Method for preparing indole derivative with high selectivity

Abstract

The invention relates to a method for preparing an indole derivative with high selectivity, which comprises the following steps: forming benzotitanole from an aryl Grignard reagent, titanate, cobalt salt, ligand and alkyne under the action of a deprotonation reagent, and reacting with N, N-dichloroamine in situ to obtain the indole derivative. The method has the advantages that various indole compounds can be prepared in a one-pot way with high selectivity; the transition metal Ti is a cheap metal with high abundance and low toxicity, and the cobalt catalyst system is simple and cheap. The method has the advantages of mild reaction conditions, tolerance to various sensitive functional groups, high regioselectivity, wide application range and easiness in amplification.

Description

Technical Field

[0001] The present invention relates to the field of heterocyclic compounds and drug synthesis, and in particular to a method for preparing indole heterocyclic compounds and related bioactive substances with high selectivity. Background Art

[0002] Indole compounds are very common and important structural units in the fields of natural products, drugs, pesticides and dyes [Gribble, GW Indole Ring Synthesis: from Natural Products to Drug Discovery; Wiley: Chichester, 2016.], and their structure is shown in bold in the chemical structure below.

[0003]

[0004] Numerous indole derivatives have become important drugs or adjuvants on the market. For example, melatonin is widely used in health products and has the function of improving sleep quality. Sumatriptan is an important clinical drug for the treatment of migraines; and Rucaparib is an important targeted drug for the treatment of recurrent ovarian cancer and prostate cancer. Arbidol is a non-nucleoside broad-spectrum antiviral drug used to treat upper respiratory tract infections caused by influenza A and B viruses. Recent studies have shown that it has anti-new coronavirus activity. Indomethacin is a non-steroidal anti-inflammatory drug used for antipyretic and analgesic purposes; and Bazedoxifene is a non-steroidal estrogen receptor modulator that can be used for osteoporosis. In addition, there are many natural indole products or synthetic indole compounds that show strong pharmaceutical activity and are expected to become or have entered clinical trials [Seen, SB; Gong, Y.; Ashton, M. The application of the Fischer indole synthesis in medicinal chemistry, Advances in Heterocyclic Chemistry, 2023, 139, 1-85.].

[0005] Given the wide range of uses and important properties of indole derivatives, the efficient synthesis of these compounds has always been a key topic in organic synthesis. There are at least ten well-known reactions related to the synthesis of indoles. The numerous known indole syntheses can be roughly divided into two categories: one is the preparation of ortho-functionalized nitrogen-containing compounds through cyclization of ortho-groups such as halogens and alkynyls; the other is the preparation of aromatic amine derivatives through ortho-CH cyclization. Based on the C-H activation process, the second type of method is clearly more atom-economical than the first. Among them, the classic and well-known method is the Fisher indole synthesis (see I in the reaction formula below). It should be noted that in recent years, transition metal chemistry has achieved a lot of results in C-H activation reactions, so the second type of method involving transition metals has also been greatly developed (see III and IV in the reaction formula below).

[0006]

[0007] Although the above-mentioned method for preparing indoles via ortho-CH cyclization has obvious advantages, it also has some insurmountable drawbacks: (1) the aromatic ring and the side chain (H a / H b and R 2 / R 3 ) regioselectivity issues; (2) the transition metals used are mostly noble metals, such as Pd, Ru, Rh, etc.; (3) the reaction conditions are severe, such as in Fisher indole synthesis, which often requires proton acid and needs to be carried out under heating conditions. Summary of the Invention

[0008] The present invention aims to overcome the shortcomings of existing CH cyclization-type indole synthesis methods, such as the difficulty in overcoming regioselectivity problems and the use of noble metals and complex ligands, thereby providing a method for preparing indole derivatives that has a wide range of applications, does not require noble metals, and has high chemoselectivity and regioselectivity.

[0009] To achieve the above objectives, the present invention adopts a new technical solution to realize a method for preparing indole derivatives with high chemical selectivity and high regioselectivity, which comprises:

[0010] Aryl Grignard reagent, titanate, cobalt salt and ligand form alkyne to form benzotitanium ole under the action of deprotonating reagent, and N,N-dichloroamine is added in situ to obtain indole derivatives.

