate or ethyl 3-oxo-3-phenylpropionate.

[0031] The structural formula of ethyl 3-oxobutyrate is as follows:

[0032]

[0033] The structural formula of ethyl 3-oxo-3-phenylpropionate is as follows:

[0034]

[0035] Preferably,

[0036] The preparation method of the Cs2CO3 / SiO2 catalyst is as follows: Cs2CO3 and silica gel are mixed in water and stirred for 0.5 hours. Water is removed under reduced pressure distillation and the obtained solid is dried at 45°C for 6 hours. The weight volume ratio of Cs2CO3, silica gel and water is 15g:85g:20mL.

[0037] The present invention has the following technical effects:

[0038] The present invention provides an efficient synthesis method for preparing substituted 4,5-dihydrofuran-3-carboxylates starting from substituted β-nitrostyrene and acyl acetate in the presence of a solid base Cs2CO3 / SiO2. The reaction is carried out in a DMF medium at 110°C under mild reaction conditions and the pure product is obtained in good yield. Therefore, the method represents an attractive alternative for obtaining dihydrofuran derivatives. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 is the hydrogen nuclear magnetic resonance spectrum of compound 3a.

[0040] Figure 2 is the carbon NMR spectrum of compound 3a.

[0041] Figure 3 is the hydrogen NMR spectrum of compound 3b.

[0042] Figure 4 is the carbon NMR spectrum of compound 3b.

[0043] Figure 5 is the H NMR spectrum of compound 3c.

[0044] Figure 6 is the carbon NMR spectrum of compound 3c.

[0045] Figure 7 is the H NMR spectrum of compound 3d.

[0046] Figure 8 is the carbon NMR spectrum of compound 3d.

[0047] Fig. 9 is the hydrogen NMR spectrum of compound 3e.

[0048] Fig.10 is the carbon NMR spectrum of compound 3e.

[0049] Fig.11 is the H NMR spectrum of compound 3f.

[0050] Fig.12 is the carbon NMR spectrum of compound 3f.

[0051] Fig.13 This is the hydrogen NMR spectrum of compound 3g.

[0052] Fig.14 This is the carbon NMR spectrum of compound 3g.

[0053] Fig.15 is the H NMR spectrum of compound 3h.

[0054] Fig.16is the carbon NMR spectrum of compound 3h.

[0055] Fig.17 is the H NMR spectrum of compound 3i.

[0056] Fig.18 is the carbon NMR spectrum of compound 3i.

[0057] Fig.19 is the H NMR spectrum of compound 3j.

[0058] Fig. 20 is the carbon NMR spectrum of compound 3j.

[0059] Fig.21 This is the hydrogen NMR spectrum of compound 3k.

[0060] Fig. 22 is the carbon NMR spectrum of compound 3k.

[0061] Fig.23 is the hydrogen NMR spectrum of compound 3l.

[0062] Fig.24 is the carbon NMR spectrum of compound 3l.

[0063] Fig.25 This is the hydrogen NMR spectrum of compound 3m.

[0064] Fig.26 is the carbon NMR spectrum of compound 3m.

[0065] Fig. 27 is the hydrogen NMR spectrum of compound 3n.

[0066] Fig.28 is the carbon NMR spectrum of compound 3n. DETAILED DESCRIPTION

[0067] In order to make the purpose, technical solutions and advantages of the present invention more clear, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments.

[0068] The detection method and materials involved in the present invention are described as follows:

[0069] Recorded in a Bruker AV-400 spectrometer 1 H NMR (400 MHz) and 13 C NMR (100 MHz) spectra with tetramethylsilane (δ=0 ppm) as internal standard in CDCl3 solution. J values ​​are given in Hertz.

[0070] IR spectra were collected in a Nicolet FT-IR 5DX spectrometer and the samples were loaded in neat form.

[0071] High resolution ESI mass spectra were obtained on a UHR-TOF Maxis (ESI) mass spectrometer. Flash chromatography was performed on silica gel (230-400 mesh) eluting with ethyl acetate-hexane mixtures. All reactions were monitored by thin layer chromatography (TLC).

[0072] All reagents and solvents were purchased from commercial suppliers and purified by standard techniques.

