Method for synthesizing trans-isopentenyl substituted indolone through nickel catalysis

Abstract

The invention relates to a method for synthesizing trans-isopentenyl substituted indolone under the catalysis of transition metal nickel. Specifically, a metal nickel catalyst (Ni (cod) 2) and tricyclohexylphosphine (PCy3) are used as ligands, C3 unsubstituted indolone is used as a nucleophilic reagent to react with isoprene, and a trans-isopentenyl substituted indolone product is obtained. And then taking the product as a reaction raw material, and carrying out nucleophilic substitution reaction on the product and halogenated alkane under an alkaline condition to obtain the 3, 3-disubstituted indolone with divergent functional groups. According to the invention, isoprene is used as a reaction precursor, a trans-isopentenyl substituted indolone product is obtained with high activity and selectivity, a nucleophilic substitution reaction is relayed, and a new strategy is provided for flexibly and conveniently introducing functional groups with different steric hindrances and electrical properties.

Description

Technical Field

[0001] This invention relates to a method for the nickel-catalyzed synthesis of trans-isopentenyl-substituted indolones, and relates to the field of synthesizing trans-isopentenyl-substituted indolones. Background Technology

[0002] Indolones are common skeletal structures in various drug molecules and natural alkaloids, especially those with an anti-isopentenyl substituent at the C3 position, which have attracted much attention due to their wide range of biological activities. In the traditional transition metal-catalyzed allylic alkylation strategy to construct pentenyl-substituted indolones, the C3 substituent of the indolone participates in the formation of reactive intermediates, playing a crucial role in controlling the reactivity and selectivity of the reaction. Therefore, when these substituents are removed, not only is the reactivity inhibited, but it also leads to the problem of various byproducts that are difficult to control. Furthermore, directly assembling isoprene onto indolones is more challenging than using common pre-activated pentenyl precursors.

[0003] This work describes a nickel-catalyzed functionalization reaction of isoprene, achieving the anti-isopentenylation of C3-unsubstituted indolones. This method not only possesses high reactivity and atom economy but also high chemoselectivity and regioselectivity. Furthermore, the exposed CH bond at the carbonyl α-position allows the resulting anti-isopentenyl-substituted indolone product to undergo nucleophilic substitution reactions with various electrophiles under basic conditions, achieving the synthesis of 3,3-disubstituted indolones. This provides a new strategy for more flexibly and conveniently introducing sterically hindered and electrochemically charged functional groups into chemical reactions.

[0004] In summary, this work describes an innovative method for synthesizing anti-isoprenyl-substituted indolones with high activity and selectivity by reacting unactivated indolones with isoprene under nickel catalysis. Summary of the Invention

[0005] The purpose of this invention is to provide a method for the nickel-catalyzed synthesis of anti-isopentenyl-substituted indolones.

[0006]

[0007] The specific operating steps are as follows:

[0008] Reaction Equation 1:

[0009] Under a nitrogen atmosphere, 0.02 mmol of nickel catalyst (Ni(cod)2), 0.04 mmol of tricyclohexylphosphine ligand (PCy3), 0.20 mmol of indolone 1, 0.40 mmol of isoprene 2, 0.20 mmol of basic additive (Cs2CO3), and 2.0 mL of tetrahydrofuran solvent (THF) were added sequentially to the reaction flask, and the reaction was carried out at 60 °C for 24 hours. After the reaction was completed, the anti-isoprenyl substituted indolone 3 was isolated.

[0010] Reaction Equation 2:

[0011] Under a nitrogen atmosphere, 0.10 mmol of trans-isopentenyl-substituted indole 3, 0.12 mmol of additive base (NaH), 0.5 mL of nitrogen, dimethylformamide (DMF), and 0.20 mmol of haloalkane (R) were added sequentially to the reaction flask. 2 X) The reaction was carried out at 0°C to room temperature for 12 hours; after the reaction was completed, 3,3-disubstituted indolone 4 was isolated.

[0012] This invention utilizes a nickel catalyst (Ni(cod)2) and tricyclohexylphosphine (PCy3) as ligands, and an unsubstituted C3 indole ketone as a nucleophile to react with isoprene to obtain an anti-isopentenyl-substituted indole ketone product. This product is then used as a reactant in a nucleophilic substitution reaction with a haloalkane under alkaline conditions to yield a 3,3-disubstituted indole ketone with divergent functional groups. This invention uses isoprene as a precursor to obtain the anti-isopentenyl-substituted indole ketone product with high activity and selectivity, followed by a nucleophilic substitution reaction, providing a new strategy for flexibly and conveniently introducing functional groups with different steric hindrances and electrochemical properties.

[0013] The present invention has the following advantages:

[0014] First, the anti-isopentenylation of C3-unsubstituted indolones was achieved in a nickel-catalyzed functionalization reaction of isoprene. This method not only possesses high reactivity and atom economy but also high chemoregioselectivity. Furthermore, the exposed CH bond at the carbonyl α-position allows the resulting anti-isopentenyl-substituted indolone products to undergo nucleophilic substitution reactions with various electrophiles, enabling the synthesis of 3,3-disubstituted indolones. This provides a new strategy for more flexibly and conveniently introducing sterically hindered and electrochemically charged functional groups into chemical reactions. Detailed Implementation

[0015] To better understand Equation 1 in this invention, the following examples are provided. The reaction raw materials and results of Examples 1-18 are shown in Table 1, wherein raw material 1 is a known compound.

[0016] Table 1. Reaction results for different indoleket substrates

[0017]

[0018]

[0019]

[0020]

[0021]

[0022] Example 1

[0023] Under a nitrogen atmosphere, 0.02 mmol of nickel catalyst (Ni(cod)2), 0.04 mmol of tricyclohexylphosphine ligand (PCy3), 0.20 mmol of indolone 1a, 0.40 mmol of isoprene 2, 0.20 mmol of basic additive (Cs2CO3), and 2.0 mL of tetrahydrofuran solvent (THF) were added sequentially to the reaction flask, and the reaction was carried out at 60 °C for 24 hours. After the reaction was completed, the anti-isoprenyl substituted indolone 3a was obtained by column chromatography with a yield of 94%. The structure of the compound was identified by NMR (1H and 1C) and high-resolution mass spectrometry.