[0011] The reaction mechanism of the method described in the present invention is shown in the following formula:

[0012]

[0013] Preferably, the aryl group in the aryl Grignard reagent is one of phenyl, substituted phenyl, naphthyl, and substituted naphthyl, and the substituent in the substituted phenyl or substituted naphthyl is one or more of alkyl, alkoxy, halogen, phenyl, keto, ester, cyano, and amide.

[0014] Preferably, the titanate comprises Ti(OR)2[(OCH2CH2)2NR'], wherein R=alkyl group with 1 to 4 carbon atoms, and R' is methyl group or alkyl group containing O or N, preferably CH2CH2NMe2.

[0015] Preferably, the cobalt salt is CoX2 (X=Cl, Br), Co(acac)2, Co(acac)3; and the ligand is one of 2,2′-bipyridine, o-phenanthroline, tetramethylethylenediamine (TMEDA) or 1,3-dimethylpropyleneurea (DMPU).

[0016] Preferably, the alkyne is a disubstituted alkyne, and the substituent is one or two of an alkyl group, an aryl group, a ketone group, an ester group, a cyano group, and an amide group.

[0017] Preferably, the general formula of the N,N-dichloramine is RNCl2, wherein R is an aliphatic group, an aromatic group or a benzyl group.

[0018] Preferably, the deprotonating agent is 2,4,6-trimethylphenylmagnesium bromide, 2,6-dimethylphenylmagnesium bromide or tert-butylmagnesium chloride.

[0019] Preferably, the solvent used in the reaction of the present invention is one or a mixture of at least two of tetrahydrofuran, toluene and diethyl ether.

[0020] Preferably, the molar ratio of the aryl Grignard reagent, titanate, alkyne, deprotonating agent, and RNC12 is 1.0:1.0:(1.0-1.5):(1.5-2.0):(1.0-1.5). The catalyst dosage is 10-20 mol%. The molar ratio of the cobalt salt to the ligand in the catalyst is 1.0:(2-4).

[0021] Preferably, the reaction temperature of the aryl Grignard reagent, titanate, cobalt salt and ligand with alkyne to form benzotitanol is 20-45°C; the subsequent reaction temperature with the electrophilic reagent is -20-25°C, and the electrophilic reagent is RNCl2.

[0022] Among the methods for preparing indoles from aromatic amine derivatives via ortho-CH cyclization, the classic and well-known method is the Fisher indole synthesis. This method often produces a mixture of 4-substituted and 6-substituted indoles that is difficult to separate in the cyclization of meta-substituted phenylhydrazones. 1 CH2COCH2R 2The phenylhydrazone cyclization formed also causes the production of two indole isomer mixtures due to the tautomerism of hydrazone. These two types of regioselectivity problems have always been a difficult problem to solve in the current existing methods. Simultaneously, in the Fischer indole synthesis, if there is an electron-withdrawing sensitive group on the aromatic ring of phenylhydrazone, such as COOEt, CN, etc., the cyclization requires severe conditions, not only the cyclization yield is low, but also the destruction of the sensitive group can be caused. The indole synthesis method of the present invention is through the breakthrough of the reaction type and the innovation of the reaction mechanism, thereby obtaining a kind of operational route with strong feasibility. Through careful design, continuous summary and repeated exploration, new mechanisms and measures have been proposed, namely utilizing Co / Ti synergy for the first time, carrying out regioselectivity (H a / H b ) cobaltation to form a cobalt-titanium synergistic bimetallic complex in which the Co center reacts regioselectively with the alkyne (R 2 / R 3 ) is added to form benzotitanol with high regioselectivity (see reaction mechanism). Benzotitanol reacts with RNCl2 in situ (which can be in the presence of a Cu salt, which can be CuCN·2LiCl) to form an indole derivative. It should be noted that the synthesis method of the present invention not only solves the two types of regioselectivity in previous synthesis methods, but also exhibits high functional group tolerance (chemical selectivity); whether on the aromatic ring or on the alkyne, sensitive groups such as ester, ketone, amide and cyano groups can be tolerated. The reaction of the present invention not only discovered and utilized the cobalt-titanium synergistic bimetallic complex for the first time, but also discovered a new method for forming benzotitanol under mild conditions. This is not only an innovation in indole synthesis, but also a breakthrough and innovation in the chemical synthesis of benzotitanol.

