Method for high-selectivity preparation of benzothiophene, benzphosphino-role and indene ketene derivatives

Abstract

The invention relates to a method for preparing benzothiophene, benzophosphino-role and indene ketene derivatives with high selectivity. The method comprises the following steps: forming benzotitano-role from an aryl Grignard reagent, titanate, cobalt salt, a ligand and alkyne under the action of a deprotonation reagent; and reacting with a sulfur-containing dichloro compound, a phosphine-containing dichloro compound or carbonic ester in situ to respectively obtain a benzothiophene derivative, a benzo phosphino role derivative and an indene ketene derivative. The preparation method has the advantages that the benzothiophene derivative, the benzo phosphino-role derivative and the indene ketene derivative can be prepared by a one-pot method with high selectivity; the catalyst system is simple and cheap; the reaction conditions are mild, various sensitive functional groups are tolerated, and the regioselectivity is high. The method disclosed by the invention is a novel universal preparation method, can be used for preparing different products from the same main raw materials, and is wide in application range and easy to amplify.

Description

Technical Field

[0001] The present invention relates to the fields of heterocyclic compounds, functional materials and drug synthesis, and in particular to a method for highly selectively preparing benzothiophene derivatives, benzophosphonole derivatives and indenone derivatives and related functional material molecules and bioactive substances. Background Art

[0002] Benzothiophene, benzophosphonole, and indenone are very common and important structural units in the fields of natural products, pharmaceuticals, and materials science. Their structures are shown in bold in the chemical structure below.

[0003]

[0004] Many benzothiophene derivatives have become important drugs on the market. For example, raloxifene (Compound I) is a clinically important breast cancer treatment drug, while Compound (II) is a promising microtubule inhibitor [Treguier, B.; Lawson, M.; Bernadat, G.; et al. ACS Comb. Sci. 2014, 16, 702.]. Furthermore, many benzothiophenes also have great application potential in materials science [Iino, H.; Usui, T.; Hanna, J.-i. Nat. Commun. 2015, 6, 6828.].

[0005] Benzophosphonotriene has unique optical, electronic, and physical properties and has attracted widespread attention in the field of materials science. For example, compound (III) has strong cell imaging capabilities [Wang, C.; Fukazawa, A.; Taki, M.; et al. Angew. Chem., Int. Ed. 2015, 54, 15213.], while compound (IV) is an organic photovoltaic material with good performance [Tsuji, H.; Sato, K.; Sato, Y. et al. Chem. Asian J. 2010, 5, 1294.].

[0006] Indenone skeletons are widely present in natural products, and a large number of such compounds exhibit biological or pharmaceutical activities. For example, compound (V) has COX-2 inhibition and is expected to be used in the anti-inflammatory and analgesic treatment of rheumatoid arthritis and osteoarthritis [Liu, F.; Li, Y.; Wang, X. et al. Org. Chem. Front., 2021, 8, 3847.]. Compound (VI) is a PPAR receptor antagonist and has the potential to treat type II diabetes [Ahn, JH; Shin, MS; Jung, SH et al. J. Med. Chem., 2006, 49, 4781.].

[0007] Given the widespread applications and significant activity of these three classes of compounds, efficient synthesis of these compounds has always been a key topic in organic synthesis. Numerous methods have been developed for their synthesis, with the more typical methods shown below.

[0008]

[0009] Method (I) is to obtain these three types of compounds by cyclization of o-haloacetylenic compounds, and the outstanding advantage is that there is no H in the CH cyclization. a / H b Regioselectivity issues. Method (II) is usually completed by intramolecular electrophilic substitution or transition metal CH activation. a / H b Regioselectivity problem. Method (III) is accomplished by using an intramolecular electrophilic substitution reaction promoted by a protonic acid or a Lewis acid. When there is an electron-withdrawing group on the aromatic ring, the reaction becomes difficult and requires stronger reaction conditions. a / H b The regioselectivity problem also shows poor functional group tolerance. Method (IV) generally requires a noble metal such as Pd and an appropriate oxidant; a / H b Regioselectivity issues, due to the tautomerism of the side chains, also exist R 2 / R 3 Regional selectivity issues.

