CN114292277A - Indoline tetrahydropyrane compound and preparation method thereof - Google Patents

Abstract

The invention discloses a class of indoline-tetrahydropyran compounds and a preparation method thereof, belonging to the field of organic synthesis. The preparation method comprises the following steps: adding Pd ₂ (dba) ₃ •CHCl ₃ and Ligand, then add solvent, stir and complex for 5 minutes, then add 3-nitroindole (II) and alkenyl carbonate (III) in turn; after the reaction is completed, separate and purify to obtain indoline tetrahydropyran Compound (I); the indoline-containing tetrahydropyran-containing compound provided by the present invention contains an easily functionalized group, which is convenient for derivatization and synthesis of other polycyclic compounds, and can provide more information for the research and development of new drugs and the screening of drugs. Multiple candidate molecules; and the preparation method of the present invention has the advantages of novelty, simplicity, simple operation, mild reaction conditions and high yield.

Description

Indoline tetrahydropyran compounds and preparation method thereof

technical field

The invention relates to the field of organic synthesis, in particular to an indolinotetrahydropyran compound and a preparation method thereof.

Background technique

Asymmetric dearomatization is a difficult point in the field of organic synthesis. At present, the main research direction is electron-rich aromatic compounds, such as indole, naphthol, etc., which mainly utilize the inherent nucleophilicity of these compounds. In recent years, 3-nitroindoles, as a class of electron-poor heteroaromatics, have attracted extensive interest among organic chemists, especially in palladium-catalyzed dearomatization [3+2] cycloaddition reactions. The field has a very important position.

However, there are only 2 cases of dearomatization [4+2] cycloaddition reactions involving palladium-catalyzed 3-nitroindole, and both are Π-allylpalladium 1,4-[N, C] Dipolar reactive intermediates react with 3-nitroindole (Chin. Chem. Lett., 2019, 30, 1512–1514; Synlett., 2020, 31, 916–924).

Furthermore, so far, the dearomatization [4+2] cycloaddition of Π-allylpalladium 1,4-[O,C] dipolar-active intermediate with 3-nitroindole has not been See reports, it is likely that the nucleophilicity of oxygen is weaker than that of carbon and nitrogen, which makes the first step of dearomatization addition difficult.

On the other hand, alkenyl carbonates can form Π-allylpalladium 1,4-[O,C] dipolar active intermediates under the action of palladium, which have been successfully used in [4+2] cycloadditions reaction, and the research on dearomatization has not been reported yet.

SUMMARY OF THE INVENTION

One of the objectives of the present invention is to provide a new class of indolinotetrahydropyrans to solve the above problems.

In order to achieve the above object, the technical scheme adopted in the present invention is as follows: the indoline tetrahydropyran compound has the structure shown in the following structural formula (I):

In the above structural formula, the R ¹ group is an electron-withdrawing substituent, and the R ² group is a mono- or multi-substituent group, and the substituent group is selected from one of hydrogen, alkyl, alkoxy, nitro or halogen.

As a preferred technical solution, the electron withdrawing substituent is selected from one of p-methylbenzenesulfonyl, benzenesulfonyl, acyl or ester group.

The invention discloses for the first time a new class of indoline-tetrahydropyran compounds and a preparation method thereof. The compound contains an easily functionalized group, which is convenient for derivatization and synthesis of other chiral polycyclic compounds, and can be used for the research and development of new drugs and medicines. screening provides more candidate molecules.

The present invention realizes the dearomatization [4+2] reaction of Π-allylpalladium 1,4-[O,C] dipolar active intermediate and 3-nitroindole, which has very important significance: Not only is it the first case to use Π-allylpalladium 1,4-[O,C] dipolar active intermediates to achieve the dearomatization of electron-poor aromatic heterocycles, and the resulting indolinenotetrahydropyran Compounds exist widely in life-active molecules, have diverse biological activities, and are an important source for the development of new drugs.

More specifically, the application value of the above-mentioned compounds disclosed in the present invention lies in: many of the existing indoline tetrahydropyran compounds have very good biological activities, and it can be reasonably predicted that this large class of compounds synthesized by the present invention can be reasonably predicted. Compounds also have certain biological activities, thus providing a sufficient source of compounds for the screening of drug activities; in addition, it can provide more candidate molecules for the research and development of new drugs and drug screening, especially high-throughput screening, enriching the library of such compounds.

