A dihydroindole derivative and its preparation method and product

Abstract

This invention discloses a 2,3-disubstituted dihydroindole derivative and its preparation method. The method involves adding an o-sulfonamide aldehyde imine of formula III, a sulfonate salt of formula IV, and a base to a reaction solvent, followed by a reaction to obtain the derivative. This invention also discloses an indole derivative and its preparation method. The method involves adding an o-sulfonamide aldehyde imine of formula III, a sulfonate salt of formula IV, and potassium carbonate to a propylene oxide solvent. After the reaction is complete, lithium chloride is added, and the derivative is obtained after the reaction. This invention directly obtains 2,3-disubstituted dihydroindole derivative I or indole derivative II through a [4+1] cycloaddition tandem reaction of thioylide and o-sulfonamide aldehyde imine, without the need for functional group pre-assembly. The reactants are inexpensive and readily available, involve no transition metals, are green and efficient, operate under mild conditions, have a wide range of applicable substrates, achieve high reaction yields, and are simple to operate. This provides a new route for the efficient synthesis of indole skeletons.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a dihydroindole derivative and a method for preparing indole derivatives and products thereof. Background Technology

[0002] Nitrogen heterocycles are widely found in bioactive natural products and pharmaceutical compounds. Dihydroindole and indole heterocyclic compounds are the core structures of many drugs and alkaloid natural products, exhibiting a range of different biological activities. For example, the following compounds reported in the literature (S.Takano, M.Moriya and K.Ogasawara.Enantiocontrolledtotal syntheses of(-)-physovenine and(-)-physostigmine.J.Org.Chem.1991,56,5982–5984.;SAKozmin,T.Iwama,Y.Huang and VHRawal.An Efficient Approach to Aspidosperma Alkaloids via[4+2]Cycloadditions of Aminosiloxydienes:Stereocontrolled Total Synthesis of(±)-Tabersonine.Gram-Scale CatalyticAsymmetric Syntheses of(+)-Tabersonine and(+)-16-Methoxytabersonine.Asymmetric Syntheses of(+)-Aspidospermidine and(-)-Quebrachamine.J.Am.Chem.Soc.2002,124,4628–4641.;Y.Iwama,K.Okano,K.Sugimoto andH.Tokuyama.Enantiocontrolled Total Synthesis of(-)-Mersicarpine.Chem.Eur.J.2013,19,9325–9334.):

[0003]

[0004] In recent years, research on the synthesis methods of this type of compound has greatly attracted the interest of researchers.

[0005] In 2014, Xiao et al. (Li, TS; Tan, F.; Lu, LQ; Wei, Y.; Wang, YN; Liu, YY; Yang, QQ; Chen. J. A symmetric trapping of zwitterionic intermediates by sulfur ylides in a palladium-catalyzed decarboxylation-cycloaddition sequence. Nat Commun. 2014. 5, 5500.) reported that the target product was obtained by intramolecular asymmetric decarboxylation cyclization of oxazinone with sulfur ylides under the action of Pd and chiral ligands.

[0006]

[0007] In 2016, Xiao et al. (Wang, Q.; Qi, XT; Li, TR; Yuan, ZG; Zhang, K.; Li, BJ; Iron-Catalyzed Decarboxylative (4+1) Cycloadditions: Exploiting the Reactivity of Ambident Iron-Stabilized Intermediates. Angew. Chem. Int. Ed. 2016, 128, 2890–2894.) used vinylbenzoxazinone and thioyl ylide as raw materials to carry out S-catalysis under the catalysis of Fe and ligands. N 2' substitution yields a zwitterionic intermediate, followed by S... N 2. Substitution yields the target product.

[0008]

[0009] In 2016, Xiao et al. (Wang, Q.; Li, TR.; Li, MM.; Zhang, K. Catalytic Asymmetric [4+1] Annulation of Sulfur Ylides with Copper-Allenylidene Intermediates. J. Am. Chem. Soc. 2016, 138, 8360-8363.) utilized the reaction of copper and chiral ligands with ethynyloxazinone to remove one molecule of CO2, generating a resonance-stable copper-propylene intermediate. Subsequently, the intermediate selectively captures sulfide ylides, undergoing intramolecular S... N The reaction proceeded to yield the target product.

[0010]

[0011] In 2018, Shibata et al. (Punna, N.; Das, P.; Gouverneur, V. Highly Diastereoselective Synthesis of Trifluoromethyl Indolines by Interceptive Benzylic Decarboxylative Cycloaddition of Nonvinyl, Trifluoromethyl Benzoxazinanones with Sulfur Ylides under Palladium Catalysis. Org. Lett. 2018, 20, 1526-1529.) introduced a CF3 group onto benzoxazinanones with the help of palladium and ligands, which reacted with sulfur ylides to synthesize the target product with high efficiency and high diastereoselectivity.

[0012]

[0013] In 2020, Shibata et al. (Gannarapu, MR; Zhou, J.; Jiang, BY Two Catalytic Annulation Modes via Cu-Allenylidenes with Sulfur Ylides that Are Dominated by the Presence or Absence of Trifluoromethyl Substituents. iScience 2020, 23, 100994.) reported the decarboxylation [4+1] cyclization of 4-methyl-4-propynylbenzoxazinone by sulfur ylides, and the enantioselective synthesis of the target product under Cu catalysis.

[0014]

[0015] To date, the vast majority of synthetic methods rely on complex, multi-step pre-assembly of open-chain precursor molecules prior to the final intramolecular ring-closing reaction. This pre-assembly process often restricts the introduction of many functional groups. The use of transition metals such as palladium is uneconomical and environmentally unfriendly. Furthermore, many methods have relatively low yields, making industrial-scale production difficult. Summary of the Invention

[0016] This invention provides a method for preparing dihydroindole derivatives. Based on the [4+1] tandem cyclization reaction of o-sulfonamide aldehyde imine and thioylide, this method achieves the green and efficient synthesis of a series of dihydroindole derivatives. This method requires no pre-assembly, no transition metal catalysis, uses inexpensive and readily available raw materials, operates under mild reaction conditions, and has a wide range of applicable substrates. It provides a new, industrially viable route for the synthesis of dihydroindole derivatives.