[0024] The test data is as follows:

[0025] 1-Methyl-3-(2-methylbut-3-en-2-yl)indolin-2-one(3a): Yellow solid, (mp40-42℃), 40.4mg, 94% yield, R f =0.3 (PE:EA = 10:1). 1 H NMR (400MHz, Chloroform-d) δ7.32(d,J=7.5Hz,1H),7.26(t,J=7.7Hz,1H),6.97(t,J=7.5Hz,1H),6.77(d,J=7.9Hz,1H),5.95(dd,J =17.4,10.7Hz,1H),5.03(dd,J=10.8,1.1Hz,1H),4.95(dd,J=17.5,1.1Hz,1H),3.22(s,1H),3.16(s,3H),1.33(s,3H),1.07(s,3H). 13HRMS calculated for C 14 H 18 NO + [M+H] + 216.1383, found 216.1385.

[0026] Example 2:

[0027] The operation process and conditions were the same as in Example 1, except that the indoleone compounds described in Table 1 were different, and the reaction temperature was 80°C. The yield of product 3b was 94%, and the structure of the compound was identified by NMR (1H and 1C) and high-resolution mass spectrometry.

[0028] The test data is as follows:

[0029]

[0030] 1,5-Dimethyl-3-(2-methylbut-3-en-2-yl)indolin-2-one(3b): Yellow oil, 43.3 mg, 94% yield, R f =0.4 (PE:EA = 10:1). 1 H NMR(400MHz,Chloroform-d)δ7.14(s,1H),7.06(d,J=7.8Hz,1H),6.66(d,J=7.8Hz,1H),5.95(dd,J=17.4,10.7Hz,1H),5. 03(dd,J=10.7,1.1Hz,1H),4.96(dd,J=17.5,1.2Hz,1H),3.18(s,1H),3.14(s,3H),2.31(s,3H),1.31(s,3H),1.08(s,3H). 13 C HRMS calculated for C 15 H 20 NO +[M+H] + 230.1539, found 230.1535.

[0031] Example 3:

[0032] The operating procedures and conditions were the same as in Example 1, except that the indoleone compounds described in Table 1 were different. The product yield was 86%, and the structure of the compound was identified by NMR (1H, 1C, and fluorine spectra) and high-resolution mass spectrometry.

[0033] The test data is as follows:

[0034] 5-Fluoro-1-methyl-3-(2-methylbut-3-en-2-yl)indolin-2-one(3c): Yellowsolid, (mp47-49℃), 40.1mg, 86% yield, R f =0.4 (PE:EA = 10:1). 1 H NMR(400MHz,Chloroform-d)δ7.09(dd,J=8.8,2.6,1H),6.96(td,J=8.8,2.7Hz,1H),6.68(dd,J=8.5,4.3Hz,1H),5.93(dd,J=17 .5,10.7Hz,1H),5.07(dd,J=10.7,1.0Hz,1H),4.97(dd,J=17.4,1.0Hz,1H),3.21(s,1H),3.15(s,3H),1.35(s,3H),1.03(s,3H). 13 C NMR(101MHz,Chloroform-d)δ175.72,158.42(d,J=238.8Hz),145.11,140.79,128.63(d,J=8.5Hz),114.18(d, J=3.6Hz), 113.94 (d, J=1.7Hz), 112.83, 107.70 (d, J=8.3Hz), 54.46 (d, J=1.9Hz), 40.64, 26.09, 25.84, 21.94. 19 F NMR(376MHz,Chloroform-d)δ-121.62.HRMScalculated for C 14 H 17 FNO + [M+H] + 234.1289, found 234.1287.

[0035] Example 4:

[0036] The operation process and conditions were the same as in Example 1, except that the indoleone compounds described in Table 1 were different, and the reaction temperature was 70°C. The product yield was 78% after 3 days, and the structure of the compound was identified by NMR (1H and 1C) and high-resolution mass spectrometry.

[0037] The test data is as follows:

[0038]

[0039] 5-Chloro-1-methyl-3-(2-methylbut-3-en-2-yl)indolin-2-one(3d): Yellowoil, 38.9mg, 78% yield, R f =0.3 (PE:EA = 10:1). 1 H NMR(400MHz,Chloroform-d)δ7.30(d,J=2.2Hz,1H),7.23(td,J=8.3,2.1Hz,1H),6.68(d,J=8.2Hz,1H),5.91(dd,J=17.4,1 0.7Hz,1H),5.07(dd,J=10.7,1.0Hz,1H),4.96(dd,J=17.4,1.0Hz,1H),3.20(s,1H),3.14(s,3H),1.33(s,3H),1.04(s,3H). 13 HRMS calculated for C 14 H 17 ClNO + [M+H] + 250.0993, found 250.0996.

[0040] Example 5:

[0041] The operation process and conditions were the same as in Example 1, except that the indoleone compounds described in Table 1 were different, and the reaction temperature was 90°C. The yield of product 3e was 74%, and the structure of the compound was identified by NMR (1H and 1C) and high-resolution mass spectrometry.

[0042] The test data is as follows:

[0043]

[0044] 5-Bromo-1-methyl-3-(2-methylbut-3-en-2-yl)indolin-2-one(3e): Yellowoil, 43.5mg, 74% yield, R f =0.3 (PE:EA = 10:1). 1 H NMR(400MHz,Chloroform-d)δ7.43(d,J=2.0Hz,1H),7.38(td,J=8.2,2.0Hz,1H),6.64(d,J=8.2Hz,1H),5.91(dd,J=17.4,1 0.7Hz,1H),5.07(dd,J=10.7,1.0Hz,1H),4.97(dd,J=17.4,1.0Hz,1H),3.20(s,1H),3.13(s,3H),1.33(s,3H),1.04(s,3H). 13 HRMS calculated for C 14 H 17 BrNO + [M+H] + 294.0488, found 294.0496.

[0045] Example 6:

[0046] The operation process and conditions were the same as in Example 1, except that the indoleone compounds described in Table 1 were different, and the reaction temperature was 100°C. The yield of product 3f was 79%, and the structure of the compound was identified by NMR (1H and 1C) and high-resolution mass spectrometry.