[0010] From the above analysis, it is not difficult to see that the preparation of benzothiophene, benzophosphonofluoro and indenone derivatives by ortho-CH cyclization has the difficult-to-overcome problem of H a / H b or R 2 / R 3Regioselectivity issues. It's also important to emphasize that in the synthesis of these heterocyclic compounds, the starting materials generally contain corresponding heteroatoms, such as sulfur atoms in thiophene. This means that these syntheses can only produce a single type of heterocycle from a single heteroatom-containing starting material (e.g., S atoms to benzothiophene). To date, divergent synthetic methods have not been established that allow different heterocycle types to be synthesized from the same main raw material by introducing different heteroatoms later. Summary of the Invention

[0011] The present invention aims to overcome the shortcomings of existing C-H cyclization-type synthesis methods, such as regioselectivity problems and versatility issues, thereby providing a method for preparing benzothiophene, benzophosphonofluoro and indenone derivatives with a wide range of applications, no need for precious metals, and high chemoselectivity and regioselectivity.

[0012] To achieve the above objectives, the present invention adopts a new technical solution to realize a method for preparing benzothiophene, benzophosphonole and indenone derivatives with high chemical selectivity and high regioselectivity, the method comprising:

[0013] Aromatic Grignard reagents, titanates, cobalt salts and ligands react with alkynes under the action of deprotonating agents to form benzotitanol, which reacts in situ with dichlorides or carbonates containing heteroatoms (such as sulfur or phosphorus) to obtain derivatives such as benzothiophene, benzophosphonol and indenone.

[0014] The reaction mechanism of the method described in the present invention is shown in the following formula:

[0015]

[0016] 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.

[0017] 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.

[0018] Preferably, the cobalt salt is CoX2 (X = Cl, Br), Co(acac)2, Co(acac)3; the ligand is one of 1,2-bis(diphenylphosphino)ethane, trimethylphosphine, tri-n-butylphosphine, tricyclohexylphosphine, triphenylphosphine, 2,2′-bipyridine, o-phenanthroline, tetramethylethylenediamine (TMEDA) or 1,3-dimethylpropyleneurea (DMPU).

[0019] 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, an amide group, and a silicon group.

[0020] Preferably, the sulfur-containing dichloride includes SCl2, SOCl2 or SO2Cl2; the phosphorus-containing dichloride is RPCl2 or RPOCl2, wherein R is an aliphatic group, an aromatic group or a benzyl group; and the carbonate is CO(OR)2, wherein R is an aliphatic group or an aromatic group.

[0021] Preferably, the deprotonating agent is 2,4,6-trimethylphenylmagnesium bromide, 2,6-dimethylphenylmagnesium bromide or tert-butylmagnesium chloride.

[0022] 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.

[0023] Preferably, the molar ratio of the aromatic Grignard reagent, titanate, alkyne, deprotonating agent, and dichloride is 1.0:1.0:(1.0-1.5):(1.0-1.5):(1.5-2.0), and the molar ratio of the aromatic Grignard reagent, titanate, alkyne, deprotonating agent, and carbonate is 1.0:1.0:(1.0-1.5):(1.0-1.5):(1.0-1.5); the amount of catalyst used is 10-20 mol%; and the molar ratio of cobalt salt to ligand in the catalyst is 1.0:(2-4).

[0024] Preferably, the reaction temperature of the aromatic 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 -20-65°C, and the electrophilic reagent can be a dichloride or carbonate containing a heteroatom (such as sulfur or phosphorus).

