Preparation method of C2-site alkylated indole compound

Abstract

The invention discloses a preparation method of C2-site alkylated indole compounds, and belongs to the field of organic synthesis. According to the method, 3-iodoindole with indole N-H protected by p-toluenesulfonyl, epoxypropane and olefin as starting materials are stirred to react in an organic solvent at the temperature of 60-100 DEG C under the action of a palladium catalyst, norbornene, a phosphine ligand, an accelerant and alkali, and disubstituted indole with indole C2 site alkylation and C3 site alkenylation can be obtained. The raw materials used in the method are cheap and easy to obtain, the reaction process is mild, the substrate universality is good, and the method has high step economy and practicability.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemical synthesis, and particularly relates to a method for preparing a C2-alkylated indole compound. Background Art

[0002] C2-alkylated indoles are widely used in the fields of anti-cancer and anti-inflammatory, so alkylation modification of the C2 position of indoles is of great significance. For the pyrrole ring part in the indole structure, C3-alkylation is relatively easier and can be achieved through Friedel-Crafts alkylation, allyl alkylation and conjugate addition. However, traditional C2-alkylation of indoles is slightly more difficult, and usually requires deprotonation of the C2 position and then nucleophilic substitution to complete the construction of C2-alkylation. This method usually has harsh reaction conditions, low selectivity and limited substrate range (JMC.2015.9480). Therefore, it is challenging to develop a more direct and selective C2-alkylation method for indoles.

[0003] With the extensive research of researchers, metal-catalyzed CH activation has gradually become an important method for C2 alkylation of indole. From the perspective of atom economy and step economy, the direct alkylation reaction catalyzed by transition metal-catalyzed carbon-hydrogen activation is very attractive (Adv.Synth.Catal.2021.2723, AsianJ.Org.Chem.2020.326, Adv.Synth.Catal.2015.2403). At present, the construction of C2 alkylated indoles by metal catalysis mainly involves the following substrates: alkyl halides, olefins, allyl alcohols, etc. (NewJ.Chem.2021.13692). The C2 alkylation reactions of indole carried out under the above reaction conditions have their own substrate applicability ranges, and the universality of functional groups is limited. At present, there is still no literature reporting that the C2 alkylation of indole can be achieved with step economy while the C3 position also undergoes olefination reaction. Summary of the invention

[0004] In order to solve the problems existing in the prior art, the object of the present invention is to provide a method for preparing C2-alkylated indole compounds.

[0005] To achieve the above purpose, the technical solution provided by the present invention is as follows:

[0006] Under the protection of inert gas, 3-iodo-1-toluenesulfonyl-1H-indole derivative A, epoxide B and olefin derivative C are used as starting materials, and under the action of palladium catalyst D, norbornene derivative E, phosphine ligand F, promoter G and base H, the mixture is stirred in an organic solvent I at 60-100° C. until the reaction is completed, and the reaction mixture is filtered, concentrated and purified by column chromatography to obtain C2 alkylated indole compound J as shown in the reaction formula. The reaction formula of the reaction is shown as follows:

[0007]

[0008] Where n represents R 1 The number of , 0≤n≤4;

[0009] R 1 is C1-C2 alkyl, C1-C2 alkoxy, ester, cyano, nitro, sulfonyl or halogen; when n≥2, each R 1 Same or different;

[0010] R 2 is hydrogen, C1-C5 alkyl, sulfonyl or halogen;

[0011] R 3 is hydrogen, C1-C5 alkyl, sulfonyl or halogen;

[0012] R 4 is hydrogen, ester group, aryl group, cyano group, nitro group;

[0013] Furthermore, the molar ratio of the indole derivative A, the epoxy compound B, the olefin derivative C, the palladium catalyst D, the norbornene derivative E, the phosphine ligand F, and the base H is (1-2): (5-10): (1-3): (0.05-0.5): (1-5): (0.2-1): (1-5).

[0014] Further, the palladium catalyst D is one of palladium acetate, bis(cyanobenzene)palladium dichloride, bis(acetylacetone)palladium, palladium chloride, tris(dibenzylideneacetone)dipalladium, palladium trifluoroacetate, bis(acetonitrile)palladium chloride, bistriphenylphosphinepalladium dichloride, and tetrakis(triphenylphosphine)palladium, among which palladium acetate is preferred.