The second purpose of the present invention is to provide a preparation method of the above-mentioned indoline tetrahydropyran compounds, the technical scheme adopted is: adding Pd ₂ (dba) ₃ ·CHCl ₃ and a ligand in the reaction test tube , then add the solvent, after stirring and complexing, add 3-nitroindole (II) and alkenyl carbonate (III) in turn, after the reaction is completed, separate and purify to obtain indoline tetrahydropyran compounds (I ),in,

The 3-nitroindole (II) has the following structure:

The alkenyl carbonate (III) has the following structure:

Its reaction formula is:

As a preferred technical solution: the stirring and complexing time is 1-30 min, more preferably 5 min, and the complexing can be completed while ensuring the efficiency.

As a preferred technical scheme: the reaction solvent is selected from one of toluene, mesitylene, dichloromethane, chloroform, tetrahydrofuran, ether, acetonitrile, ethanol, methanol, 1,4-dioxane, chlorobenzene or Various mixes.

The reaction solvent is further preferably acetonitrile because the yield of the reaction is the highest.

As a preferred technical solution: the ligand is a phosphine ligand, and triphenylphosphine is further preferred because the yield is high and triphenylphosphine is easy to obtain and cheap.

As a preferred technical solution: the minimum amount of the catalyst (Pd ₂ (dba) ₃ ·CHCl ₃ /PPh ₃ ) is 1 mol%.

As a preferred technical solution: the reaction temperature is 0°C to 50°C.

40°C is further preferred because the reaction yield is high and energy consumption is low.

Compared with the prior art, the advantages of the present invention are: the present invention realizes the first example of Π-allylpalladium 1,4-[O,C] dipolar active intermediate and 3-nitroindole of the dearomatization For the first time, a series of new indoline-tetrahydropyran compounds and their synthesis methods were disclosed for the [4+2] cycloaddition reaction. These compounds contain easily functionalized groups, which are convenient for derivatization and synthesis of other chiral compounds. Polycyclic compounds can provide more candidate molecules for the research and development of new drugs and drug screening, especially high-throughput screening, and enrich the library of such compounds; moreover, the method of the invention has the advantages of mild reaction conditions, easy availability of raw materials and catalysts, and easy operation. It has the advantages of simplicity, low catalyst dosage (as low as 1 mol%), and high yield (99% yield).

Description of drawings

Fig. 1 is the hydrogen spectrogram of the I-a that embodiment 1 makes;

Fig. 2 is the carbon spectrogram of the I-a that embodiment 1 makes;

FIG. 3 is a single crystal diagram of I-a prepared in Example 1. FIG.

Detailed ways

The present invention will be further described below with reference to the accompanying drawings.

The raw materials, solvents, catalysts, molecular sieves, etc. used in the present invention are all commercially available.

Example 1: Synthesis of compound I-a

Pd ₂ (dba) ₃ ·CHCl ₃ and the ligand were added into a dry reaction test tube, then the solvent was added, and after stirring and complexing for 5 minutes, 0.1 mmol of 3-nitroindole II-a was added successively, Base carbonate III-a 0.15mmol; after the reaction is complete, the crude product is separated and purified by column chromatography to obtain compound Ia, different reaction conditions are shown in Table 1, and the specific reaction process is as follows:

Table 1 Different reaction conditions

In Table 1, "x" represents the amount of catalyst Pd ₂ (dba) ₃ ·CHCl ₃ , and "y" represents the amount of ligand.

It can be seen from Table 1 that the catalyst Pd ₂ (dba) ₃ ·CHCl ₃ 5 mol % and PPh ₃ (15 mol %), acetonitrile as a solvent, and a reaction temperature of 40° C. is a more preferred solution.

The obtained compound I-a is a white solid with a purity of >99% detected by HPLC; >20:1 dr, m.p. 148.4-150.2°C.

Structure identification: hydrogen spectrum ¹ H NMR (600MHz, CDCl ₃ ) see Figure 1: δ7.80 (d, J=8.4Hz, 2H), 7.61 (d, J=8.2Hz, 1H), 7.42-7.38 (m, 1H), 7.32(d, J=7.6Hz, 1H), 7.26(d, J=8.4Hz, 2H), 7.11-7.07(m, 1H), 6.51(s, 1H), 4.87(d, J=2.3 Hz,1H),4.75(d,J=2.3Hz,1H),4.30(dd,J=15.8,1.8Hz,1H),4.08(dd,J=15.8,2.2Hz,1H),3.31(dt,J = 14.0, 1.8 Hz, 1H), 3.21 (d, J=14.0 Hz, 1H), 2.38 (s, 3H). Carbon spectrum ¹³ C NMR (151 MHz, CDCl ₃ ) see Figure 2: δ 145.1, 142.6, 136.8, 134.7 ,132.5,129.9,127.7,126.0,125.1,124.6,114.5,111.9,92.7,91.6,63.0,36.2,21.7.HRMS(ESI-TOF)calcd.for C ₁₉ H ₁₉ N ₂ O ₅ S[M+H] ^+387.1009 ; found: 387.1006.