[0023] The synthetic method for preparing indole heterocyclic compounds provided by the present invention has the following advantages:

[0024] 1) High chemical selectivity and regioselectivity.

[0025] 2) The transition metal Ti used is abundant in the earth's crust, cheap, low in toxicity, and biocompatible.

[0026] 3) Use cheap cobalt salts and simple ligands as catalysts.

[0027] 4) Multi-step reactions are carried out in one pot, without the need for separation of intermediates, under mild conditions, easy to scale up, and suitable for industrial production.

[0028] 5) Wide range of applications, atomic economy and low cost. DETAILED DESCRIPTION

[0029] The present invention is further described in detail below with reference to the following examples. However, it should be noted that the present invention is not limited to the following examples.

[0030] Example 1 Preparation of 1-benzyl-5-methyl-2,3-diphenyl-1H-indole

[0031]

[0032] Under argon, Ti-1 (1560 mg, 5.0 mmol) was added to a 50 mL dry three-necked round-bottom flask and dissolved in 10 mL of anhydrous THF. 5.0 mL of 4-methylphenylmagnesium bromide solution (1 M in THF, 5.0 mmol) was syringed in and slowly added dropwise to the system over 10-15 minutes at room temperature. Stirring was continued for 1.5 hours after the addition was complete to obtain the corresponding titanium reagent. CoBr2 (109 mg, 0.5 mmol) and 2,2'-bipyridine (156 mg, 1.0 mmol) were added to the system and stirred for two hours. 7.5 mL of 2,4,6-trimethylphenylmagnesium bromide solution (1 M in THF, 7.5 mmol) was slowly added dropwise to the system. After reacting at room temperature for 2 hours, 1,2-diphenylacetylene (1069 mg, 6.0 mmol) was added and stirring continued until the reaction was complete (TLC monitoring, approximately 12 hours).

[0033] The system was cooled to -10°C, and CuCN·2LiCl (523 mg, 3 mmol) and BnNCl2 (968 mg, 5.5 mmol) were weighed. The reaction mixture was slowly returned to room temperature and stirred until completion (TLC monitoring, approximately 4 h). 50 mL of distilled water was added to quench the reaction. After stirring and filtration, the mixture was extracted with CH2Cl2 (50 mL x 3). The resulting organic phases were combined and back-extracted with saturated aqueous NaCl (50 mL x 3). The mixture was then dried over anhydrous Na2SO4 pellets. The solvent was concentrated by filtration and purified by column chromatography to obtain 1307 mg of the desired product in a 70% yield.

[0034] The product is a yellow solid; IR (cm -1 ,KBr):3005,2951,1621,1452,1139,871,757; 1 H NMR (CDCl3, 400MHz) δ (ppm) 7.63 (s, 1H), 7.40–7.25 (m, 12H), 7.19 (m, 2H), 7.05 (t, J = 7.9Hz, 3H), 5.29 (s, 2H), 2.48 (s, 3H); 13C NMR(CDCl3,101MHz)δ(ppm)138.4,138.1,135.5,135.4,132.0,131.2,130.1,129.9,128.8,128.5, 128.3,128.2,127.7,127.2,126.2,125.6,124.0,119.4,115.4,110.3,47.7,21.6; HRMS(ESI+)m / z calcd for C 28 H 24 N + [M+H] + 374.1909,Found 374.1911.

[0035] Example 2 Preparation of 1-benzyl-5-methyl-2,3-diphenyl-1H-indole

[0036]

[0037] According to the above reaction route and the operation of Example 1, Ti-2 (255 mg, 1 mmol) was used instead of Ti-1, and the yield was 22%.