[0015] Furthermore, the norbornene derivative E is one of: 2-cyano-5-norbornene, 5-norbornene-2-ol, 5-norbornene-2-yl acetate, 5-norbornene-2-carboxylic acid, 5-norbornene-2-carboxylic acid methyl ester, and norbornene, among which norbornene is preferred.

[0016] Further, the phosphine ligand F is: 1,2-bis(diphenylphosphino)ethane, 2-(dicyclohexylphosphino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, 4 -(di-tert-butylphosphino)-N,N-dimethylaniline, tri(2-furanyl)phosphine, tri(2-methoxyphenyl)phosphine, tri(3-methoxyphenyl)phosphine, tri(3-chlorophenyl)phosphine, tri(4-fluorophenyl)phosphine, tri(4-methoxyphenyl)phosphine, tri(4-chlorophenyl)phosphine, tri(o-methylphenyl)phosphine, tri(pentafluorophenyl)phosphine, triphenylphosphine, among which tri(2-furanyl)phosphine is preferred.

[0017] Furthermore, the accelerator G is: Molecular sieve.

[0018] Further, for every 1 mmol of indole substrate A, 50-200 mg of Molecular sieve.

[0019] Furthermore, the base H is one of cesium acetate, sodium acetate, potassium acetate, sodium acetate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, and disodium hydrogen phosphate, among which sodium acetate is preferred.

[0020] Furthermore, the solvent I is one of 1,4-dioxane, ethylene glycol dimethyl ether, 1,2-dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone, among which N-methylpyrrolidone is preferred.

[0021] Furthermore, in the preparation method, the heating process can use an oil bath, which can be silicone oil or paraffin oil; the filtration process uses a sand core funnel and filters under reduced pressure; the concentration process can use atmospheric distillation or reduced pressure distillation, preferably using a rotary evaporator to concentrate under reduced pressure; the purification process is to obtain a pure product through column chromatography.

[0022] The method of the present invention can efficiently prepare C2 alkylated indole. Compared with the prior art, the present invention has the following advantages:

[0023] 1. The main raw materials involved in the present invention are iodoindole, propylene oxide and olefins. These raw materials can be commercial reagents without special treatment, and are low in price and in a wide variety;

[0024] 2. The present invention can simultaneously realize the alkylation of indole C2 and the olefination of indole C3. The one-step reaction to generate C2 and C3 disubstituted indoles has better step economy compared to the two-step reaction that may be required before;

[0025] 3. The reaction involved in the method of the present invention has good tolerance and universality to functional groups, and the substituents can be alkyl, alkoxy, cyano, ester, nitro, halogen atoms (F, Cl, Br), etc.

[0026] 4. The method of the present invention can be used for large-scale (gram-level) preparation, laying a good foundation for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 Compound J-6 1 H-NMR (400MHz, CDCl3) chart;

[0028] Figure 2 Compound J-6 13 C-NMR (100 MHz, CDCl3) chart. DETAILED DESCRIPTION

[0029] The following are specific embodiments of the present invention, which further describe the technical solutions of the present invention, but the present invention is not limited to these embodiments.

[0030] Example 1: Preparation of Compound J-1

[0031]