Single crystal diffraction experiment:

Single crystal cultivation: The main component compound I-a (40 mg) obtained in Example 1 was dissolved in 20 mL of ethanol, and left standing at room temperature for 7 days, a single crystal was precipitated, and the single crystal was collected for single crystal diffraction test, as shown in Figure 3 .

The test parameters are shown in Table 2:

Table 2 Single crystal test parameters

Example 2: Synthesis of Compound I-b

Pd ₂ (dba) ₃ ·CHCl ₃ (5mol%) and PPh ₃ (15mol%) were added to a dry reaction test tube, then the solvent was added, and after stirring and complexing for 5 minutes, 3-nitroindole Ⅱ was added in sequence -b 0.1 mmol, alkenyl carbonate III-a 0.15 mmol; after the completion of the reaction (24h), the crude product was separated and purified by column chromatography to obtain compound Ib.

White solid; 35.9 mg, 97% yield; >20:1 dr; m.p. 174.3-175.0°C.

Structure identification: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.98 (d, J=7.5 Hz, 2H), 7.75-7.68 (m, 1H), 7.64-7.57 (m, 2H), 7.55-7.44 ( m, 3H), 7.20-7.10(m, 1H), 6.52(s, 1H), 4.92(s, 1H), 4.75(s, 1H), 4.26(d, J＝15.7Hz, 1H), 3.70(d , J=15.7Hz, 1H), 3.45 (d, J=14.2Hz, 1H), 3.33-3.26 (m, 1H). ¹³ C NMR (101MHz, DMSO-d ₆ )δ141.9, 137.2, 137.0, 134.3, 132.5 ,129.5,127.4,126.0,125.4,124.5,113.3,111.5,91.7,90.9,62.2,33.8.HRMS(ESI-TOF)calcd.forC ₁₈ H ₁₆ N ₂ NaO ₅ S[M+Na] ⁺ 395.0672; found: 395.0675.

Example 3: Synthesis of Compound I-c

Pd ₂ (dba) ₃ ·CHCl ₃ (5mol%) and PPh ₃ (15mol%) were added to a dry reaction test tube, then the solvent was added, and after stirring and complexing for 5 minutes, 3-nitroindole Ⅱ was added in sequence -c 0.1 mmol, alkenyl carbonate III-a 0.15 mmol. After the reaction was completed (24h), the crude product was separated and purified by column chromatography to obtain compound Ic.

Colorless oil; 11.9 mg, 48% yield; >20:1 dr;.

Structure identification: ¹ H NMR (600MHz, DMSO-d ₆ )δ8.75(s, 1H), 8.15-8.10(m, 1H), 7.68-7.64(m, 1H), 7.43-7.38(m, 2H), 5.27(s, 1H), 5.05(s, 2H), 5.02(s, 1H), 4.52(s, 2H), 1.95(s, 3H). ¹³ C NMR(151MHz, DMSO-d ₆ )δ169.9,138.9, ^found _{_ _ _ _} : 275.1027.

Example 4: Synthesis of Compound I-d

Pd ₂ (dba) ₃ ·CHCl ₃ (5mol%) and PPh ₃ (15mol%) were added to a dry reaction test tube, then the solvent was added, and after stirring and complexing for 5 minutes, 3-nitroindole Ⅱ was added in sequence -d 0.1 mmol, alkenyl carbonate III-a 0.15 mmol. After the reaction was completed (24h), the crude product was separated and purified by column chromatography to obtain compound Id.

White solid; 25.2 mg, 88% yield; >20:1 dr; m.p. 93.4-94.5°C.

Structural identification: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.81-7.67 (m, 1H), 7.59 (dd, J=7.6, 1.3 Hz, 1H), 7.52-7.43 (m, 1H), 7.19- 7.13(m, 1H), 6.37(s, 1H), 4.97(s, 1H), 4.80(s, 1H), 4.28(dd, J=15.3, 1.4Hz, 1H), 3.90-3.82(m, 4H) , 3.48 (d, J=14.2Hz, 1H), 3.37 (dt, J=14.2, 1.8Hz, 1H). ¹³ C NMR (101MHz, DMSO-d ₆ )δ152.4,143.0,137.5,132.1,125.6,125.2, 123.8, 114.6, 111.4, 91.8, 88.5, 62.8, 53.3, 34.4. HRMS (ESI-TOF) calcd. for C ₁₄ H ₁₄ N ₂ NaO ₅ [M+Na] ⁺ 313.0795; found: 313.0799.

