5-(1h-indol-1-yl)-dihydrofuran-2-(3h)-ones and methods for their synthesis

Abstract

This invention discloses a 5-(1H-indol-1-yl)-dihydrofuran-2-(3H)-one compound and its synthetic method. The synthetic method involves reacting 2-ethynylaniline and 3-butenoic acid in an organic solvent under an air atmosphere with a palladium catalyst, ligand, oxidant, and additives to obtain the 5-(1H-indol-1-yl)-dihydrofuran-2-(3H)-one compound. This invention constructs a series of highly functionalized 5-(1H-indol-1-yl)-dihydrofuran-2-(3H)-one compounds, exhibiting extremely high step economy and atom economy. Furthermore, the method is characterized by readily available and simple starting materials, safe operation, good regioselectivity, and broad substrate universality.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to a class of 5-(1H-indol-1-yl)-dihydrofuran-2-(3H)-one compounds and their synthesis methods. Background Technology

[0002] Indole and γ-butyrolactone, as nitrogen- and oxygen-containing heterocyclic skeletons, are widely found in natural products and drug molecules, possessing important biological and pharmacological activities, such as anti-inflammatory, anticancer, antibacterial, and antihypertensive effects. Their unique chemical properties and biological activities have made indole and γ-butyrolactone compounds of great interest in materials science, agricultural chemistry, and pharmaceutical research. Currently, there is considerable research on single indole or γ-butyrolactone compounds, while research on compounds containing both indole and γ-butyrolactone skeletons is relatively limited. Therefore, 5-(1H-indole-1-yl)-dihydrofuran-2-(3H)-one compounds, as compounds containing both indole and γ-butyrolactone skeletons, require a method for synthesis that would have significant synthetic chemical implications and medical research value.

[0003] To achieve the above objectives, we focused on two special synthetic building blocks—2-ethynylaniline and 3-butenoic acid. First, 2-ethynylaniline is widely used in the synthesis of heterocyclic compounds. Utilizing transition metal-catalyzed tandem cyclization of 2-ethynylaniline, various indole compounds can be obtained very efficiently and conveniently (Itaru, N.; Uichiro, Y.; Dschun, S.; Sayaka, K.; Yoshinori, Y. Angew. Chem., Int. Ed. 2007, 46, 2284.; Antonio, A.; Sandro, C.; Giancarlo, F.; Fabio, M.; Luca, MP J Org. Chem. 2005, 70, 6213.; Qu, C.; Zhang, S.; Du, H.; Zhu, C. Chem. Commun. 2016, 52, 14400.; Raju, K.; Arun, S.; Vinod, K. Org. Lett. 2016, 18, 2636.; Li, J.; Li, C.; Yang, S.; An, Y.; Wu, W.; Jiang, H J Org. Chem. 2016, 81, 2875.). However, the 2-ethynylaniline used in this type of reaction mostly requires pre-protection of the free amino group, which is cumbersome. Moreover, the synthesized compounds are generally C3-functionalized indole compounds, and examples of N1-functionalized molecules are still rare. Secondly, 3-butenoic acid, as a non-activated olefin, contains multiple active functional groups such as carbon-carbon double bonds and carboxyl groups, making it a key synthon for the synthesis of γ-butyrolactone.However, in existing reports, most studies protect the carboxyl group of 3-butenoic acid through directing groups such as 8-aminoquinoline, utilizing only the carbon-carbon double bond of 3-butenoic acid in the reaction, resulting in low utilization of the active functional group (Nimmagadda, SK; Liu, M.; Karunananda, MK; Gao, DW; Apolinar, O.; Chen, JS; Liu, P.; Engle, KM; Angew. Chem., Int. Ed., 2019, 58, 3923.; Wang, C.; Xiao, G.; Guo, T.; Ding, Y.; Wu, X.; Loh, TP; J Am. Chem. Soc., 2019, 58, 3923.; Wang, C.; Xiao, G.; Guo, T.; Ding, Y.; Wu, X.; Loh, TP; J Am. Chem. Soc., 2019, 2019, 58, 3923.). 018,140,9332.;Wang,H.;Bai,Z.;Jiao,T.;Deng,Z.;Tong,H.;He,G.;Peng,Q.;Chen, GPJAm.Chem.Soc.,2018,140,3542-3546.;Lv,H.;Xiao ,L.;Zhao,D.;Zhou,Q.;Chem.Sci.,2018,9,6839.;Shen,H.;Zhang,L.;Chen,S.;Feng,J.;Zhang,B.;Zhang,Y.;Zhang,X.;Wu,Y.;Gong,L.ACS Catal., 2018, 9, 791.; Wei, C.; Ye, X.; Xing, Q.; Hu, Y.; Xie, Y.; Shi, X. Org. Biomol. Chem., 2019, 17, 6607.).

[0004] In summary, there is an urgent need to develop a method for preparing 5-(1H-indol-1-yl)-dihydrofuran-2-(3H)-one compounds directly from 2-ethynylaniline and 3-butenoic acid via a tandem cyclization reaction without pre-installing protecting or directing groups. This reaction not only boasts high procedural economy but also holds promising application prospects. Summary of the Invention

[0005] The purpose of this invention is to address the shortcomings and deficiencies of existing technologies by providing 5-(1H-indol-1-yl)-dihydrofuran-2-(3H)-one compounds and their synthetic methods. This method uses readily available 2-ethynylaniline and 3-butenoic acid as raw materials, with palladium trifluoroacetate as a catalyst, 2,9-dimethyl-1,10-phenanthroline as a ligand for catalysis, 2,6-dimethyl-1,4-benzoquinone as an oxidant, anhydrous lithium acetate as an additive, and fluorobenzene as a solvent to synthesize 5-(1H-indol-1-yl)-dihydrofuran-2-(3H)-one compounds. This method features mild conditions, economical operation steps, safety, and wide substrate applicability, showing promising application prospects in research and practical production.