[0025] In the reported methods for preparing derivatives such as benzothiophene, benzophosphonoline and indenone by ortho-CH cyclization, the cyclization of meta-substituted aryl sulfide or phosphine derivatives often produces a mixture of 4-substituted and 6-substituted products that is difficult to separate. At the same time, the preparation method involving asymmetric disubstituted alkynes will also produce a mixture of two isomers. These two types of regioselectivity problems have always been difficult to solve in the current existing methods. On the other hand, in the synthesis of these heterocyclic compounds reported, heteroatoms need to be introduced into the starting materials in advance, which limits the entire synthetic route to heterocyclic compounds limited by this heteroatom. The synthetic method of benzothiophene, benzophosphonoline and indenone derivatives in the present invention is a process route with strong feasibility through breakthroughs in reaction types and innovations in reaction mechanisms. After careful design, continuous summary and repeated exploration, new mechanisms and measures are proposed, namely, for the first time, the synergistic effect of Co / Ti is used to carry out regioselectivity (H a / Hb ) 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 YCl2 or carbonate in situ (which can be in the presence of a Cu salt, which can be CuCN·2LiCl) to form corresponding benzothiophene, benzophosphonole and indenone derivatives. It should be noted that the synthesis method of the present invention not only solves the two types of regioselectivity problems in previous synthesis methods, but also exhibits high functional group tolerance (chemical selectivity); whether on aromatic rings or alkynes, sensitive groups such as ester groups, ketone groups, amide groups 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 the synthesis of benzoheterocycles and indenones, but also a breakthrough and innovation in the chemical synthesis of benzotitanol.

[0026] The synthetic method for preparing benzothiophene, benzophosphonoazole and indenone provided by the present invention has the following advantages:

[0027] 1) High chemical selectivity and regioselectivity.

[0028] 2) The transition metal Ti used is abundant in the earth's crust, cheap, low in toxicity, and biocompatible.

[0029] 3) Use cheap cobalt salts and simple ligands as catalysts.

[0030] 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.

[0031] 5) Wide range of applications and low cost. DETAILED DESCRIPTION

[0032] 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.

[0033] Example 1 Preparation of 2,3-diethyl dicarboxylate-5-cyanobenzo[b]thiophene

[0034]

[0035] 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-cyanophenylmagnesium chloride lithium chloride 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, diethyl butynedioate (1021 mg, 6.0 mmol) was added and stirring continued until the reaction was complete (TLC monitoring, approximately 12 hours).

[0036] The system was cooled to -20°C, and SCl₂ (566 mg, 5.5 mmol) was weighed and stirred at this temperature until the reaction was complete (TLC monitoring, approximately 4 hours). 50 mL of distilled water was added to the system to quench the reaction. After stirring and filtering, 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 986 mg of the desired product, diethyl 2,3-dicarboxylate-5-cyanobenzo[b]thiophene, in a 65% yield.

[0037] The product is yellow oily liquid; IR (cm -1 ,KBr):3056,2918,2238,1769,1574,1412,1326,1233,725,655; 1 H NMR(CDCl3,400MHz,)δ(ppm)8.09–8.01(m,2H),7.60(dd,J=5.5,1.1Hz,1H),4.49(q ,J=7.1Hz,2H),4.39(q,J=7.1Hz,2H),1.48(t,J=7.1Hz,3H),1.39(t,J=7.1Hz,3H); 13 C NMR (CDCl3, 100MHz) δ (ppm) 168.3, 166.7, 141.6, 132.7, 132.6, 131.4, 131.3, 129.2, 127.9, 118.1, 112.5, 61.2, 61.1, 13.9, 13.8; HRMS (ESI+) m / z calcd forC 15 H 14 NO4S + [M+H]+ 304.0644,Found 304.0642.

[0038] Example 2-1 Preparation of 2,3-diethyl dicarboxylate-5-cyanobenzo[b]thiophene

[0039]

[0040] According to the above reaction scheme and the operation of Example 1, Ti-2 (255 mg, 1 mmol) was used instead of Ti-1, and the yield was 24%.

[0041] Example 2-2 Preparation of 2,3-diethyl dicarboxylate-5-cyanobenzo[b]thiophene

[0042]

[0043] According to the above reaction route and the operation according to Example 1, Ti-3 (299 mg, 1 mmol) was used instead of Ti-1, and the yield was 14%.

[0044] Example 2-3 Preparation of 2,3-diethyl dicarboxylate-5-cyanobenzo[b]thiophene

[0045]

[0046] 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 23%.

[0047] Example 2-4 Preparation of 2,3-diethyl dicarboxylate-5-cyanobenzo[b]thiophene

[0048]

[0049] According to the above reaction scheme and the operation of Example 1, Ti-5 (354 mg, 1 mmol) was used instead of Ti-1, and the yield was 26%.