[0032] Pd(OAc)2 (0.02 mmol, 4.4 mg, 0.10 eq.), tri(2-furyl)phosphine (0.04 mmol, 9.2 mg, 0.20 eq.), norbornene (0.60 mmol, 56.0 mg, 3.00 eq.), sodium acetate (0.20 mmol, 27.20 mg, 1.00 eq.) were added in sequence to a Schlenk tube (10 mL) pre-equipped with a magnetic stirrer and thoroughly dried. Molecular sieves (50.0 mg / mmol), 3-iodo-1-Ts-1H-indole (0.20 mmol, 80.0 mg, 1.00 eq.), glycidyl phenyl ether (1.00 mmol, 150.0 mg, 5.00 eq.), tert-butyl acrylate (0.20 mmol, 25.6 mg, 1.00 eq.) and N-methylpyrrolidone (2 mL). After the addition of the above reagents, argon gas was connected through a double row of pipes to replace the air. The above reaction solution was stirred at room temperature for about 5 minutes and then continued to stir in an oil bath pot set at 80°C for 24 hours. After the reaction was completed, diatomaceous earth was pad and filtered to remove insoluble matter. The filtrate was extracted with ethyl acetate and water, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered and collected, and concentrated under reduced pressure to obtain a crude product. The target product J-1 (100.6 mg, yield 92%) was obtained as a brown oil by purification by column chromatography (eluent: ethyl acetate:petroleum ether=1:10, V:V). 1 H NMR (400MHz, CDCl3) δ8.23(d,J=8.0Hz,1H),7.83(d,J=16.1Hz,2H),7.60(d,J=8.0Hz,2H),7.26(s,4H),7.18(d,J=8.1Hz,2H),6. 96(s,3H),6.50(d,J=16.2Hz,1H),4.49(s,1H),4.14–3.98(m,2H),3.53(d,J=3.6Hz,2H),2.63(s,1H),2.33(s,3H),1.52(s,9H). 13 C NMR (101MHz, CDCl3) δ166.7,158.7,145.5,139.5,137.2,135.7,134.6,130.2(2C),129.6(2C),127.9,126.5 (2C),125.3,124.6,121.6,121.3,120.4,119.0,115.5,114.8(2C),80.7,71.1,70.8,31.0,28.4(3C),21.7.

[0033] Example 2: Preparation of Compound J-2

[0034]

[0035] The operation steps and conditions are the same as those in Example 1, except that the feed amounts are halved, and the indole substrate used is 3-iodo-6-methyl-1-Ts-1H-indole (0.1 mmol, 41.1 mg), to obtain compound J-2 (brown oil, 50.0 mg, yield 90%). 1H NMR (400MHz, CDCl3) δ8.05 (s, 1H), 7.80 (d, J = 16.1Hz, 1H), 7.66 (d, J = 8.1Hz, 1H), 7.62–7. 55(m,2H),7.32–7.24(m,2H),7.18(d,J=8.2Hz,2H),7.16–7.11(m,1H),6.95(ddt,J=8.7,7 .7,1.0Hz,3H),6.47(d,J=16.1Hz,1H),4.47(s,1H),4.08(dd,J=9.5,3.6Hz,1H),4.00(dd, J=9.5,5.7Hz,1H),3.56–3.42(m,2H),2.64(s,1H),2.49(s,3H),2.34(s,3H),1.52(s,9H). 13 C NMR (101MHz, CDCl3) δ166.71,158.61,145.40,138.84,137.61,135.76,135.52,134.67,130.17,129.61,126.37,126. 00,125.50,121.34,121.27,120.04,118.92,115.59,114.79,80.64,71.03,70.71,30.97,29.84,28.37,22.12,21.73.

[0036] Example 3: Preparation of Compound J-3

[0037]

[0038] The operation steps and conditions are the same as those in Example 1, except that the feed amounts are halved, and the indole substrate used is 6-bromo-3-iodo-1-Ts-1H-indole (0.1mmol, 47.6mg), to obtain compound J-3 (brown oil, 57.0mg, yield 90%). 1 HNMR(400MHz, CDCl3)δ8.43(d,J=1.7Hz,1H),7.78(d,J=16.2Hz,1H),7.67– 7.56(m,3H),7.43(dd,J=8.5,1.8Hz,1H),7.33–7.26(m,3H),7.23(d,J=8.2H z,2H),7.02–6.90(m,3H),6.43(d,J=16.1Hz,1H),4.56–4.43(m,1H),4.17–4 .06(m,1H),4.07–3.94(m,1H),3.51–3.44(m,2H),2.36(s,3H),1.52(s,9H). 13C NMR (101MHz, CDCl3) δ166.43,158.53,145.88,139.85,137.81,135.38,134.12,130.37(2C),129.65(2C),127.86,126.71, 126.47(2C),121.94,121.44,121.37,119.06,118.59,118.45,114.77(2C),80.86,71.02,70.60,30.97,28.35(3C),21.78.

