CN114539097B - A kind of multi-substituted alkenyl cyanide and its synthetic method - Google Patents

Abstract

The invention discloses a polysubstituted alkenyl cyanide and a synthesis method thereof. Under the nitrogen or inert atmosphere, the sulfonium salt which is easy to prepare, has structural diversity and multiple reaction centers is used as a raw material, the ketene cyanide is used as a synthon, and the polysubstituted alkenyl cyanide is synthesized under the alkaline condition. Compared with the reported method for synthesizing the alkenyl cyano compound, the method has the advantages of cheap and easily obtained raw materials, simple and convenient operation, mild synthesis reaction conditions, good stereoselectivity of products, high reaction efficiency and diversity of functional groups.

Description

A kind of multi-substituted alkenyl cyanide and its synthetic method

technical field

The invention belongs to the technical field of chemical organic synthesis, and in particular relates to a multi-substituted alkenyl cyanide and a synthesis method thereof.

Background technique

Multi-substituted alkenyl cyanides are ubiquitous in many natural products, pharmaceuticals and agrochemicals, and molecular materials, and they can also serve as versatile precursors for a range of amine, amide, aldehyde, ketone, and carboxylic acid functional groups. Due to their remarkable biological activity, unique plasticity, and wide range of uses, the synthesis of polysubstituted alkenyl cyanides has received continuous attention from chemists.

At present, there are not many methods for preparing alkenyl cyanides, and there are 4 synthetic methods reported in the literature. Related preparation methods are: 1) reaction of allyl halide and potassium cyanide (J.Am.Chem.Soc.1982,104,1560-1568); 2) conjugate addition of alkyne nitrile and organic Grignard reagent Reaction (Org.Lett.2002,4,659-661); 3) Nickel and cobalt co-catalyzed hydrocyanation of alkynes (ACSCatal.2019,9,3360-3365); 4) Copper trifluoroacetate catalyzed pyridine-directed Condensation reactions of olefins with α-iminonitriles (Synlett2019, 30, 203-206). However, the above methods often have harsh reaction conditions, poor stability of raw materials, difficulty in long-term storage, and narrow scope of substrate application. Therefore, the application of multi-substituted alkenyl cyanides in synthesis is limited to a certain extent.

In view of the lack of synthesis methods for multi-substituted alkenyl cyanides, a series of multi-substituted alkenyl cyanides with different structures were synthesized by cyanation reaction using multi-substituted alkenyl sulfonium salts that are easy to prepare, have structural diversity and multiple reaction centers cyano compounds.

Contents of the invention

The object of the present invention is to provide a method for easily obtaining raw materials, mild reaction conditions, wide application range of substrates, and simple and convenient synthesis of multi-substituted alkenyl cyano compounds.

In order to achieve the above object, the technical scheme of the present invention is as follows:

A kind of multi-substituted alkenyl cyanide, its molecular structure I is as follows:

R ¹ is selected from methyl, ethyl or aryl; R ² is selected from methyl, ethyl, aryl, naphthalene ring, furan ring, thiophene ring or pyridine ring; R ³ is selected from hydrogen, methyl, ethyl, Benzyl, aryl, naphthalene ring, furan ring, thiophene ring or pyridine ring; wherein the aryl group is selected from phenyl, with substituents on the benzene ring, and the substituents on the benzene ring are selected from methyl, methoxy 1-5 of fluorine, chlorine, bromine, iodine, trifluoromethyl, and nitro, and the number of substituents is 1-5.

A kind of synthetic method of above-mentioned multi-substituted alkenyl cyanide, take the multi-substituted alkenyl sulfonium salt II which is easy to prepare, have structural diversity and multiple reaction centers as starting material, palladium (Pd) salt as catalyst, organophosphorus The compound is a ligand, and reacts with cuprous cyanide in a common solvent under alkaline conditions to generate multi-substituted alkenyl cyanide I;

The molecular structural formula of polysubstituted alkenylsulfonium salt II is as follows:

R ¹ is selected from methyl, ethyl or aryl; R ² is selected from methyl, ethyl, aryl, naphthalene ring, furan ring, thiophene ring or pyridine ring; R ³ is selected from hydrogen, methyl, ethyl, Benzyl, aryl, naphthalene ring, furan ring, thiophene ring or pyridine ring; wherein the aryl group is selected from phenyl, and the benzene ring has a substituent, and the benzene ring has a substituent selected from methyl, methoxy 1-5 of fluorine, chlorine, bromine, iodine, trifluoromethyl, and nitro, and the number of substituents is 1-5; n is selected from an integer of 0-3;

The reaction formula of synthetic route is:

Further, in the above technical scheme, the molar ratio of the multi-substituted alkenylsulfonium salt II to cuprous cyanide is 1:1-1:3, preferably the molar ratio is 1:1.5;

The palladium salt is one or two of palladium chloride, palladium trifluoroacetate, palladium acetate (Pd(OAc) ₂ ), palladium hydroxide, tetraacetonitrile palladium tetrafluoroborate, bis(acetonitrile) palladium chloride, palladium acetylacetonate More than one species, wherein the reaction takes palladium acetate as the best catalyst, and the molar ratio of polysubstituted alkenylsulfonium salt II to palladium salt is 1:0.01-1:0.3, and the preferred molar ratio is 1:0.02-1:0.2;

