A method for synthesizing tri-substituted ethylene based on alkyl group transfer strategy

Abstract

The application belongs to the technical field of organic chemistry, and particularly relates to a synthesis method of tri-substituted ethylene based on an alkyliden transfer strategy. The synthesis method comprises that, in the presence of an alkali or rare earth complex catalyst, a double (hetero) aryl methane or aryl heteroaryl methane and an alpha, beta-unsaturated ketone are subjected to an alkyliden transfer reaction in an organic solvent to form a corresponding tri-substituted ethylene product. The method has the advantages of small catalyst consumption, mild conditions, no additional additives, easy-to-obtain raw materials, strong reaction universality, simple operation, no salt-type waste, and only one organic by-product, i.e., a ketone, which is a widely used chemical raw material and meets the development requirements of green chemistry. In addition, the alpha, beta-unsaturated ketone is a new alkylidenating agent for diaryl methane compounds, is stable, has flexible and changeable structure, has excellent utility in the construction of a multi-substituted olefin compound library, and greatly improves the yield of the tri-substituted ethylene product.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic chemistry, and particularly relates to a method for synthesizing tri-substituted ethylene. BACKGROUND

[0002] The formation and cleavage of carbon-carbon double bonds are important basic reactions in organic chemistry, which have wide applications in the fields of pharmaceutical synthesis (Angew. Chem. Int. Ed. 2016, 55, 3552-3565.), material preparation (Nat. Chem. 2023, 15, 475-482.), and polymer degradation (Science 2022, 377, 1561-1566.). With the unremitting efforts of researchers, the cleavage and transformation of carbon-carbon double bonds have made great progress (Coord. Chem. Rev. 2020, 413, 213213.). Among them, olefin metathesis is one of the most representative modes of carbon-carbon double bond cleavage and transformation, which has promoted the development of olefin chemistry as an important method for the recombination of carbon-carbon double bonds (Chem. Rev. 2010, 110, 1746-1787.). The oxidation of olefins to ketones or aldehydes is also a common and important mode of carbon-carbon double bond cleavage (Chem. Rev. 2014, 114, 8613-8661.). In addition, cross-metathesis of olefins with other unsaturated functional groups has also made some progress (Chem. Rev. 2004, 104, 1317-1382; Chem. Rev. 2021, 121, 9359-9406; Nature, 2016, 533, 374). However, the known carbon-carbon double bond cleavage and transformation reactions mainly generate two new unsaturated bonds, which cannot meet the diversity needs of organic synthesis reactions. Therefore, developing new modes of carbon-carbon double bond transformation is still an important topic in organic chemistry.

[0003]

[0004] Alkylidenation as an important strategy for regulating the biological activity and functional properties of organic molecules belongs to the reactions frequently involved in organic synthesis. Traditionally, the alkylidenation of organic molecules mainly uses the condensation of active CH bonds with aldehydes (ketones), the dehalogenation coupling reaction of dihaloalkanes with carbonyl reagents in the presence of metal reducing agents (J. Am. Chem. Soc. 1986, 108, 7408-7410; J. Am. Chem. Soc. 1997, 119, 12159-12169.). How to further develop intermolecular alkylidenation methods suitable for other types of organic compounds to meet the diversity needs of organic synthesis will be an important topic, but there has been little progress so far.

[0005] Polysubstituted ethylenic molecules have important position in the fields of medicine, material, etc. Molecules with triaryl ethylene structure can bind with estrogen receptor (ER), thus can simulate the effect of natural estrogen and produce the effect of antagonists or agonists. At present, some triaryl ethylene molecules have been applied to treat estrogen-dependent diseases, for example, tamoxifen A is used to treat breast cancer (Curr. Org. Chem. 2012, 16, 335-352.), afimoxifene B is used to treat cyclic breast pain (Proc. Natl. Acad. Sci. USA 2001, 98, 8880-8884.), clomiphene C is used to treat infertility (Reprod. Sci. 2013, 20, 739-744.). In addition, triaryl ethylene can also be used to prepare organic light-emitting diode (OLED) due to its aggregation-induced emission property (J. Org. Chem. 2005, 70, 2778-2792). If the alkylidyne transfer can be realized by diaryl methane and alkene, a new environment-friendly and versatile polysubstituted ethylene synthesis method can be provided.

[0006] SUMMARY

[0007] The present application aims to provide a tri-substituted ethylene synthesis method based on alkylidyne transfer strategy, which has mild reaction conditions, good versatility, easily available raw materials and simple operation.

[0008] The tri-substituted ethylene synthesis method based on alkylidyne transfer strategy provided by the present application uses α, β-unsaturated ketone as alkylidyne source, and the specific steps are as follows:

[0009] The α, β-unsaturated ketone (1) is reacted with bis(hetero)aryl methane (2) in an organic solvent at 60-120℃ for 0.5-12h using base or rare earth complex as catalyst; after the reaction is completed, tri-substituted ethylene (3) and unsaturated ketone hydrogenation dealkylidyne product (4) are obtained through separation and purification; and the reaction formula is as follows:

[0010]

[0011] In the formula, Ar 1 , Ar 3 is selected from various substituted and non-substituted aryl or heteroaryl; Ar 2 is selected from various substituted and non-substituted heteroaryl; R 1 is selected from hydrogen, alkyl, (non-) substituted aryl or heteroaryl; R 2 is selected from alkyl, (non-) substituted aryl or heteroaryl;

[0012] The catalyst is selected from alkali (alkaline earth) metal hydroxide (carbonate, or bicarbonate) and its alkoxy (amine, alkyl) complex, common organic amine (such as pyridine, triethylamine, TMEDA, etc.), or rare earth trialkyl (aryl, amine) complex;

[0013] The alkali (alkaline earth) metal is Li, Na, K, Cs, Mg, Ca, Ba; and the rare earth metal is Sc, Y, La-Lu;

[0014] The molar ratio of the catalyst to the α, β-unsaturated ketone (1) is 0.02-0.3;

[0015] The molar ratio of the reactant α, β-unsaturated ketone (1) to the bis(hetero)aryl methane (2) is 1.4-0.6;

[0016] The organic solvent is selected from benzene, toluene, xylene, mesitylene, tetrahydrofuran, hexane, N, N-dimethylformamide, 1, 4-dioxane, DME, etc.