[0039] Example 4: Preparation of Compound J-4

[0040]

[0041] The operation steps and conditions are the same as those in Example 1, except that the feed amounts are halved, and the indole substrate used is 3-iodo-5-methyl-1-Ts-1H-indole (0.1 mmol, 41.1 mg), to obtain compound J-4 (brown oil, 61.0 mg, yield 86%). 1 H NMR(400MHz, CDCl3)δ8.10(d,J=8.6Hz,1H),7.82(d,J=16.1Hz,1H),7.63–7.54(m ,3H),7.32–7.24(m,2H),7.21–7.13(m,3H),7.00–6.90(m,3H),6.48(d,J=16.1Hz ,1H),4.56–4.44(m,1H),4.09(dd,J=9.5,3.6Hz,1H),4.01(dd,J=9.5,5.7Hz,1H) ,3.58–3.46(m,2H),2.71(d,J=5.7Hz,1H),2.45(s,3H),2.32(s,3H),1.54(s,9H). 13 C NMR (101MHz, CDCl3) δ166.72,158.60,145.36,139.48,135.62,135.32,134.75,134.32,130.12(2C),129.58(2C),128.03,126 .64,126.39(2C),121.32,121.24,120.38,118.75,115.09,114.78(2C),80.67,71.02,70.71,30.99,28.36(3C),21.69,21.54.

[0042] Example 5: Preparation of Compound J-5

[0043]

[0044] The operation steps and conditions were the same as those in Example 1, except that the indole substrate used was 3-iodo-5-methoxy-1-Ts-1H-indole (0.2 mmol, 55.4 mg), and compound J-5 (purple oil, 94.0 mg, yield 81%) was obtained. 1 H NMR(400MHz, CDCl3)δ8.13(d,J=9.2Hz,1H),7.80(d,J=16.2Hz,1H),7.61–7.53(m,2H),7.32–7 .26(m,2H),7.20(d,J=2.5Hz,1H),7.20–7.14(m,2H),6.96(dddd,J=8.7,6.7,2.7,1.1Hz,4H),6 .43(d,J=16.1Hz,1H),4.55–4.45(m,1H),4.09(dd,J=9.5,3.6Hz,1H),4.01(dd,J=9.5,5.7Hz, 1H), 3.86 (s, 3H), 3.50 (dd, J = 6.4, 2.8Hz, 2H), 2.67 (d, J = 5.7Hz, 1H), 2.33 (s, 3H), 1.52 (s, 9H). 13 C NMR (101MHz, CDCl3) δ166.65,158.62,157.30,145.41,140.06,135.55,134.60,131.69,130.13(2C),129.60(2C),129.03,126 .37(2C),121.42,121.29,118.99,116.33,114.81(2C),113.20,103.92,80.71,71.07,70.74,55.97,31.09,28.37(3C),21.70.

[0045] Example 6: Preparation of Compound J-6

[0046]

[0047] The operation steps and conditions are the same as those in Example 1, except that the feed amounts are halved, and the indole substrate used is 5-bromo-3-iodo-1-Ts-1H-indole (0.1mmol, 47.6mg), to obtain compound J-6 (brown oil, 48.2mg, yield 77%). 1HNMR (400MHz, CDCl3) δ8.11(d,J=8.9Hz,1H),7.90(d,J=2.0Hz,1H),7.77(d,J=16.2Hz,1H),7.62– 7.54(m,2H),7.45(dd,J=9.0,1.9Hz,1H),7.28(dd,J=8.7,7.3Hz,2H),7.20(d,J=8.2Hz,2H),7.01 –6.90(m,3H),6.41(d,J=16.2Hz,1H),4.48(td,J=6.1,3.8Hz,1H),4.10(dd,J=9.3,3.5Hz,1H),4. 01(dd,J=9.4,5.6Hz,1H),3.50(d,J=6.4Hz,2H),2.62(d,J=6.0Hz,1H),2.35(s,3H),1.53(s,9H). 13 C NMR (101MHz, CDCl3) δ166.42,158.52,145.84,140.52,135.85,135.33,133.99,130.31(2C),129.64(2C),129.55,128.18, 126.42(2C),123.05,121.97,121.36,118.25,118.16,116.81,114.76(2C),80.92,71.01,70.65,31.00,28.35(3C),21.75.