Example 5: Synthesis of Compound I-e

Pd ₂ (dba) ₃ ·CHCl ₃ (5mol%) and PPh ₃ (15mol%) were added to a dry reaction test tube, then the solvent was added, and after stirring and complexing for 5 minutes, 3-nitroindole Ⅱ was added in sequence -e 0.1 mmol, alkenyl carbonate III-a 0.15 mmol; after the completion of the reaction (24h), the crude product was separated and purified by column chromatography to obtain compound Ie.

Yellow solid; 25.9 mg, 71% yield; >20:1 dr; m.p. 59.0-60.8°C.

Structure identification: ¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.75(s, 1H), 7.59(d, J=7.0Hz, 1H), 7.50-7.45(m, 3H), 7.44-7.39(m, 2H), 7.36(d, J＝7.0Hz, 1H), 7.19-7.12(m, 1H), 6.45(s, 1H), 5.34(s, 2H), 4.97(s, 1H), 4.80(s, 1H) ),4.29(d,J＝15.4Hz,1H),3.88(dd,J＝15.4,1.9Hz,1H),3.49(d,J＝14.2Hz,1H),3.38(dt,J＝14.2,1.9Hz ,1H). ¹³ C NMR (101MHz, DMSO-d ₆ )δ151.7,143.0,137.5,135.9,132.2,128.5,128.2,127.6,125.7,125.2,123.9,114.6,111.4,91.7,88.6,67.3,62.8,34 .HRMS(ESI-TOF) _{calcd.for C20H18N2NaO5} [ _{M +} Na] ⁺ 389.1108; found: 389.1113.

Example 6: Synthesis of Compound I-f

Pd ₂ (dba) ₃ ·CHCl ₃ (5mol%) and PPh ₃ (15mol%) were added to a dry reaction test tube, then the solvent was added, and after stirring and complexing for 5 minutes, 3-nitroindole Ⅱ was added in sequence -f 0.1 mmol, alkenyl carbonate III-a 0.15 mmol. After the reaction was completed (24h), the crude product was separated and purified by column chromatography to obtain compound If.

White solid; 28.7mg, 86% yield; >20:1dr; m.p.33.8-35.0°C

Structure identification: ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.83-7.59 (m, 1H), 7.55 (d, J=7.4Hz, 1H), 7.48-7.43 (m, 1H), 7.15-7.10 ( m, 1H), 6.29(s, 1H), 4.96(s, 1H), 4.79(s, 1H), 4.27(d, J=15.4Hz, 1H), 3.88(d, J=15.4Hz, 1H), 3.43(d, J=14.3Hz, 1H), 3.40-3.39(m, 1H), 1.53(s, 9H). ¹³ C NMR (151MHz, DMSO-d ₆ ) δ 150.8, 143.2, 137.7, 132.1, 125.8, 125.0 , 123.5, 114.7, 111.3, 91.7, 88.7, 82.2, 62.9, 34.4, 27.8. HRMS(ESI-TOF) calcd. for C ₁₇ H ₂₀ N ₂ NaO ₅ [M+Na] ⁺ 355.1264; found: 355.1274.

Example 7: Synthesis of Compound I-g

Pd ₂ (dba) ₃ ·CHCl ₃ (5mol%) and PPh ₃ (15mol%) were added to a dry reaction test tube, then the solvent was added, and after stirring and complexing for 5 minutes, 3-nitroindole Ⅱ was added in sequence -g 0.1 mmol, alkenyl carbonate III-a 0.15 mmol; after the completion of the reaction (24 h), the crude product was separated and purified by column chromatography to obtain compound Ig.

White solid; 41.4 mg, 98% yield; >20:1 dr; m.p. 109.6-111.8°C

Structure identification: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.87 (d, J=8.4 Hz, 2H), 7.50-7.44 (m, 2H), 7.42-7.37 (m, 2H), 7.17 (dd, J=7.0, 1.9Hz, 1H), 6.46 (s, 1H), 4.94 (d, J=2.1Hz, 1H), 4.79 (d, J=2.1Hz, 1H), 4.40 (dd, J=16.0, 1.6 Hz, 1H), 3.96(dd, J=16.0, 2.1Hz, 1H), 3.53(d, J=14.0Hz, 1H), 3.43-3.39(m, 1H), 2.36(s, 3H). ¹³ C NMR (101MHz, DMSO-d ₆ )δ145.3,144.3,136.9,134.0,133.7,130.8,130.0,127.8,125.2,123.0,112.4,111.3,92.8,91.7,62.4,32.2,21.1.HRMS(ESI-TOF)calcd. for _{C19H17ClN2NaO5S} [M ^+Na]+ _{443.0439 ;} found: _443.0444 .