[0006] The objective of this invention is achieved through the following technical solution.

[0007] A method for synthesizing a 5-(1H-indol-1-yl)-dihydrofuran-2-(3H)-one compound, comprising the following steps:

[0008] In an air atmosphere, 2-ethynylaniline and 3-butenoic acid react in an organic solvent under the action of a catalyst, ligand, oxidant, and additive to obtain the 5-(1H-indol-1-yl)-dihydrofuran-2-(3H)-one compound.

[0009] The structural formula of 2-ethynylaniline is as follows:

[0010]

[0011] The structural formula of the 3-butenoic acid is as follows:

[0012]

[0013] The structural formula of the 5-(1H-indol-1-yl)-dihydrofuran-2-(3H)-ketone compound is as follows:

[0014]

[0015] Among them, R 1 The quantity is 5, R 1 Each is independently selected from one of hydrogen, halogen, or organic group; specifically, R 1 Selected from one of hydrogen, 4-methyl, 4-chloro, 4,5-dimethyl, and 6-methoxy; R 2 Selected from one of the organic groups, specifically, R 2 It is selected from one of phenyl, 4-pentylphenyl, 4-phenylphenyl, 4-tert-butylphenyl, 4-trimethylsilylphenyl, 4-methoxyphenyl, 4-acetylphenyl, 3-methylphenyl, 2-naphthyl, 3-thiophene, n-butyl, and cyclopentyl.

[0016] Further, the catalyst is at least one of palladium trifluoroacetate and palladium pivalate, and the molar ratio of the amount of palladium catalyst added to 2-ethynylaniline is 0.05 to 0.20:1.

[0017] Further, the ligand is at least one of 2,9-dimethyl-1,10-phenanthroline, 2,9-diphenyl-1,10-phenanthroline, and 2,9-dichloro-1,10-phenanthroline, and the molar ratio of the amount of the ligand added to 2-ethynylaniline is 0.10 to 0.20:1.

[0018] Further, the oxidant is at least one of 2-methyl-1,4-benzoquinone, 2,5-dimethyl-1,4-benzoquinone, and 2,6-dimethyl-1,4-benzoquinone, and the molar ratio of the amount of oxidant added to 2-ethynylaniline is 1.0 to 1.5:1.

[0019] Further, the additive is at least one of anhydrous lithium acetate, anhydrous sodium acetate, and anhydrous potassium acetate, and the molar ratio of the additive to 2-ethynylaniline is 0.2 to 0.6:1.

[0020] Furthermore, the organic solvent is at least one of trifluorotoluene, fluorobenzene, and chlorobenzene.

[0021] Furthermore, the concentration of the 2-ethynylaniline is 0.2–0.4 mmol / mL.

[0022] Furthermore, the molar ratio of the added 3-butenoic acid to 2-ethynylaniline is 1.5 to 2:1.

[0023] Furthermore, the reaction is carried out under stirring. The stirring speed is 300-500 rpm.

[0024] Furthermore, the reaction temperature is 60-70°C; the reaction time is 10-12 hours.

[0025] Further, after the reaction is completed, the reaction solution is separated and purified. The separation and purification operation is as follows: saturated sodium bicarbonate solution is added to the reaction solution, and the mixture is extracted with ethyl acetate at least three times. The organic phases are combined, dried over anhydrous magnesium sulfate, filtered, and the organic solvent is removed under reduced pressure to obtain the crude product. The crude product is then purified by column chromatography to obtain the 5-(1H-indol-1-yl)-dihydrofuran-2-(3H)-one compound. Even further, the eluent for the column chromatography is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 2 to 5:1.

[0026] The above-described synthetic method yielded 5-(1H-indol-1-yl)-dihydrofuran-2-(3H)-one compounds.

[0027] The aforementioned 5-(1H-indol-1-yl)-dihydrofuran-2-(3H)-one compounds possess both an indole ring and a γ-butyrolactone ring, and are expected to be used in medical fields such as anti-tumor and anti-proliferation.

[0028] The reaction principle of the synthesis method of this invention is that, under the action of catalyst, ligand, oxidant and additive, 2-ethynylaniline and 3-butenoic acid undergo an intermolecular tandem cyclization reaction to generate 5-(1H-indol-1-yl)-dihydrofuran-2-(3H)-one compound.

[0029] The chemical reaction equations for the synthesis process are shown below:

[0030]

[0031] In the formula, R 1 and R 2 The optional groups are the same as above.

[0032] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0033] (1) This invention develops a method for synthesizing 5-(1H-indol-1-yl)-dihydrofuran-2-(3H)-one compounds with potential application value by intermolecular tandem cyclization reaction of 2-ethynylaniline and 3-butenoic acid. The basic raw material 2-ethynylaniline can be synthesized from inexpensive o-iodoaniline and terminal alkynes. It has the characteristics of simple and readily available raw materials, inexpensive operation, mild conditions, high atom economy and wide substrate applicability.

[0034] (2) The present invention uses a one-pot method to synthesize 5-(1H-indol-1-yl)-dihydrofuran-2-(3H)-one compounds, which does not involve high temperature and high pressure, does not require special atmosphere protection, the reaction is safe and controllable, and the yield of the product can reach more than 70%.

[0035] (3) The synthesis method of the present invention is novel and efficient, and has good tolerance to functional groups, so it is expected to be applied to actual industrial production and further derivatization. Attached Figure Description

[0036] Figure 1 and Figure 2 These are the proton and carbon spectra of the target product obtained in Example 1, respectively.

[0037] Figure 3 and Figure 4 These are the proton and carbon spectra of the target product obtained in Example 2, respectively.

[0038] Figure 5 and Figure 6 These are the proton and carbon spectra of the target product obtained in Example 3, respectively.