[0050] Example 2-5 Preparation of 2,3-diethyl dicarboxylate-5-cyanobenzo[b]thiophene

[0051] According to the above reaction route and the operation according to Example 1, CoCl2 was used instead of CoBr2, and the yield was 48%.

[0052] Example 2-6 Preparation of 2,3-diethyl dicarboxylate-5-cyanobenzo[b]thiophene

[0053]

[0054] According to the above reaction route and the operation of Example 1, dppe was used instead of 2,2'-bipyridine, and the yield was 20%.

[0055] Example 2-7 Preparation of 2,3-diethyl dicarboxylate-5-cyanobenzo[b]thiophene

[0056] According to the above reaction route and the operation of Example 1, PBu3 was used instead of 2,2'-bipyridine, and the yield was 31%.

[0057] Example 2-8 Preparation of 2,3-diethyl dicarboxylate-5-cyanobenzo[b]thiophene

[0058] According to the above reaction route and the operation of Example 1, PPh3 was used instead of 2,2'-bipyridine, and the yield was 35%.

[0059] Example 2-9 Preparation of 2,3-diethyl dicarboxylate-5-cyanobenzo[b]thiophene

[0060] According to the above reaction route and the operation of Example 1, 1,2'-bipyridine was replaced by o-phenanthroline, and the yield was 44%.

[0061] Example 2-10 Preparation of 2,3-diethyl dicarboxylate-5-cyanobenzo[b]thiophene

[0062] According to the above reaction route and the operation of Example 1, tetramethylethylenediamine (TMEDA) was used instead of 2,2'-bipyridine, and the yield was 52%.

[0063] Example 2-11 Preparation of 2,3-diethyl dicarboxylate-5-cyanobenzo[b]thiophene

[0064] According to the above reaction route and the operation of Example 1, 1,3-dimethylpropyleneurea (DMPU) was used instead of 2,2'-bipyridine, and the yield was 56%.

[0065] Example 2-12 Preparation of 2,3-diethyl dicarboxylate-5-cyanobenzo[b]thiophene

[0066] According to the above reaction route and the operation according to Example 1, the reaction temperature (before adding SCl2) was 0°C and the yield was 44%.

[0067] Example 2-13 Preparation of 2,3-diethyl dicarboxylate-5-cyanobenzo[b]thiophene

[0068] According to the above reaction route and the operation according to Example 1, the reaction temperature (before adding SCl2) was 45°C and the yield was 57%.

[0069] Example 2-14 Preparation of 2,3-diethyl dicarboxylate-5-cyanobenzo[b]thiophene

[0070] 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 53%.

[0071] Example 2-15 Preparation of 2,3-diethyl dicarboxylate-5-cyanobenzo[b]thiophene

[0072] 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 60%.

[0073] Example 3 Preparation of 2,3-diethyl dicarboxylate-5-cyanobenzo[b]thiophene-1-oxide

[0074]

[0075] 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-cyanophenylmagnesium chloride lithium chloride 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, diethyl butynedioate (1021 mg, 6.0 mmol) was added and stirring continued until the reaction was complete (TLC monitoring, approximately 12 hours).

[0076] The system was cooled to -20°C, and CuCN·2LiCl (523 mg, 3 mmol) and SOCl2 (654 mg, 5.5 mmol) were weighed and added to the reaction system. Stir at this temperature for 2 hours, then the reaction temperature was returned to room temperature and stirring continued until the reaction was complete (TLC monitoring, approximately 6 hours). 50 mL of distilled water was added to quench the reaction, stirred, filtered, and 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 878 mg of the desired product in a 55% yield.

[0077] The product is yellow oily liquid; IR (cm -1,KBr):3021,2901,1701,1764,1660,1563,1312,1126,831; 1 H NMR(CDCl3,400MHz,)δ(ppm)8.74(dd,J=3.1,1.0Hz,1H),7.71(dd,J=5.2,1.0Hz,1H),7.51(dd,J=5.2, 3.2Hz, 1H), 4.35 (q, J = 4.8Hz, 2H), 4.29 ( q, J = 4.8Hz, 2H), 1.33 ( t, J = 4.8Hz, 3H), 1.23 ( t, J = 4.8Hz, 3H); 13 C NMR (CDCl3, 100MHz,) δ (ppm) 166.8, 165.1, 159.2, 144.2, 137.8, 132.3, 131.8, 130.8, 127.5, 127.3, 118.7, 60.5, 60.4, 14.6, 14.4; HRMS (ESI+) m / z calcd for C 15 H 14 NO5S + [M+H] + 320.0593,Found 320.0591.