[0048] Example 7: Preparation of Compound J-7

[0049]

[0050] The operation steps and conditions are the same as those in Example 1, except that the indole substrate used is 3-iodo-1-Ts-1H-indole-5-carboxylic acid ethyl ester (0.2mmol, 94.0mg), and compound J-7 (brown oil, 97.0mg, yield 81%) is obtained. 1H NMR(400MHz, CDCl3)δ8.39(d,J=9.0Hz,1H),8.00–7.93(m,2H),7.90(d,J=8.9Hz,1H),7.84(d, J=2.1Hz,1H),7.76(s,1H),7.45(dd,J=9.0,2.1Hz,1H),7.40(d,J=8.3Hz,2H),7.26–7.24(m,1 H),7.23–7.20(m,1H),6.87–6.81(m,2H),6.77(d,J=8.4Hz,2H),6.69(d,J=2.0Hz,1H),6.40(d ,J=16.3Hz,1H),4.17(qd,J=7.1,2.1Hz,2H),2.40(s,3H),2.23(s,3H),1.26(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ166.73,146.10,145.83,136.69,134.84,134.76,1 34.67,133.77,132.33,131.94,130.84,130.73,130.49(2C),129.90,129 .55(2C),128.45,127.45(2C),126.77(2C),126.39,125.47,120.31,120. 17,120.00,119.37,117.32,114.63,109.99,60.69,21.85,21.65,14.38.

[0051] Example 8: Preparation of Compound J-8

[0052]

[0053] The operation steps and conditions are the same as those in Example 1, except that the indole substrate used is 3-iodo-6-methoxy-1-Ts-1H-indole (0.2mmol, 85.4mg), and compound J-8 (light yellow solid, 74.0mg, yield 66%) is obtained. 1H NMR (400MHz, CDCl3) δ7.83–7.74 (m, 2H), 7.66 (d, J = 8.7Hz, 1H), 7.62–7.55 (m,2H),7.31–7.26(m,2H),7.19(d,J=8.1Hz,2H),7.00–6.90(m,4H),6.45( d,J=16.1Hz,1H),4.48(s,1H),4.17–4.06(m,1H),4.00(dd,J=9.5,5.7Hz,1 H),3.89(s,3H),3.55–3.40(m,2H),2.62(s,1H),2.34(s,3H),1.52(s,9H). 13 C NMR (101MHz, CDCl3) δ166.69,158.62,158.20,145.48,138.37,138.33,135.63,134.63,130.18(2C),129.70(2C),129.59,126.37( 2C),121.51,121.25,120.94,118.94,114.80(2C),114.68,113.28,100.02,80.65,71.05,70.69,55.90,31.02,28.36(3C),21.72.

[0054] Example 9: Preparation of Compound J-9

[0055]

[0056] The operation steps and conditions are the same as those in Example 1, except that the indole substrate used is 5-chloro-3-iodo-1-Ts-1H-indole (0.2mmol, 86.2mg), and compound J-9 (brown oil, 76.5mg, yield 66%) is obtained. 1H NMR(400MHz, CDCl3)δ9.13(d,J=1.5Hz,1H),8.74–8.67(m,1H),8.10(dd,J=8.4,1.5Hz,1H),8.04– 7.97(m,2H),7.90(d,J=6.8Hz,2H),7.78(dd,J=8.4,1.4Hz,1H),7.40(d,J=8.2Hz,2H),7.29(d,J= 16.3Hz,1H),7.02–6.96(m,1H),6.96–6.90(m,2H),6.78(d,J=8.1Hz,2H),6.46(d,J=16.3Hz,1H), 4.16(q,J=7.1Hz,2H),4.01(s,3H),3.98(s,3H),2.38(s,3H),2.18(s,3H),1.23(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ167.10,167.01,166.68,146.13,145.72,137.80,135.42,1 34.82,134.79,134.60,134.13,133.55,132.07,130.90,130.56(2C),129.63(2C ),127.86,127.51(2C),127.13,126.85(2C),125.97,124.88,120.46,120.42,12 0.32,119.78,117.91,115.40,110.51,60.66,52.58,52.50,21.83,21.57,14.36.