[0047] The test data is as follows:

[0048]

[0049] 5-Methoxy-1-methyl-3-(2-methylbut-3-en-2-yl)indolin-2-one(3f): Yellowsolid, (mp52-54℃), 38.8mg, 79% yield, R f =0.3 (PE:EA = 4:1). 1HNMR(400MHz,Chloroform-d)δ6.97(d,J=2.6Hz,1H),6.79(td,J=8.4,2.6Hz,1H),6.67(d,J=8.5Hz,1H),5.96(dd,J=17.4,10.7Hz ,1H),5.05(dd,J=10.7,1.1Hz,1H),4.96(dd,J=17.4,1.1Hz,1H),3.77(s,3H),3.20(s,1H),3.14(s,3H),1.34(s,3H),1.04(s,3H). 13 C HRMS calculated for C 15 H 20 NO2 + [M+H] + 246.1489, found 246.1492.

[0050] Example 7:

[0051] The operation process and conditions were the same as in Example 1, except that the indoleone compounds described in Table 1 were different, and the reaction temperature was 80°C. The yield of the product was 80% (3g). The structure of the compound was identified by NMR (1H NMR, 1C NMR, and 1N NMR) and high-resolution mass spectrometry.

[0052] The test data is as follows:

[0053]

[0054] 6-Chloro-1-methyl-3-(2-methylbut-3-en-2-yl)indolin-2-one (3g): Whitesolid, (mp69-71℃), 40.4mg, 81% yield, R f =0.3 (PE:EA = 10:1). 1H NMR(400MHz,Chloroform-d)δ7.22(d,J=8.1,1H),6.94(td,J=8.0,1.9Hz,1H),6.77(d,J=2.0Hz,1H),5.91(dd,J=17.4,10 .7Hz,1H),5.04(dd,J=10.7,1.0Hz,1H),4.94(dd,J=17.5,1.0Hz,1H),3.19(s,1H),3.14(s,3H),1.32(s,3H),1.03(s,3H). 13 HRMS calculated for C 14 H 17 ClNO + [M+H] + 250.0993, found 250.0993.

[0055] Example 8:

[0056] The operating procedures and conditions were the same as in Example 1, except that the indoleone compounds described in Table 1 were different. The product yield was 81% after 3 hours, and the structure of the compounds was identified by NMR (1H and 1C) and high-resolution mass spectrometry.

[0057] The test data is as follows:

[0058]

[0059] 6-Chloro-1-methyl-3-(2-methylbut-3-en-2-yl)indolin-2-one(3h):Whitesolid, (mp69-71℃), 40.4mg, 81% yield, R f =0.3 (PE:EA = 10:1). 1H NMR(400MHz,Chloroform-d)δ7.22(d,J=8.1,1H),6.94(td,J=8.0,1.9Hz,1H),6.77(d,J=2.0Hz,1H),5.91(dd,J=17.4,10 .7Hz,1H),5.04(dd,J=10.7,1.0Hz,1H),4.94(dd,J=17.5,1.0Hz,1H),3.19(s,1H),3.14(s,3H),1.32(s,3H),1.03(s,3H). 13 HRMS calculated for C 14 H 17 ClNO + [M+H] + 250.0993, found 250.0993.

[0060] Example 9:

[0061] The operation process and conditions were the same as in Example 1, except that the indoleone compounds described in Table 1 were different, and the reaction temperature was 90°C. The yield of product 3i was 70%, and the structure of the compound was identified by NMR (1H and 1C) and high-resolution mass spectrometry.

[0062] The test data is as follows:

[0063]

[0064] 6-Bromo-1-methyl-3-(2-methylbut-3-en-2-yl)indolin-2-one(3i): Yellowoil, 41.2mg, 70% yield, R f =0.3 (PE:EA = 10:1). 1H NMR(400MHz,Chloroform-d)δ7.22(d,J=7.9Hz,1H),6.94(td,J=8.0,1.9Hz,1H),6.76(d,J=2.0Hz,1H),5.90(dd,J=1 7.4,10.7Hz,1H),5.04(d,J=10.8Hz,1H),4.94(d,J=17.5Hz,1H),3.18(s,1H),3.14(s,3H),1.32(s,3H),1.03(s,3H). 13 CNMR(101MHz,Chloroform-d)δ176.00,146.03,145.06,133.81,126.70,125.38,121.29,112.71,108.25,53.90,40.59,26.02,25.77,22.10.HRMScalculated for C 14 H 17 BrNO + [M+H] + 294.0488, found 294.0477.

[0065] Example 10:

[0066] The operation process and conditions were the same as in Example 1, except that the indoleone compounds described in Table 1 were different, and the reaction temperature was 100°C. The yield of product 3j was 85%, and the structure of the compound was identified by NMR (1H and 1C) and high-resolution mass spectrometry.

[0067] The test data is as follows:

[0068]

[0069] 6-Methoxy-1-methyl-3-(2-methylbut-3-en-2-yl)indolin-2-one(3j): Yellowoil, 41.9mg, 85% yield, R f =0.4 (PE:EA = 4:1). 1H NMR(400MHz,Chloroform-d)δ7.20(d,J=8.3Hz,1H),6.47(dd,J=8.2,2.4Hz,1H),6.36(d,J=2.4Hz,1H),5.93(dd,J=17.4,10.7Hz, 1H),5.02(dd,J=10.7,1.2Hz,1H),4.94(dd,J=17.5,1.2Hz,1H),3.82(s,3H),3.17(s,1H),3.13(s,3H),1.30(s,3H),1.05(s,3H). 13 C NMR(101MHz,Chloroform-d)δ176.77,160.04,146.09,145.52,126.42,118.98,112.24,105.23,95.57,55.44,53.88,40.50,25.93,25.65,22.35.HRMS calculated for C 15 H 20 NO2 + [M+H] + 246.1489, found 246.1493.

[0070] Example 11:

[0071] The operation process and conditions were the same as in Example 1, except that the indoleone compounds described in Table 1 were different, and the reaction temperature was 100°C. The product yield was 80%, and the structure of the compound was identified by NMR (1H and 1C) and high-resolution mass spectrometry.

[0072] The test data is as follows:

[0073]

[0074] Methyl-1-methyl-3-(2-methylbut-3-en-2-yl)-2-oxoindoline-6-carboxylate(3k): Yellow solid, (mp52-54℃), 43.9mg, 80% yield, R f =0.3 (PE:EA = 4:1). 1H NMR(400MHz,Chloroform-d)δ7.69(dd,J=7.8,1.6Hz,1H),7.41(d,J=1.5Hz,1H),7.38(d,J=7.8Hz,2H),5.92(dd,J=17.4,10.7Hz, 1H),5.05(dd,J=10.8,1.0Hz,1H),4.94(dd,J=17.5,1.0Hz,1H),3.92(s,3H),3.26(s,1H),3.20(s,3H),1.34(s,3H),1.04(s,3H). 13 C NMR(101MHz,Chloroform-d)δ175.71,166.87,145.16,144.96,132.45,130.09, 125.66,123.32,112.80,108.04,54.39,52.28,40.78,26.11,25.85,22.18.HRMS calculated forC 16 H 20 NO3 + [M+H] + 274.1438, found 274.1435.