[0039] Figure 7 and Figure 8 These are the proton and carbon spectra of the target product obtained in Example 4, respectively.

[0040] Figure 9 and Figure 10 These are the proton and carbon spectra of the target product obtained in Example 5, respectively.

[0041] Figure 11 and Figure 12 These are the proton and carbon spectra of the target product obtained in Example 6, respectively.

[0042] Figure 13 and Figure 14 These are the proton and carbon spectra of the target product obtained in Example 7, respectively.

[0043] Figure 15 and Figure 16 These are the proton and carbon spectra of the target product obtained in Example 8, respectively.

[0044] Figure 17 and Figure 18 These are the proton and carbon spectra of the target product obtained in Example 9, respectively.

[0045] Figure 19 and Figure 20 These are the proton and carbon spectra of the target product obtained in Example 10, respectively.

[0046] Figure 21 and Figure 22 These are the proton and carbon spectra of the target product obtained in Example 11, respectively.

[0047] Figure 23 and Figure 24 These are the proton and carbon spectra of the target product obtained in Example 12, respectively.

[0048] Figure 25 and Figure 26 These are the proton and carbon spectra of the target product obtained in Example 13, respectively.

[0049] Figure 27 and Figure 28 These are the proton and carbon spectra of the target product obtained in Example 14, respectively.

[0050] Figure 29 and Figure 30 These are the proton and carbon spectra of the target product obtained in Example 15, respectively.

[0051] Figure 31 and Figure 32 These are the hydrogen spectrum and carbon spectrum of the target product obtained in Example 16, respectively. Detailed Implementation

[0052] The technical solution of the present invention will be further described in detail below with reference to specific embodiments and accompanying drawings, but the scope of protection and implementation of the present invention are not limited thereto.

[0053] Example 1

[0054] 0.2 mmol of 2-phenylethynylaniline, 0.01 mmol of palladium trifluoroacetate, 0.03 mmol of 2,9-dimethyl-1,10-phenanthroline, 0.25 mmol of 2,6-dimethyl-1,4-benzoquinone, 0.05 mmol of anhydrous lithium acetate, 0.30 mmol of 3-butenoic acid, and 1 mL of fluorobenzene solvent were added to a reaction tube. The mixture was stirred at 70 °C and 330 rpm for 12 hours in air. After stirring was stopped, 10 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over 1.5 g of anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography using a 5:1 (v / v) mixture of petroleum ether and ethyl acetate to obtain the target product in 76% yield.

[0055] The proton and carbon spectra of the obtained target product are as follows: Figure 1 and Figure 2 As shown, the structural characterization data is as follows:

[0056] 1 H NMR(400MHz, CDCl3) δ7.64(d,J=7.2Hz,1H),7.53-7.40(m,5H),7.30(d,J=8.0Hz,1H),7.26 -7.18(m,2H),6.69-6.47(m,2H),2.92-2.82(m,1H),2.80-2.63(m,2H),2.58-2.46(m,1H).;

[0057] 13 C NMR (101MHz, CDCl3) δ174.5,141.0,135.3,131.9,129.6,129.4,128.8,128.6,122.7,121.4,111.4,105.0,85.9,28.9,26.2.;

[0058] IRν max (KBr):2923,2817,1771,1626,1516,1352,1162,940,689cm -1 ;

[0059] HRMS(ESI)Calcd for C 18 H 16 NO2, [M+H]+ :278.1176,found 278.1171.

[0060] Based on the above data, the structure of the target product is inferred as follows:

[0061]

[0062] Example 2

[0063] 0.2 mmol of 2-phenylethynyl-4-methylaniline, 0.02 mmol of palladium pentanoate, 0.03 mmol of 2,9-diphenyl-1,10-phenanthroline, 0.20 mmol of 2,5-dimethyl-1,4-benzoquinone, 0.05 mmol of anhydrous lithium acetate, 0.40 mmol of 3-butenoic acid, and 1 mL of fluorobenzene solvent were added to a reaction tube. The mixture was stirred at 70 °C and 330 rpm for 12 hours in air. After stirring was stopped, 10 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over 1.5 g of anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography using a 5:1 (v / v) mixture of petroleum ether and ethyl acetate to obtain the target product in 70% yield.

[0064] The proton and carbon spectra of the obtained target product are as follows: Figure 3 and Figure 4 As shown, the structural characterization data is as follows:

[0065] 1 H NMR (400MHz, CDCl3) δ7.52-7.38(m,6H),7.18(d,J=8.4Hz,1H),7.06(d,J=8.4Hz,1H),6.56(t,J =7.6Hz,1H),6.48(s,1H),2.91-2.81(m,1H),2.80-2.63(m,2H),2.56-2.48(m,1H),2.45(s,3H);

[0066] 13 C NMR (101MHz, CDCl3) δ174.6,141.2,133.6,132.1,130.8,129.8,129.5,128.8,128.5,124.2,121.1,111.0,104.6,86.0,29.0,26.1,21.3;

[0067] IRν max (KBr):2950,2859,1781,1465,1331,1178,984,875,765cm -1 ;

[0068] HRMS(ESI)Calcd for C 19 H 18 NO2, [M+H] + :292.1332found 292.1325.

[0069] Based on the above data, the structure of the target product is inferred as follows:

[0070]

[0071] Example 3

[0072] 0.2 mmol of 2-phenylethynyl-4-chloroaniline, 0.02 mmol of palladium trifluoroacetate, 0.03 mmol of 2,9-dichloro-1,10-phenanthroline, 0.30 mmol of 2,6-dimethyl-1,4-benzoquinone, 0.04 mmol of anhydrous sodium acetate, 0.30 mmol of 3-butenoic acid, and 1.5 mL of chlorobenzene solvent were added to a reaction tube. The mixture was stirred at 60 °C and 300 rpm for 12 hours in air. After stirring was stopped, 10 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over 1.5 g of anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography using a 3:1 (v / v) mixture of petroleum ether and ethyl acetate as the eluent. The target product was obtained in 61% yield.