[0017] The separation and purification of the reaction product is carried out after the reaction is completed, the reaction solvent is evaporated, the residue is separated and purified by column chromatography, and the target product is obtained after drying. The eluent used is a mixture of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 20:1-1:1.

[0018] The present application uses inexpensive common inorganic bases, or organic bases, or simple rare earth complexes as catalysts, realizes the alkylidene transfer between α, β-unsaturated ketones and bis(hetero)aryl methanes, and provides a practical new method for the synthesis of tri-substituted ethylene.

[0019] The beneficial effects of the present application mainly include:

[0020] (1) The method of the present application has strong universality and good functional group tolerance, and satisfactory yield can be obtained for various substituted diaryl methane compounds tested. The reaction not only provides a new idea for the synthesis of tri-substituted ethylene compounds, but also provides a general new strategy for the construction of a small molecule library related to medicine rich in 1, 1-diaryl-substituted olefins.

[0021] (2) The reaction process of the present application is relatively mild, does not require additional additives, has high selectivity and is clean. The known alkylidenation method of diaryl methane usually needs to use a stoichiometric amount of base or reducing agent, which inevitably produces a large amount of salt-type waste, while the only by-product produced by the present method is ketone, which is a chemical raw material with wide application. Therefore, the method of the present application is more green and has high application value.

[0022] (3) The advantages of the α, β-unsaturated ketone as a new type of alkylidene reagent are stability, easy availability and flexible structure, which has excellent potential in building a library of polysubstituted olefin compounds. A large number of tri-substituted olefins as medicines, pesticides, functional materials or intermediates for preparing them can be efficiently and in high yield prepared by the method.

[0023] (4) The simple α, β-unsaturated ketone can be used as an alkylidene reagent, which is an important breakthrough, not only having important theoretical significance, but also providing a reference for developing a new carbon-carbon double bond construction method based on the metathesis reaction of α, β-unsaturated ketone. DETAILED DESCRIPTION

[0024] The application is further described below by examples.

[0025] Example 1, the reaction route is as follows:

[0026]

[0027] At room temperature, α-phenylchalcone (1a, 0.20 mmol), bis-benzothiazolylmethane (2a, 0.20 mmol) and a catalyst KOH (0.04 mmol) were added to a 10 mL reaction bottle with magnetic stirring, 1.0 mL of solvent toluene was added, and the reaction bottle was sealed. The reaction bottle was placed on a heating module with a pre-set temperature, and stirred at 80°C for 3 h. After the reaction was completed, saturated ammonium chloride solution was added to quench the reaction, and then extracted with ethyl acetate, and the organic layers were combined, dried with anhydrous sodium sulfate, and the solvent was removed by reduced pressure distillation, and the crude product was purified by column chromatography (eluent: V 石油醚 乙酸乙酯 = 20:1 to 10:1) to obtain compounds 3a and 4a, the yield of compound 3a was 65%, and the yield of compound 4a was 64%.

[0028] NMR data (3a): 1 H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 8.20 (d, J = 8.2 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.57 (t, J = 7.7 Hz, 1H), 7.48 (t, J = 7.0 Hz, 2H), 7.37 (t, J = 7.6 Hz, 1H), 7.31-7.20 (m, 5H). 13 ​C NMR (100 MHz, CDC13) δ 167.3, 164.1, 153.6, 153.3, 138.6, 136.4, 135.6, 134.2, 130.3, 129.5, 128.5, 128.1, 126.4, 126.3, 125.9, 125.3, 124.0, 123.3, 121.9, 121.5.

[0029] Example 2, reaction scheme is:

[0030]

[0031] According to the method described in Example 1 and the reactant and catalyst dosage, under the same conditions, 1b reacts with an equivalent amount of 2a, and is separated and purified (eluent: V 石油醚 乙酸乙酯 = 20:1 to 10:1) to obtain the corresponding transalkylation products 3b and 4a, with yields of 54% and 67%, respectively.

[0032] NMR data (3b): 1 H NMR (400 MHz, CDC13) δ 8.25-8.16 (m, 2H), 8.05 (d, J = 8.2 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.48 (t, J = 7.7 Hz, 2H), 7.36 (t, J = 7.6 Hz, 1H), 7.25 (dd, J = 8.3, 5.4 Hz, 2H), 6.92 (t, J = 8.6 Hz, 2H). 13 CNMR (100 MHz, CDC13) δ 167.1, 163.9, 163.2 (d, J = 250.1 Hz), 153.6, 153.3, 137.3, 136.4, 135.6, 132.3, 132.2, 130.4 (d, J = 3.4 Hz), 127.9, 126.5, 126.4, 126.1, 125.4, 124.1, 123.4, 121.9, 121.5, 115.8 (d, J = 21.7 Hz). 19 F NMR (376 MHz, CDC13) δ -109.87.

[0033] Example 3, reaction scheme is:

[0034]

[0035] According to the method described in Example 1 and the reactant and catalyst dosage, under the same conditions, 1c reacts with an equivalent amount of 2a, and is separated and purified (eluent: V 石油醚 ​V 乙酸乙酯 = 20:1 to 5:1) to give the corresponding transalkylation products 3c and 4a in 65% and 70% yield, respectively.