[0075] Example 12:

[0076] The operation process and conditions were the same as in Example 1, except that the indoleone compounds described in Table 1 were different, and the reaction temperature was 100°C. The yield of product 3l was 75%, and the structure of the compound was identified by NMR (1H and 1C) and high-resolution mass spectrometry.

[0077] The test data is as follows:

[0078]

[0079] 1,7-Dimethyl-3-(2-methylbut-3-en-2-yl)indolin-2-one(3l): Yellow oil, 34.4mg, 75% yield, R f =0.4 (PE:EA = 10:1). 1H NMR(400MHz,Chloroform-d)δ7.16(d,J=7.4Hz,1H),6.98(d,J=7.7Hz,1H),6.84(t,J=7.6Hz,1H),5.94(dd,J=17.4,10.7Hz,1H ),5.03(dd,J=10.7,1.1Hz,1H),4.93(dd,J=17.4,1.1Hz,1H),3.45(s,3H),3.17(s,1H),2.56(s,3H),1.31(s,3H),1.05(s,3H). 13 C HRMS calculated for C 15 H 20 NO + [M+H] + 230.1539, found 230.1541.

[0080] Example 13:

[0081] The operation process and conditions were the same as in Example 1, except that the indoleone compounds described in Table 1 were different, and the reaction temperature was 70°C. The product yield was 70% (3m). The structure of the compound was identified by NMR (1H, 1C, and 1N NMR) and high-resolution mass spectrometry.

[0082] The test data is as follows:

[0083]

[0084] 1-Methyl-3-(2-methylbut-3-en-2-yl)-7-(trifluoromethyl)indolin-2-one(3m): Yellow oil, 39.7mg, 70% yield, R f =0.6 (PE:EA = 10:1). 1H NMR(400MHz,Chloroform-d)δ7.54(d,J=8.1Hz,1H),7.49(d,J=7.4Hz,1H),7.02(t,J=7.8Hz,1H),5.91(dd,J=17.4,10.7Hz,1 H),5.06(dd,J=10.7,1.0Hz,1H),4.93(dd,J=17.4,1.0Hz,1H),3.37(q,J=2.5Hz,3H),3.21(s,1H),1.33(s,3H),1.01(s,3H). 13 C NMR(101MHz,Chloroform-d)δ176.76,144.91,142.71,129.41,129.08,125.97(q,J=6.2Hz),123.71(d ,J=271.5Hz),120.57,112.93,111.86(d,J=32.8Hz),52.70,40.97,28.49(q,J=6.6Hz),25.74,21.84. 19 FNMR(376MHz,Chloroform-d)δ-52.88.HRMS calculated for C 15 H 17 F3NO + [M+H] + 284.1257, found284.1257.

[0085] Example 14:

[0086] The operation process and conditions were the same as in Example 1, except that the indoleone compounds described in Table 1 were different, and the reaction temperature was 100°C. The yield of product 3n was 65%, and the structure of the compound was identified by NMR (1H and 1C) and high-resolution mass spectrometry.

[0087] The test data is as follows:

[0088]

[0089] 1-Methyl-3-(2-methylbut-3-en-2-yl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one(3s): Colorless oil, 28.0mg, 65% yield, R f =0.3 (PE:EA = 3:1). 1HNMR(400MHz,Chloroform-d)δ8.14(d,J=5.2Hz,1H),7.52(d,J=7.3Hz,1H),6.86(dd,J=7.3,5.3Hz,1H),5.90( dd,J=17.4,10.7Hz,1H),5.05(d,J=10.7Hz,1H),4.94(d,J=17.4Hz,1H),3.24(s,3H),1.34(s,3H),1.03(s,3H). 13 HRMS calculated for C 13 H 17 N2O + [M+H] + 217.1335, found217.1335.

[0090] Example 15:

[0091] The operation process and conditions were the same as in Example 1, except that the indoleone compounds described in Table 1 were different, and the reaction temperature was 70°C. The yield of product 3O was 83%, and the structure of the compound was identified by NMR (1H and 1C) and high-resolution mass spectrometry.

[0092] The test data is as follows:

[0093]

[0094] 1-Ethyl-3-(2-methylbut-3-en-2-yl)indolin-2-one(3b): Yellow oil, 38.1mg, 83% yield, R f =0.4 (PE:EA = 10:1). 1H NMR(400MHz,Chloroform-d)δ7.33(d,J=7.5Hz,1H),7.25(t,J=7.7Hz,1H),6.96(t ,J=7.5Hz,1H),6.79(d,J=7.8Hz,1H),5.94(dd,J=17.4,10.7Hz,1H),5.03(dd,J=10 .8,1.1Hz,1H),4.95(dd,J=17.4,1.1Hz,1H),3.85(dq,J=14.4,7.2Hz,1H),3.60(dq ,J=14.3,7.2Hz,1H),3.19(s,1H),1.33(s,3H),1.22(t,J=7.2Hz,3H),1.07(s,3H). 13 C NMR(101MHz,Chloroform-d)δ175.71,145.37,143.89,127.90,127.28,126.16,12 1.24,112.35,107.62,54.20,40.58,34.27,25.77,22.29,12.60.HRMScalculated for C 15 H 20 NO + [M+H] + 230.1539, found 230.1543.

[0095] Example 16:

[0096] The operation process and conditions were the same as in Example 1, except that the indoleone compounds described in Table 1 were different, and the reaction temperature was 100°C. The product 3p yield was 80%, and the structure of the compound was identified by NMR (1H and 1C) and high-resolution mass spectrometry.