[0073] The proton and carbon spectra of the obtained target product are as follows: Figure 5 and Figure 6 As shown, the structural characterization data is as follows:

[0074] 1 H NMR (400MHz, CDCl3) δ7.61 (dd, J = 2.0, 0.8Hz, 1H), 7.53-7.43 (m, 5H), 7.24-7.17 (m, 2H), 6. 55(t,J=7.6Hz,1H),6.50(s,1H),2.85-2.79(m,1H),2.79-2.66(m,2H),2.60-2.50(m,1H);

[0075] 13 C NMR (101MHz, CDCl3) δ174.21,142.4,133.6,131.4,130.6,129.6,129.0,128.9,127.1,122.8,120.8,112.3,104.4,85.7,28.9,26.4;

[0076] IRν max(KBr):2924,2856,1784,1629,1438,1355,1113,869,757cm -1 ;

[0077] HRMS(ESI)Calcd for C 18 H 13 ClNO2,[MH] + :310.0640,found 310.0642.

[0078] Based on the above data, the structure of the target product is inferred as follows:

[0079]

[0080] Example 4

[0081] 0.2 mmol of 2-phenylethynyl-4,5-dimethylaniline, 0.03 mmol of palladium pentanoate, 0.02 mmol of 2,9-dimethyl-1,10-phenanthroline, 0.30 mmol of 2,5-dimethyl-1,4-benzoquinone, 0.12 mmol of anhydrous lithium acetate, 0.35 mmol of 3-butenoic acid, and 0.5 mL of fluorobenzene solvent were added to a reaction tube. The mixture was stirred at 70 °C and 330 rpm for 12 hours in air. After stirring was stopped, 10 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over 1.5 g of anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography using a 5:1 (v / v) mixture of petroleum ether and ethyl acetate as the eluent. The target product was obtained in 70% yield.

[0082] The proton and carbon spectra of the obtained target product are as follows: Figure 7 and Figure 8 As shown, the structural characterization data is as follows:

[0083] Based on the above data, the structure of the target product is inferred as follows:

[0084] 1 H NMR (400MHz, CDCl3) δ7.50-7.37(m,6H),7.06(s,1H),6.54(t,J=7.6Hz,1H),6.44(s, 1H),2.89-2.81(m,1H),2.80-2.62(m,2H),2.51-2.42(m,1H),2.36(d,J=13.2Hz,6H);

[0085] 13C NMR (101MHz, CDCl3) δ174.6,140.3,134.4,132.2,131.7,130.1,129.5,128.7,128.3,127.8,121.4,111.9,104.5,86.1,29.0,26.1,20.8,19.9;

[0086] IRν max (KBr):2927,2859,1784,1603,1465,1335,1157,929,765cm -1 ;

[0087] HRMS(ESI)Calcd for C 20 H 18 NO2, [MH] + :304.1343,found 304.1346.

[0088] Based on the above data, the structure of the target product is inferred as follows:

[0089]

[0090] Example 5

[0091] 0.2 mmol of 2-phenylethynyl-6-methoxyaniline, 0.01 mmol of palladium pentanoate, 0.03 mmol of 2,9-dimethyl-1,10-phenanthroline, 0.25 mmol of 2-methyl-1,4-benzoquinone, 0.12 mmol of anhydrous potassium acetate, 0.35 mmol of 3-butenoic acid, and 2.0 mL of trifluorotoluene solvent were added to a reaction tube. The mixture was stirred at 70 °C and 500 rpm for 12 hours in air. After stirring was stopped, 10 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over 1.5 g of anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography using a 3:1 (v / v) mixture of petroleum ether and ethyl acetate as the eluent. The target product was obtained in 32% yield.

[0092] The proton and carbon spectra of the obtained target product are as follows: Figure 9 and Figure 10 As shown, the structural characterization data is as follows:

[0093] 1H NMR (400MHz, CDCl3) δ7.53-7.42(m,5H),7.26-7.23(m,1H),7.14(t,J=7.6Hz,1H),6.75(d,J=8.0Hz,1H), 6.58(t,J=7.6Hz,1H),6.52(s,1H),3.95(s,3H),2.80-2.68(m,2H),2.66-2.55(m,1H),2.50-2.40(m,1H);

[0094] 13 C NMR (101MHz, CDCl3) δ175.9,146.6,142.1,132.1,129.5,128.8,128.5,125.5,122.2,113.9,104.7,104.6,85.8,55.8,29.7,28.7;

[0095] IRν max (KBr):2929,2845,1782,1581,1420,1326,1151,937,733cm -1 ;

[0096] HRMS(ESI)Calcd for C 19 H 18 NO3, [M+H] + :308.1278,found 308.1281.

[0097] Based on the above data, the structure of the target product is inferred as follows:

[0098]

[0099] Example 6

[0100] 0.2 mmol of 2-(4-pentylphenyl)ethynylaniline, 0.01 mmol of palladium trifluoroacetate, 0.04 mmol of 2,9-dimethyl-1,10-phenanthroline, 0.25 mmol of 2,6-dimethyl-1,4-benzoquinone, 0.06 mmol of anhydrous sodium acetate, 0.30 mmol of 3-butenoic acid, and 0.5 mL of fluorobenzene solvent were added to a reaction tube. The mixture was stirred at 70 °C and 330 rpm for 12 hours in air. After stirring was stopped, 10 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over 1.5 g of anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography using a 5:1 (v / v) mixture of petroleum ether and ethyl acetate as the eluent. The target product was obtained in 63% yield.