[0036] NMR data (3c): 1 H NMR (400 MHz, CDC13) δ 8.21 (d, J = 8.2 Hz, 1H), 8.18 (s, 1H), 8.02 (d, J = 8.1 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 7.9 Hz, 1H), 7.57 (t, J = 7.7 Hz, 1H), 7.46 (dd, J = 14.3, 7.2 Hz, 2H), 7.33 (t, J = 7.6 Hz, 1H), 7.19 (d, J = 8.8 Hz, 2H), 6.74 (d, J = 8.8 Hz, 2H), 3.74 (s, 3H). 13 C NMR (100 MHz, CDC13) δ 167.8, 164.6, 160.8, 153.7, 153.4, 138.4, 136.5, 135.4, 132.3, 128.4, 127.4, 126.7, 126.35, 126.29, 125.9, 125.8, 125.1, 124.0, 123.2, 122.3, 122.0, 121.4, 114.1, 55.3.

[0037] Example 4, reaction scheme:

[0038]

[0039] According to the method described in Example 1 and the dosage of reactants and catalyst, under the same conditions, 1d was reacted with an equivalent amount of 2a, and separated and purified (eluent: V 石油醚 V 乙酸乙酯 = 20:1 to 5:1) to give the corresponding transalkylation products 3c and 4a in 65% and 70% yield, respectively.

[0040] NMR data (3d): 1 H NMR (400 MHz, CDC13) δ 8.21 (d, J = 8.2 Hz, 1H), 8.18 (s, 1H), 8.02 (d, J = 8.1 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 7.9 Hz, 1H), 7.57 (t, J = 7.7 Hz, 1H), 7.46 (dd, J = 14.3, 7.2 Hz, 2H), 7.33 (t, J = 7.6 Hz, 1H), 7.19 (d, J = 8.8 Hz, 2H), 6.74 (d, J = 8.8 Hz, 2H), 3.74 (s, 3H). 13C NMR (100 MHz, CDC13) δ 167.9, 165.6, 161.8, 154.7, 137.4, 136.2, 135.4, 132.1, 128.1, 127.2, 126.8, 126.4, 126.3, 126.2, 125.9, 125.1, 124.1, 123.2, 122.7, 122.2, 122.0, 114.1, 34.3.

[0041] Example 5, reaction scheme is:

[0042]

[0043] According to the method described in Example 1 and the reactant and catalyst dosage, under the same conditions, 1b reacts with an equivalent amount of 2a, and is separated and purified (eluent: V 石油醚 / V 乙酸乙酯 = 20:1 to 10:1), to obtain the corresponding transalkylation products 3b and 4a, with yields of 45% and 46%, respectively.

[0044] NMR data (3e): 1 H NMR (400 MHz, CDC13) δ 8.25 (s, 1H), 8.14 (d, J = 7.8 Hz, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.62-7.57 (m, 1H), 7.50-7.45 (m, 1H), 7.29-7.20 (m, 1H), 7.19 (d, J = 8.8 Hz, 2H), 6.74 (d, J = 8.8 Hz, 2H). 13 C NMR (100 MHz, CDC13) δ 168.1, 166.6, 160.8, 150.7, 136.4, 135.2, 135.0, 131.9, 129.1, 127.0, 126.8, 126.4, 126.1, 126.0, 125.7, 125.1, 124.1, 123.7, 122.2, 116.9.

[0045] Example 6, reaction scheme is:

[0046]

[0047] According to the method described in Example 1 and the reactant and catalyst dosage, under the same conditions, 1f reacts with an equivalent amount of 2a, and is separated and purified (eluent: V 石油醚 / V 乙酸乙酯 = 20:1 to 10:1), to obtain the corresponding transalkylation products 3f and 4a, with yields of 37% and 40%, respectively.

[0048] NMR data (3f): 1 H NMR (400 MHz, CDC13) δ 8.30 (s, 1H), 8.18 (d, J = 7.9 Hz, 1H), 8.10 (d, J = 7.9 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.68 - 7.60 (m, 1H), 7.50 - 7.45 (m, 1H), 7.30 - 7.22 (m, 1H), 7.21 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.4 Hz, 2H), 4.66 (s, 3H). 13 C NMR (100 MHz, CDC13) δ 168.4, 166.3, 160.5, 150.6, 136.4, 135.4, 135.1, 131.2, 128.1, 127.7, 126.9, 126.4, 126.3, 126.0, 125.7, 125.1, 125.0, 124.7, 122.4, 116.9, 35.1.

[0049] Example 7, reaction scheme is:

[0050]

[0051] According to the method described in Example 1 and the dosage of reactants and catalyst, under the same conditions, 1 g of 2a was reacted with an equivalent amount of 2a, and separated and purified (eluent: V 石油醚 / V 乙酸乙酯 = 20:1 to 10:1) to obtain the corresponding transalkylation products 3a and 4b, with yields of 66% and 69%, respectively.

[0052] Example 8, reaction scheme is:

[0053]

[0054] According to the method described in Example 1 and the dosage of reactants and catalyst, under the same conditions, 1 g of 2a was reacted with an equivalent amount of 2a, and separated and purified (eluent: V 石油醚 / V 乙酸乙酯 = 20:1 to 10:1) to obtain the corresponding transalkylation products 3a and 4b, with yields of 66% and 69%, respectively.

[0055] Example 9, reaction scheme is:

[0056]

[0057] According to the method described in Example 1 and the reactant and catalyst dosage, under the same conditions, 1i reacts with an equivalent amount of 2a, and is separated and purified (eluent: V 石油醚 / V 乙酸乙酯 = 20:1 to 10:1) to obtain the corresponding transalkylation products 3a and 4d, with yields of 63% and 62%, respectively.

[0058] Example 10, the reaction scheme is:

[0059]

[0060] According to the method described in Example 1 and the reactant and catalyst dosage, under the same conditions, 1j reacts with an equivalent amount of 2a, and is separated and purified (eluent: V 石油醚 / V 乙酸乙酯 = 20:1 to 10:1) to obtain the corresponding transalkylation products 3a and 4e, with yields of 66% and 66%, respectively.