[0073] Na2CO3 / SiO2 or K2CO3 / SiO2 (15%) was prepared by the reported method: A mixture of 15 g Na2CO3 or K2CO3 in 20 ml water and 85 g silica gel was stirred at room temperature for 0.5 h. Water was removed by rotary evaporator under reduced pressure, and the resulting solid was dried in vacuum at 45°C for 6 hours.

[0074] The Cs2CO3 / SiO2 catalyst was prepared as follows: 15 g of Cs2CO3 and 85 g of silica gel were mixed in 20 mL of water and stirred for 0.5 h. The water was removed under reduced pressure distillation and the resulting solid was dried at 45°C for 6 h.

[0075] Example 1 Screening of reaction conditions

[0076] Using (E)-1-methoxy-4-(2-nitrovinyl)benzene (1a) and ethyl 3-oxobutanoate (2a) as substrates, various reaction conditions were studied to optimize the synthesis of ethyl 4-(4-methoxyphenyl)-2-methyl-4,5-dihydrofuran-3-carboxylate (3a) (see Table 1).

[0077] The synthetic route is as follows:

[0078]

[0079] Synthesis method steps: First, (E)-1-methoxy-4-(2-nitrovinyl)benzene (1a) and ethyl 3-oxobutyrate (2a) were treated with Et3N in DMF at 110°C overnight, wherein the molar ratio of 1a, 2a to Et3N was 1:1:0.2, to prepare dihydrofuranate 3a with a yield of 5% (see Table 1, item 1). The reaction conditions for synthesizing 3a were optimized according to Table 1.

[0080] Table 1. Optimized reaction conditions for the synthesis of 3a

[0081]

[0082]

[0083] All reactions were carried out with (E)-1-methoxy-4-(2-nitrovinyl)benzene (1a, 179 mg, 1.0 mmol), ethyl 3-oxobutanoate (2a) and a base in 10.0 mL of solvent.

[0084] In order to efficiently form dihydrofuran ester 3a, various bases were tested (see Table 1, items 2-7). Among the screened bases, the reaction was completed in DMF in the presence of DABCO and DBU (see Table 1, items 2-3), and the product 3a was obtained with a yield of 62% and 70%, respectively. Using inorganic bases Cs2CO3 and K2CO3, dihydrofuran ester 3a was also obtained with a yield of 51% and 50%, respectively (see Table 1, items 4 and 5). In the next reaction, a solid base (15% Cs2CO3 / SiO2) was used for the cyclization reaction. The reaction was vigorously carried out at 110°C for 8 hours, and 3a was isolated with a yield of 91% (item 6). Cs2CO3 / SiO2 was replaced with K2CO3 / SiO2, and 3a was obtained with a yield of 82% after 8 hours at 110°C (item 7). The above results show that Cs2CO3 (15%) / SiO2 has the highest efficiency and can prepare 3a with a yield of 91% (see Table 1, item 6). Among various solvents, only DMF shows an increase in yield (see Table 1, items 6, 8-10). As solvents, low-boiling THF, PhMe and EtOH are not favorable for the reaction (see Table 1, items 8, 9 and 10). When the reaction is carried out at 120°C, the yield of 3a decreases (see Table 1, item 11). When the amount of Cs2CO3 / SiO2 used is reduced to 0.15 equivalents, the product yield decreases slightly (see Table 1, item 12), and further increasing the amount of Cs2CO3 / SiO2 has no obvious contribution (see Table 1, item 13). When the amount of ethyl 3-oxobutyrate (2a) is increased to 1.5 or 2.0 equivalents, the product yield does not improve significantly (see Table 1, items 14-15).

[0085] The molecular structure of dihydrofuranate 3a was elucidated by its spectral analysis. In the infrared (IR) spectrum, the -1 The sharp absorption band at is attributed to the C(3)-CO2Et stretching frequency. The mass spectrum of 3a shows m / z = 285.1117 [M+Na] + The molecular ion peak of 3a is consistent with the proposed structure. 1 The H nuclear magnetic resonance (NMR) spectrum showed two pairs of non-identical dihydrofuran protons at 4.64 ppm (1H) and 4.24 ppm (2H) doublets-triplets. The 1H chemical shifts were consistent with the protons in the dihydrofuran carboxylate 3a. 1 H-decoupling 13The C NMR spectrum showed 13 different signals, including a group of ethyl ester signals consistent with the proposed structure. A CO2Et group and a methyl group on the dihydrofuran ring appeared at 168.8, 59.2, 14.3, and 14.5 ppm, respectively, and a methoxy group on the aromatic ring appeared at 55.4 ppm.