[0038] Example 3 Preparation of 1-benzyl-5-methyl-2,3-diphenyl-1H-indole

[0039]

[0040] According to the above reaction scheme and the operation according to Example 1, Ti-3 (299 mg, 1 mmol) was used instead of Ti-1, and the yield was 19%.

[0041] Example 4 Preparation of 1-benzyl-5-methyl-2,3-diphenyl-1H-indole

[0042]

[0043] According to the above reaction route and the operation of Example 1, Ti-4 (374 mg, 1 mmol) was used instead of Ti-1, and the yield was 21%.

[0044] Example 5 Preparation of 1-benzyl-5-methyl-2,3-diphenyl-1H-indole

[0045]

[0046] According to the above reaction route and the operation of Example 1, Ti-5 (354 mg, 1 mmol) was used instead of Ti-1, and the yield was 22%.

[0047] Example 6 Preparation of 1-benzyl-5-methyl-2,3-diphenyl-1H-indole

[0048] According to the above reaction scheme and the operation according to Example 1, CoCl2 (12.9 mg, 0.1 mmol) was used instead of CoBr2, and the yield was 57%.

[0049] Example 7 Preparation of 1-benzyl-5-methyl-2,3-diphenyl-1H-indole

[0050] According to the above reaction route and the operation of Example 1, PBu3 was used instead of 2,2'-bipyridine, and the yield was 49%.

[0051] Example 8 Preparation of 1-benzyl-5-methyl-2,3-diphenyl-1H-indole

[0052] According to the above reaction route and the operation of Example 1, PPh3 was used instead of 2,2'-bipyridine, and the yield was 37%.

[0053] Example 9 Preparation of 1-benzyl-5-methyl-2,3-diphenyl-1H-indole

[0054] According to the above reaction scheme and the operation of Example 1, 2,2'-bipyridine was replaced by o-phenanthroline (36.0 mg, 0.2 mmol), and the yield was 59%.

[0055] Example 10 Preparation of 1-benzyl-5-methyl-2,3-diphenyl-1H-indole

[0056] According to the above reaction scheme and the operation of Example 1, tetramethylethylenediamine (TMEDA) (23.2 mg, 0.2 mmol) was used instead of 2,2'-bipyridine, and the yield was 56%.

[0057] Example 11 Preparation of 1-benzyl-5-methyl-2,3-diphenyl-1H-indole

[0058] According to the above reaction scheme and the operation of Example 1, 1,3-dimethylpropyleneurea (DMPU) (25.6 mg, 0.2 mmol) was used instead of 2,2'-bipyridine, and the yield was 63%.

[0059] Example 12 Preparation of 1-benzyl-5-methyl-2,3-diphenyl-1H-indole

[0060] According to the above reaction route and the operation according to Example 1, the reaction temperature (before adding BnNCl2) was 45°C and the yield was 67%.

[0061] Example 13 Preparation of 1-benzyl-5-methyl-2,3-diphenyl-1H-indole

[0062] According to the above reaction route and the operation of Example 1, when BnNCl2 was added, no CuCN·2LiCl was added, and the yield was 57%.

[0063] Example 14 Preparation of 1-benzyl-5-methyl-2,3-diphenyl-1H-indole

[0064] According to the above reaction scheme and the operation of Example 1, tetrahydrofuran was replaced by a tetrahydrofuran / toluene mixture (volume ratio = 3:1) in the reaction, and the yield was 61%.

[0065] Example 15 Preparation of 1-benzyl-5-methyl-2,3-diphenyl-1H-indole

[0066] According to the above reaction scheme and the operation of Example 1, tetrahydrofuran was replaced by a tetrahydrofuran / diethyl ether mixture (volume ratio = 3:1) in the reaction, and the yield was 63%.

[0067] Example 16 Preparation of ethyl 4,5-dichloro-2-methyl-1-phenyl-1H-indole-3-carboxylate

[0068]

[0069] According to the above reaction scheme and the operation of Example 1, 1097 mg of the target product was obtained by replacing the 4-methylphenylmagnesium bromide solution with 3,4-dichlorophenylmagnesium chloride lithium solution, replacing 1,2-diphenylacetylene with ethyl 2-butynoate (673 mg, 6 mmol), and replacing dichlorobenzylamine with dichloroaniline (891 mg, 5.5 mmol). The yield was 63%.