[0057] Example 10: Preparation of Compound J-10

[0058]

[0059] The operation steps and conditions are the same as those in Example 1, except that the feed amounts are halved, and the indole substrate used is 6-chloro-3-iodo-1-Ts-1H-indole (0.1mmol, 43.2mg), to obtain compound J-10 (brown oil, 37.5mg, yield 63%). 1HNMR (400MHz, CDCl3) δ8.27(d,J=1.8Hz,1H),7.78(d,J=16.2Hz,1H),7.70(d,J=8.5 Hz,1H),7.64–7.58(m,2H),7.32–7.26(m,3H),7.25–7.20(m,2H),7.01–6.89(m,3H), 6.43(d,J=16.2Hz,1H),4.54–4.42(m,1H),4.10(dd,J=9.4,3.6Hz,1H),4.01(dd,J= 9.5,5.6Hz,1H),3.50–3.47(m,2H),2.59(d,J=5.9Hz,1H),2.36(s,3H),1.52(s,9H). 13 C NMR (101MHz, CDCl3) δ166.46,158.54,145.85,139.96,137.53,135.38,134.17,131.35,130.35(2C),129.63(2C),126.46( 2C),126.32,125.12,121.86,121.35,121.10,118.54,115.60,114.76(2C),80.84,71.03,70.61,30.99,28.34(3C),21.76.

[0060] Example 11: Preparation of Compound J-11

[0061]

[0062] The operation steps and conditions are the same as those of Example 1, except that the indole substrate used is 6-fluoro-3-iodo-1-Ts-1H-indole (0.2 mmol, 83.1 mg), and compound J-11 (brown oil, 69.3 mg, yield 63%) is obtained. 1H NMR (400MHz, CDCl3) δ7.99 (dd, J=10.3, 2.4Hz, 1H), 7.79 (d, J=16.1Hz, 1H), 7.72 (dd, J= 8.8,5.3Hz,1H),7.65–7.56(m,2H),7.32–7.26(m,2H),7.24–7.20(m,2H),7.07(td,J=8. 8,2.4Hz,1H),6.99–6.93(m,3H),6.45(d,J=16.1Hz,1H),4.48(s,1H),4.17–4.07(m,1H) ,4.01(dd,J=9.5,5.6Hz,1H),3.55–3.42(m,2H),2.68(s,1H),2.35(s,3H),1.52(s,9H). 13 C NMR (101MHz, CDCl3) δ166.50,161.07(d,J=242.6Hz),158.57,145.80,139.70(d,J =3.5Hz),137.47(d,J=12.2Hz),135.40,134.29,130.31(2C),129.63(2C),126.47( 2C),124.11,121.68,121.34,121.19(d,J=9.8Hz),118.58,114.78(2C),112.77(d ,J=23.8Hz),103.00(d,J=29.0Hz),80.80,71.04,70.64,31.01,28.35(3C),21.75.

[0063] Example 12: Preparation of Compound J-12

[0064]

[0065] The operation steps and conditions are the same as those of Example 1, except that the indole substrate used is 5-cyano-3-iodo-1-Ts-1H-indole (0.2mmol, 84.4mg), and compound J-12 (brown oil, 55.6mg, yield 50%) is obtained. 1H NMR (400MHz, CDCl3) δ8.33(d,J=8.8Hz,1H),8.11(d,J=1.6Hz,1H),7.79(d,J=16. 2Hz,1H),7.65–7.57(m,2H),7.33–7.27(m,3H),7.24(d,J=8.3Hz,2H),7.03–6.89( m,3H),6.43(d,J=16.3Hz,1H),4.47(s,1H),4.12(dd,J=9.4,3.6Hz,1H),4.03(dd ,J=9.5,5.5Hz,1H),3.51(d,J=6.4Hz,2H),2.63(s,1H),2.36(s,3H),1.54(s,9H). 13 C NMR (101MHz, CDCl3) δ171.31,166.21,158.46,158.41,146.28,141.57,138.8 5,135.17,133.51,130.47,129.68,129.66,128.14(d,J=3.4Hz),127.95,126. 49,125.03,122.64,121.49,121.43,119.24,118.15,116.11,114.73,114.66, 108.14,81.15,71.05,70.56,68.69(d,J=1.5Hz),65.53,31.01,28.32,21.77.