[0061] Example 11, the reaction scheme is:

[0062]

[0063] According to the method described in Example 1 and the reactant and catalyst dosage, under the same conditions, 1k reacts with an equivalent amount of 2a, and is separated and purified (eluent: V 石油醚 / V 乙酸乙酯 = 20:1 to 10:1) to obtain the corresponding transalkylation products 3a and 4f, with yields of 53% and 57%, respectively.

[0064] Example 12, the reaction scheme is:

[0065]

[0066] According to the method described in Example 1 and the reactant and catalyst dosage, under the same conditions, 1l reacts with an equivalent amount of 2a, and is separated and purified (eluent: V 石油醚 / V 乙酸乙酯 = 20:1 to 3:1) to obtain the corresponding transalkylation products 3a and 4g, with yields of 32% and 35%, respectively.

[0067] Example 13, the reaction scheme is:

[0068]

[0069] According to the method described in Example 1 and the reactant and catalyst dosage, under the same conditions, 1m reacts with an equivalent amount of 2a, and is separated and purified (eluent: V 石油醚 / V 乙酸乙酯= 10:1 to 3:1) to give the corresponding transalkylated products 3a and 4h in 54% and 57% yield, respectively.

[0070] Example 14, reaction scheme:

[0071]

[0072] According to the method described in Example 1 and the reactant and catalyst dosage, under the same conditions, 1n reacts with an equivalent amount of 2a, and is separated and purified (eluent: V 石油醚 / V 乙酸乙酯 = 20:1 to 10:1) to give the corresponding transalkylated products 3a and 4i in 60% and 59% yield, respectively.

[0073] Example 15, reaction scheme:

[0074]

[0075] According to the method described in Example 1 and the reactant and catalyst dosage, under the same conditions, 1o reacts with an equivalent amount of 2a, and is separated and purified (eluent: V 石油醚 / V 乙酸乙酯 = 20:1 to 10:1) to give the corresponding transalkylated products 3a and 4j in 42% and 36% yield, respectively.

[0076] Example 16, reaction scheme:

[0077]

[0078] According to the method described in Example 1 and the reactant and catalyst dosage, under the same conditions, 1p reacts with an equivalent amount of 2a, and is separated and purified (eluent: V 石油醚 / V 乙酸乙酯 = 20:1 to 10:1) to give the corresponding transalkylated products 3a and 4k in 52% and 53% yield, respectively.

[0079] Example 17, reaction scheme:

[0080]

[0081] According to the method described in Example 1 and the reactant and catalyst dosage, under the same conditions, 1q reacts with an equivalent amount of 2a, and is separated and purified (eluent: V 石油醚 / V 乙酸乙酯 = 20:1 to 10:1) to give the corresponding transalkylated products 3b and 4l in 43% and 46% yield, respectively.

[0082] Example 18, reaction scheme:

[0083]

[0084] According to the method described in Example 1 and the reactant and catalyst dosage, under the same conditions, 1r reacts with an equivalent amount of 2a, and is separated and purified (eluent: V 石油醚 / V 乙酸乙酯 = 20:1 to 10:1), to obtain the corresponding transalkylation products 3a and 4m, with yields of 35% and 37%, respectively.

[0085] Example 19, the reaction scheme is:

[0086]

[0087] According to the method described in Example 1 and the reactant and catalyst dosage, under the same conditions, 1s reacts with an equivalent amount of 2a, and is separated and purified (eluent: V 石油醚 / V 乙酸乙酯 = 20:1 to 10:1), to obtain the corresponding transalkylation products 3a and 4n, with yields of 44% and 52%, respectively.

[0088] Example 20, the reaction scheme is:

[0089]

[0090] According to the method described in Example 1 and the reactant and catalyst dosage, under the same conditions, 1a reacts with an equivalent amount of 2a, and is separated and purified (eluent: V 石油醚 / V 乙酸乙酯 = 10:1 to 1:1), to obtain the corresponding transalkylation products 3g and 4a, with yields of 45% and 56%, respectively.

[0091] NMR data (3g): 1 H NMR (400 MHz, CDC13) δ 8.75 (d, J = 4.3 Hz, 1H), 8.63 (d, J = 4.2 Hz, 1H), 7.90 (s, 1H), 7.71 - 7.41 (m, 3H), 7.28 - 7.20 (m, 2H), 7.18 - 7.09 (m, 4H), 7.04 - 6.94 (m, 3H). 13 C NMR (100 MHz, CDC13) δ 158.4, 157.7, 150.2, 149.3, 140.3, 136.9, 136.4, 136.3, 132.4, 129.7, 128.0, 127.6, 125.9, 122.4, 122.3, 122.1.

[0092] Example 21, the reaction scheme is:

[0093]

[0094] Following the procedure described in Example 1 and reactant and catalyst dosage, under the same conditions, reaction of 1a with equivalent of 2c, separation and purification (eluent: V 石油醚 / V 乙酸乙酯 = 10:1 to 1:1) to give the corresponding transalkylation products 3h and 4a in 41% and 52% yield, respectively.

[0095] NMR data (3h): 1 H NMR (400 MHz, CDC13) δ 7.99 (s, 1H), 7.73 - 7.51 (m, 3H), 7.29 - 7.24 (m, 2H), 7.21 - 7.13 (m, 4H), 7.09 - 7.00 (m, 3H). 13 C NMR (100 MHz, CDC13) δ 158.6, 157.8, 150.3, 149.5, 140.1, 136.4, 136.3, 136.0, 132.0, 129.2, 128.1, 127.9, 126.9, 122.6, 122.3, 121.8.