[0101] The proton and carbon spectra of the obtained target product are as follows: Figure 11 and Figure 12 As shown, the structural characterization data is as follows:

[0102] 1 H NMR (400MHz, CDCl3) δ7.63(dd,J=6.8,1.6Hz,1H),7.40(d,J=7.6Hz,2H),7.32-7.26(m,3H),7.26-7.17(m,2H),6.60(t,J=7.6Hz,1 H),6.53(s,1H),2.92-2.82(m,1H),2.80-2.63(m,4H),2.57-2.47(m,1H),1.70-1.63(m,2H),1.41-1.33(m,4H),0.95-0.89(m,3H);

[0103] 13 C NMR (101MHz, CDCl3) δ174.5,143.7,141.2,135.3,129.5,129.5,129.2,128.9,12 2.5,121.3,121.3,111.3,104.6,85.9,35.7,31.5,31.1,29.0,26.1,22.5,14.0;

[0104] IRν max (KBr):2947,2816,1770,1622,1516,1326,1153,940,620cm -1 ;

[0105] HRMS(ESI)Calcd for C 23 H 26 NO2, [M+H] + :348.1958,found 348.1953.

[0106] Based on the above data, the structure of the target product is inferred as follows:

[0107]

[0108] Example 7

[0109] 0.2 mmol of 2-(4-phenylphenyl)ethynylaniline, 0.03 mmol of palladium pentanoate, 0.03 mmol of 2,9-dichloro-1,10-phenanthroline, 0.30 mmol of 2-dimethyl-1,4-benzoquinone, 0.05 mmol of anhydrous lithium acetate, 0.40 mmol of 3-butenoic acid, and 1 mL of fluorobenzene solvent were added to a reaction tube. The mixture was stirred at 65 °C and 450 rpm for 12 hours in air. After stirring was stopped, 10 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over 1.5 g of anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography using a 4:1 (v / v) mixture of petroleum ether and ethyl acetate as the eluent. The target product was obtained in 63% yield.

[0110] The proton and carbon spectra of the obtained target product are as follows: Figure 13 and Figure 14 As shown, the structural characterization data is as follows:

[0111] 1 H NMR (400MHz, CDCl3) δ7.71(d,J=8.0Hz,2H),7.68-7.62(m,3H),7.58(d,J=8.4Hz,2H),7.48(t,J=7.6Hz,2H),7.42-7.37(m,1H),7.3 2(d,J=8.0Hz,1H),7.28-7.19(m,2H),6.65(t,J=7.6Hz,1H),6.61(s,1H),2.97-2.87(m,1H),2.86-2.67(m,2H),2.61-2.50(m,1H);

[0112] 13 C NMR (101MHz, CDCl3): δ174.5,141.5,140.8,140.2,135.4,130.8,129.9,129.5,1 28.9,127.8,127.5,127.1,122.7,121.4,121.4,111.5,105.0,86.0,29.0,26.2;

[0113] IRν max (KBr):2903,2855,1773,1615,1496,1352,1163,938,638cm -1 ;

[0114] HRMS(ESI)Calcd for C 24 H 20 NO2, [M+H] +:354.1489,found 354.1482.

[0115] Based on the above data, the structure of the target product is inferred as follows:

[0116]

[0117] Example 8

[0118] 0.2 mmol of 2-(4-tert-butylphenyl)ethynylaniline, 0.02 mmol of palladium trifluoroacetate, 0.02 mmol of 2,9-dimethyl-1,10-phenanthroline, 0.30 mmol of 2,6-dimethyl-1,4-benzoquinone, 0.06 mmol of anhydrous lithium acetate, 0.35 mmol of 3-butenoic acid, and 2 mL of chlorobenzene solvent were added to a reaction tube. The mixture was stirred at 70 °C and 330 rpm for 12 hours in air. After stirring was stopped, 10 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over 1.5 g of anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography using a 5:1 (v / v) mixture of petroleum ether and ethyl acetate as the eluent. The target product was obtained in 70% yield.

[0119] The proton and carbon spectra of the obtained target product are as follows: Figure 15 and Figure 16 As shown, the structural characterization data is as follows:

[0120] 1 H NMR (400MHz, CDCl3) δ7.63(d,J=6.8Hz,1H),7.50(d,J=8.4Hz,2H),7.43(d,J=8.4Hz,2H),7.29(d,J=8.0Hz,1H),7.24- 7.15(m,2H),6.60(t,J=7.6Hz,1H),6.54(s,1H),2.95-2.85(m,1H),2.83-2.66(m,2H),2.58-2.49(m,1H),1.38(s,9H);

[0121] 13 C NMR (101MHz, CDCl3) δ174.5,151.8,141.2,135.2,129.6,129.3,129.0,125.8,122.5,121.3,121.3,111.4,104.6,86.0,34.7,31.3,29.0,26.1;

[0122] IRν max(KBr):2946,2800,1771,1628,1514,1346,1162,931,683cm -1 ;

[0123] HRMS(ESI)Calcd for C 22 H 22 NO2, [MH] + :332.1656,found 332.1658.

[0124] Based on the above data, the structure of the target product is inferred as follows:

[0125]

[0126] Example 9

[0127] 0.2 mmol of 2-(4-trimethylsilylphenyl)ethynylaniline, 0.03 mmol of palladium trifluoroacetate, 0.03 mmol of 2,9-diphenyl-1,10-phenanthroline, 0.20 mmol of 2,6-dimethyl-1,4-benzoquinone, 0.05 mmol of anhydrous lithium acetate, 0.30 mmol of 3-butenoic acid, and 1 mL of chlorobenzene solvent were added to a reaction tube. The mixture was stirred at 70 °C and 330 rpm for 12 hours in air. After stirring was stopped, 10 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over 1.5 g of anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography using a 5:1 (v / v) mixture of petroleum ether and ethyl acetate to obtain the target product in 64% yield.