[0017] A method for preparing a dihydroindole derivative includes: adding o-sulfonamide aldehyde imine of formula III, sulfonate salt of formula IV, and base to a reaction solvent; after the reaction is completed, post-treatment is performed to obtain a 2,3-disubstituted dihydroindole derivative of formula I; or, after the above reaction is completed, lithium chloride is added; after the reaction is completed, post-treatment is performed to obtain an indole derivative of formula II.

[0018]

[0019] Wherein, the R 1 Selected from H, halogens, and C1-C3 alkyl groups;

[0020] The R 2 Selected from methyl-substituted benzenesulfonyl, methylsulfonyl, benzenesulfonyl, and nitro-substituted benzenesulfonyl;

[0021] The R 3 The alkoxy group is selected from aryl, heteroaryl, 3-6 membered cycloalkyl, and C1-C5 alkoxy group, wherein the aryl and heteroaryl groups may be further substituted by the following substituents: C1-C3 alkoxy group and halogen.

[0022] Preferably, the o-sulfonamide aldehyde imine of formula III, the sulfonate salt of formula IV, and potassium carbonate are added to propylene oxide solvent to form a reaction system in a reaction environment. After the reaction is completed, the 2,3-disubstituted dihydroindole derivative of formula I is obtained by post-treatment.

[0023] The specific synthetic route involved in the reaction is shown below:

[0024]

[0025] This preparation method involves the formation of a sulfur ylide from sulfonium salt IV in the presence of potassium carbonate, followed by further attack on o-sulfonamide aldehyde imine III. Hydrogen migration then occurs. Next, nitrogen negatively attacks the α-carbon of the sulfur ylide, resulting in ring closure via the removal of dimethyl sulfide. Finally, the removal of one molecule of dimethyl sulfide yields dihydroindole derivative I.

[0026] Preferably, the o-sulfonamide aldehyde imine of formula III, the sulfonate salt of formula IV, and potassium carbonate are added to propylene oxide solvent to form a reaction system in a reaction environment. After the reaction is completed, lithium chloride is added to form a reaction system in a reaction environment. After the reaction is completed, the indole derivative of formula II is obtained by post-treatment.

[0027] The specific synthetic route involved in the reaction is shown below:

[0028]

[0029] This preparation method involves the formation of a sulfur ylide from sulfonium salt IV in the presence of potassium carbonate, followed by further attack on o-sulfonamide aldehyde imine III. Subsequently, hydrogen migration occurs. Then, nitrogen negatively attacks the α-carbon of the sulfur ylide, resulting in ring closure by the removal of dimethyl sulfide and the loss of one molecule of dimethyl sulfide to yield dihydroindole derivative I. Finally, indole derivative II is obtained in the presence of lithium chloride.

[0030] After the reaction is complete, the products can be separated by silica gel column chromatography. For example, for 2,3-disubstituted dihydroindole derivatives of formula I, petroleum ether:ethyl acetate can be used as the eluent for silica gel column chromatography. For indole derivatives of formula II, petroleum ether:ethyl acetate can be used as the eluent for silica gel column chromatography.

[0031] Preferably, the R 1 Selected from H, F, Cl, Br, methyl; the R 2 Selected from Ts, methylsulfonyl, benzenesulfonyl, and nitro-substituted benzenesulfonyl; The R 3 The group is selected from phenyl, thienyl, cyclopropyl, and tert-butyloxy, and the phenyl and thienyl groups may be further substituted with the following substituents: methoxy, Br, and Cl.

[0032] As a preferred option, when R 2 =Ts,R 3 =Ph, R 1 It is one of Cl, F, Me, and Br. When R 1 When =H, R 3 =Ph, R 2 It is one of MeSO2; p-NO2C6H4Ph. Wherein, when R... 1 =H,R 2 When =Ts, R 3 It is one of MeOC6H4; MeOC6H4; BrC6H4; MeOC6H4; ClC6H4; 2-thienyl; cyclopropyl; -Ot-Bu.

[0033] As a preferred option, when R 2 =Ts,R 3 =Ph, R1 It is one of Cl, Br, and Me. When R 1 When =H, R 3 =Ph, R 2 For PhSO2. Where, when R 1 =H,R 2 When =Ts, R 3 It is one of MeOC6H4 and ClC6H4.

[0034] Preferably, the alkali is selected from one or more of potassium carbonate, potassium phosphate, sodium methoxide, cesium carbonate, DIPEA, and potassium bicarbonate. More preferably, the alkali is selected from potassium carbonate.

[0035] Preferably, the reaction solvent is selected from one or more of acetonitrile, dichloroethane, diethyl ether, THF, and propylene oxide. More preferably, the reaction solvent is propylene oxide. As one embodiment, the amount of propylene oxide used is 0.5–3 mL per equiv; more preferably, 1.0 mL per equiv.

[0036] Preferably, the molar ratio of o-sulfonamide aldehyde imine, sulfonium salt, and base is 1:1 to 2:1 to 2; more preferably, it is 1:1 to 1.5:1 to 1.5; even more preferably, it is 1:1.1 to 1.5:1.1 to 1.5; most preferably, it is 1:1.1 to 1.3:1.1 to 1.3; as a preferred option, the molar ratio is 1:1.2:1.2.

[0037] When preparing the indole derivative of Formula II, the molar ratio of o-sulfonamide aldehyde imine, sulfonium salt, base, and lithium chloride is 1:1–2:1–2:1.5–6. More preferably, it is 1:1–1.5:1–1.5:2.5–6; even more preferably, it is 1:1.1–1.5:1.1–1.5:3.5–6; most preferably, it is 1:1.1–1.3:1.1–1.3:3.5–5; as a preferred embodiment, the molar ratio is 1:1.2:1.2:4.