[0086] After obtaining the optimal reaction conditions, we turned our attention to the substrate scope of the reaction (see Table 2). The reaction tolerates a variety of substituents on the phenyl ring of the β-nitrostyrene substrate, including electron-donating groups such as MeO, Me and electron-withdrawing groups such as Br, Cl. The results show that β-nitrostyrenes with Br and Cl substituents are slightly unfavorable compared to β-nitrostyrenes with electron-donating groups such as MeO, Me on the phenyl ring (see Table 2, compare 3a with 3d, 3l with 3m). The reaction is tailored to the position of the substituents on the aromatic ring, and the yields of para-substituted β-nitrostyrenes are slightly higher than those of meta- and ortho-substituted substrates, resulting in good yields of products 3a, 3d, 3l, and 3m. Multi-substituted β-nitrostyrenes are also well tolerated, giving products 3h and 3i in good yields. In addition, heteroatom-containing nitroethylene such as (E)-3-(2-nitrovinyl)furan and (E)-2-(2-nitrovinyl)thiophene were also converted to products 3g and 3j.

[0087] Synthesis of 4,5-dihydrofuran-3-carboxylates (3a-3n) via [3+2] cyclization of β-nitroarylethylenes (1a-1n) and acylacetic acid esters (ethyl 3-oxobutyrate 2a or ethyl 3-oxo-3-phenylpropionate 2b)

[0088]

[0089] The reaction materials and reaction conditions for the synthesis of products 3a-n are shown in Table 2:

[0090] Table 2:

[0091]

[0092] The structural formulas of products 3a-3n are as follows:

[0093]

[0094] All reactions were carried out with substituted β-nitroarylethylenes (1a-1n, 1 mmol), plus ethyl 3-oxobutyrate 2a or ethyl 3-oxo-3-phenylpropionate 2b (1 mmol) and catalyst Cs2CO3 / SiO2 (15%, 435 mg, 0.2 mmol) in 10.0 mL DMF at 110°C.

[0095] On the basis of these studies, a plausible mechanism is proposed in Scheme 1. First, the proton is removed from the α-position of the acylacetate 2a-b to give intermediate A, which then undergoes aza-Michael addition to the β-nitroarylethene 1a-n to give intermediate B. Next, intermediate B undergoes resonance to gain a proton to form intermediate C. Tautomerization of intermediate C gives enolate intermediate D, which undergoes intramolecular nucleophilic attack on the electron-deficient carbon of the nitrogen-carbon double bond to give dihydrofuran intermediate E. Finally, nitrous acid is removed to give the desired products 3a-n.

[0096] Example 2

[0097] According to the optimization results of Example 1, the method for synthesizing substituted 4,5-dihydrofuran-3-carboxylates 3a-n is as follows:

[0098] To a mixture of substituted β-nitroarylethylene (i.e., 1a-1n, same as in Example 1, 1.0 mmol), and ethyl 3-oxobutyrate (2a) or ethyl 3-oxo-3-phenylpropionate (2b) (1.0 mmol) in DMF (10.0 mL), Cs2CO3 / SiO2 (15%, 435 mg, 0.2 mmol) was added. The mixture was stirred at 110°C in an oil bath for 6-12 h. After the reaction was completed (monitored by TLC, EtOAc / hexane, 1 / 4, silica gel), the solid base was removed by filtration, and then the solvent was removed by distillation under reduced pressure. Water (10.0 mL) was added to the residue, and the resulting mixture was extracted with ethyl acetate (2×10 mL). Then, the combined ethyl acetate layer was washed with water (10 mL) and brine (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (EtOAc / hexane, 1 / 20, silica gel) to afford the desired products 3a-n.