[0078] Example 4 Preparation of 2-methyl-3-ethylcarboxylate-4,5-difluorobenzo[b]thiophene-1,1-dioxy

[0079]

[0080] According to the above reaction scheme and the operation according to Example 1, 3,4-difluorophenylmagnesium bromide solution was used instead of 4-cyanophenylmagnesium chloride lithium chloride solution, 2-butynoic acid ethyl ester (673 mg, 6 mmol) was used instead of butynedioic acid diethyl ester, and SO2Cl2 (742 mg, 5.5 mmol) was used instead of SCl2. After purification, 764 mg of the target product was obtained in a yield of 53%.

[0081] The product is yellow oily liquid; IR (cm -1 ,KBr):3107,2091,1774,1669,1523,1426,1320,801,629; 1 H NMR (CDCl3, 400MHz) δ (ppm) 7.15 (d, J = 2.3Hz, 1H), 7.04 (d, J = 2.2Hz, 1H), 4.37 (q, J = 4.8Hz, 2H), 2.82 (s, 3H), 1.54 (t, J = 4.8Hz, 3H); 13C NMR (CDCl3, 150MHz) δ (ppm) 168.6, 159.6 (d, J = 7.6Hz), 154.3 (d, J = 8.7Hz), 153.2 (d, J = 7.8Hz), 149.8 (d, J = 7.6Hz), 142.3 (dd,J=13.3,4.0Hz),128.2,121.08(dd,J=56.3,22.4Hz),111.81(dd,J=63.8,18.9Hz),60.9,16.44(d,J=19.8Hz),12.5; 19 F NMR(CDCl3,376MHz)δ(ppm)-98.22(d,J=8.2Hz),-109.50(d,J=10.7Hz); HRMS(ESI+)m / zcalcd for C 12 H 11 F2O2S + [M+H] + 289.0346,Found 289.0348.

[0082] Example 5 Preparation of 1-phenyl-2,3-di(thiophen-2-yl)benzo[f]phosphinoindole 1-oxide

[0083]

[0084] 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 2-naphthylmagnesium bromide (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 (1 M in THF, 7.5 mmol) was slowly added dropwise to the system. After reacting at room temperature for 2 hours, 1,2-dithiopheneacetylene (1142 mg, 6.0 mmol) was added to the reaction system and stirring was continued until the reaction was complete (TLC monitoring, approximately 12 hours).

[0085] The system was cooled to -20°C, and CuCN·2LiCl (523 mg, 3 mmol) and phenylphosphine dichloride (1072 mg, 5.5 mmol) were added to the reaction system. The reaction system was then heated to reflux and stirred until the reaction was complete (TLC monitoring, approximately 12 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 1145 mg of the desired product in a 52% yield.

[0086] The product is yellow oily liquid; IR (cm -1 ,KBr):3185,3087,1743,1587,1381,1250,1194,832,710; 1 H NMR(CDCl3,400MHz,)δ(ppm)8.24–8.16(m,3H),7.98–7.93(m,2H),7.89(d,J=8.7Hz,1H),7.79(d,J=8.7Hz,1 H),7.56(s,1H),7.53–7.46(m,3H),7.36(ddd,J=8.4,7.0,1.4Hz,2H),7.24–7.22(m,2H),7.07–7.03(m,2H); 13 C NMR (CDCl3, 100MHz,) δ (ppm) 140.0 (d, J = 4.1Hz), 139.3 (d, J = 4.3Hz), 137.8 (d, J = 17.9Hz), 13 7.1,134.7,134.1(d,J=6.0Hz),132.1,131.8(d,J=4.3Hz),129.9(d,J=4.3Hz),128.9,127.9 (t,J=5.8Hz),127.5(d,J=4.4Hz),127.3(d,J=4.7Hz),126.4(d,J=3.3Hz),126.2,126.1,125 .4(d,J=4.8Hz),124.9,124.3(d,J=17.5Hz),123.7,123.5,122.7,121.0(d,J=3.5Hz),118.5; 31 P NMR(CDCl3,162MHz,)δ(ppm)31.9; HRMS(ESI+)m / z calcd for C 26 H 18 OPS2 + [M+H] +441.0537,Found 441.0533.