[0038] This invention can be carried out directly at room temperature. Preferably, the reaction environment is an air atmosphere at a room temperature of 25 degrees Celsius. The reaction is carried out in an air atmosphere at room temperature with stirring.

[0039] Preferably, after the reaction of o-sulfonamide aldehyde imine and sulfonate salt is completed, the lithium chloride is added directly to the reaction system without post-processing.

[0040] The reaction time of the aforementioned reaction system is 8h to 12h.

[0041] The present invention also provides a method for preparing an indole derivative, comprising adding a 2,3-disubstituted indole derivative of formula I and lithium chloride to a reaction solvent, and after the reaction is completed, obtaining an indole derivative of formula II through post-treatment;

[0042]

[0043] The R 1 R 2 R 3 Limited to any of the above technical solutions.

[0044] Preferably, the molar ratio of the 2,3-disubstituted dihydroindole derivative shown in Formula I to lithium chloride is 1:1.5 to 6; the reaction solvent is selected from one or more of acetonitrile, dichloroethane, diethyl ether, THF, and propylene oxide.

[0045] A 2,3-disubstituted dihydroindole derivative has the structure shown in Formula I below:

[0046]

[0047] The R 1 Selected from H, halogens, and C1-C3 alkyl groups;

[0048] The R 2 Selected from methyl-substituted phenylsulfonyl, methylsulfonyl, benzenesulfonyl, and nitro-substituted benzenesulfonyl;

[0049] The R 3 The alkoxy group is selected from aryl, heteroaryl, 3-6 membered cycloalkyl, and C1-C5 alkoxy group, wherein the aryl and heteroaryl groups may be further substituted by the following substituents: C1-C3 alkoxy group and halogen.

[0050] Preferably, the R 1 Selected from H, F, Cl, Br, methyl; the R 2 Selected from Ts, methylsulfonyl, and nitro-substituted benzenesulfonyl; The R 3 The group is selected from phenyl, thienyl, cyclopropyl, and tert-butyloxy, and the phenyl and thienyl groups may be further substituted with the following substituents: methoxy, Br, and Cl.

[0051] As a further preferred option, when R 2 =Ts,R 3 =Ph, R 1 It is one of Cl, F, Me, and Br. When R 1 When =H, R 3 =Ph, R 2 It is one of MeSO2; p-NO2C6H4Ph. Wherein, when R... 1 =H,R2 When =Ts, R 3 It is one of MeOC6H4; MeOC6H4; BrC6H4; MeOC6H4; ClC6H4; 2-thienyl; cyclopropyl; Ot-Bu.

[0052] As a preferred embodiment, the structure is shown in the following formula:

[0053]

[0054] An indole derivative, with the structure shown in Formula II:

[0055] The R 1 Selected from H, halogens, and C1-C3 alkyl groups;

[0056] The R 2 Selected from methyl-substituted benzenesulfonyl, methylsulfonyl, benzenesulfonyl, and nitro-substituted benzenesulfonyl;

[0057] The R 3 Selected from aryl and heteroaryl groups, wherein the aryl and heteroaryl groups may be further substituted by the following substituents: C1-C3 alkoxy groups, halogens.

[0058] And R 1 R 2 R 3 Do not choose the following combination at the same time: R 1 For H, R 2 For Ts, R 3 It is a phenyl group.

[0059] Preferably, the R 1 Selected from H, F, Cl, Br, methyl; the R 2 Selected from Ts, methylsulfonyl, and nitro-substituted benzenesulfonyl; The R 3 Selected from phenyl and thiophene groups, wherein the phenyl and thiophene groups may be further substituted with the following substituents: methoxy, Br, Cl.

[0060] As a preferred option, when R 2 =Ts,R 3 =Ph, R 1 It is one of Cl, Br, and Me. When R 1 When =H, R 3 =Ph, R 2 For PhSO2. Where, when R 1 =H,R 2 When =Ts, R 3 It is one of MeOC6H4 and ClC6H4.

[0061] The following compounds are preferred:

[0062]

[0063] Compared with the prior art, the present invention has the following advantages:

[0064] 1. Unlike traditional methods for constructing dihydroindole skeletons, this method does not require prior pre-assembly of functional groups. It can be achieved directly through a tandem cycloaddition reaction of thioylide and o-sulfonamide aldehyde imine.

[0065] 2. The reaction does not use expensive transition metal catalysts, the raw materials are inexpensive, and it is environmentally friendly.

[0066] 3. The reaction conditions are mild, the operation is simple, the substrates are widely applicable, and the functional groups are highly compatible, showing promising application prospects; therefore, this invention has significant theoretical innovation value and implementation value.

[0067] In summary, this invention directly yields 2,3-disubstituted dihydroindole derivatives or indole derivatives via a [4+1] cycloaddition tandem reaction of thioylide and o-sulfonamide aldehyde imine, without the need for functional group pre-assembly. The reaction uses inexpensive and readily available raw materials, involves no transition metals, is green and efficient, operates under mild conditions, has a wide range of applicable substrates, achieves high yields, and is simple to operate. It provides a new route for the efficient synthesis of indole skeletons. Detailed Implementation

[0068] Example 1

[0069] In an air atmosphere, o-sulfonamide aldehyde imine 1a (78.8 mg, 0.2 mmol, 1.0 eq.), 2 mL of propylene oxide, thioyl ylide salt 2a (62.4 mg, 0.24 mmol, 1.2 eq.), and K₂CO₃ (33.2 mg, 0.24 mmol, 1.2 eq.) were added sequentially to a 10 mL Schlenk tube. The reaction was allowed to proceed for approximately 8 hours until the starting material was completely eliminated. Rapid separation and purification were performed by column chromatography (petroleum ether:ethyl acetate = 8:1 as the developing solvent), followed by concentration under reduced pressure to give 83.0 mg of a white solid 3a, with a yield of 81%. 1 H NMR (400MHz, CDCl3) δ8.08(d,J=7.6Hz,2H),7.68–7.59(m,4H),7.50(t,J=7.6Hz,2H),7.38(t,J=6.7Hz,2H),7.27(d,J=7.1Hz,2 H),7.15(t,J=7.4Hz,1H),5.54(d,J=2.5Hz,1H),4.92(dd,J=10.1,1.9Hz,1H),3.36(d,J=10.2Hz,1H),2.36(s,3H),1.26(s,9H). 13C NMR (101MHz, CDCl3) δ194.66,145.20,141.87,134.61,134.12,134.00,130.69,130.46,130.21,129. 44,128.85,127.59,126.06,125.64,116.93,71.26,60.28,58.60,24.09,21.62.HRMS(ESI)calcd.for C 26 H 29 N₂O₅S₂[M+H + ]:513.1512,found:513.1509.