[0096] Example 22, reaction scheme:

[0097]

[0098] Following the procedure described in Example 1 and reactant and catalyst dosage, under the same conditions, reaction of 1a with equivalent of 2d, separation and purification (eluent: V 石油醚 / V 乙酸乙酯 = 20:1 to 10:1) to give the corresponding transalkylation products 3i and 4a in 60% and 63% yield, respectively.

[0099] NMR data (3i): 1 H NMR (400 MHz, CDC13) δ 8.70 - 8.65 (m, 2H), 7.75 (s, 1H), 7.55 - 7.30 (m, 3H), 7.29 - 7.23 (m, 2H), 7.20 - 7.11 (m, 6H), 7.10 - 7.04 (m, 2H), 7.02 - 6.93 (m, 2H). 13 C NMR (100 MHz, CDC13) δ 158.9, 148.2, 144.3, 137.4, 136.6, 136.5, 130.1, 128.6, 128.5, 128.0, 127.9, 126.8, 118.7.

[0100] Example 23, reaction scheme:

[0101]

[0102] Following the procedure described in Example 1 and the reactants and catalyst loading, under the same conditions, 1a was reacted with an equivalent of 2e, isolated and purified (eluent: V 石油醚 / V 乙酸乙酯 = 10:1 to 3:1) to give the corresponding transalkylation products 3j and 4a in 42% and 49% yield, respectively.

[0103] NMR data (3j): 1 H NMR (400 MHz, CDC13) δ 8.67 (ddd, J = 4.8, 1.9, 0.9 Hz, 1H), 7.85 (s, 1H), 7.55 (td, J = 7.7, 1.9 Hz, 1H), 7.45 - 7.34 (m, 3H), 7.31 - 7.23 (m, 2H), 7.19 - 7.10 (m, 4H), 7.10 - 7.03 (m, 2H), 6.97 (d, J = 8.0 Hz, 1H). 13 CNMR (100 MHz, CDC13) δ 159.0, 149.4, 140.6, 139.3, 136.9, 136.5, 131.0, 130.4, 130.2, 129.2, 128.1, 127.8, 127.4, 122.6, 122.1.

[0104] Example 24, Reaction Scheme:

[0105]

[0106] Following the procedure described in Example 1 and the reactants and catalyst loading, under the same conditions, 1t was reacted with an equivalent of 2e, isolated and purified (eluent: V 石油醚 / V 乙酸乙酯 = 10:1 to 3:1) to give the corresponding transalkylation products 3k and 4a in 36% and 40% yield, respectively.

[0107] NMR data (3k): 1 H NMR (400 MHz, CDC13) δ 8.56 (ddd, J = 4.8, 1.9, 0.9 Hz, 1H), 7.48 (td, J = 7.7, 1.9 Hz, 1H), 7.43 - 7.35 (m, 2H), 7.35 - 7.28 (m, 1H), 7.23 - 7.15 (m, 2H), 7.07 (ddd, J = 7.5, 4.8, 1.2 Hz, 1H), 6.95 (q, J = 7.1 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 1.76 (d, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDC13) δ 158.7, 149.1, 141.5, 138.7, 136.2, 130.0, 128.4, 128.2, 127.1, 121.9, 121.5, 15.5.

[0108] Example 25, reaction scheme is:

[0109]

[0110] According to the method described in Example 1 and the reactant and catalyst dosage, under the same conditions, 1u reacted with equivalent amount of 2e, separated and purified (eluent: V 石油醚 / V 乙酸乙酯 = 10:1 to 3:1), to obtain the corresponding transalkylation products 3l and 4a, with a yield of 43% and 47%, respectively.

[0111] NMR data (3l): 1 H NMR (400 MHz, CDC13) δ 8.43 (d, J = 6.0 Hz, 1H), 7.82 (s, 1H), 7.72-7.23 (m, 3H), 7.07-6.36 (m, 5H), 1.60 (s, 9H). 13 C NMR (100 MHz, CDC13) δ 159.2, 150.1, 144.2, 139.5, 138.5, 130.3, 130.1, 128.3, 127.3, 122.5, 122.0, 35.2, 21.1.

[0112] Example 26, reaction scheme is:

[0113]

[0114] According to the method described in Example 1 and the reactant and catalyst dosage, under the same conditions, 1v reacted with equivalent amount of 2e, separated and purified (eluent: V 石油醚 / V 乙酸乙酯 = 10:1 to 3:1), to obtain the corresponding transalkylation products 3m and 4a, with a yield of 50% and 52%, respectively.

[0115] NMR data (3m): 1H NMR (400 MHz, CDC13) δ 8.51 (d, J = 5.4 Hz, 1H), 7.67 - 7.14 (m, 3H), 7.07 - 6.60 (m, 5H), 6.43 (d, J = 15.8 Hz, 1H), 2.21 - 2.15 (m, 1H), 1.84 - 1.82 (m, 2H), 1.76 (dt, J = 13.0, 3.6 Hz, 2H), 1.69 - 1.65 (m, 1H), 1.35 - 1.28 (m, 2H), 1.24 - 1.18 (m, 3H). 13 C NMR (100 MHz, CDC13) δ 156.5, 149.5, 141.5, 139.5, 136.5, 131.0, 130.1, 128.3, 127.5, 121.5, 121.1, 41.1, 32.7, 26.4, 26.1.

[0116] Example 27, reaction scheme is:

[0117]

[0118] According to the method described in Example 1 and the dosage of reactants and catalyst, under the same conditions, 1a reacts with an equivalent of 2f, and is separated and purified (eluent: V 石油醚 乙酸乙酯 = 10:1 to 3:1) to obtain the corresponding transalkylation products 3n and 4a, with a yield of 38% and 40%, respectively.