Example 8: Synthesis of Compound I-h

Pd ₂ (dba) ₃ ·CHCl ₃ (5mol%) and PPh ₃ (15mol%) were added to a dry reaction test tube, then the solvent was added, and after stirring and complexing for 5 minutes, 3-nitroindole Ⅱ was added in sequence -h 0.1 mmol, alkenyl carbonate III-a 0.15 mmol; after the completion of the reaction (24 h), the crude product was separated and purified by column chromatography to obtain compound Ih.

White solid; 46.0 mg, 99% yield; >20:1dr; m.p.69.2-71.4°C;

Structure identification: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.87 (d, J=8.4 Hz, 2H), 7.53 (dd, J=8.0, 1.1 Hz, 1H), 7.41-7.35 (m, 3H) ,7.32(dd,J＝8.0,1.1Hz,1H),6.46(s,1H),4.92(d,J＝2.2Hz,1H),4.79(d,J＝2.2Hz,1H),4.40(dd, J=16.0, 1.6Hz, 1H), 3.99 (dd, J=16.0, 2.0Hz, 1H), 3.59 (d, J=14.0Hz, 1H), 3.40 (dt, J=14.0, 2.0Hz, 1H), 2.36(s,3H). ¹³ C NMR (101MHz, DMSO-d ₆ )δ145.2, 144.4, 136.8, 133.9, 133.7, 129.9, 128.5, 127.8, 124.6, 119.3, 112.8, 111.2, 93.4, 91.7, 62.4, 32.1, 21.1. HRMS (ESI-TOF) _calcd . for _{C19H17BrN2NaO5S} [M+Na] ⁺ _488.9915 ; found: _488.9918 .

Example 9: Synthesis of Compound I-i

Pd ₂ (dba) ₃ ·CHCl ₃ (5mol%) and PPh ₃ (15mol%) were added to a dry reaction test tube, then the solvent was added, and after stirring and complexing for 5 minutes, 3-nitroindole Ⅱ was added in sequence -i 0.1 mmol, alkenyl carbonate III-a 0.15 mmol. After the reaction was completed (24h), the crude product was separated and purified by column chromatography to obtain compound Ii.

White solid; 40.6 mg, 99% yield; >20:1dr; m.p.99.3-100.5°C;

Structure identification: ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.84 (d, J=8.3 Hz, 2H), 7.38 (d, J=8.3 Hz, 2H), 7.33-7.29 (m, 2H), 6.89 (dd,J＝6.1,2.4Hz,1H),6.32(s,1H),5.02(d,J＝2.4Hz,1H),4.78(d,J＝2.4Hz,1H),4.34(d,J＝ 15.9Hz, 1H), 3.93(d, J=15.9Hz, 1H), 3.40-3.37(m, 2H), 2.34(s, 3H), 2.19(s, 3H). ¹³ C NMR(151MHz, DMSO-d ₆ ) δ145.0,142.8,137.5,136.9,134.3,132.1,130.0,127.7,126.8,124.2,111.1,111.0,93.5,91.6,62.8,32.9,21.1,17.8.HRMS(ESI-TOF)calcd.for C ₂₀ H _20N2NaO5S [M ₊ Na] ⁺ _423.0985 ; found: 423.0992.

Example 10: Synthesis of Compound I-j

Pd ₂ (dba) ₃ ·CHCl ₃ (5mol%) and PPh ₃ (15mol%) were added to a dry reaction test tube, then the solvent was added, and after stirring and complexing for 5 minutes, 3-nitroindole Ⅱ was added in sequence -j 0.1 mmol, alkenyl carbonate III-a 0.15 mmol; after the completion of the reaction (24h), the crude product was separated and purified by column chromatography to obtain compound Ij.

White solid; 38.3 mg, 95% yield; >20:1 dr; m.p. 152.4-155.2°C.

Structure identification: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.83 (d, J=8.1 Hz, 2H), 7.55-7.47 (m, 2H), 7.40 (d, J=8.1 Hz, 2H), 7.36 -7.28(m, 1H), 6.49(s, 1H), 4.93(s, 1H), 4.78(s, 1H), 4.31(d, J=15.8Hz, 1H), 3.77(d, J=15.8Hz, 1H), 3.45(d, J=14.1Hz, 1H), 3.29(d, J=14.1Hz, 1H), 2.36(s, 3H);

¹³ C NMR (101 MHz, DMSO-d ₆ ) δ 158.8 (d, J=241.6 Hz), 145.0, 138.4 (d, J=2.0 Hz), 136.8, 134.1, 130.0, 127.7 (d, J=9.0 Hz) ,127.5,119.4(d,J＝23.9Hz),115.0(d,J＝8.5Hz),113.0(d,J＝25.3Hz),111.8,91.6(d,J＝1.9Hz),91.4,62.3,33.9 ,21.0;

HRMS (ESI-TOF) _calcd . for _{C19H17FN2NaO5S} [M+Na] ⁺ _427.0734 ; found: _427.0740 .