[0070] The reaction formula is as follows:

[0071]

[0072] Optimization experiment: Following the steps of Example 1, the base and reaction solvent were replaced with the corresponding compounds in the table below, and the yields were as follows:

[0073]

[0074]

[0075] Based on the optimization results, potassium carbonate was chosen as the base and propylene oxide was chosen as the solvent, resulting in a higher yield. Subsequent examples will verify the results with different substrates under these optimized conditions.

[0076] Example 2

[0077] Except for replacing the o-sulfonamide aldehyde imine shown in structural formula 1a in Example 1 with the o-sulfonamide aldehyde imine shown in structural formula 1b, the other operating steps are the same as in Example 1, and a white solid 3b is obtained by separation, with a yield of 87%.

[0078] 1 H NMR (600MHz, CDCl3) δ8.18(d,J=7.4Hz,2H),7.72(d,J=7.7Hz,2H),7.67–7.59(m,2H),7.53(t,J=7.3Hz,2H),7.34(t,J=7.9Hz,1H) ,7.29(d,J=7.6Hz,2H),7.10(d,J=7.9Hz,1H),6.05(s,1H),4.89(d,J=6.4Hz,1H),3.16(d,J=6.0Hz,1H),2.38(s,3H),1.36(s,9H). 13C NMR (151MHz, CDCl3) δ194.55,145.14,144.33,134.54,134.46,134.31,132.19,131.71,130.40,129. 82,128.83,127.83,127.61,125.72,115.62,70.53,61.18,57.80,24.13,21.70.HRMS(ESI)calcd.for C 26 H 28 ClN2O5S2[M+H + ]:547.1123,found:547.1120.

[0079] The reaction formula is as follows:

[0080]

[0081] Example 3

[0082] Except for replacing the o-sulfonamide aldehyde imine shown in structural formula 1a in Example 1 with the o-sulfonamide aldehyde imine shown in structural formula 1c, the other operating steps are the same as in Example 1, and a white solid 3c is obtained by separation, with a yield of 80%. 1 H NMR (400MHz, CDCl3) δ8.19–8.11(m,2H),7.65(d,J=8.2Hz,3H),7.42–7.34(m,2H),7.29–7.26(m,2H),7.21–7.1 4(m,3H),5.51(d,J=2.6Hz,1H),4.92(dd,J=10.2,2.2Hz,1H),3.30(d,J=10.3Hz,1H),2.38(s,3H),1.29(s,9H). 13 C NMR (101MHz, CDCl3) δ193.29, 166.44 (d, J = 256.5Hz), 145.29, 141.91, 133.92, 132.38 (d, J = 9.6Hz), 131.08 (d, J = 2.9Hz), 130.82 ,130.29(d,J=2.6Hz),127.64,125.95,125.75,117.15,116.21,115.99,71.32,60.40,58.63,24.16,21.67.HRMS(ESI)calcd.for C 26 H 28 FN2O5S2[M+H + ]:531.1418,found:531.1409.

[0083] The reaction formula is as follows:

[0084]

[0085] Example 4

[0086] Except for replacing the o-sulfonamide aldehyde imine shown in structural formula 1a in Example 1 with the o-sulfonamide aldehyde imine shown in structural formula 1d, the other operating steps were the same as in Example 1, and a white solid was obtained after separation for 3 days, with a yield of 91%. 1 H NMR (400MHz, CDCl3) δ8.00–7.93(m,2H),7.64–7.54(m,3H),7.44(t,J=7.8Hz,2H),7.29–7.24(m,4H),7.23–7. 17(m,1H),5.57(s,1H),4.87(d,J=10.7Hz,1H),3.38(d,J=10.7Hz,1H),2.49(s,3H),2.40(s,3H),1.34(s,9H). 13 C NMR (101MHz, CDCl3) δ194.02,145.48,140.51,134.86,134.58,133.76,133.65,133.06,132.78,130.18, 129.22,128.67,128.33,127.60,123.25,71.14,60.04,57.35,24.17,21.61,19.79.HRMS(ESI)calcd.for C 27 H 31 N₂O₅S₂[M+H + ]:527.1669,found:527.1669.

[0087] The reaction formula is as follows:

[0088]

[0089] Example 5

[0090] Except for replacing the o-sulfonamide aldehyde imine shown in structural formula 1a in Example 1 with the o-sulfonamide aldehyde imine shown in structural formula 1e, the other operating steps are the same as in Example 1, and a white solid 3e is obtained by separation, with a yield of 85%. 1H NMR (400MHz, CDCl3) δ8.09–8.02(m,2H),7.81(d,J=1.4Hz,1H),7.72–7.60(m,3H),7.51(t,J=7.7Hz,2H),7.32(d,J=8.1Hz,2H),7.30–7. 27(m,1H),7.24(d,J=8.1Hz,1H),5.54(d,J=2.7Hz,1H),4.84(dd,J=10.3,2.5Hz,1H),3.40(d,J=10.3Hz,1H),2.40(s,3H),1.26(s,9H). 13 C NMR (101MHz, CDCl3) δ194.19,145.59,143.25,134.37,133.96,130.43,129.51,129.46,128.99,1 28.72,127.61,127.32,124.63,119.93,71.55,60.42,58.19,24.14,21.74.HRMS(ESI)calcd.for C 26 H 28 BrN2O5S2[M+H + ]:591.0618,found:591.0615.