[0099] The reaction materials and reaction conditions for the synthesis of products 3a-n are shown in Table 3:

[0100]

[0101] The detection data of products 3a-n are as follows:

[0102] 3a: 4-(4-methoxyphenyl)-2-methyl-4,5-dihydrofuran-3-carboxylic acid ethyl ester, yellow oil 239 mg, yield: 91%; 1H NMR (400MHz, CDCl3) δ (ppm): 7.09 (d, J = 8.8Hz, 2H), 6.79 (d, J = 8.8Hz, 2H), 4.64 (dt, J1 = 4.4Hz, J2 = 11.6Hz, 1H ),4.24(dt,J1=4.4Hz,J2=11.6Hz,,2H),4.04-3.94(m,2H),3.71(s,3H),2.28(s,3H),1.08(t,J=6.8Hz;3H); 13 C NMR (100MHz, DMSO-d6) δ (ppm): 168.8, 165.1, 158.3, 136.6, 128.4, 114.1, 107.3, 78.8, 59.2, 55.4, 47.0, 14.5, 14.3; IR (KBr, cm -1 )ν:2980,1697,1642,1512,1465,1383,1315,1279,1246,916; HR-MS(ESI)calcd.for C 15 H 18 NaO4[(M+Na) + ]:285.1103; found:285.1117.(3a compound CAS:1609547-35-4)

[0103] 3b: 4-(3-methoxyphenyl)-2-methyl-4,5-dihydrofuran-3-carboxylic acid ethyl ester, yellow oil, 250 mg, yield: 88%; 1 H NMR (400MHz, CDCl3) δ (ppm): 7.20 (dd, J = 7.6Hz and 8.8Hz, 1H), 6.80 (d, J = 7.6Hz, 1H), 6.75-6.73 (m, 2H), 4.70 (dd, J = 9.6Hz and 8.8Hz,2H),4.32-4.24(m,2H),4.06-3.96(m,2H),3.78(s,3H),2.31(d,J=1.2Hz,3H),1.09(t,J=7.2Hz;3H); 13 C NMR (100MHz, CDCl3) δ (ppm): 170.1, 166.0, 156.7, 132.0, 127.6, 127.3, 120.4, 110.2, 104.8, 78.1, 59.2, 55.4, 41.3, 14.3, 14.2; IR (KBr, cm -1)ν:2980,2837,1698,1642,1602,1490,1384,1315,1255,777,702; HR-MS(ESI)calcd.for C 15 H 18 NaO4[(M+Na) + ]:285.1103;found:285.1118.

[0104] 3c: 4-(2-methoxyphenyl)-2-methyl-4,5-dihydrofuran-3-carboxylic acid ethyl ester, yellow oil, 256 mg, yield: 90%; 1 H NMR (400MHz, CDCl3) δ (ppm): 7.18 (dd, J=8.0Hz and 1.6Hz, 1H), 7.03 (dd, J=7.6Hz and 1.6Hz, 1H), 6.87 (dd, J=7.6Hz and 7.6Hz,1H),6.84(d,J=8.4Hz,1H),4.73-4.65(m,2H),4.16-4.15(m,1H),4.09-3.98(m,2H),3.81(s,3H),2.31(s,3H),1.07(t,J=6.8Hz;3H); 13 C NMR (100MHz, CDCl3) δ (ppm): 169.2, 165.6, 159.7, 145.8, 129.4, 119.6, 113.0, 107.1, 59.3, 55.1, 48.3, 14.2, 13.1; IR (KBr, cm -1 )ν:2979,2838,1698,1641,1491,1285,1170,1133,753; HR-MS(ESI)calcd.for C 15 H 18 NaO4[(M+Na) + ]:285.1103; found:285.1127.

[0105] 3d: 4-(4-bromophenyl)-2-methyl-4,5-dihydrofuran-3-carboxylic acid ethyl ester, yellow oil, 296 mg, yield: 89%; 1 H NMR (400MHz, CDCl3) δ (ppm): 7.39 (d, J = 8.4Hz, 2H), 7.07 (d, J = 8.4Hz, 2H), 4.69 (t, J = 1 1.2Hz,1H),4.28-4.23(m,2H),4.06-3.94(m,2H),2.29(s,3H),1.08(t,J=6.8Hz;3H); 13C NMR (100MHz, CDCl3) δ (ppm): 169.4, 164.4, 143.2, 131.5, 128.9, 120.5, 107.0, 78.2, 59.7, 47.9, 14.2, 14.1; IR (KBr, cm -1 )ν:2980,1698,1642,1487,1104,1079,1010,990,966,780,718; HR-MS(ESI)calcd.for C 14 H 15 BrNaO3[(M+Na) + ]:333.0103; found:333.0097.(3d compound CAS:1268355-91-4)