[0128] The proton and carbon spectra of the obtained target product are as follows: Figure 17 and Figure 18 As shown, the structural characterization data is as follows:

[0129] 1 H NMR (400MHz, CDCl3) δ7.65-7.63(m,3H),7.49(d,J=8.0Hz,2H),7.31-7.18(m,3H),6.60(t,J=7 .6Hz,1H),6.56(s,1H),2.97-2.87(m,1H),2.86-2.66(m,2H),2.58-2.49(m,1H),0.32(s,9H);

[0130] 13C NMR (101MHz, CDCl3) δ174.5,141.3,141.2,135.3,133.8,132.2,129.6,128.7,122.7,121.4,111.5,104.9,86.0,29.0,26.1,-1.2;

[0131] IRν max (KBr):2930,2855,1784,1629,1456,1342,1252,1111,746cm -1 ;

[0132] HRMS(ESI)Calcd for C 21 H 24 NO2Si,[M+H] + :350.1571,found 350.1564.

[0133] Based on the above data, the structure of the target product is inferred as follows:

[0134]

[0135] Example 10

[0136] 0.2 mmol of 2-(4-methoxyphenyl)ethynylaniline, 0.03 mmol of palladium pentanoate, 0.03 mmol of 2,9-dimethyl-1,10-phenanthroline, 0.25 mmol of 2,6-dimethyl-1,4-benzoquinone, 0.05 mmol of anhydrous lithium acetate, 0.30 mmol of 3-butenoic acid, and 1 mL of fluorobenzene solvent were added to a reaction tube. The mixture was stirred at 70 °C and 330 rpm for 12 hours in air. After stirring was stopped, 10 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over 1.5 g of anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography using a 3:1 (v / v) mixture of petroleum ether and ethyl acetate as the eluent. The target product was obtained in 50% yield.

[0137] The proton and carbon spectra of the obtained target product are as follows: Figure 19 and Figure 20 As shown, the structural characterization data is as follows:

[0138] 1H NMR (400MHz, CDCl3) δ7.62(d,J=7.6Hz,1H),7.41(d,J=8.4Hz,2H),7.29-7.16(m,3H),6.99(d,J=8.4Hz,2H) ,6.56(t,J=7.6Hz,1H),6.49(s,1H),3.85(s,3H),2.90-2.81(m,1H),2.79-2.61(m,2H),2.54-2.45(m,1H);

[0139] 13 C NMR (101MHz, CDCl3) δ174.6,159.9,140.9,135.1,130.9,129.4,124.1,122.4,121.2,121.1,114.2,111.2,104.4,85.9,55.4,28.9,26.1;

[0140] IRν max (KBr):2944,2814,1773,1610,1563,1307,1162,939,697.cm -1 ;

[0141] HRMS(ESI)Calcd for C 19 H 18 NO3, [M+H] + :308.1281,found 308.1275.

[0142] Based on the above data, the structure of the target product is inferred as follows:

[0143]

[0144] Example 11

[0145] 0.2 mmol of 2-(4-acetylphenyl)ethynylaniline, 0.01 mmol of palladium pentanoate, 0.03 mmol of 2,9-dimethyl-1,10-phenanthroline, 0.25 mmol of 2,5-dimethyl-1,4-benzoquinone, 0.05 mmol of anhydrous lithium acetate, 0.35 mmol of 3-butenoic acid, and 2 mL of trifluorotoluene solvent were added to a reaction tube. The mixture was stirred at 60 °C and 330 rpm for 10 hours in air. After stirring was stopped, 10 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over 1.5 g of anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography using a 3:1 (v / v) mixture of petroleum ether and ethyl acetate as the eluent. The target product was obtained in 72% yield.

[0146] The proton and carbon spectra of the obtained target product are as follows: Figure 21 and Figure 22 As shown, the structural characterization data is as follows:

[0147] 1 H NMR (400MHz, CDCl3) δ8.05(d,J=8.4Hz,2H),7.66(d,J=7.2Hz,1H),7.61(d,J=8.4Hz,2H),7.35-7.26(m,2H),7.22(td,J=8.0 ,6.8,1.6Hz,1H),6.64(s,1H),6.58(t,J=7.6Hz,1H),2.92-2.86(m,1H),2.85-2.69(m,2H),2.64(s,3H),2.61-2.51(m,1H);

[0148] 13 C NMR (101MHz, CDCl3) δ197.3,174.2,139.8,136.7,136.5,135.8,129.5,129.4,128.8,123.3,121.7,111.5,106.2,85.8,28.9,26.6,26.2;

[0149] IRν max (KBr):2935,2825,1771,1607,1494,1362,1162,923,666.cm -1 ;

[0150] HRMS(ESI)Calcd for C 20 H 18 NO3, [M+H] + :320.1281,found 320.1275.

[0151] Based on the above data, the structure of the target product is inferred as follows:

[0152]

[0153] Example 12

[0154] 0.2 mmol of 2-(3-methylphenyl)ethynylaniline, 0.03 mmol of palladium trifluoroacetate, 0.03 mmol of 2,9-dimethyl-1,10-phenanthroline, 0.25 mmol of 2,6-dimethyl-1,4-benzoquinone, 0.07 mmol of anhydrous potassium acetate, 0.40 mmol of 3-butenoic acid, and 1 mL of chlorobenzene solvent were added to a reaction tube. The mixture was stirred at 70 °C and 330 rpm for 10 hours in air. After stirring was stopped, 10 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over 1.5 g of anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography using a 5:1 (v / v) mixture of petroleum ether and ethyl acetate to obtain the target product in 62% yield.