[0097] The test data is as follows:

[0098]

[0099] 1-Benzyl-3-(2-methylbut-3-en-2-yl)indolin-2-one(3p): Yellow solid, (mp41-43℃), 46.6mg, 80% yield, R f =0.5 (PE:EA = 10:1). 1H NMR(400MHz,Chloroform-d)δ7.35(d,J=7.4Hz,1H),7.31(d,J=4.4Hz,4H),7.30–7.2 0(m,3H),7.16(t,J=7.7Hz,1H),6.95(t,J=7.6Hz,1H),6.69(d,J=7.8Hz,1H),5.98(dd ,J=17.4,10.7Hz,1H),5.08(d,J=15.6Hz,1H),5.06(dd,J=10.77,1.13Hz,1H),5.00(d d,J=17.5,1.1Hz,1H),4.70(d,J=15.6Hz,1H),3.33(s,1H),1.39(s,3H),1.16(s,3H). 13 C NMR(101MHz,Chloroform-d)δ176.20,145.35,144.03,136.17,128.69,127.92,127.49,1 27.40,127.04,126.08,121.56,112.58,108.63,54.32,43.57,40.73,26.06,22.59.HRMS calculated forC 20 H 22 NO + [M+H] + 292.1696, found 292.1693.

[0100] Example 17:

[0101] The operation process and conditions were the same as in Example 1, except that the indoleone compounds described in Table 1 were different, and the reaction temperature was 60°C. The product yield was 90%, and the structure of the compound was identified by NMR (1H and 1C) and high-resolution mass spectrometry.

[0102] The test data is as follows:

[0103]

[0104] 1-Allyl-3-(2-methylbut-3-en-2-yl)indolin-2-one(3e): Yellow oil, 43.4 mg, 90% yield, R f =0.5 (PE:EA = 10:1). 1H NMR(400MHz,Chloroform-d)δ7.34(d,J=7.5Hz,1H),7.22(t,J=7.7Hz,2H),6.97(t,J=7.6Hz,1H),6.77(d, J=7.8Hz,1H),5.96(dd,J=17.4,10.7,1H),5.81(ddt,J=17.2,10.4,5.2Hz,1H),5.21(ddt,J=17.1,1.6,1.6 Hz,1H),5.19(ddt,J=10.4,1.5,1.5Hz,1H),5.04(dd,J=10.7,1.1Hz,1H),4.96(dd,J=17.4,1.1Hz,1H),4.4 9(ddt,J=16.3,5.0,1.8Hz,1H),4.13(ddt,J=16.4,5.4,1.6Hz,1H),3.26(s,1H),1.35(s,3H),1.10(s,3H). 13 C NMR(101MHz,Chloroform-d)δ175.82,145.35,144.01,131.61,127.87,127.03,1 26.03,121.45,117.28,112.48,108.45,54.28,42.03,40.61,25.85,22.46.HRMS calculated for C 16 H 20 NO + [M+H] + 242.1539, found 242.1543.

[0105] Example 18:

[0106] The operation process and conditions were the same as in Example 1, except that the indoleone compounds described in Table 1 were different, and the reaction temperature was 60°C. The yield of product 3r was 86%, and the structure of the compound was identified by NMR (1H and 1C spectra) and high-resolution mass spectrometry.

[0107] The test data is as follows:

[0108]

[0109] 1-(3-Methylbut-2-en-1-yl)-3-(2-methylbut-3-en-2-yl)indolin-2-one(3r): Yellow oil, 46.5mg, 86% yield, R f =0.6 (PE:EA = 10:1). 1H NMR(400MHz,Chloroform-d)δ7.32(d,J=7.4Hz,1H),7.23(t,J=7.7Hz,2H),6.95(t,J=7.6 Hz,1H),6.75(d,J=7.8Hz,1H),5.96(dd,J=17.4,10.7Hz,1H),5.12(t,J=6.6Hz,1H),5.03 (dd,J=10.8,1.1Hz,1H),4.95(dd,J=17.5,1.1Hz,1H),4.36(dd,J=15.4,6.2Hz,1H),4.20 (dd,J=15.5,7.0Hz,1H),3.22(s,1H),1.82(s,3H),1.71(s,3H),1.33(s,3H),1.08(s,3H). 13 C NMR(101MHz,Chloroform-d)δ175.63,145.48,144.18,136.30,127.83,127.18,125.99, 121.26,118.65,112.30,108.17,54.27,40.59,37.73,25.75,25.62,22.34,18.17.HRMS calculated forC 18 H 24 NO + [M+H] + 270.1852, found 270.1853.

[0110] To better understand Equation 2 (Step 2) in this invention, the following examples illustrate the process. The reaction materials and results of Examples 1-11 are shown in Table 1, where R... 2 X are all known compounds.

[0111] Table 2. Reaction results with different electrophilic reagents

[0112]

[0113]

[0114]

[0115] Step Two, Example 1

[0116] Under a nitrogen atmosphere, 0.10 mmol of trans-isopentenyl-substituted indolone 3a, 0.12 mmol of additive base (NaH), 0.5 mL of nitrogen, dimethylformamide (DMF), and 0.20 mmol of benzyl bromide (BnBr) were added sequentially to a reaction flask, and the reaction was carried out at 0 °C to room temperature for 12 hours. After the reaction was completed, 3,3-disubstituted indolone 4a was obtained by column chromatography with a yield of 94%. The structure of the compound was identified by NMR (1H and 1C) and high-resolution mass spectrometry.

[0117] The test data is as follows:

[0118]

[0119] 3-Benzyl-1-methyl-3-(2-methylbut-3-en-2-yl)indolin-2-one(4a):Whitesolid, (mp68-70℃), 29.1mg, 95% yield, R f =0.3 (PE:EA = 20:1). 1 H NMR(700MHz,Chloroform-d)δ7.36(d,J=7.5Hz,1H),7.11(t,J=7.7Hz,1H),6.97( t,J=7.5Hz,1H),6.95–6.90(m,3H),6.79–6.75(m,2H),6.48(d,J=7.7Hz,1H),6.2 3(dd,J=17.5,10.8Hz,1H),5.16(d,J=10.8Hz,1H),5.07(d,J=17.5Hz,1H),3.42( d,J=12.9Hz,1H),3.03(d,J=12.9Hz,1H),2.91(s,3H),1.27(s,3H),1.09(s,3H). 13 C NMR(101MHz,Chloroform-d)δ178.12,144.28,143.98,136.61,129.99,129.79,127.66,127. 24,126.09,125.93,121.06,113.59,107.24,59.97,42.03,37.85,25.58,22.66,22.34.HRMS calculated for C 21 H 24 NO + [M+H] + 306.1852, found 306.1848.