[0091] The reaction formula is as follows:

[0092]

[0093] Example 6

[0094] Except for replacing the o-sulfonamide aldehyde imine shown in structural formula 1a in Example 1 with the o-sulfonamide aldehyde imine shown in structural formula 1f, the other operating steps are the same as in Example 1, and a white solid 3f is obtained by separation, with a yield of 86%. 1 H NMR (400MHz, CDCl3) δ8.07(d,J=7.4Hz,2H),7.67–7.58(m,3H),7.55(d,J=8.3Hz,1H),7.49(t,J=7.7Hz,2H),7.28(d,J=8.2Hz,2H),7 .22–7.14(m,2H),5.46(d,J=2.4Hz,1H),4.87(dd,J=10.4,2.2Hz,1H),3.04(d,J=10.4Hz,1H),2.38(s,3H),2.33(s,3H),1.28(s,9H). 13C NMR (101MHz, CDCl3) δ194.62,145.09,139.46,135.90,134.59,133.98,133.77,131.48,130.89,130.16, 129.40,128.76,127.60,126.32,117.30,71.44,60.21,58.46,24.09,21.57,21.10.HRMS(ESI)calcd.for C 27 H 31 N₂O₅S₂[M+H + ]:527.1669,found:527.1667.

[0095] The reaction formula is as follows:

[0096]

[0097] Example 7

[0098] Except for replacing the o-sulfonamide aldehyde imine shown in structural formula 1a in Example 1 with the o-sulfonamide aldehyde imine shown in structural formula 1g, the other operating steps were the same as in Example 1, and 3g of white solid was obtained by separation, yield: 65%. 1 H NMR (400MHz, CDCl3) δ8.08(d,J=7.4Hz,2H),7.65(t,J=7.0Hz,1H),7.52(t,J=7.3Hz,2H),7.45(d,J=7.4Hz,1H),7.40–7 .31(m,2H),7.09(t,J=7.1Hz,1H),5.91(s,1H),5.03(d,J=8.6Hz,1H),4.90(d,J=9.4Hz,1H),3.17(s,3H),1.34(s,9H). 13 C NMR (101MHz, CDCl3) δ195.08,142.02,134.64,134.19,130.94,129.59,129.08,128. 49,126.63,123.96,112.66,72.64,60.42,58.43,39.72,24.27.HRMS(ESI)calcd.for C 20 H 25 N₂O₅S₂[M+H + ]:437.1199,found:437.1203.

[0099] The reaction formula is as follows:

[0100]

[0101] Example 8

[0102] Except for replacing the o-sulfonamide aldehyde imine shown in structural formula 1a in Example 1 with the o-sulfonamide aldehyde imine shown in structural formula 1h, the other operating steps are the same as in Example 1, and a yellow solid is obtained after 3h, with a yield of 82%. 1 H NMR (400MHz, CDCl3) δ8.30(d,J=8.8Hz,2H),8.15–8.00(m,4H),7.65(t,J=7.4Hz,1H),7.53(t,J=7.8Hz,3H),7.38(t,J=6 .9Hz,2H),7.14(t,J=7.5Hz,1H),5.84(d,J=2.9Hz,1H),4.97(dd,J=9.5,2.7Hz,1H),4.21(d,J=9.4Hz,1H),1.29(s,9H). 13 C NMR (101MHz, CDCl3) δ194.36,150.66,143.56,141.34,134.59,134.37,131.03,129.53,129.30,1 29.08,128.91,126.35,125.38,124.65,114.89,71.69,60.61,58.89,24.21.HRMS(ESI)calcd.for C 25 H 26 N3O7S2[M+H + ]:544.1207,found:544.1193.

[0103] The reaction formula is as follows:

[0104]

[0105] Example 9

[0106] Except for replacing the sulfonium salt shown in structural formula 2a in Example 1 with the sulfonium salt shown in structural formula 2b, the other operating steps are the same as in Example 1, and a white solid 3i is obtained by separation, with a yield of 83%. 1H NMR(400MHz, CDCl3)δ7.65(d,J=8.1Hz,1H),7.59–7.52(m,3H),7.52–7.46(m,1H), 7.43(d,J=7.6Hz,1H),7.39–7.34(m,1H),7.25(d,J=8.3Hz,2H),7.16(td,J=7.5,0. 7Hz,1H),7.05–6.99(m,1H),6.94(d,J=8.3Hz,1H),5.55(d,J=2.7Hz,1H),4.99(dd, J=10.4,2.6Hz,1H),3.72(s,3H),2.97(d,J=10.5Hz,1H),2.38(s,3H),1.27(s,9H). 13 C NMR (101MHz, CDCl3) δ197.57,158.29,145.21,141.92,134.09,133.80,131.67,131.19,130.40,130.11,127.53,1 26.31,126.05,125.84,121.08,117.34,111.30,74.49,60.11,57.74,55.44,24.10,21.65.HRMS(ESI)calcd.forC 27 H 31 N₂O₆S₂[M+H + ]:543.1618,found:543.1617.

[0107] The reaction formula is as follows:

[0108]

[0109] Example 10

[0110] Except for replacing the sulfonium salt with structural formula 2a in Example 1 with the sulfonium salt shown in structural formula 2c, the other operating steps are the same as in Example 1, and a white solid 3j is obtained by separation, with a yield of 89%. 1 H NMR (400MHz, CDCl3) δ7.71–7.63(m,4H),7.59–7.54(m,1H),7.46–7.33(m,3H),7.27(d,J=8.2Hz,2H),7.19–7.13(m,2H ), 5.49 (d, J = 2.7Hz, 1H), 4.92 (dd, J = 10.3, 2.5Hz, 1H), 3.84 (s, 3H), 3.27 (d, J = 10.3Hz, 1H), 2.38 (s, 3H), 1.28 (s, 9H). 13C NMR (101MHz, CDCl3) δ194.32,159.86,145.16,141.81,135.77,133.95,130.67,130.54,130.16,129.78,127.55, 126.03,125.68,122.05,121.03,117.05,113.19,71.49,60.25,58.51,55.48,24.08,21.59.HRMS(ESI)calcd.for C 27 H 31 N₂O₆S₂[M+H + ]:543.1618,found:543.1615.