[0087] Example 6 Preparation of N, N-3-trimethyl-1,2-diphenyl-1H-phosphaindole-4-carboxamide

[0088]

[0089] According to the above reaction scheme and the operation of Example 6, 3-N,N-dimethylbenzamidomagnesium chloride lithium chloride solution was used instead of 2-naphthylmagnesium bromide solution, phenylpropyne (697 mg, 6 mmol) was used instead of 1,2-dithienylacetylene, and phenylphosphine dichloride (984 mg, 5.5 mmol) was used instead of phenylphosphine dichloride to obtain 984 mg of the target product after purification in a yield of 53%.

[0090] The product is yellow oily liquid; IR (cm -1 ,KBr):3045,2692,1675,1584,1418,1376,951,768; 1 H NMR(CDCl3,400MHz)δ(ppm)7.92(dd,J=7.8,1.3Hz,1H),7.87–7.83(m,1H),7.45(td,J=7.5,1.4Hz,1H),7.37–7.32 (m,2H),7.29–7.25(m,4H),7.17(dd,J=7.6,1.1Hz,1H),7.11–7.06(m,3H),3.00(s,3H),2.94(s,3H),2.43(s,3H); 13 C NMR (CDCl3, 101MHz) δ (ppm) 160.8, 134.0, 133.9, 132.4 (d, J = 11.5Hz), 131.8, 131.7, 131.2 (d, J = 2.6Hz), 130.2 (d, J = 11.3Hz), 129. 7(d,J=6.7Hz),128.7,128.6,127.0(d,J=11.0Hz),126.1(d,J=6.5Hz),124.6,120.9(d,J=19.0Hz),114.3,114.2,39.9,36.5,15.1; 31 P NMR(CDCl3,162MHz)δ(ppm)-3.6; HRMS(ESI+)m / z calcd for C 24 H 23 NOP + [M+H] + 372.1517,Found 372.1516.

[0091] Example 7 3,5,6-Trimethyl-2-(trimethylsilyl)-1H-inden-1-one

[0092]

[0093] 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 3,4-dimethylphenylmagnesium bromide (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, trimethylsilyl propyne (673 mg, 6.0 mmol) was added to the reaction system and stirring was continued until the reaction was complete (TLC monitoring, approximately 12 hours).

[0094] Diethyl carbonate (650 mg, 5.5 mmol) was added to the above reaction system. The reaction system was heated to reflux and stirred at this temperature until the reaction was complete (TLC monitoring, approximately 10 h). 50 mL of distilled water was added to quench the reaction. After stirring and filtering, 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 758 mg of the desired product in a 62% yield.

[0095] The product is yellow oily liquid; IR (cm -1 ,KBr):3028,2934,2634,1623,1536,1437,1321,851,756; 1 H NMR (CDCl3, 400MHz) δ (ppm) 7.58 (s, 1H), 7.30 (s, 1H), 2.18 (d, J = 10.3Hz, 6H), 2.10 (s, 3H), 0.53 (s, 9H); 13 C NMR(CDCl3,101MHz)δ(ppm)170.6,149.4,146.7,145.0,142.1,134.2,130.4,123.3,118.7,18.97,18.95,18.6,-1.3; HRMS(ESI+)m / z calcd forC 15 H 21 OSi+ [M+H] + 245.1362,Found 245.1366.

[0096] Example 8 Preparation of Raloxifene (8)

[0097]

[0098] 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 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, S1 (2181 mg, 6 mmol) was added and stirring continued until the reaction was complete (TLC monitoring, approximately 12 hours).

[0099] The system was cooled to -20°C, and SCl2 (566 mg, 5.5 mmol) was weighed and stirred at this temperature until the reaction was complete (TLC monitoring, approximately 4 h). 50 mL of distilled water was added to the system to quench the reaction. After stirring and filtering, 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 1774 mg of the desired product 8-1 in a 67% yield.