Example 11: Synthesis of Compound I-k

Pd ₂ (dba) ₃ ·CHCl ₃ (5mol%) and PPh ₃ (15mol%) were added to a dry reaction test tube, then the solvent was added, and after stirring and complexing for 5 minutes, 3-nitroindole Ⅱ was added in sequence -k 0.1 mmol, alkenyl carbonate III-a 0.15 mmol; after the completion of the reaction (24h), the crude product was separated and purified by column chromatography to obtain compound Ik.

White solid; 40.6 mg, 97% yield; >20:1 dr; m.p. 113.0-115.4°C.

Structure identification: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.85 (d, J=8.4 Hz, 2H), 7.70 (dd, J=1.7, 0.9 Hz, 1H), 7.55-7.47 (m, 2H) ,7.41(d,J＝8.1Hz,2H),6.49(s,1H),4.94(s,1H),4.78(s,1H),4.29(d,J＝15.8Hz,1H),3.73(d, J=15.8Hz, 1H), 3.50 (d, J=14.3Hz, 1H), 3.29 (d, J=14.3Hz, 1H), 2.36 (s, 3H);

¹³ C NMR (101MHz, DMSO-d ₆ )δ145.1, 141.0, 136.7, 134.1, 132.4, 130.0, 128.3, 127.8, 127.5, 125.7, 114.9, 111.9, 91.4, 91.2, 62.3, 33.6, 21.1;

HRMS (ESI-TOF) _calcd . for _{C19H17ClN2NaO5S} [M+Na] ⁺ _443.0439 ; found: _443.0445 .

Example 12: Synthesis of Compound I-1

Pd ₂ (dba) ₃ ·CHCl ₃ (5mol%) and PPh ₃ (15mol%) were added to a dry reaction test tube, then the solvent was added, and after stirring and complexing for 5 minutes, 3-nitroindole Ⅱ was added in sequence -l 0.1 mmol, alkenyl carbonate III-a 0.15 mmol; after the reaction is complete (24h), the crude product is separated and purified by column chromatography to obtain compound Il.

White solid; 46.4 mg, 99% yield; >20:1dr; m.p.154.8-156.4°C

Structure identification: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.85 (d, J=8.3 Hz, 2H), 7.81 (d, J=2.1 Hz, 1H), 7.64 (dd, J=8.7, 2.1 Hz) ,1H),7.45(d,J＝8.7Hz,1H),7.41(d,J＝8.3Hz,2H),6.49(s,1H),4.94(s,1H),4.78(s,1H),4.29 (d, J=16.0Hz, 1H), 3.72 (dd, J=16.0, 2.1Hz, 1H), 3.51 (d, J=14.1Hz, 1H), 3.28 (dt, J=14.1, 2.1Hz, 1H) ,2.36(s,3H);

¹³ C NMR (101MHz, DMSO-d ₆ )δ145.1, 141.4, 136.7, 135.2, 134.1, 130.0, 128.4, 128.1, 127.5, 116.0, 115.3, 111.9, 91.4, 91.2, 62.3, 33.5, 21.1;

HRMS (ESI-TOF) _calcd . for _{C19H17BrN2NaO5S} [M+Na] ⁺ _488.9915 ; found: _488.9917 .

Example 13: Synthesis of Compound I-m

Pd ₂ (dba) ₃ ·CHCl ₃ (5mol%) and PPh ₃ (15mol%) were added to a dry reaction test tube, then the solvent was added, and after stirring and complexing for 5 minutes, 3-nitroindole Ⅱ was added in sequence -m 0.1 mmol, alkenyl carbonate III-a 0.15 mmol; after the completion of the reaction (24 h), the crude product was separated and purified by column chromatography to obtain compound Im.