[0119] NMR data (3n): 1 H NMR (400 MHz, CDC13) δ 7.87 (s, 1H), 7.56 (td, J = 7.8, 1.9 Hz, 1H), 7.44 - 7.34 (m, 3H), 7.30 - 7.24 (m, 2H), 7.17 - 7.07 (m, 6H), 6.96 (d, J = 8.0 Hz, 1H), 2.25 (s, 3H). 13 C NMR (100 MHz, CDC13) δ 158.9, 149.4, 140.8, 139.8, 137.0, 136.6, 131.2, 1306, 130.2, 129.0, 128.1, 127.6, 127.2, 122.6, 121.9, 35.2.

[0120] Example 28, reaction scheme is:

[0121]

[0122] According to the method described in Example 1 and the dosage of reactants and catalyst, under the same conditions, 1a reacts with an equivalent of 2g, and is separated and purified (eluent: V​石油醚 / V 乙酸乙酯 = 10:1 to 3:1) to give the corresponding transalkylation products 3o and 4a in 46% and 49% yield, respectively.

[0123] NMR data (3o): 1 H NMR (400 MHz, CDC13) δ 7.54 (t, J = 7.7 Hz, 1H), 7.39 - 7.29 (m, 5H), 7.15 - 7.09 (m, 5H), 7.02 - 6.94 (m, 3H), 2.60 (s, 3H). 13 C NMR (100 MHz, CDC13) δ 159.0, 158.9, 142.1, 141.8, 137.2, 137.0, 129.8, 129.6, 128.6, 128.0, 127.7, 127.4, 127.1, 122.8, 121.9, 24.9.

[0124] Example 29, reaction scheme:

[0125]

[0126] According to the method described in Example 1 and the dosage of reactants and catalyst, under the same conditions, 1a was reacted with an equivalent of 2h, and separated and purified (eluent: V 石油醚 / V 乙酸乙酯 = 10:1 to 3:1) to give the corresponding transalkylation products 3p and 4a in 41% and 40% yield, respectively.

[0127] NMR data (3p): 1 H NMR (400 MHz, CDC13) δ 8.72 - 8.68 (m, 1H), 7.89 (s, 1H), 7.60 - 7.49 (m, 1H), 7.46 - 7.36 (m, 2H), 7.32 - 7.22 (m, 2H), 7.16 - 7.08 (m, 4H), 7.10 - 7.03 (m, 2H), 6.97 (d, J = 8.0 Hz, 1H). 13 C NMR (100 MHz, CDC13) δ 159.3, 149.4, 141.6, 138.9, 135.9, 135.5, 131.2, 130.1, 129.8, 129.3, 128.0, 127.1, 127.0, 123.2, 123.0.

[0128] Example 30, reaction scheme:

[0129]

[0130] According to the method and reactant and catalyst dosage described in Example 1, under the same conditions, 1a was reacted with an equivalent of 2i, and separated and purified (eluent: V 石油醚 / V 乙酸乙酯 = 10:1 to 3:1) to obtain the corresponding transalkylation products 3q and 4a in yields of 40% and 42%, respectively.

[0131] NMR data (3q): 1 H NMR (400 MHz, CDC13) δ 8.70 (d, 1H), 7.88 (s, 1H), 7.60-7.49 (m, 1H), 7.46-7.36 (m, 2H), 7.33-7.25 (m, 2H), 7.20-7.12 (m, 4H), 7.10-7.03 (m, 2H), 6.97 (d, J = 8.0 Hz, 1H), 4.23 (s, 6H). 13 C NMR (100 MHz, CDC13) δ 158.3, 149.2, 140.6, 137.2, 134.9, 134.5, 131.0, 130.0, 129.4, 129.1, 127.4, 127.0, 126.8, 123.2, 123.0, 38.2.

[0132] Examples 30-78: Effect of different catalysts on the reaction.

[0133] Examples 31-33: The operations of Examples 1, 10, and 20 were repeated under the condition that the catalyst was replaced by NaOH, except that the other reaction conditions were unchanged, to sequentially obtain Examples 31-33.

[0134] Examples 34-36: The operations of Examples 1, 10, and 20 were repeated under the condition that the catalyst was replaced by K2CO3, except that the other reaction conditions were unchanged, to sequentially obtain Examples 34-36.

[0135] Examples 37-39: The operations of Examples 1, 10, and 20 were repeated under the condition that the catalyst was replaced by KHCO3, except that the other reaction conditions were unchanged, to sequentially obtain Examples 37-39.

[0136] Examples 40-42: The operations of Examples 1, 10, and 20 were repeated under the condition that the catalyst was replaced by tBuOK, except that the other reaction conditions were unchanged, to sequentially obtain Examples 40-42.

[0137] Examples 43-45: The operations of Examples 1, 10, and 20 were repeated under the condition that the catalyst was replaced by nBuLi, except that the other reaction conditions were unchanged, to sequentially obtain Examples 43-45.

[0138] Examples 46-48: The procedures of Examples 1, 10, 20 were repeated except that the catalyst was replaced by KHMDS instead of KOH, to give Examples 46-48, respectively.

[0139] Examples 49-51: The procedures of Examples 1, 10, 20 were repeated except that the catalyst was replaced by CsOH instead of KOH, to give Examples 49-51, respectively.

[0140] Examples 52-54: The procedures of Examples 1, 10, 20 were repeated except that the catalyst was replaced by Mg(OH)2instead of KOH, to give Examples 52-54, respectively.

[0141] Examples 55-57: The procedures of Examples 1, 10, 20 were repeated except that the catalyst was replaced by Ca(OH)2instead of KOH, to give Examples 55-57, respectively.

[0142] Examples 58-60: The procedures of Examples 1, 10, 20 were repeated except that the catalyst was replaced by Ba(OH)2instead of KOH, to give Examples 58-60, respectively.

[0143] Examples 61-63: The procedures of Examples 1, 10, 20 were repeated except that the catalyst was replaced by Sc(C5Me5)3instead of KOH, to give Examples 61-63, respectively.