[0066] Example 13: Preparation of Compound J-13

[0067]

[0068] The operation steps and conditions are the same as those in Example 1, except that the indole substrate used is 4-chloro-3-iodo-1-Ts-1H-indole (0.2mmol, 61.2mg) to obtain compound J-13 (brown oil, 40.5mg, yield 35%). 1H NMR(400MHz, CDCl3)δ8.34(d,J=9.2Hz,1H),7.98–7.90(m,2H),7.86(d,J=9.0H z,1H),7.65(s,1H),7.36(d,J=8.1Hz,2H),7.31–7.23(m,2H),7.12–7.06(m,1H ),6.98–6.93(m,2H),6.90(dd,J=9.1,2.5Hz,1H),6.82(d,J=8.1Hz,2H),6.39– 6.29(m,2H),3.92(s,3H),3.61(s,3H),2.36(s,3H),2.22(s,3H),1.42(s,9H). 13 C NMR (101MHz, CDCl3) δ166.38,157.43,156.76,145.44,145.14,135.14,135.0 9,134.82,134.54,132.91,132.07,130.32(2C),129.67,129.40(2C),128.84, 128.72,127.34(2C),126.84(2C),120.87,119.90,117.31,114.76,114.34,11 3.86,111.54,104.05,102.56,80.47,56.04,55.56,28.23(3C),21.78,21.52.

[0069] Example 14: Preparation of Compound J-14

[0070]

[0071] The operation steps and conditions are the same as those of Example 1, except that the feed amount is increased by 50%, and the indole substrate used is 5-fluoro-3-iodo-1-Ts-1H-indole (0.3mmol, 124.5mg), to obtain compound J-14 (brown oil, 70.6mg, yield 41%). 1H NMR (400MHz, CDCl3) δ8.34(d,J=8.9Hz,1H),8.00(d,J=2.0Hz,1H),7.97–7. 92(m,2H),7.85(d,J=8.8Hz,1H),7.73(s,1H),7.59(dd,J=9.0,2.0Hz,1H),7 .38(td,J=8.7,1.4Hz,3H),7.14(d,J=16.3Hz,1H),6.88–6.83(m,3H),6.82– 6.76(m,2H),6.35(d,J=16.3Hz,1H),2.39(s,3H),2.25(s,3H),1.44(s,9H). 13 C NMR (101MHz, CDCl3) δ166.05,146.03,145.82,137.12,134.83,134.67,13 3.84,133.46,132.69,132.37,130.57,130.51(2C),129.57(2C),129.03,1 28.98,128.06,127.45(2C),126.76(2C),123.40,123.16,121.94,119.43, 118.48,117.67,117.48,114.97,109.92,80.82,28.25(3C),21.84,21.75.

[0072] Example 15: Preparation of Compound J-17

[0073]

[0074] The operation steps and conditions are the same as those in Example 1, except that the feed amounts are halved, and the propylene oxide substrate used is 1,2-butylene oxide (0.5 mmol, 36.5 mg, 5.00 equiv.), to obtain compound J-15 (brown oil, 19.2 mg, yield 41%). 1H NMR (400MHz, CDCl3) δ8.25–8.17(m,1H),7.84–7.72(m,2H),7.58(d,J=8.2Hz,2H),7 .36–7.28(m,2H),7.18(d,J=8.1Hz,2H),6.48(d,J=16.0Hz,1H),3.99(d,J=6.8Hz,1 H),3.40(dd,J=14.6,4.2Hz,1H),3.23(dd,J=14.5,8.1Hz,1H),2.33(s,3H),2.09(d ,J=0.8Hz,1H),1.99(s,1H),1.69–1.58(m,1H),1.53(s,9H),1.04(t,J=7.4Hz,3H). 13 C NMR (101MHz, CDCl3) δ166.78,145.39,140.89,137.12,135.73,134.88,130.12(2C),127.82,126.40(2C) ,125.17,124.53,121.16,120.35,118.55,115.43,80.67,73.75,34.49,30.28,28.37(3C),21.70,10.13.

[0075] The specific embodiments described herein are merely examples of the spirit of the present invention. Those skilled in the art may make various modifications or additions to the specific embodiments described or replace them in similar ways, but they will not deviate from the spirit of the present invention or exceed the scope defined by the appended claims.