White solid; 36.6 mg, 89% yield; >20:1dr; m.p.169.2-171.9°C;

Structure identification: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.17 (d, J=1.5 Hz, 1H), 7.94-7.90 (m, 3H), 7.61 (d, J=8.5 Hz, 1H), 7.44 (d,J＝8.1Hz,2H),6.61(s,1H),4.95(d,J＝2.2Hz,1H),4.78(d,J＝2.2Hz,1H),4.28(dd,J＝15.8, 1.8Hz, 1H), 3.61 (dd, J=15.8, 2.0Hz, 1H), 3.54 (d, J=14.2Hz, 1H), 3.33-3.28 (m, 1H), 2.37 (s, 3H);

¹³ C NMR (101MHz, DMSO-d ₆ )δ145.5, 145.4, 137.1, 136.3, 134.1, 130.2, 127.6, 126.9, 118.0, 113.7, 112.2, 106.4, 91.2, 90.9, 62.3, 33.4, 21.1;

HRMS (ESI-TOF) calcd. for _{C20H17N3NaO5S} [ _M +Na] ⁺ _434.0781 ; found: _434.0784 .

Example 14: Synthesis of Compound I-n

Pd ₂ (dba) ₃ ·CHCl ₃ (5mol%) and PPh ₃ (15mol%) were added to a dry reaction test tube, then the solvent was added, and after stirring and complexing for 5 minutes, 3-nitroindole Ⅱ was added in sequence -n 0.1 mmol, alkenyl carbonate III-a 0.15 mmol; after the completion of the reaction (24h), the crude product was separated and purified by column chromatography to obtain compound In.

White solid; 38.9 mg, 97% yield; >20:1dr; m.p.134.0-136.2°C;

Structure identification: ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.83 (d, J=8.4 Hz, 2H), 7.39-7.37 (m, 3H), 7.28 (s, 1H), 7.26 (d, J= 8.4Hz, 1H), 6.47(s, 1H), 4.92(d, J=2.2Hz, 1H), 4.76(d, J=2.2Hz, 1H), 4.26(dd, J=15.7, 1.9Hz, 1H) ,3.74(dd,J=15.7,2.2Hz,1H),3.41(s,1H),3.28(dt,J=14.1,2.2Hz,1H),2.34(s,3H),2.22(s,3H);

¹³ C NMR (151MHz, DMSO-d ₆ )δ144.8, 139.8, 137.1, 134.3, 134.0, 133.0, 129.9, 127.5, 126.2, 125.3, 113.3, 111.5, 91.9, 91.1, 62.2, 33.9, 21.0, 20.3;

HRMS (ESI-TOF) calcd. for _{C20H20N2NaO5S} [ _{M +} Na] ⁺ _423.0985 ; found: 423.0995.

Example 15: Synthesis of Compound I-o

Pd ₂ (dba) ₃ ·CHCl ₃ (5mol%) and PPh ₃ (15mol%) were added to a dry reaction test tube, then the solvent was added, and after stirring and complexing for 5 minutes, 3-nitroindole Ⅱ was added in sequence -o 0.1 mmol, alkenyl carbonate III-a 0.15 mmol; after the completion of the reaction (24h), the crude product was separated and purified by column chromatography to obtain compound Io.

White solid; 40.4 mg, 96% yield; >20:1dr; m.p.149.5-151.6°C;

Structure identification: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.89 (d, J=8.4 Hz, 2H), 7.56 (d, J=8.2 Hz, 1 H), 7.46-7.41 (m, 3H), 7.22 (dd,J＝8.2,1.9Hz,1H),6.54(s,1H),4.92(d,J＝2.3Hz,1H),4.77(d,J＝2.1Hz,1H),4.28(dd,J＝ 15.8,1.5Hz,1H),3.70(dd,J=15.9,2.1Hz,1H),3.45(d,J=14.1Hz,1H),3.29(dt,J=14.0,2.0Hz,1H),2.37( s, 3H);

¹³ C NMR (101MHz, DMSO-d ₆ )δ145.3, 143.2, 136.9, 136.7, 134.1, 130.1, 127.5, 127.2, 125.0, 124.4, 113.0, 111.8, 91.3, 91.2, 62.2, 33.6, 21.1;

HRMS (ESI-TOF) _calcd . for _{C19H17ClN2NaO5S} [M+Na] ⁺ _443.0439 ; found: _443.0446 .

Example 16: Synthesis of Compound I-p

Pd ₂ (dba) ₃ ·CHCl ₃ (5mol%) and PPh ₃ (15mol%) were added to a dry reaction test tube, then the solvent was added, and after stirring and complexing for 5 minutes, 3-nitroindole Ⅱ was added in sequence -p 0.1 mmol, alkenyl carbonate III-a 0.15 mmol; after the completion of the reaction (24h), the crude product was separated and purified by column chromatography to obtain compound Ip.