[0106] 3e: 4-(3-bromophenyl)-2-methyl-4,5-dihydrofuran-3-carboxylic acid ethyl ester, yellow oil, 306 mg, yield: 87%; 1 H NMR (400MHz, CDCl3) δ (ppm): 7.34-7.32 (m, 2H), 7.17-7.11 (m, 2H), 4.70 (t, J = 9.6 Hz,1H),4.31-4.27(m,2H),4.09-3.94(m,2H),2.31(s,3H),1.08(t,J=6.8Hz;3H); 13 CNMR (100MHz, CDCl3) δ (ppm): 169.6, 165.4, 146.5, 130.3, 130.0, 129.8, 125.9, 122.5, 106.9, 78.2, 59.4, 48.0, 14.2, 14.1; IR (KBr, cm -1 )ν:2980,1699,1642,1430,1384,1253,1203,992,920; HR-MS(ESI)calcd.for C 14 H 15 BrNaO3[(M+Na) + ]:333.0103; found:333.0099.

[0107] 3f: 4-(2-bromophenyl)-2-methyl-4,5-dihydrofuran-3-carboxylic acid ethyl ester, yellow oil, 273 mg, yield: 82%; 1H NMR (400MHz, CDCl3) δ (ppm): 7.52 (d, J = 8.8Hz, 1H), 7.23 (dd, J = 7.6Hz and 7.6Hz, 1H), 7.13 (dd, J = 1.6Hz and 8.0Hz,1H),7.08-7.04(m,1H),4.83-4.75(m,1H),4.17-4.15(m,1H),4.07-3.97(m,2H),2.32(s,3H),1.06(t,J=6.8Hz;3H); 13 C NMR (100MHz, CDCl3) δ (ppm): 170.6, 165.5, 142.9, 132.6, 128.2, 128.0, 127.6, 123.8, 105.3, 77.7, 59.4, 47.2, 14.3, 14.1; IR (KBr, cm -1 )ν:2980,1699,1641,1467,1439,1384,1315,1206,1082,756; HR-MS(ESI)calcd.for C 14 H 15 NaO3[(M+Na) + ]:333.0103; found:333.0097.

[0108] 3g: 5-methyl-2,3-dihydro-[3,3'-bifuran]-4-carboxylic acid ethyl ester, yellow oil, 218 mg, yield: 89%; 1 H NMR (400MHz, CDCl3) δ (ppm): 7.31 (d, J = 2.4Hz, 1H), 7.26 (s, 1H), 6.27 (s, 1H), 4.57 (t, J =9.6Hz,1H),4.29-4.21(m,2H),4.15-4.01(m,2H),2.23(s,3H),1.16(t,J=7.6Hz;3H); 13 CNMR (100MHz, CDCl3) δ (ppm): 168.9, 165.6, 143.0, 138.9, 127.4, 109.3, 106.3, 77.4, 59.4, 38.6, 14.2 (2C); IR (KBr, cm -1 )ν:2982,1697,1642,1384,1317,1108,1023,982,935,779,728; HR-MS(ESI)calcd.for C 12 H 14 NaO4[(M+Na) +]:245.0790; found:245.0784.(3g compound CAS:2703113-99-7)

[0109] 3h: 4-(2,4-dichlorophenyl)-2-methyl-4,5-dihydrofuran-3-carboxylic acid ethyl ester, yellow oil, 281 mg, yield: 90%, 1 H NMR (400MHz, CDCl3) δ (ppm): 7.36 (d, J = 2.0Hz, 1H), 7.17 (dd, J = 2.0Hz and 8.4Hz, 1H), 7.06 (d, J = 8.4Hz, 1H), 4.79-4.72 (m, 2H), 4.14 (dd, J = 11.2Hz and 16.0Hz,1H),4.09-3.97(m,2H),2.32(s,3H),1.08(t,J=7.2Hz,3H); 13 C NMR (100MHz, CDCl3) δ (ppm): 170.8, 165.3, 139.9, 133.8, 132.9, 132.8, 128.9, 127.3, 104.8, 77.4, 59.5, 44.2, 14.3, 14.2; IR (KBr, cm -1 )ν:2981,1701,1643,1470,1387,1315,1206,1083,991,866; HR-MS(ESI)calcd.for C 14 H 14 Cl2NaO3[(M+Na) + ]:323.0218;found:323.0222.