[0070] The product is yellow oily liquid; IR (cm -1 ,KBr):3051,2087,1758,1477,1346,1159,722,591; 1 H NMR(CDCl3,400MHz)δ(ppm)7.65–7.62(m,2H),7.34–7.31(m,2H),7.30–7.27(m,2H) ),7.26(d,J=5.1Hz,1H),4.07(q,J=4.8Hz,2H),2.42(s,3H),0.97(t,J=4.8Hz,3H); 13 C NMR(CDCl3,101MHz)δ(ppm)169.1,141.6,139.7,137.1,131.9,131.2,130.6,13 0.2,128.5,128.0,127.0,123.2,121.8,60.9,21.0,13.7; HRMS(ESI+)m / zcalcd for C18 H 16 Cl2NO2 + [M+H] + 348.0558,Found 348.0557.

[0071] Example 17 Preparation of Bazedoxifene Acetate Isomer I (17)

[0072]

[0073] Under argon, Ti-1 (1560 mg, 5.0 mmol) was added to a 50 mL dry three-necked round-bottom flask and dissolved in 10 mL of anhydrous THF. 5.0 mL of 3-isopropoxyphenylmagnesium bromide (1 M in THF, 5.0 mmol) was syringed in and slowly added dropwise to the mixture over 10-15 minutes at room temperature. Stirring was continued for 1.5 hours after the addition was complete to obtain the corresponding titanium reagent. CoBr2 (109 mg, 0.5 mmol) and 2,2'-bipyridine (156 mg, 1.0 mmol) were added to the mixture and stirred for two hours. 7.5 mL of 2,4,6-trimethylphenylmagnesium bromide solution (1 M in THF, 7.5 mmol) was slowly added dropwise to the mixture. After reacting at room temperature for 2 hours, 4-(1-propynyl)anisole (877 mg, 6.0 mmol) was added and stirring continued until the reaction was complete (TLC monitoring, approximately 12 hours).

[0074] The system was cooled to -10°C, and CuCN·2LiCl (523 mg, 3 mmol) and S1 (1745 mg, 5.5 mmol) were weighed. The reaction mixture was slowly returned to room temperature and stirred until completion (TLC monitoring, approximately 4 h). 50 mL of distilled water was added to quench the reaction. After stirring and filtration, the mixture was extracted with CH2Cl2 (50 mL x 3). The resulting organic phases were combined and back-extracted with saturated aqueous NaCl (50 mL x 3). The mixture was then dried over anhydrous Na2SO4 pellets. The solvent was concentrated by filtration and purified by column chromatography to obtain 1817 mg of the desired product 17-1 in a 69% yield.

[0075] The purified product 17-1 was dissolved in 50 mL of dichloromethane and cooled to -78°C. BBr3 (7.5 g, 30 mmol) was then added dropwise. The mixture was slowly warmed to room temperature and stirred for 24 hours. The reaction was quenched by the addition of 60 mL of methanol, stirred thoroughly, and filtered. The filter cake was washed with CH2Cl2 (50 mL × 3). The combined organic phases were washed with saturated aqueous NaCl (50 mL × 3) and dried over anhydrous Na2SO4 pellets. After filtration, the solvent was concentrated by rotary evaporation. The resulting crude product was dissolved in a mixture of ethyl acetate and ethanol (35 mL, EtOAc:EtOH = 2.5:1). Glacial acetic acid (0.4 mL, 6 mmol) was slowly added dropwise to the reaction system at room temperature and stirred for 2 hours. After completion of the reaction, the reaction system was filtered and washed with ethyl acetate to obtain 17 (1592 mg, 60%) as a white solid.