White solid; 36.0 mg, 90% yield; >20:1dr; m.p.160.2-162.3°C;

Structure identification: ¹ H NMR (600MHz, DMSO-d ₆ ) δ 7.87 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H), 7.34 (d, J=7.8 Hz, 1H) ), 7.29(s, 1H), 6.93(d, J＝7.8Hz, 1H), 6.49(s, 1H), 4.90(d, J＝2.4Hz, 1H), 4.74(d, J＝2.4Hz, 1H) ),4.24(dd,J＝15.8,1.8Hz,1H),3.68(dd,J＝15.8,2.2Hz,1H),3.39(s,1H),3.27(dt,J＝14.0,2.0Hz,1H) ,2.35(s,3H),2.33(s,3H);

¹³ C NMR (151MHz, DMSO-d ₆ )δ144.9, 142.9, 142.2, 137.2, 134.5, 130.0, 127.5, 125.2, 125.1, 123.3, 113.7, 111.5, 91.7, 91.2, 62.2, 33.9, 21.5, 21.1;

HRMS (ESI-TOF) calcd. for _{C20H20N2NaO5S} [ _{M +} Na] ⁺ _423.0985 ; found: 423.0989.

Example 17: Synthesis of Compound I-q

Pd ₂ (dba) ₃ ·CHCl ₃ (5mol%) and PPh ₃ (15mol%) were added to a dry reaction test tube, then the solvent was added, and after stirring and complexing for 5 minutes, 3-nitroindole Ⅱ was added in sequence -q 0.1 mmol, alkenyl carbonate III-a 0.15 mmol; after the completion of the reaction (24 h), the crude product was separated and purified by column chromatography to obtain compound Iq.

White solid; 35.9 mg, 90% yield; >20:1dr; m.p.149.0-151.2°C;

Structure identification: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.72 (d, J=8.3 Hz, 2H), 7.45-7.39 (m, 3H), 7.28 (d, J=7.5 Hz, 1H), 7.22 -7.16(m, 1H), 6.63(s, 1H), 4.90(s, 1H), 4.77(s, 1H), 4.38(d, J=15.2Hz, 1H), 3.93(d, J=15.2Hz, 1H), 3.37(s, 2H), 2.38(s, 3H), 2.14(s, 3H);

¹³ C NMR (101MHz, DMSO-d ₆ )δ144.4, 142.0, 136.9, 136.8, 135.1, 130.1, 129.2, 127.4, 126.6, 126.1, 123.7, 111.9, 92.0, 91.8, 63.6, 35.5, 21.1, 20.3;

HRMS (ESI-TOF) calcd. for _{C20H20N2NaO5S} [ _{M +} Na] ⁺ _423.0985 ; found: 423.0990.

The above descriptions are only preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements and improvements made within the spirit and principles of the present invention shall be included in the protection of the present invention. within the range.

Claims (10)

1. The indoline tetrahydropyran compound is characterized by having a structure shown as a structural formula (I):

in the above structural formula, R¹The radical being an electron-withdrawing substituent R²The substituent is selected from one of hydrogen, alkyl, alkoxy, nitro or halogen.

2. The indoline tetrahydropyran compound according to claim 1, wherein the electron-withdrawing substituent is selected from one of p-methyl benzenesulfonyl, acyl, or ester groups.

3. The method for producing an indoline tetrahydropyran compound according to claim 1 or 2, characterized by: adding Pd into a reaction tube₂(dba)₃·CHCl₃Adding a ligand, adding a solvent, stirring for complexing, sequentially adding 3-nitroindole (II) and alkenyl carbonate (III), after the reaction is finished, separating and purifying to obtain an indoline tetrahydropyran compound (I), wherein,

the 3-nitroindole (II) has the following structure:

the alkenyl carbonate (III) has the following structure:

4. the production method according to claim 3, characterized in that: the stirring and complexing time is 1-30 min.

5. The production method according to claim 3, characterized in that: the reaction solvent is one or more of toluene, mesitylene, dichloromethane, chloroform, tetrahydrofuran, diethyl ether, acetonitrile, ethanol, methanol, 1, 4-dioxane and chlorobenzene.

6. The method of claim 5, wherein: the reaction solvent is acetonitrile.

7. The production method according to claim 3, characterized in that: the catalyst is tris (dibenzylidene acetone) bisPalladium (Pd)₂(dba)₃·CHCl₃) And a phosphine ligand.

8. The production method according to claim 3, characterized in that: the catalyst is used in an amount of at least 1 mol%.

9. The production method according to claim 3, characterized in that: the reaction temperature is from 0 ℃ to 50 ℃.

10. The method of claim 9, wherein: the reaction temperature of the 9 is 40 ℃.

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