[0120] Example 2:

[0121] The operation process and conditions are the same as in Step 2, Example 1, except that the haloalkanes (R) described in Table 1 are different. 2 Compound X) is different. Product 4b has a yield of 99%, and the structure of the compound was identified by NMR (1H and 1C) and high-resolution mass spectrometry.

[0122] The test data is as follows:

[0123]

[0124] 3-(4-(Tert-butyl)benzyl)-1-methyl-3-(2-methylbut-3-en-2-yl)indolin-2-one(4b): White solid, (mp118-120℃), 36.9mg, 99% yield, R f =0.6 (PE:EA = 20:1). 1 HNMR(400MHz,Chloroform-d)δ7.38(d,J=7.5Hz,1H),7.12(t,J=7.7Hz,1H),6.98(t,J= 7.6Hz,1H),6.95–6.91(m,2H),6.68–6.64(m,2H),6.47(d,J=7.7Hz,1H),6.23(dd,J=17. 5,10.9Hz,1H),5.14(dd,J=10.8,1.4Hz,1H),5.05(dd,J=17.5,1.3Hz,1H),3.37(d,J=1 2.8Hz,1H),3.00(d,J=12.9Hz,1H),2.87(s,3H),1.27(s,3H),1.15(s,9H),1.09(s,3H). 13 C NMR(101MHz,Chloroform-d)δ178.12,148.63,144.40,144.07,133.38,130.13,129.56,127.60,125 .96,124.03,121.05,113.45,107.18,59.96,41.99,37.39,34.14,31.24,25.53,22.78,22.33.HRMS calculated for C 25 H 32 NO + [M+H] + 362.2478, found 362.2478.

[0125] Example 3:

[0126] The operation process and conditions are the same as in Step 2, Example 1, except that the haloalkanes (R) described in Table 1 are different. 2 Compound X is different. The product 4c yield is 99%, and the structure of the compound was identified by NMR (1H and 1C) and high-resolution mass spectrometry.

[0127] The test data is as follows:

[0128]

[0129] 4-((1-Methyl-3-(2-methylbut-3-en-2-yl)-2-oxoindolin-3-yl)methyl)benzonitrile(4c): White solid, (mp100-102℃), 34.2mg, 99% yield, R f =0.3 (PE:EA = 10:1). 1 H NMR(400MHz,Chloroform-d)δ7.34(d,J=7.5Hz,1H),7.24–7.17(m,2H),7.14(t,J=7 .7Hz,1H),6.98(t,J=7.6Hz,1H),6.89–6.85(m,2H),6.52(d,J=7.7Hz,1H),6.18(dd, J=17.5,10.8Hz,1H),5.16(dd,J=10.8,1.2Hz,1H),5.07(dd,J=17.5,1.2Hz,1H),3. 44(d,J=12.7Hz,1H),3.05(d,J=12.7Hz,1H),2.91(s,3H),1.24(s,3H),1.06(s,3H). 13 C NMR(101MHz,Chloroform-d)δ177.54,144.07,143.50,142.58,131.04,130.75,128.92,128.19, 125.87,121.38,118.92,114.04,109.91,107.62,59.80,42.13,37.94,25.63,22.50,22.25.HRMS calculated for C 22 H 23 N2O + [M+H] + 331.1805, found 331.1804.

[0130] Example 4:

[0131] The operation process and conditions are the same as in Step 2, Example 1, except that the haloalkanes (R) described in Table 1 are different. 2 Compound X is different. The product yield was 99% after 4 days, and the structure of the compound was identified by NMR (H1N, C1N, and fluorine NMR) and high-resolution mass spectrometry.

[0132] The test data is as follows:

[0133]

[0134] 1-Methyl-3-(2-methylbut-3-en-2-yl)-3-(4-(trifluoromethyl)benzyl)indoli n-2-one(4d): Colorless solid, (mp105-107℃), 38.7mg, 99% yield, R f =0.4 (PE:EA = 20:1). 1 H NMR(400MHz,Chloroform-d)δ7.37(d,J=7.5Hz,1H),7.20–7.16(m,2H),7.14(t,J= 7.7Hz,1H),6.99(t,J=7.6Hz,1H),6.88(m,2H),6.52(d,J=7.8Hz,1H),6.21(dd,J= 17.5,10.8Hz,1H),5.17(dd,J=10.8,1.2Hz,1H),5.08(dd,J=17.5,1.2Hz,1H),3.4 5(d,J=12.7Hz,1H),3.07(d,J=12.8Hz,1H),2.90(s,3H),1.26(s,3H),1.08(s,3H). 13 C NMR(101MHz,Chloroform-d)δ177.70,144.18,143.67,140.93(q,J=1.5Hz),130.29,129.22,128.0 4,125.87,124.13(q,J=3.8Hz),121.28,113.87,107.54,59.80,42.11,37.60,25.58,22.56,22.26. 19 F NMR(376MHz,Chloroform-d)δ-62.46.HRMScalculated for C 22 H 23 F3NO + [M+H] + 374.1726, found 374.1729.

[0135] Example 5:

[0136] The operation process and conditions are the same as in Step 2, Example 1, except that the haloalkanes (R) described in Table 1 are different. 2 Compound X is different. The product 4e yield is 86%, and the structure of the compound was identified by NMR (1H and 1C) and high-resolution mass spectrometry.

[0137] The test data is as follows:

[0138]

[0139] 1-Methyl-3-(3-methylbut-2-en-1-yl)-3-(2-methylbut-3-en-2-yl)indolin-2-one(4e): Colorless oil, 24.3mg, 86% yield, R f =0.3 (PE:EA = 20:1). 1 H NMR(400MHz,Chloroform-d)δ7.23(t,J=7.7Hz,1H),7.19(d,J=7.2Hz,1H),6.98(t,J=7.5 Hz,1H),6.75(d,J=7.7Hz,1H),6.08(dd,J=17.5,10.8Hz,1H),5.06(dd,J=10.9,1.3Hz,1H ),4.97(dd,J=17.5,1.4Hz,1H),4.35(t,J=7.2Hz,1H),3.14(s,3H),2.77(dd,J=14.1,7.2 Hz,1H),2.50(dd,J=14.1,7.1Hz,1H),1.50(s,3H),1.39(s,3H),1.15(s,3H),1.00(s,3H). 13 CNMR(101MHz,Chloroform-d)δ178.82,144.59,143.97,134.14,130.79,127.54,125.36,12 1.23,118.50,113.15,107.15,58.22,41.81,30.22,25.75,25.70,22.54,22.01,18.07.HRMS calculated for C 19 H 26 NO + [M+H] + 284.2009, found 284.2012.