[0076] The product 17-1 is a yellow oily liquid, IR (cm -1 ,KBr):3057,2857,1648,1535,1454,1229,1134,852,629; 1 H NMR(CD3SOCD3,400MHz)δ(ppm)7.16–7.11(m,2H),7.02(dd,J=8.7,6.4Hz,1H),6.86–6.82(m,2H),6.79(d,J=2.4Hz,2H),6.71(d,J=2.6Hz,3H),6.60–6. 53(m,1H),5.06(s,2H),4.44–4.26(m,3H),4.00(s,3H),2.79(t,J=6.0Hz,2H ),2.68–2.57(m,3H),2.08(s,3H),1.78(d,J=6.7Hz,6H),1.56–1.44(m,9H); 13 C NMR(CD3SOCD3,101MHz)δ(ppm)157.9,157.7,156.8,151.4,138.6,132.2,131.9,131.2,129.7,127.8,122.6, 115.9,114.8,111.8,111.3,107.0,66.3,64.7,56.4,55.5,31.5,27.9,27.1,24.2,21.8,10.0; HRMS(ESI+)m / z calcd for C 34 H 43 N2O3 + [M+H] + 527.3274,Found 527.3276.

[0077] The product 17 was a white solid, IR (cm -1 ,KBr):3051,2867,1720,1621,1320,1260,1192,1059,843,809; 1 H NMR (CD3SOCD3, 400MHz) δ (ppm) 7.19 (s, 1H), 7.13 (d, J = 8.0Hz, 2H), 7.02 (d, J = 8.5Hz, 1H), 6.83 (d, J = 8.0Hz, 2H), 6.71 (m, 4H), 6.56 (d, J=7.5Hz,1H),5.06(s,2H),3.88(d,J=5.1Hz,2H),2.81(d,J=5.2Hz,2H),2.66(s,4H),2.08(s,3H),1.87(s,3H),1.48(d,J=9.3Hz,8H); 13 C NMR (CD3SOCD3, 151MHz) δ (ppm) 172.7, 157.9, 157.7, 151.4, 138.6, 131.9, 131.3, 131.2, 129.7, 127.8, 122. 7,115.9,114.8,111.8,111.3,107.0,103.0,66.5,56.5,55.6,46.6,28.1,27.1,21.8,10.0; HRMS(ESI+)m / z calcd for C 32 H 39 N2O5 + [M+H] + 531.2859,Found 531.2856.

[0078] Example 18 Preparation of Bazedoxifene Acetate Isomer II (18)

[0079]

[0080] According to the above reaction scheme and the operation of Example 17, 3-methoxyphenylmagnesium bromide was used instead of 3-isopropoxyphenylmagnesium bromide to obtain 1645 mg of the target product after purification in an overall yield of 62%.

[0081] The product 18-1 was a yellow solid, IR (cm -1 ,KBr):3061,1622,1583,1476,1348,1023,910,821; 11H NMR(CDCl3, 400 MHz) δ (ppm) 8.27 (d, J = 8.3 Hz, 1H), 7.94 (d, J = 8.8 Hz, 2H), 7.58–7.42 (m, 3H), 6.98 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 6.75 (d, J = 8.3 Hz, 1H), 4.13 (s, 2H), 3.88 (d, J = 15.9 Hz, 6H), 3.00 (s, 2H), 2.82 (s, 4H), 1.68 (s, 4H), 1.61 (s, 4H), 1.42 (s, 3H), 0.86 (d, J = 7.0 Hz, 2H); 13 13C NMR(CDCl3, 101 MHz) δ (ppm) 150.9, 150.6, 144.3, 139.8, 134.3, 131.3, 130.32, 130.28, 129.3, 129.3, 125.1, 122.6, 117.9, 115.1, 114.3, 114.1, 56.3, 56.1, 55.9, 55.5, 31.7, 29.78, 29.75, 28.5, 27.1; HRMS(ESI+) m / z calcd for C 32 H 39 N2O3 + [M + H] + 499.2961, Found 499.2964.