[0110] 3i: 4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-phenyl-4,5-dihydrofuran-3-carboxylic acid ethyl ester, yellow oil, 323 mg, yield: 80%; 1 HNMR (400MHz, CDCl3) δ (ppm): 7.83 (d, J = 7.2Hz, 2H), 7.46-7.38 (m, 3H), 6.81-6.76 (m, 3H), 4. 83-4.77(m,1H),4.44-4.38(m,2H),4.23(s,4H),4.00(q,J=7.2Hz,2H),1.05(t,J=7.2Hz,3H); 13C NMR (100MHz, CDCl3) δ (ppm): 165.9, 164.9, 143.5, 142.4, 137.4, 130.5, 129.9, 129. 5,127.6,120.2,117.2,115.9,107.6,78.1,64.4,64.3,59.6,49.2,14.0; IR(KBr,cm -1 )ν:2980,2878,1697,1625,1594,1439,1287,1200,1125,1071,765,694; HR-MS(ESI)calcd.for C 21 H 20 NaO5[(M+Na) + ]:375.1209; found:375.1218.

[0111] 3j: 2-phenyl-4-(thiophen-2-yl)-4,5-dihydrofuran-3-carboxylic acid ethyl ester, yellow oil, 297 mg, yield: 92%; 1 H NMR (400MHz, CDCl3) δ (ppm): 7.84 (d, J = 7.6Hz, 2H), 7.48-7.39 (m, 3H), 7.18 (dd, J = 1.2Hz and 4.8Hz,1H),6.97-6.94(m,2H),4.84-4.77(m,2H),4.53(dd,J=16.0Hz and10.4Hz,1H),4.10-4.03(m,2H),1.09(t,J=7.2Hz,3H); 13 C NMR (100MHz, CDCl3) δ (ppm): 166.2, 164.6, 147.5, 130.7, 129.6, 129.5, 127.7, 126.9, 123.9, 123.8, 107.4, 77.8, 59.8, 44.9, 14.0; IR (KBr, cm -1 )ν:3068,2980,2897,1701,1625,1372,1329,1294,1193,999,764,695; HR-MS(ESI)calcd.for C 17 H 16 NaO3S[(M+Na) + ]:323.0718; found:323.0732.(3j compound CAS:1609547-42-3)

[0112] 3k: 2-phenyl-4-(o-tolyl)-4,5-dihydrofuran-3-carboxylic acid ethyl ester, yellow oil, 278 mg, yield: 89%; 1 H NMR (400MHz, DMSO-d6) δ (ppm): 7.90-7.89 (m, 2H), 7.45-7.42 (m, 3H), 7.29 (d, J = 7.2Hz, 1H), 7.19-7. 12(m,3H),4.93-4.82(m,2H),4.39-4.35(m,1H),4.03-3.97(m,2H),2.44(s,3H),1.03-0.99(m,3H); 13 C NMR (100MHz, CDCl3) δ (ppm): 166.4, 164.9, 142.3, 135.2, 130.6, 130.2, 129.9, 129.5 (2C),127.7(2C),126.6(2C),126.5,107.3,77.6,59.6,45.4,19.8,13.9; IR(KBr,cm -1 )ν:2979,1700,1627,1599,1492,1371,1215,1087,1030,727,589; HR-MS(ESI)calcd.for C 20 H 20 NaO3[(M+Na) + ]:331.1310; found:331.1320.

[0113] 3l: 2-phenyl-4-(p-tolyl)-4,5-dihydrofuran-3-carboxylic acid ethyl ester, yellow oil, 308 mg, yield: 93%; 1 HNMR(400MHz,DMSO-d6)δ(ppm):7.91(d,J=7.6Hz,2H),7.64-7.57(m,3H),7.30( d,J=8.4Hz,2H),7.27(d,J=8.4Hz,2H),4.99(t,J=9.2Hz,1H),4.60(dd,J=4.8Hz and10.0Hz,1H),4.48(dd,J=4.8Hz and 10.0Hz,1H),4.02(q,J=7.2Hz,3H),2.41(s,3H),1.08(t,J=7.2Hz,3H); 13C NMR (100MHz, DMSO-d6) δ (ppm): 170.4, 169.1, 146.1, 140.9, 135.8, 134.8, 134.4, 134.3, 132.1, 132.0, 112.5, 83.0, 64.3, 53.8, 25.8, 18.9; IR (KBr, cm -1 )ν:2980,1700,1626,1370,1328,1229,1200,1026,764,694; HR-MS(ESI)calcd.forC 20 H 20 NaO3[(M+Na) + ]:331.1310; found:331.1317.