[0140] Example 6:

[0141] The operation process and conditions are the same as in Step 2, Example 1, except that the haloalkanes (R) described in Table 1 are different. 2 Compound X is different. The yield of product 4f is 95%, and the structure of the compound was identified by NMR (1H and 1C) and high-resolution mass spectrometry.

[0142] The test data is as follows:

[0143]

[0144] (E)-3-(3,6-Dimethylhepta-2,5-dien-1-yl)-1-methyl-3-(2-methylbut-3-en-2-yl)indolin-2-one(4f): Colorless oil, 32.0mg, 95% yield, R f =0.6 (PE:EA = 20:1). 1 HNMR(400MHz,Chloroform-d)δ7.26–7.16(m,2H),6.97(t,J=7.5Hz,1H),6.74(d,J=7.8Hz,1H),6 .09(dd,J=17.5,10.8Hz,1H),5.06(dd,J=10.8,1.4Hz,1H),4.97(dd,J=17.5,1.4Hz,1H),4.81(t, J=5.3Hz,1H),4.41(t,J=7.3Hz,1H),3.13(s,3H),2.76(dd,J=13.8,7.2Hz,1H),2.53(dd,J=13.8 ,7.7Hz,1H),1.68–1.66(m,2H),1.59(s,3H),1.48(s,3H),1.46(s,3H),1.16(s,3H),1.01(s,3H). 13 C NMR(101MHz,Chloroform-d)δ178.84,144.55,144.01,137.91,131.09,130.81,127.55,125.44,124.11,121.23,118 .56,113.15,107.13,58.37,41.75,39.69,30.20,26.78,25.71,25.63,22.55,22.06,17.56,16.40.HRMScalculated for C 23 H 32 NO + [M+H] +338.2478, found 338.2489.

[0145] Example 7:

[0146] The operation process and conditions are the same as in Step 2, Example 1, except that the haloalkanes (R) described in Table 1 are different. 2 Compound X is different. The product yield was 99% (4g). The structure of the compound was identified by NMR (1H and 1C) and high-resolution mass spectrometry.

[0147] The test data is as follows:

[0148]

[0149] 1-Methyl-3-(2-methylbut-3-en-2-yl)-3-(prop-2-yn-1-yl)indolin-2-one(4g): White solid, (mp53-55℃), 25.2mg, 99% yield, R f =0.3 (PE:EA = 20:1). 1 H NMR (400MHz, Chloroform-d) δ7.34–7.23(m,2H),7.04(t,J=7.6Hz,1H),6.82(d,J=7.8Hz,1H),6.06(dd,J=17.4,10.8Hz,1H),5.10(dd,J=10.8,1.2Hz,1H ),5.00(dd,J=17.5,1.2Hz,1H),3.20(s,3H),2.91(dd,J=16.3,2.6Hz,1H),2 .70(dd,J=16.3,2.7Hz,1H),1.56(t,J=2.6Hz,1H),1.12(s,3H),1.01(s,3H). 13 C NMR(101MHz,Chloroform-d)δ177.85,144.86,143.07,129.79,128.18,125.35,121 .64,113.97,107.46,79.94,69.50,57.19,41.56,25.96,22.36,22.22,22.08.HRMS calculated for C 17 H 20 NO + [M+H] + 254.1539, found 254.1542.

[0150] Example 8:

[0151] The operation process and conditions are the same as in Step 2, Example 1, except that the haloalkanes (R) described in Table 1 are different. 2 Compound X is different. The product yield was 99% after 4 hours, and the structure of the compound was identified by NMR (1H and 1C) and high-resolution mass spectrometry.

[0152] The test data is as follows:

[0153]

[0154] 2-(1-Methyl-3-(2-methylbut-3-en-2-yl)-2-oxoindolin-3-yl)acetonitrile(4h): White solid, (mp114-116℃), 24.9mg, 98% yield, R f =0.5 (PE:EA = 5:1). 1 H NMR (400MHz, Chloroform-d) δ7.35(t,J=7.8Hz,1H),7.30(d,J=7.5Hz,1H),7.09(t,J=7.6Hz,1H),6.88(d,J=7.8Hz,1H),6.05(dd,J=17.5,10.8Hz,1H ),5.19(dd,J=10.8,1.0Hz,1H),5.07(dd,J=17.5,1.0Hz,1H),3.23(s,3H) ,2.98(d,J=16.4Hz,1H),2.85(d,J=16.4Hz,1H),1.12(s,3H),1.02(s,3H). 13 C NMR(101MHz,Chloroform-d)δ176.31,144.41,142.05,129.31,127.71,125.38, 122.35,116.82,115.12,108.34,54.91,41.74,26.27,21.95,21.93,21.53.HRMS calculated for C 16 H 19 N2O + [M+H] + 255.1492, found 255.1497.

[0155] Example 9:

[0156] The operation process and conditions are the same as in Step 2, Example 1, except that the haloalkanes (R) described in Table 1 are different. 2Compound X is different. Product 4i has a yield of 96%, and the structure of the compound was identified by NMR (1H and 1C) and high-resolution mass spectrometry.

[0157] The test data is as follows:

[0158]

[0159] 1,3-Dimethyl-3-(2-methylbut-3-en-2-yl)indolin-2-one(4i):Colorlessoil,22.0mg,96%yield,R f =0.4 (PE:EA = 10:1). 1 H NMR(400MHz,Chloroform-d)δ7.30–7.19(m,2H),7.00(t,J=7.5Hz,1H),6.80(d,J=7.8Hz,1H),6.01(dd,J=17.4,10.8H z,1H),5.05(dd,J=10.8,1.3Hz,1H),4.97(dd,J=17.5,1.3Hz,1H),3.18(s,3H),1.33(s,3H),1.15(s,3H),0.99(s,3H). 13 C HRMS calculated for C 15 H 20 NO + [M+H] + 230.1539, found 230.1540.

[0160] Example 10:

[0161] The operation process and conditions are the same as in Step 2, Example 1, except that the haloalkanes (R) described in Table 1 are different. 2 Compound X is different. Product 4j has a yield of 81%, and the structure of the compound was identified by NMR (1H and 1C) and high-resolution mass spectrometry.