[0144] Examples 64-66: The procedures of Examples 1, 10, 20 were repeated except that the catalyst was replaced by Y[N(SiMe3)2]3instead of KOH, to give Examples 64-66, respectively.

[0145] Examples 67-69: The procedures of Examples 1, 10, 20 were repeated except that the catalyst was replaced by La(CH2C6H5)3instead of KOH, to give Examples 67-69, respectively.

[0146] Examples 70-72: The procedures of Examples 1, 10, 20 were repeated except that the catalyst was replaced by Lu(C5Me5)3instead of KOH, to give Examples 70-72, respectively.

[0147] Examples 73-75: The procedures of Examples 1, 10, 20 were repeated except that the catalyst was replaced by NEt3instead of KOH, to give Examples 73-75, respectively.

[0148] Examples 76-78: The procedures of Examples 1, 10, 20 were repeated except that the catalyst was replaced by pyridine instead of KOH, to give Examples 76-78 in turn.

[0149] Examples 79-81: The procedures of Examples 1, 10, 20 were repeated except that the catalyst was replaced by TMEDA instead of KOH, to give Examples 79-81 in turn.

[0150] The results are shown in Table 1 below

[0151] Table 1

[0152] No. Catalyst Product (3) yield (%) Product (4) yield (%) Examples 31-33 NaOH 34-58 41-59 Examples 34-36 [K2CO3] 4-9 6-10 Examples 37-39 [KHCO3] 5-10 7-11 Examples 40-42 tBuOK 46-65 57-67 Examples 43-45 nBuLi 36-58 45-56 Examples 46-48 KHMDS 44-65 52-64 Examples 49-51 CsOH 39-60 50-61 Examples 52-54 Mg(OH)2 25-33 30-35 Examples 55-57 Ca(OH)2 26-34 30-34 Examples 58-60 <![CDATA[Ba(OH)2]]> 30-39 35-43 Examples 61-63 Sc(C5Me5)3 32-48 40-49 Examples 64-66 [Y[N(SiMe3)2]3]] 34-54 44-55 Examples 67-69 La(CH2C6H5)3 35-53 45-54 Examples 70-72 Lu(C5Me5)3 30-49 39-50 Examples 73-75 NEt3 15-23 18-24 Examples 76-78 Pyridine 11-19 18-20 Examples 79-81 TMEDA 21-30 24-35 .

[0153] It can be seen that potassium hydroxide and potassium alkoxide are the best catalysts.

[0154] Examples 82-93: Effect of different catalyst amounts on the reaction.

[0155] Examples 82-84: The procedures of Examples 1, 2, 10 were repeated except that the amount of catalyst was reduced from 20 mol% to 2 mol%, to give Examples 82-84 in turn.

[0156] Examples 85-87: The procedures of Examples 1, 2, 10 were repeated except that the amount of catalyst was reduced from 20 mol% to 10 mol%, to give Examples 85-87 in turn.

[0157] Examples 88-90: The procedures of Examples 1, 2, 10 were repeated except that the amount of catalyst was reduced from 20 mol% to 15 mol%, to give Examples 88-90 in turn.

[0158] Examples 91-93: The procedures of Examples 1, 2, 10 were repeated except that the amount of catalyst was increased from 20 mol% to 30 mol%, to give Examples 91-93 in turn.

[0159] The results are shown in Table 2 below

[0160] Table 2

[0161] No. Catalyst amount Product (3) yield (%) Product (4) yield (%) Examples 82-84 2 mol % 9-11 12-17 Examples 85-87 10 mol % 34-56 40-56 Examples 88-90 15 mol % 40-62 50-62 Examples 91-93 30 mol % 44-66 57-67 .

[0162] It can be seen that the optimum amount of catalyst is 20%.

[0163] Examples 94-105: Effect of molar ratio of different reactants, α,β-unsaturated ketone (1) and bis(hetero)arylmethane (2), on the reaction.

[0164] Examples 94-96: The procedures of Examples 1, 2 and 10 were repeated with the exception that the molar ratio of reactants (1) and (2) was changed to 1.4 to give Examples 94-96, respectively.

[0165] Examples 97-99: The procedures of Examples 1, 2 and 10 were repeated with the exception that the molar ratio of reactants (1) and (2) was changed to 1.2 to give Examples 97-99, respectively.

[0166] Examples 100-102: The procedures of Examples 1, 2 and 10 were repeated with the exception that the molar ratio of reactants (1) and (2) was changed to 0.8 to give Examples 100-102, respectively.

[0167] Examples 103-105: The procedures of Examples 1, 2 and 10 were repeated with the exception that the molar ratio of reactants (1) and (2) was changed to 0.6 to give Examples 103-105, respectively.

[0168] The results are shown in Table 3 below.

[0169] Table 3

[0170] No. Molar ratio of reactants Product (3) yield (%) Product (4) yield (%) Examples 94-96 1.4 43-67 57-66 Examples 97-99 1.2 42-66 57-68 Examples 100-102 0.8 41-60 44-60 Examples 103-105 0.6 39-59 50-60

[0171] It can be seen that the molar ratio of 1.0 is already optimal.

[0172] Examples 106-129: Effect of different solvents on the reaction.

[0173] Examples 106-108: The procedures of Examples 1, 2 and 10 were repeated with the exception that the solvent was changed from toluene to benzene to give Examples 106-108, respectively.

[0174] Examples 109-111: The procedures of Examples 1, 2 and 10 were repeated with the exception that the solvent was changed from toluene to o-xylene to give Examples 109-111, respectively.

[0175] Examples 112-114: The procedures of Examples 1, 2 and 10 were repeated with the exception that the solvent was changed from toluene to mesitylene to give Examples 112-114, respectively.

[0176] Examples 115-117: Except for replacing the solvent from toluene with tetrahydrofuran, the operations of Examples 1, 2, and 10 were repeated with all other reaction conditions remaining unchanged to obtain Examples 115-117 in sequence.