[0100] The resulting product 8-1 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. 60 mL of methanol was added to the system to quench the reaction, which was then thoroughly stirred and filtered. The filter cake was washed with CH2Cl2 (50 mL × 3). The organic phases were combined, washed with saturated aqueous NaCl solution (50 mL × 3), and dried over anhydrous Na2SO4 pellets. After filtration, the solvent was concentrated by rotary evaporation. The resulting crude product was purified by column chromatography to obtain 1515 mg of the target product 8 in a total yield of 64%.

[0101] The product 8-1 is a yellow oily liquid, IR (cm -1 ,KBr):2945,1721,1606,1574,1439,1257,1046,881; 11H NMR(CD3SOCD3, 400 MHz) δ (ppm) 7.67 (d, J = 5.8 Hz, 2H), 7.31 (d, J = 1.1 Hz, 1H), 7.21 (dd, J = 5.8, 1.6 Hz, 1H), 7.14 (t, J = 5.1 Hz, 2H), 6.94 (dJ = 5.6 Hz, 2H), 6.84–6.80 (m, 1H), 6.64 (dd, J = 5.6, 2.2 Hz, 2H), 4.45 (s, 2H), 4.40–4.30 (m, 1H), 3.77 (s, 3H), 3.06 (s, 2H), 2.35 (d, J = 8.9 Hz, 4H), 2.13 (s, 2H), 1.79 (d, J = 4.5 Hz, 6H), 1.50 (dd, J = 9.6, 4.1 Hz, 4H); 13 13C NMR(CD3SOCD3, 101 MHz) δ (ppm) 173.6, 157.4, 156.7, 149.8, 142.0, 139.0, 135.5, 135.0, 130.9, 130.3, 127.8, 126.1, 124.1, 118.0, 115.6, 112.9, 106.3, 62.0, 61.4, 48.4, 31.5, 27.1, 24.3, 21.0, 19.9. HRMS(ESI+) m / z calcd for C 32 1 36 1 + [M+H] + 530.236, Found 530.2362.

[0102] The product 8 is a yellow solid, IR (cm -1 , KBr): 3012, 2972, 1686, 1559, 1427, 1342, 1232, 1125, 855; 1 1H NMR(CD3SOCD3, 400 MHz) δ (ppm) 9.73 (s, 2H), 7.61 (d, J = 5.7 Hz, 2H), 7.30 (s, 1H), 7.21 (d, J = 5.8 Hz, 1H), 7.14 (d, J = 5.5 Hz, 2H), 6.87 (d, J = 5.7 Hz, 2H), 6.85–6.77 (m, 1H), 6.64 (d, J = 8.4 Hz, 2H), 4.03 (t, J = 3.7 Hz, 2H), 2.56 (t, J = 3.7 Hz, 2H), 2.34 (s, 4H), 2.05 (s, 2H), 1.44 - 1.39 (m, 4H); 13C NMR(CD3SOCD3,101MHz)δ(ppm)193.1,163.4,158.4,156.0,140.8,139.8,132.8,132.3,130 .22,130.16,124.3,123.8,116.2,115.7,115.0,110.4,107.7,54.9,34.8,31.2,26.1,24.4.

[0103] Example 9 Preparation of Estrogen Receptor Ligand (9)

[0104]

[0105] 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 2,4-dimethoxyphenylmagnesium bromide (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, 4-(1-propynyl)anisole (877 mg, 6.0 mmol) was added to the reaction system and stirring was continued until the reaction was complete (TLC monitoring, approximately 12 hours).

[0106] Diethyl carbonate (650 mg, 5.5 mmol) was added to the above reaction system. The reaction system was heated to reflux and stirred at this temperature until the reaction was complete (TLC monitoring, approximately 10 h). 50 mL of distilled water was added to quench the reaction. After stirring and filtering, 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 product was then dried over anhydrous Na2SO4 pellets. The solvent was concentrated by filtration and purified by column chromatography to obtain 1009 mg of the desired product 9-1 in a 65% yield.