[0155] The proton and carbon spectra of the obtained target product are as follows: Figure 23 and Figure 24 As shown, the structural characterization data is as follows:

[0156] 1 H NMR (400MHz, CDCl3) δ7.65-7.63(m,3H),7.49(d,J=8.0Hz,2H),7.31-7.18(m,3H),6.60(t,J=7 .6Hz,1H),6.56(s,1H),2.97-2.87(m,1H),2.86-2.66(m,2H),2.58-2.49(m,1H),0.32(s,9H);

[0157] 13 C NMR (101MHz, CDCl3) δ174.6,141.2,138.6,135.3,131.9,130.3,129.4,129.4,128.7,126.6,122.5,121.3,111.3,104.8,85.9,28.9,26.2,21.4.;

[0158] IRν max (KBr):2947,2881,1664,1610,1527,1330,1146,947,610cm -1 ;

[0159] HRMS(ESI)Calcd for C 19 H 18 NO2, [M+H] + :292.1332,found 292.1325.

[0160] Based on the above data, the structure of the target product is inferred as follows:

[0161]

[0162] Example 13

[0163] 0.2 mmol of 2-(2-naphthyl)ethynylaniline, 0.02 mmol of palladium pentanoate, 0.03 mmol of 2,9-dimethyl-1,10-phenanthroline, 0.25 mmol of 2,6-dimethyl-1,4-benzoquinone, 0.05 mmol of anhydrous lithium acetate, 0.40 mmol of 3-butenoic acid, and 0.5 mL of fluorobenzene solvent were added to a reaction tube. The mixture was stirred at 70 °C and 330 rpm for 12 hours in air. After stirring was stopped, 10 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over 1.5 g of anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography using a 4:1 (v / v) mixture of petroleum ether and ethyl acetate as the eluent. The target product was obtained in 72% yield.

[0164] The proton and carbon spectra of the obtained target product are as follows: Figure 25 and Figure 26 As shown, the structural characterization data is as follows:

[0165] 1 H NMR (400MHz, CDCl3) δ7.98-7.95(m,1H),7.94-7.87(m,3H),7.66(dd,J=7.2,1.6Hz,1H),7.59(dd,J=8.4,2.0Hz,1H),7.56-7.5 2(m,2H),7.32(d,J=8.0Hz,1H),7.27-7.19(m,2H),6.67-6.60(m,2H),2.92-2.82(m,1H),2.78-2.59(m,2H),2.51-2.42(m,1H);

[0166] 13 C NMR (101MHz, CDCl3) δ174.5,141.1,135.5,133.2,133.0,129.6,129.3,128.8,128.6,1 28.2,127.8,126.9,126.9,126.9,122.8,121.5,121.4,111.4,105.4,86.0,29.0,26.2;

[0167] IRν max (KBr):925,2836,1772,1608,1502,1361,1162,942,635cm -1 ;

[0168] HRMS(ESI)Calcd for C 22 H 18 NO2, [M+H] + :328.1332,found 328.1327.

[0169] Based on the above data, the structure of the target product is inferred as follows:

[0170]

[0171] Example 14

[0172] 0.2 mmol of 2-(3-thienyl)ethynylaniline, 0.02 mmol of palladium trifluoroacetate, 0.04 mmol of 2,9-dichloro-1,10-phenanthroline, 0.25 mmol of 2,6-dimethyl-1,4-benzoquinone, 0.05 mmol of anhydrous sodium acetate, 0.30 mmol of 3-butenoic acid, and 1 mL of fluorobenzene solvent were added to a reaction tube. The mixture was stirred at 65 °C and 500 rpm for 10 hours in air. After stirring was stopped, 10 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over 1.5 g of anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography using a 3:1 (v / v) mixture of petroleum ether and ethyl acetate as the eluent. The target product was obtained in 64% yield.

[0173] The proton and carbon spectra of the obtained target product are as follows: Figure 27 and Figure 28 As shown, the structural characterization data is as follows:

[0174] 1 H NMR (400MHz, CDCl3) δ77.63-7.61(m,1H),7.46(dd,J=4.8,3.2Hz,1H),7.43(dd,J=3.2,1.6Hz,1H),7.30-7.27(m,1 H),7.26-7.17(m,3H),6.65(t,J=7.6Hz,1H),6.57(s,1H),2.93-2.83(m,1H),2.82-2.65(m,2H),2.60-2.51(m,1H);

[0175] 13 C NMR (101MHz, CDCl3) δ174.5,135.7,135.2,132.4,129.3,128.5,126.7,125.0,122.7,121.3,121.3,111.1,105.1,85.7,8.9,26.2;

[0176] IRνmax (KBr):2926,2853,1782,1457,1334,1176,1019,939,745.cm -1 ;

[0177] HRMS(ESI)Calcd for C 16 H 14 NO2, [M+H] + :284.0740,found 284.0734.

[0178] Based on the above data, the structure of the target product is inferred as follows:

[0179]

[0180] Example 15

[0181] 0.2 mmol of 2-(1-hexynyl)aniline, 0.03 mmol of palladium trifluoroacetate, 0.03 mmol of 2,9-dimethyl-1,10-phenanthroline, 0.25 mmol of 2,6-dimethyl-1,4-benzoquinone, 0.05 mmol of anhydrous potassium acetate, 0.35 mmol of 3-butenoic acid, and 1 mL of chlorobenzene solvent were added to a reaction tube. The mixture was stirred at 60 °C and 420 rpm for 12 hours in air. After stirring was stopped, 10 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over 1.5 g of anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography using a 3:1 (v / v) mixture of petroleum ether and ethyl acetate to obtain the target product in 54% yield.

[0182] The proton and carbon spectra of the obtained target product are as follows: Figure 29 and Figure 30 As shown, the structural characterization data is as follows:

[0183] 1 H NMR (400MHz, CDCl3) δ7.55-7.51(m,1H),7.19-7.09(m,3H),6.58(t,J=7.6Hz,1H),6.30(s,1H),3.03-2.85(m ,3H),2.77-2.73(m,2H),2.71-2.64(m,1H),1.75-1.67(m,2H),1.45(q,J=7.2Hz,2H),0.97(t,J=7.2Hz,3H);

[0184] 13C NMR (101MHz, CDCl3) δ174.4,140.5,134.6,129.5,121.7,120.7,120.6,110.7,102.1,85.1,30.8,29.1,26.8,26.6,22.5,13.8;

[0185] IRν max (KBr):2929,2861,1782,1682,1455,1349,1115,938,746cm -1 ;

[0186] HRMS(ESI)Calcd for C 16 H 18 NO2, [MH] + :256.1343,found 256.1342.