[0114] 3m: 4-(4-chlorophenyl)-2-phenyl-4,5-dihydrofuran-3-carboxylic acid ethyl ester, yellow oil, 305 mg, yield: 87%; 1 H NMR (400MHz, CDCl3) δ (ppm): 7.88-7.86 (m, 2H), 7.48-7.40 (m, 3H), 7.29 (d, J = 8.8Hz, 2H), 7.25 (d, J = 8.8Hz, 2H), 4.85 (t, J = 9.2Hz, 1H), 4.49 (dd, J = 4.8Hz and 9.6Hz,1H),4.43(dd,J=4.8Hz and 9.6Hz,1H),4.01(q,J=7.2Hz,2H),1.04(t,J=7.6Hz,3H); 13 CNMR (100MHz, CDCl3) δ (ppm): 166.3, 164.6, 142.6, 132.6, 130.8, 129.5, 128.7, 127.7, 107.4, 77.8, 59.7, 59.7, 49.4, 47.8, 14.0; IR (KBr, cm -1 )ν:2981,2890,1700,1627,1447,1229,1088,1015,694,641; HR-MS(ESI)calcd.for C 19 H 17 ClNaO3[(M+Na) + ]:351.0764; found:351.0771.

[0115] 3n: 4-(3-chlorophenyl)-2-phenyl-4,5-dihydrofuran-3-carboxylic acid ethyl ester, yellow oil, 315 mg, yield: 90%; 1H NMR (400MHz, CDCl3) δ (ppm): 7.89-7.86 (m, 2H), 7.47-7.41 (m, 3H), 7.31 (d, J = 1.6Hz, 1H), 7.25 -7.20(m,3H),4.89-4.82(m,1H),4.52-4.45(m,2H),4.05-4.97(m,2H),1.04(t,J=7.2Hz,3H); 13 C NMR (100MHz, CDCl3) δ (ppm): 166.5, 164.6, 146.1, 134.3, 130.8, 129.9, 129.5 ,127.7,127.5,127.4,127.1,125.5,107.1,77.6,59.8,49.7,14.0; IR(KBr,cm -1 )ν:2980,1700,1625,1625,1370,1330,1228,1200,1028,764,695; HR-MS(ESI)calcd.for C 19 H 17 ClNaO3[(M+Na) + ]:351.0764; found:351.0774.

[0116] The above are only embodiments of the present invention, and are not intended to limit the patent scope of the present invention. Any equivalent transformations made using the contents of the present invention specification, or directly or indirectly applied in other related technical fields, are also included in the patent protection scope of the present invention.

Claims

1. A method for synthesizing a dihydrofuran derivative, characterized in that: The reaction route is as follows: The specific steps of the method are as follows: using β-nitroarylethylene as shown in formula I and acylacetate as shown in formula II as raw materials, using Cs2CO3 / SiO2 as a catalyst, and using DMF as a reaction solvent, synthesizing a dihydrofuran derivative as shown in formula III through a [3+2] cycloaddition reaction; the reaction time is 6-12 hours, and the reaction temperature is 110°C; In formula I and formula III, Ar is selected from any one of the following groups: Ar in formula I and formula III is the same; In formula II and formula III, R is methyl or phenyl; R in formula II and formula III is the same.

2. The synthesis method according to claim 1, characterized in that The molar ratio of the beta-nitroarylethylene, acylacetic acid ester and catalyst is 1:1:0.

2.

3. The synthesis method according to claim 1, characterized in that The acyl acetate represented by formula II is ethyl 3-oxobutyrate or ethyl 3-oxo-3-phenylpropionate; The structural formula of ethyl 3-oxobutyrate is as follows: The structural formula of ethyl 3-oxo-3-phenylpropionate is as follows:

4. The synthesis method according to claim 1, characterized in that The preparation method of the Cs2CO3 / SiO2 catalyst is as follows: Cs2CO3 and silica gel are mixed in water and stirred for 0.5h; water is removed under reduced pressure distillation and the obtained solid is dried at 45°C for 6h, and the weight volume ratio of Cs2CO3, silica gel and water is 15g:85g:20mL.

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