[0107] The resulting product 9-1 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. 60 mL of methanol was added to the system to quench the reaction, which was then thoroughly stirred and filtered. The filter cake was washed with CH2Cl2 (50 mL × 3). The organic phases were combined, washed with saturated aqueous NaCl solution (50 mL × 3), and dried over anhydrous Na2SO4 pellets. After filtration, the solvent was concentrated by rotary evaporation. The resulting crude product was purified by column chromatography to obtain 818 mg of the desired product 9 in an overall yield of 61%.

[0108] Product 9-1 is yellow oily liquid, IR (cm -1 ,KBr):3102,2892,1669,1594,1466,1378,1256,1056,832; 1 H NMR (CDCl3, 400MHz) δ (ppm) 7.62 (s, 1H), 7.53 (d, J = 5.8Hz, 2H), 7.36 (s, 1H) ,6.89(d,J=5.9Hz,2H),3.87(s,3H),3.84(s,3H),3.81(s,3H),2.29(s,3H); 13 C NMR(CDCl3,101MHz)δ(ppm)190.8,164.1,161.3,160.4,142.2,132.8,130.1,1 28.2,125.1,122.5,114.4,105.2,98.7,55.8,55.6,55.5,22.8; HRMS(ESI+)m / z calcd for C 19 H 19 O4 + [M+H] + 311.1283,Found 311.1284.

[0109] The product 9 was a yellow solid, IR (cm -1 ,KBr):3091,2886,1671,1544,1457,1232,1157,1077,847; 1 H NMR(CD3SOCD3,400MHz,)δ(ppm)8.28(s,1H),8.18(s,1H),8.09(s,1H),7.79(d,J=5.8H z,2H),7.70(d,J=1.8Hz,1H),7.59(d,J=5.8Hz,2H),7.43(d,J=1.2Hz,1H),2.15(s,3H); 13C NMR(CD3SOCD3,101MHz)δ(ppm)164.3,141.9,139.6,138.6,134.9,132.5,130.7,128.0,125.3,122.2,119.5,118.8,115.0,22.0; HRMS(ESI+)m / z calcd for C 16 H 13 O4 + [M+H] + 269.0814,Found 269.0816.

[0110] The method for preparing benzothiophene, benzophosphonole and indenone with high selectivity according to the present invention was also used to synthesize the compounds shown in the following table, and the specific details are not described in detail one by one:

[0111]

[0112]

[0113] 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.

[0114] Any content not described in detail in the present invention can be based on conventional technical knowledge in the art.

[0115] 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 benzothiophene, benzophosphonole and indenone derivatives 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 sulfur-containing dichlorides, phosphorus-containing dichlorides or carbonates to obtain benzothiophene derivatives, benzophosphonol derivatives and indenone derivatives, respectively.

2. The method 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 according to claim 1, characterized in that 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 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 1,2-bis(diphenylphosphino)ethane, trimethylphosphine, tri-n-butylphosphine, tricyclohexylphosphine, triphenylphosphine, 2,2′-bipyridine, o-phenanthroline, tetramethylethylenediamine, and 1,3-dimethylpropyleneurea.

5. The method according to claim 1, wherein 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, an amide group, and a silicon group.

6. The method according to claim 1, characterized in that The sulfur-containing dichloride includes SCl2, SOCl2 or SO2Cl2; the phosphorus-containing dichloride is RPCl2 or RPOCl2, wherein R is an aliphatic group, an aromatic group or a benzyl group; the carbonate is CO(OR)2, wherein R is an aliphatic group or an aromatic group.

7. The method according to claim 1, characterized in that The deprotonating agent is 2,4,6-trimethylphenylmagnesium bromide, 2,6-dimethylphenylmagnesium bromide or tert-butylmagnesium chloride.

8. The method according to claim 1, characterized in that The molar ratio of the aromatic Grignard reagent, titanate, alkyne, deprotonating agent and dichloride is 1.0:1.0:(1.0-1.5):(1.0-1.5):(1.5-2.0); the molar ratio of the aromatic Grignard reagent, titanate, alkyne, deprotonating agent and carbonate is 1.0:1.0:(1.0-1.5):(1.0-1.5):(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 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 sulfur-containing dichloride, phosphorus-containing dichloride or carbonate is -20-65°C.

Images