Claims

1. A method for preparing a C2-alkylated indole compound, It is characterized in that The preparation method is as follows: under the protection of inert gas, 3-iodo-1-toluenesulfonyl-1H-indole derivative A, epoxide B and olefin derivative C are used as starting materials, and under the action of palladium catalyst D, norbornene derivative E, phosphine ligand F, promoter G and base H, the mixture is stirred in an organic solvent I at 60-100° C. until the reaction is completed, and the reaction mixture is filtered, concentrated and purified by column chromatography to obtain C2 alkylated indole compound J as shown in the reaction formula; The reaction formula of the reaction is shown below: Where n represents R 1 The number of , 0≤n≤4; R 1 is C1-C2 alkyl, C1-C2 alkoxy, ester, cyano, nitro, sulfonyl or halogen; when n≥2, each R 1 Same or different; R 2 is hydrogen, C1-C5 alkyl, sulfonyl or halogen; R 3 is hydrogen, C1-C5 alkyl, sulfonyl or halogen; R 4 It is hydrogen, ester group, aromatic group, cyano group and nitro group.

2. The method for preparing the C2-alkylated indole compound according to claim 1, It is characterized in that The molar ratio of the indole derivative A, epoxy compound B, olefin derivative C, palladium catalyst D, norbornene derivative E, phosphine ligand F and base H is (1-2): (5-10): (1-3): (0.05-0.5): (1-5): (0.2-1): (1-5).

3. The method for preparing the C2-alkylated indole compound according to claim 1, It is characterized in that The palladium catalyst D is one of palladium acetate, di(cyanobenzene)palladium dichloride, di(acetylacetone)palladium, palladium chloride, tri(dibenzylideneacetone)dipalladium, palladium trifluoroacetate, bis(acetonitrile)palladium chloride, bistriphenylphosphinepalladium dichloride and tetrakis(triphenylphosphine)palladium.

4. The method for preparing the C2-alkylated indole compound according to claim 1, It is characterized in that The norbornene derivative E is one of 2-cyano-5-norbornene, 5-norbornene-2-ol, 5-norbornene-2-yl acetate, 5-norbornene-2-carboxylic acid, 5-norbornene-2-carboxylic acid methyl ester and norbornene.

5. The method for preparing the C2-alkylated indole compound according to claim 1, It is characterized in that The phosphine ligand F is one of 1,2-bis(diphenylphosphino)ethane, 2-(dicyclohexylphosphino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, 4-(di-tert-butylphosphino)-N,N-dimethylaniline, tri(2-furanyl)phosphine, tri(2-methoxyphenyl)phosphine, tri(3-methoxyphenyl)phosphine, tri(3-chlorophenyl)phosphine, tri(4-fluorophenyl)phosphine, tri(4-methoxyphenyl)phosphine, tri(4-chlorophenyl)phosphine, tri(o-methylphenyl)phosphine, tri(pentafluorophenyl)phosphine, and triphenylphosphine.

6. The method for preparing the C2-alkylated indole compound according to claim 1, It is characterized in that The accelerator G is: Molecular sieve.

7. The C2-alkylated indole compound according to claim 6, It is characterized in that For every 1 mmol of indole substrate A, add 50-200 mg of Molecular sieve.

8. The method for preparing the C2-alkylated indole compound according to claim 1, It is characterized in that The base H is one of cesium acetate, sodium acetate, potassium acetate, sodium acetate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate and disodium hydrogen phosphate.

9. The method for preparing the C2-alkylated indole compound according to claim 1, It is characterized in that The solvent I is one of 1,4-dioxane, ethylene glycol dimethyl ether, 1,2-dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone.

10. The method for preparing the C2-alkylated indole compound according to claim 1, It is characterized in that In the preparation method, the heating process can adopt an oil bath, which can be silicone oil or paraffin oil; the filtration process uses a sand core funnel and filters under reduced pressure; the concentration process can adopt atmospheric distillation or reduced pressure distillation, preferably using a rotary evaporator to concentrate under reduced pressure; the purification process is to obtain a pure product through column chromatography.

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