[0177] Examples 118-120: Except for replacing the solvent from toluene with hexane, the operations of Examples 1, 2, and 10 were repeated with all other reaction conditions remaining unchanged to obtain Examples 118-120 in sequence.

[0178] Examples 121-123: Except for replacing the solvent from toluene with N,N-dimethylformamide, the operations of Examples 1, 2, and 10 were repeated with all other reaction conditions remaining unchanged to obtain Examples 121-123 in sequence.

[0179] Examples 124-126: Except for replacing the solvent from toluene with 1,4-dioxane, the operations of Examples 1, 2, and 10 were repeated with all other reaction conditions remaining unchanged to obtain Examples 124-126 in sequence.

[0180] Examples 127-129: Except for replacing the solvent from toluene with DME, Examples 1, 2, and 10 were repeated with all other reaction conditions remaining unchanged to obtain Examples 127-129 in sequence.

[0181] The results are shown in Table 4 below

[0182] Table 4

[0183] No. Hydrogen source Product (3) yield (%) Product (4) yield (%) Examples 106-108 Benzene 44-65 54-65 Examples 109-111 o-Xylene 41-62 52-62 Examples 112-114 Mesitylene 42-63 51-61 Examples 115-117 Tetrahydrofuran 33-45 41-46 Examples 118-120 Hexane 38-47 45-50 Examples 121-123 N,N-Dimethylformamide 21-30 29-33 Examples 124-126 1,4-Dioxane 34-44 40-47 Examples 127-129 DME 30-41 37-41 .

[0184] It can be seen that benzene and toluene have the best effects.

[0185] Examples 130-138: Effect of different reaction temperatures on the reaction

[0186] Examples 130-132: Except for lowering the reaction temperature from 80°C to 60°C, the operations of Examples 1, 2, and 10 were repeated with all other reaction conditions remaining unchanged to obtain Examples 130-132 in sequence.

[0187] Examples 133-135: Except for increasing the reaction temperature from 80°C to 100°C, the operations of Examples 1, 2, and 10 were repeated while keeping other reaction conditions unchanged to obtain Examples 133-135 in sequence.

[0188] Examples 136-138: Except for increasing the reaction temperature from 80°C to 120°C, the operations of Examples 1, 2, and 10 were repeated with all other reaction conditions remaining unchanged to obtain Examples 136-138 in sequence.

[0189] The results are shown in Table 5 below

[0190] Table 5

[0191] No. Reaction temperature Product (3) yield (%) Product (4) yield (%) Examples 130-132 60℃ 31-40 45-53 Examples 133-135 100℃ 44-65 56-66 Examples 136-138 120℃ 43-64 54-64 .

[0192] It can be seen that the optimum reaction temperature is 80°C, and the yield will not increase if the temperature is increased.

[0193] Examples 139-147: Effect of different reaction times on the reaction

[0194] Examples 139-141: Examples 1, 2 and 10 were repeated with the reaction time shortened from 3h to 0.5h, and other reaction conditions unchanged, to obtain Examples 139-141 in turn.

[0195] Examples 142-144: The operation of Examples 1, 2 and 10 was repeated with the reaction time increased from 3h to 6h, and other reaction conditions unchanged, to obtain Examples 142-144 in turn.

[0196] Examples 145-147: The operation of Examples 1, 2 and 10 was repeated with the reaction time increased from 3h to 12h, and other reaction conditions unchanged, to obtain Examples 145-147 in turn.

[0197] The results are shown in Table 6 below

[0198] Table 6

[0199] No. Reaction time Product (3) yield (%) Product (4) yield (%) Examples 139-141 0.5h 20-31 31-39 Examples 142-144 6h 45-65 54-67 Examples 145-147 12h 44-64 56-64 .

[0200] It can be seen that the optimum reaction time is 3h, and the yield will decrease if the reaction time is shortened, and the reaction will not be affected if the reaction time is prolonged.

Claims

1. A method for synthesizing trisubstituted ethylene based on an alkylene transfer strategy, characterized in that: The specific steps are: Using a base or a rare earth complex as a catalyst, an α,β-unsaturated ketone (1) is reacted with a bis-heteroarylmethane or an aryl-heteroarylmethane (2) in an organic solvent at 60-120°C for 0.5-12 h. After the reaction is completed, the target product, trisubstituted ethylene (3), is obtained by separation and purification. The reaction formula is: ； Where Ar 1 、Ar 2 、Ar 3 、R 1 is selected from aryl or heteroaryl; R 2 is selected from alkyl, aryl or heteroaryl; The molar ratio of the catalyst to the α,β-unsaturated ketone (1) is 0.1-0.3; the molar ratio of the reactant α,β-unsaturated ketone (1) to the bis-heteroarylmethane or arylheteroarylmethane (2) is 1.4-0.6; the catalyst is selected from NaOH, t BuOK, n BuLi, KHMDS, CsOH, Mg(OH)2, Ca(OH)2, Ba(OH)2, Sc(C5Me5)3, Y[N(SiMe3)2]3, La(CH2C6H5)3, Lu(C5Me5)3 or TMEDA.

2. The method for synthesizing trisubstituted ethylene according to claim 1, wherein The organic solvent is selected from benzene, toluene, xylene, mesitylene, tetrahydrofuran, hexane, N , N -Dimethylformamide, 1,4-dioxane, DME.

3. The method for synthesizing trisubstituted ethylene according to claim 1, wherein: The separation and purification of the reaction product refers to the process of distilling off the reaction solvent after the reaction is completed, separating and purifying the residue by column chromatography, and drying to obtain the target product; the eluent used is a mixture of petroleum ether and ethyl acetate, with a volume ratio of petroleum ether to ethyl acetate of 20:1 to 1:1.

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