[0187] Based on the above data, the structure of the target product is inferred as follows:

[0188]

[0189] Example 16

[0190] 0.2 mmol of 2-(cyclopentyl)ethynylaniline, 0.04 mmol of palladium pentanoate, 0.03 mmol of 2,9-dimethyl-1,10-phenanthroline, 0.25 mmol of 2,6-dimethyl-1,4-benzoquinone, 0.05 mmol of anhydrous lithium acetate, 0.30 mmol of 3-butenoic acid, and 1 mL of fluorobenzene solvent were added to a reaction tube. The mixture was stirred at 70 °C and 330 rpm for 12 hours in air. After stirring was stopped, 10 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over 1.5 g of anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and then purified by column chromatography using a 3:1 (v / v) mixture of petroleum ether and ethyl acetate as the eluent. The target product was obtained in 48% yield.

[0191] The proton and carbon spectra of the obtained target product are as follows: Figure 31 and Figure 32 As shown, the structural characterization data is as follows:

[0192] 1H NMR (400MHz, CDCl3) δ7.56-7.50(m,1H),7.16-7.11(m,3H),6.65(t,J=6.8Hz,1H),6.31(s,1H), 3.19-3.12(m,1H),3.03-2.85(m,3H),2.72-2.62(m,1H),2.17-2.05(m,2H),1.85-1.68(m,6H);

[0193] 13 C NMR (101MHz, CDCl3) δ174.4,144.9,134.6,129.5,121.7,120.7,120.7,110.9,99.7,85.3,37.2,32.9,32.6,29.2,26.5,25.1,25.1;

[0194] IRν max (KBr):2930,2864,1783,1628,1508,1336,1148,991,747cm -1 ;

[0195] HRMS(ESI)Calcd for C 17 H 18 NO2, [MH] + :268.1343,found 268,1345.

[0196] Based on the above data, the structure of the target product is inferred as follows:

[0197]

Claims

1. A process for the synthesis of 5-(1 H indol-1-yl)-dihydrofuran-2-(3 H )-ketones, characterized in that, Includes the following steps: In an air atmosphere, 2-ethynylaniline compounds and 3-butenoic acid react in an organic solvent under the action of a palladium catalyst, ligand, oxidant, and additives to obtain the 5-(1 H -indol-1-yl)-dihydrofuran-2-(3-) H )-Ketones; The palladium catalyst is at least one of palladium trifluoroacetate and palladium pivalate. The ligand is at least one of 2,9-dimethyl-1,10-phenanthroline, 2,9-diphenyl-1,10-phenanthroline, and 2,9-dichloro-1,10-phenanthroline; The oxidant is at least one selected from 2-methyl-1,4-benzoquinone, 2,5-dimethyl-1,4-benzoquinone, and 2,6-dimethyl-1,4-benzoquinone; The additive is at least one of anhydrous lithium acetate, anhydrous sodium acetate, and anhydrous potassium acetate. The structural formula of the 2-ethynylaniline compound is as follows: The structural formula of the 3-butenoic acid is as follows: The 5-(1) H -indol-1-yl)-dihydrofuran-2-(3-) H The structural formulas of ketone compounds are as follows: Among them, R 1 Selected from one of hydrogen, 4-methyl, 4-chloro, 4,5-dimethyl, and 6-methoxy; R 2 It is selected from one of phenyl, 4-pentylphenyl, 4-phenylphenyl, 4-tert-butylphenyl, 4-trimethylsilylphenyl, 4-methoxyphenyl, 4-acetylphenyl, 3-methylphenyl, 2-naphthyl, 3-thiophene, n-butyl, and cyclopentyl.

2. The synthesis method according to claim 1, characterized in that, The molar ratio of palladium catalyst to 2-ethynylaniline compounds is 0.05~0.20:

1.

3. The method of synthesis of claim 1, wherein, The molar ratio of the ligand to the 2-ethynylaniline compound is 0.10 to 0.20:

1.

4. The method of synthesis of claim 1, wherein, The molar ratio of oxidant to 2-ethynylaniline compound is 1.0~1.5:

1.

5. The method of synthesis of claim 1, wherein, The molar ratio of the additive to the 2-ethynylaniline compound is 0.2~0.6:

1.

6. The method of synthesis of claim 1, wherein, The organic solvent is at least one of trifluorotoluene, fluorobenzene, and chlorobenzene.

7. The synthesis method according to claim 1, characterized in that, The concentration of the 2-ethynylaniline compound is 0.2~0.4 mmol / mL; the molar ratio of 3-butenoic acid to the 2-ethynylaniline compound is 1.5~2:

1.

8. The synthesis method according to claim 1, characterized in that, The reaction is carried out under stirring at a speed of 300-500 rpm; the reaction temperature is 60-70 ℃; and the reaction time is 10-12 hours.

9. The method of synthesis of claim 1, wherein, After the reaction, the reaction solution was separated and purified. The separation and purification operation was as follows: saturated sodium bicarbonate was added to the reaction solution, and the solution was extracted with ethyl acetate at least three times. The organic phases were combined, dried with anhydrous magnesium sulfate, filtered, and the organic solvent was removed by vacuum distillation to obtain the crude product. The crude product was then purified by column chromatography, with the eluent being a mixture of petroleum ether and ethyl acetate in a volume ratio of 2-5:

1. H -indol-1-yl)-dihydrofuran-2-(3-) H )-Ketone compounds.

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