[0082] Product 18 was a white solid, IR(cm -1 , KBr): 3044, 2849, 1722, 1579, 1481, 1371, 1231, 1123, 910, 853; 1 1H NMR(CD3SOCD3, 400 MHz) δ (ppm) 7.41 (dd, J = 8.7, 2.3 Hz, 1H), 7.24 (dd, J = 8.7, 2.3 Hz, 1H), 7.14–7.11 (m, 2H), 7.02 (d, J = 7.3 Hz, 2H), 6.86–6.81 (m, 3H), 6.74 (d, J = 8.6 Hz, 2H), 5.​C NMR (CD3SOCD3, 151MHz) δ (ppm) 175.3, 155.9, 155.7, 148.5, 141.5, 138.6, 130.2, 129.5, 128.6, 128.0, 126. 1,120.9,117.7,115.9,111.8,111.3,108.2,60.3,55.6,28.1,27.1,21.8,19.1,14.6,10.6; HRMS(ESI+)m / z calcd for C 32 H 39 N2O5 + [M+H] + 531.2859,Found 531.2855.

[0083] The following compounds were also synthesized using the highly selective method for preparing indole derivatives of the present invention, and the specific details are omitted for clarity:

[0084]

[0085]

[0086]

[0087] The process parameters (such as temperature, time, etc.) of the present invention can realize the method by taking upper and lower limits and interval values, and the embodiments are not listed here one by one.

[0088] Any content not described in detail in the present invention can be based on conventional technical knowledge in the art.

[0089] Finally, it should be noted that the above embodiments are intended only to illustrate the technical solutions of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions to the technical solutions of the present invention do not depart from the spirit and scope of the technical solutions of the present invention and are intended to be encompassed by the claims of the present invention.

Claims

1. A method for preparing an indole derivative with high selectivity, the method comprising: Aryl Grignard reagent, titanate, cobalt salt and ligand react with alkyne under the action of deprotonating reagent to form benzotitanol, which reacts in situ with N,N-dichloroamine to obtain indole derivatives.

2. The method for preparing indole derivatives with high selectivity according to claim 1, characterized in that: The aryl group in the aryl Grignard reagent is one of phenyl, substituted phenyl, naphthyl, and substituted naphthyl, and the substituent in the substituted phenyl or substituted naphthyl is one or at least two of alkyl, alkoxy, halogen, phenyl, ketone, ester, cyano, and amide.

3. The method for preparing indole derivatives with high selectivity according to claim 1, wherein The titanate includes Ti(OR)2[(OCH2CH2)2NR'], wherein R=alkyl group with 1 to 4 carbon atoms, and R' is methyl group or alkyl group containing O or N.

4. The method for preparing indole derivatives with high selectivity according to claim 1, wherein The cobalt salt is CoX2 (X=Cl, Br), Co(acac)2, or Co(acac)3; the ligand is one of trimethylphosphine, tri-n-butylphosphine, tricyclohexylphosphine, triphenylphosphine, 2,2′-bipyridine, o-phenanthroline, tetramethylethylenediamine, and 1,3-dimethylpropyleneurea.

5. The method for preparing indole derivatives with high selectivity according to claim 1, characterized in that: The alkyne is a disubstituted alkyne, and the substituent is one or two of an alkyl group, an aryl group, a ketone group, an ester group, a cyano group, and an amide group.

6. The method for preparing indole derivatives with high selectivity according to claim 1, characterized in that: The general formula of the N,N-dichloramine is RNCl2, wherein R is an aliphatic group, an aromatic group or a benzyl group.

7. The method for preparing indole derivatives with high selectivity according to claim 1, characterized in that: The deprotonating agent is one of 2,4,6-trimethylphenylmagnesium bromide, 2,6-dimethylphenylmagnesium bromide or tert-butylmagnesium chloride.

8. The method for preparing indole derivatives with high selectivity according to claim 1, characterized in that: The molar ratio of the aromatic Grignard reagent, titanate, alkyne, deprotonating agent and N,N-dichloroamine is 1.0:1.0:(1.0-1.5):(1.5-2.0):(1.0-1.5); the amount of the catalyst is 10-20 mol%; and the molar ratio of the cobalt salt to the ligand in the catalyst is 1.0:(2-4).

9. The method for preparing indole derivatives with high selectivity according to claim 1, characterized in that: The reaction temperature of the aryl Grignard reagent, titanate, cobalt salt and ligand with alkyne to form benzotitanol is 20-45°C; the subsequent reaction temperature with N,N-dichloroamine is -20-25°C.

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