[0111] The reaction formula is as follows:

[0112]

[0113] Example 11

[0114] Except for replacing the sulfonium salt with structural formula 2a in Example 1 with the sulfonium salt shown in structural formula 2d, the other operating steps are the same as in Example 1, and a white solid 3k is obtained by separation, with a yield of 83%. 1 H NMR (400MHz, CDCl3) δ8.16(t,J=1.8Hz,1H),8.05(d,J=7.9Hz,1H),7.77–7.72(m,1H),7.65(d,J=8.3Hz,3H),7.43–7.34(m,3H),7.28(d,J=8. 1Hz,2H),7.17(td,J=7.6,0.7Hz,1H),5.46(d,J=2.7Hz,1H),4.93(dd,J=10.3,2.5Hz,1H),3.26(d,J=10.3Hz,1H),2.39(s,3H),1.30(s,9H). 13 C NMR (101MHz, CDCl3) δ193.63,145.37,141.78,136.92,136.47,133.91,132.26,130.88,130.42,130.31,130. 27,128.15,127.68,126.03,125.84,123.21,117.19,71.52,60.44,58.52,24.20,21.70.HRMS(ESI)calcd.for C 26 H 28 BrN2O5S2[M+H + ]:591.0618,found:591.0602.

[0115] The reaction formula is as follows:

[0116]

[0117] Example 12

[0118] Except for replacing the sulfonium salt represented by structural formula 2a in Example 1 with the sulfonium salt represented by structural formula 2e, the other operating steps are the same as in Example 1, and 3l of white solid is obtained by separation, with a yield of 89%. 1 H NMR (400MHz, DMSO) δ8.06(t,J=8.9Hz,3H),7.79(d,J=8.3Hz,2H),7.46(d,J=8.1Hz,3H),7.42(d,J=7.6Hz,1H),7.36(t ,J=7.7Hz,1H),7.17–7.11(m,2H),5.51(d,J=7.5Hz,1H),4.87(t,J=8.2Hz,1H),3.90(s,3H),2.39(s,3H),1.08(s,9H). 13 C NMR(101MHz,DMSO)δ194.83,164.43,145.36,141.09,133.45,131.73,130.57,130.37,130.06,128.53,1 28.27,126.14,124.44,114.81,113.62,68.99,60.09,59.25,56.20,23.90,21.55.HRMS(ESI)calcd.for C 27 H 31 N₂O₆S₂[M+H + ]:543.1618,found:543.1627.

[0119] The reaction formula is as follows:

[0120]

[0121] Example 13

[0122] Except for replacing the sulfonium salt with structural formula 2a in Example 1 with the sulfonium salt shown in structural formula 2f, the other operating steps are the same as in Example 1, and a white solid 3m is obtained by separation, with a yield of 80%. 1H NMR (400MHz, CDCl3) δ8.09(t,J=7.5Hz,3H),7.80(d,J=8.2Hz,2H),7.72(d,J=8.5Hz,2H),7.50–7.45(m,2H),7. 44–7.35(m,2H),7.15(t,J=7.4Hz,1H),5.49(d,J=7.4Hz,1H),4.93(t,J=8.2Hz,1H),2.39(s,3H),1.13(s,9H). 13 C NMR (101MHz, CDCl3) δ200.49,150.25,145.67,144.40,139.13,137.93,135.84,135.38,135.24,134. 44,134.31,133.07,130.81,129.33,118.40,74.58,64.77,64.10,28.72,26.30.HRMS(ESI)calcd.for C 26 H 27 ClN2NaO5S2[M+Na + ]:569.0942,found:569.0939.

[0123] The reaction formula is as follows:

[0124]

[0125] Example 14

[0126] Except for replacing the sulfonium salt with structural formula 2a in Example 1 with the sulfonium salt shown in structural formula 2g, the other operating steps are the same as in Example 1, and a yellow solid 3n is obtained by separation, with a yield of 83%. 1 H NMR (400MHz, CDCl3) δ8.13(dd,J=3.9,0.6Hz,1H),7.76–7.70(m,2H),7.66–7.61(m,2H),7.41(t,J=8.1Hz,2H),7.27(d,J=8.4 Hz,2H),7.21–7.14(m,2H),5.16(d,J=2.7Hz,1H),4.98(dd,J=10.4,2.7Hz,1H),3.13–3.00(m,1H),2.39(s,3H),1.32(s,9H). 13C NMR (101MHz, CDCl3) δ187.59,145.43,141.54,140.52,136.17,135.20,133.40,130.77,130.70,130. 19,128.56,127.59,126.12,126.01,117.26,73.11,60.28,59.13,24.12,21.59.HRMS(ESI)calcd.for C 24 H 27 N₂O₅S₃[M+H + ]:519.1077,found:519.1073.

[0127] The reaction formula is as follows:

[0128]

[0129] Example 15

[0130] Except for replacing the sulfonium salt with structural formula 2a in Example 1 with the sulfonium salt shown in structural formula 2h, the other operating steps are the same as in Example 1, and a white solid 3o is obtained by separation, with a yield of 58%. 1 H NMR (400MHz, CDCl3) δ7.78(d,J=8.4Hz,1H),7.55(d,J=8.2Hz,2H),7.42(t,J=7.0Hz,2H),7.26(d,J=8.4Hz,2H),7.21(t,J=7.4Hz,1H),5.0 4(d,J=10.0Hz,1H),4.59(d,J=1.7Hz,1H),2.79–2.69(m,1H),2.41(s,1H),2.38(s,3H),1.32(s,9H),1.17–1.04(m,2H),1.03–0.95(m,2H). 13 C NMR (151MHz, CDCl3) δ205.28,145.72,140.90,133.07,131.57,130.67,130.30,127.47,126.65, 126.50,118.32,76.10,60.16,56.89,24.23,21.64,17.57,13.28,13.10.HRMS(ESI)calcd.forC 23 H 29 N₂O₅S₂[M+H + ]:477.1512,found:477.1510.