[0162] The test data is as follows:

[0163]

[0164] 3-Ethyl-1-methyl-3-(2-methylbut-3-en-2-yl)indolin-2-one(4j):Colorlessoil,19.7mg,81%yield,R f =0.5 (PE:EA = 10:1). 1 H NMR(400MHz,Chloroform-d)δ7.26(t,J=7.6Hz,1H),7.17(d,J=7.4Hz,1H),7.01 (t,J=7.5Hz,1H),6.79(d,J=7.8Hz,1H),6.03(dd,J=17.5,10.8Hz,1H),5.03(d, J=10.8Hz,1H),4.94(d,J=17.5Hz,1H),3.18(s,3H),2.12(dq,J=14.3,7.3Hz,1H ),1.82(dq,J=14.5,7.5Hz,1H),1.12(s,3H),0.99(s,3H),0.37(t,J=7.3Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ179.03,144.82,143.97,130.49,127.60,125.22 ,121.46,113.07,107.30,59.21,41.87,25.74,24.24,22.51,21.97,9.18.HRMS calculated for C 16 H 22 NO + [M+H] + 244.1696, found244.1696.

[0165] Example 11:

[0166] The operation process and conditions are the same as in Step 2, Example 1, except that the haloalkanes (R) described in Table 1 are different. 2 Compound X is different. The product yield was 43%, and the structure of the compound was identified by NMR (1H and 1C) and high-resolution mass spectrometry.

[0167] The test data is as follows:

[0168]

[0169] 3-Isopropyl-1-methyl-3-(2-methylbut-3-en-2-yl)indolin-2-one(4k):Colorless oil,11.1mg,43%yield,R f =0.5(PE:EA=10:1). 1 H NMR(400MHz,Chloroform-d)δ7.35(d,J=7.5Hz,1H),7.29(m,2H),7.02(t,J=7.6Hz,1H),6.81(d,J=7.8Hz,1H),6.24(dd,J=17.3,11.0Hz,1H),4.99(dd,J=11.0,1.4Hz,1H),4.98(dd,J=17.3,1.3Hz,1H),3.16(s,3H),2.56–2.49(m,1H),1.22(s,3H),1.15(d,J=6.9Hz,3H),1.00(s,3H),0.44(d,J=6.7Hz,3H). 13 CNMR(101MHz,Chloroform-d)δ179.73,145.46,144.89,128.97,127.62,126.89,121.13,112.02,107.39,61.24,41.61,32.37,25.58,24.17,23.21,19.63,18.89.HRMS calculated for C 17 H 24 NO + [M+H] + 258.1852,found258.1851。

Claims

1. A method for nickel-catalyzed synthesis of anti-isopentenyl-substituted indolones, characterized in that: The indoleone skeleton Ar can be one or more of the following groups: 5-methyl, 5-fluoro, 5-chloro, 5-bromo, 5-methoxy, 6-fluoro, 6-chloro, 6-bromo, 6-methoxy, methyl 6-carboxylate, 7-methyl, and 7-trifluoromethyl. Preferably, the following groups are used: Indole ketone nitrogen substituent R 1 It can be one or more of ethyl, benzyl, allyl, and isopentenyl; preferably as follows: R 2 It is one or more of benzyl, 4-tert-butylbenzyl, 4-cyanobenzyl, 4-trifluoromethylbenzyl, isopentenyl, geranyl, propargyl, acetonitrile, methyl, ethyl, and isopropyl, with the following preferred formulations:

2. The method according to claim 1, characterized in that: The specific steps for Step 1 are as follows: In an inert atmosphere (e.g., nitrogen), nickel catalyst (Ni(cod)2), tricyclohexylphosphine ligand (PCy3), indole 1, isoprene 2, basic additive (Cs2CO3), and tetrahydrofuran solvent (THF) are added to the reaction vessel, and the reaction is carried out at 60°C for 24 hours (more preferably, the reaction temperature range is 60–100°C, and the reaction time is 24–48 hours); after the reaction is completed, the anti-isoprenyl substituted indole 3 is isolated.

3. The method according to claim 1 or 2, characterized in that: The preferred molar ratio of indolone 1 to isoprene 2 is 1.0:1.0 to 1.0:4.0, and a more preferred ratio is 1.0:1.0 to 1.0:2.

0.

4. The method according to claim 1 or 2, characterized in that: The preferred molar ratio of indolone 1 to alkaline additive (Cs2CO3) is 1.0:0.5 to 1.0:2.0, and a more preferred ratio is 1.0:0.5 to 1.0:1.

0.

5. The method according to claim 1 or 2, characterized in that: The preferred molar ratio of nickel catalyst (Ni(cod)2) to tricyclohexylphosphine ligand (PCy3) is 1.0:1.0 to 1.0:2.5, more preferably 1.0:1.5 to 1.0:2.0, relative to 0.20 mmol of indolone 1, wherein the preferred amount of nickel catalyst (Ni(cod)2) added is 0.01-0.05 mmol, more preferably 0.02 mmol.

6. The method according to claim 1 or 2, characterized in that: The solvent is tetrahydrofuran (THF), and the amount of solvent used relative to 0.20 mmol of indolone 1 is preferably 1.5 to 2.5 mL, more preferably 1.9 to 2.0 mL.

7. The method according to claim 1, characterized in that: The specific steps for step two are as follows: Under an inert atmosphere (e.g., nitrogen), a trans-isopentenyl-substituted indole 3, an additive base (NaH), and nitrogen, dimethylformamide (DMF), and a haloalkane (R) are added to the reaction vessel. 2 X) React at room temperature for 12–16 hours; after the reaction is complete, 3,3-disubstituted indole 4 is isolated.

8. The method according to claim 1 or 6, characterized in that: Anti-isopentenyl substituted indolones 3, additive bases (NaH), and haloalkanes (R 2 The preferred molar ratio of X) is 1.0:1.2:1.5 to 1.0:1.2:1.5, and the more preferred ratio is 1.0:1.2:2.

0.

9. The method according to claim 1 or 6, characterized in that: The solvent is nitrogen, dimethylformamide (DMF), and the amount of solvent used is 0.3 to 0.7 mL, preferably 0.5 mL, relative to 0.10 mmol of trans-isopentenyl-substituted indolone 3.

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