[0131] The reaction formula is as follows:

[0132]

[0133] Example 16

[0134] Except for replacing the sulfonium salt shown in structural formula 2a in Example 1 with the sulfonium salt shown in structural formula 2i, the other operating steps are the same as in Example 1, and a white solid 3p is obtained by separation, with a yield of 27%. 1 H NMR (400MHz, CDCl3) δ7.70–7.58(m,3H),7.43–7.34(m,2H),7.26(d,J=7.2Hz,2H),7.20–7.11(m,1H),4.87(d d,J=10.3,2.1Hz,1H),4.46(d,J=2.4Hz,1H),2.94(d,J=10.3Hz,1H),2.38(s,3H),1.46(s,9H),1.37(s,9H). 13 C NMR (101MHz, CDCl3) δ167.52,145.14,141.22,134.18,130.64,130.55,130.06,127.25,126 .17,125.71,116.83,83.43,70.52,60.06,58.80,27.87,24.21,21.54.HRMS(ESI)calcd.for C 24 H 33 N₂O₆S₂[M+H + ]:509.1775,found:509.1766.

[0135] The reaction formula is as follows:

[0136]

[0137] Example 17

[0138] In an air atmosphere, o-sulfonamide aldehyde imine 1a (78.8 mg, 0.2 mmol, 1.0 eq.), 2 mL of propylene oxide, thioyl ylide salt 2a (62.4 mg, 0.24 mmol, 1.2 eq.), and K₂CO₃ (33.2 mg, 0.24 mmol, 1.2 eq.) were added sequentially to a 10 mL Schlenk tube. The reaction was allowed to proceed for approximately 8 hours until the starting material was completely eliminated. Then, LiCl (33.9 mg, 0.8 mmol, 4.0 eq.) was added. The reaction was allowed to proceed for approximately 8 hours until the starting material was completely eliminated. Rapid separation and purification were performed by column chromatography (petroleum ether:ethyl acetate = 8:1 as the developing solvent), followed by concentration under reduced pressure to give 58.5 mg of a white solid 4a, with a yield of 78%. 1H NMR (600MHz, CDCl3) δ8.14(d,J=8.5Hz,1H),7.98(d,J=7.4Hz,2H),7.94(d,J=8.3Hz,2H),7.62(t,J=7.4Hz,1H), 7.57(d,J=7.8Hz,1H),7.50(t,J=7.7Hz,2H),7.46(t,J=7.5Hz,1H),7.32–7.26(m,3H),6.93(s,1H),2.37(s,3H). 13 C NMR (151MHz, CDCl3) δ187.78,145.22,138.05,137.79,137.63,135.32,133.66,130.17,129.76 ,128.77,128.64,127.72,127.06,124.32,122.65,116.74,115.27,21.80.HRMS(ESI)calcd.for C 22 H 18 NO3S[M+H + ]:376.1002,found:376.0999.

[0139] The reaction formula is as follows:

[0140]

[0141] Example 18

[0142] Except for replacing the o-sulfonamide aldehyde imine shown in structural formula 1a in Example 1 with the o-sulfonamide aldehyde imine shown in structural formula 1b, the other operating steps are the same as in Example 17, and a white solid 4b is obtained by separation, with a yield of 83%. 1 H NMR (600MHz, CDCl3) δ8.04(d,J=8.4Hz,1H),7.98(dd,J=14.9,7.8Hz,4H),7.64(t,J=7.4Hz,1H) ,7.51(t,J=7.7Hz,2H),7.37(t,J=8.1Hz,1H),7.29(t,J=6.9Hz,3H),7.01(s,1H),2.38(s,3H). 13 C NMR (151MHz, CDCl3) δ187.47,145.60,138.19,138.07,137.23,135.08,133.93,130.22,129.89 ,128.73,127.80,127.74,127.65,127.54,123.98,113.74,113.61,21.81.HRMS(ESI)calcd.for C22 H 17 ClNO3S[M+H + ]:410.0612,found:410.0609.

[0143] The reaction formula is as follows:

[0144]

[0145] Example 19

[0146] Except for replacing the o-sulfonamide aldehyde imine shown in structural formula 1a in Example 1 with the o-sulfonamide aldehyde imine shown in structural formula 1e, the other operating steps are the same as in Example 17, and a white solid 4c is obtained by separation, with a yield of 63%. 1 H NMR (600MHz, CDCl3) δ8.33 (s, 1H), 7.96 (d, J = 8.0Hz, 4H), 7.63 (t, J = 7.3Hz, 1H), 7.50 (t,J=7.7Hz,2H),7.45–7.40(m,2H),7.32(d,J=8.1Hz,2H),6.87(s,1H),2.40(s,3H). 13 C NMR (151MHz, CDCl3) δ187.38,145.59,138.33,138.30,137.35,135.17,133.85,130.17,129 .92,128.70,127.78,127.47,123.66,120.86,118.26,115.97,21.84.HRMS(ESI)calcd.for C 22 H 17 BrNO3S[M+H + ]:454.0107,found:454.0102.

[0147] The reaction formula is as follows:

[0148]

[0149] Example 20

[0150] Except for replacing the o-sulfonamide aldehyde imine shown in structural formula 1a in Example 1 with the o-sulfonamide aldehyde imine shown in structural formula 1f, the other operating steps were the same as in Example 17, and a white solid was obtained after 4 days, with a yield of 66%. 1H NMR (400MHz, CDCl3) δ8.01(d,J=8.6Hz,1H),7.96(d,J=7.7Hz,2H),7.90(d,J=8.1Hz,2H),7.60(t,J=7.3H z,1H),7.47(t,J=7.6Hz,2H),7.33(s,1H),7.25(t,J=8.8Hz,3H),6.86(s,1H),2.41(s,3H),2.35(s,3H). 13 C NMR (101MHz, CDCl3) δ187.78,145.09,138.16,137.71,136.07,135.23,134.09,133.55,130.10,12 9.69,129.05,128.61,128.59,127.61,122.36,116.87,114.95,21.74,21.33.HRMS(ESI)calcd.for C 23 H 20 NO3S[M+H + ]:390.1158,found:390.1156.

[0151] The reaction formula is as follows:

[0152]

[0153] Example 21

[0154] Except for replacing the o-sulfonamide aldehyde imine shown in structural formula 1a in Example 1 with the o-sulfonamide aldehyde imine shown in structural formula 1i, the other operating steps are the same as in Example 17, and a white solid 4e is obtained by separation, with a yield of 56%. 1 H NMR (600MHz, CDCl3) δ8.15(d,J=8.5Hz,1H),8.08(d,J=7.7Hz,2H),7.99(d,J=7.5Hz,2H),7.6 3(t,J=7.3Hz,1H),7.60–7.55(m,2H),7.54–7.45(m,5H),7.31(t,J=7.5Hz,1H),6.95(s,1H). 13 CNMR (151MHz, CDCl3) δ187.62,138.29,138.01,137.83,137.53,134.08,133.70,130.16,129 .13,128.71,128.65,127.63,127.18,124.41,122.72,117.03,115.23.HRMS(ESI)calcd.for C 21 H16 NO3S[M+H + ]:362.0845,found:362.0846.

[0155] The reaction formula is as follows:

[0156]

[0157] Example 22

[0158] Except for replacing the sulfonium salt shown in structural formula 2a in Example 1 with the sulfonium salt shown in structural formula 2c, the other operating steps are the same as in Example 17, and a white solid 4f is obtained by separation, with a yield of 69%. 1 H NMR(600MHz, CDCl3)δ8.13(d,J=8.5Hz,1H),7.95(d,J=8.3Hz,2H),7.60–7.50(m,3H),7.46(t,J=7.8Hz,1H), 7.39(t,J=7.9Hz,1H),7.32–7.25(m,3H),7.17(dd,J=8.2,2.5Hz,1H),6.94(s,1H),3.86(s,3H),2.37(s,3H). 13 C NMR (151MHz, CDCl3) δ187.46,159.82,145.22,138.84,137.94,137.79,135.34,129.74,129.61,128.67,12 7.69,127.07,124.30,123.37,122.67,120.49,116.80,115.22,113.71,55.61,21.77.HRMS(ESI)calcd.for C 23 H 20 NO4S[M+H + ]:406.1108,found:406.1107.

[0159] The reaction formula is as follows:

[0160]

[0161] Example 23

[0162] Except for replacing the sulfonium salt shown in structural formula 2a in Example 1 with the sulfonium salt shown in structural formula 2f, the other operating steps are the same as in Example 17, and 4g of white solid is obtained by separation, with a yield of 76%. 1H NMR (600MHz, DMSO) δ8.04 (d, J = 7.9 Hz, 1H), 7.91 (d, J = 7.5 Hz, 2H), 7.82 (d, J = 7. 3Hz,2H),7.73–7.61(m,3H),7.56–7.48(m,1H),7.44–7.27(m,4H),2.31(s,3H). 13 C NMR (151MHz, DMSO) δ186.29,146.16,139.32,137.28,137.25,136.09,134.13,131.78,130.47, 129.52,129.06,127.77,127.50,125.11,123.53,117.80,115.25,21.52.HRMS(ESI)calcd.for C 22 H 16 ClNNaO3S[M+Na + ]:432.0432,found:432.0429. The reaction formula is as follows:

Claims

1. A method for preparing a dihydroindole derivative, characterized by, The preparation method comprises the following steps: The o-sulfonamide aldimine shown in formula III, the sulfonium salt shown in formula IV and the base are added into a reaction solvent, after the reaction is completed, the 2,3-disubstituted indoline derivative shown in formula I is obtained through post-treatment; ； wherein R is selected from the group consisting of H, halogen, C1-C3alkyl; and 1 H, halogen, C1-C3alkyl; and said R 2 selected from methyl-substituted phenylsulfonyl, methylsulfonyl, phenylsulfonyl, nitro-substituted phenylsulfonyl; said R 3 selected from the group consisting of phenyl, thienyl, cyclopropyl, tert-butyloxy, said phenyl, thienyl can be further substituted by methoxy, Br, Cl; The base is selected from potassium carbonate; The reaction solvent is selected from propylene oxide.

2. The method for preparing the dihydroindole derivative according to claim 1, characterized in that, said R 1 selected from H, F, CI, Br, methyl; said R 2 selected from Ts, methylsulfonyl, phenylsulfonyl, nitro-substituted phenylsulfonyl.

3. The method for preparing the dihydroindole derivative according to claim 1, characterized in that, The molar ratio of the o-sulfonamide aldimine, the sulfonium salt and the base is 1:1-2:1-2.

4. A process for the preparation of an indole derivative of formula II ###0003### II characterized in that, The preparation method comprises the following steps: The o-sulfonamide aldimine shown in formula III, the sulfonium salt shown in formula IV and the base are added into a reaction solvent, after the reaction is completed, the 2,3-disubstituted indoline derivative shown in formula I is obtained through post-treatment; ； The R 1 , R 2 , R 3 are as defined in claim 1 ; When the indole derivative shown in formula II is prepared, the molar ratio of the o-sulfonamide aldimine, the sulfonium salt, the base and the lithium chloride is 1:1-2:1-2:1.5-6; The base is selected from potassium carbonate; and the reaction solvent is selected from propylene oxide.

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