The base is lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium acetate, potassium acetate, cesium acetate, potassium hydroxide, potassium tert-butoxide (KO ^t Bu), lithium tert-butoxide, sodium hydride (NaH) One of them, wherein the reaction takes potassium tert-butoxide as the base, and the molar ratio of the polysubstituted alkenylsulfonium salt II to the base is 1:0.5-1:4, and the preferred molar ratio is 1:1- 1:3;

The ligands are triphenylphosphine, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, 2-dicyclohexylphosphine-2′,6′-dimethoxybiphenyl (X- PHOS), tricyclohexyl phosphine or tri-(4-methylphenyl) phosphine, wherein the reaction is the best with 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl as the catalyst, The molar ratio of polysubstituted alkenylsulfonium salt II to ligand is 1:0.1-1:1.0;

The reaction solvent is one of N,N-dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile, toluene, 1,4-dioxane, dichloromethane (DCM), ethyl acetate, and methanol One or two or more mixtures, wherein the reaction takes N,N-dimethylformamide as the solvent for the best effect, and the molar concentration of polysubstituted alkenylsulfonium salt II in the reaction solvent is 0.5-1.5M, preferably The molar concentration is 1-1.5M.

Further, in the above technical solution, the reaction time is 8-24 hours, wherein the optimal reaction time is 12-24 hours.

Further, in the above technical solution, the reaction temperature is 0-120°C, wherein the optimum reaction temperature is 30-100°C.

Further, in the above technical solution, the reaction atmosphere is nitrogen or an inert atmosphere, such as helium or argon.

Further, in the above technical scheme, after the reaction is completed, the product is separated according to a conventional separation and purification method to obtain the multi-substituted alkenyl cyanide I.

Under nitrogen or inert atmosphere, multi-substituted alkenyl cyanides were synthesized under alkaline conditions with sulfonium salts that are easy to prepare, have structural diversity and multiple reaction centers as raw materials, and cyanidene as synthons. Compared with the reported synthesis methods of alkenyl cyano compounds, the present invention has cheap and easy-to-obtain raw materials, simple operation, mild synthesis reaction conditions, good stereoselectivity of products, high reaction efficiency, and diverse functional groups.

The present invention has the following advantages:

1) The multi-substituted alkenyl sulfonium salt II, the starting material of the reaction, has structural diversity and can be used to synthesize different types of multi-substituted alkenyl cyanides I.

2) Synthon cuprous cyanide is cheap and easy to get.

3) The synthesis of multi-substituted alkenylsulfonium salt II has mild reaction conditions, high product yield and wide application range.

In a word, the present invention utilizes the types and structural diversity of polysubstituted alkenylsulfonium salts II to efficiently synthesize different types of polysubstituted alkenyl cyanides I. The raw materials are cheap and easy to obtain, the operation is simple, the yield of the target product is high, and the substrate is applicable. wide range.

detailed description

In the present invention, it can be operated according to the following technical scheme, but it does not limit the scope of protection of the present invention. Olefin compound A, sulfoxide compound B and trifluoromethanesulfonic anhydride Tf ₂ O are prepared in dichloromethane DCM The reaction is carried out under the condition of a solvent to generate polysubstituted alkenylsulfonium salt II (reaction formula 1, the definition of R ¹ , R ² , R ³ in formula A is the same as that of formula II, and the definition of n in formula B is the same as that of formula II). Then use II as raw material, palladium salt such as palladium acetate Pd(OAc) ₂ as catalyst, in the presence of base such as potassium tert-butoxide KO ^t Bu, in organic solvent such as N,N-dimethylformamide DMF , react under heating conditions (reaction formula 2). After the reaction is completed, the product is separated and characterized by conventional column chromatography or thin layer chromatography separation and purification method to obtain the multi-substituted alkenyl cyanide I.

The specific process is as follows: replace nitrogen with a 50mL round-bottom flask three times, add olefin A (5.0mmol), sulfoxide compound B (5.5mmol), and DCM in sequence in a nitrogen atmosphere, and slowly add TfO ₂ (5.5mmol), reacted for 5 hours. After the reaction, the solvent was removed under reduced pressure, and then separated by silica gel column chromatography (eluent: dichloromethane/methanol, v/v=10:1) to obtain the target product II. The target product was confirmed by nuclear magnetic resonance spectroscopy, high-resolution mass spectrometry and reference literature (Angew.Chem.Int.Ed.2018, 57, 9785-9789).

The specific process is: in a 10mL sealed tube, add alkenylsulfonium salt II (0.3mmol), CuCN (40.3mg, 0.45mmol), palladium acetate Pd(OAc) ₂ (13.5mg, 0.06mmol), tert-butanol Potassium KO ^t Bu or sodium hydride NaH (101.0 mg, 0.9 mmol) and 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl X-PHOS or triphenylphosphine (43.0 mg, 0.09 mmol) , and then replace nitrogen 3 times, then add 3 mL of N,N-dimethylformamide DMF or toluene or dimethyl sulfoxide, and stir at 80°C for 18 hours. After cooling to room temperature, the insoluble matter was removed by diatomite filtration, and the volatile components were removed under reduced pressure, and then separated by silica gel column chromatography (eluent was petroleum ether (60-90°C)/ethyl acetate, v/v =4:1), to obtain the target product I. The target product was confirmed by NMR, high-resolution mass spectrometry and reference literature.

The following examples help to further understand the present invention, but the content of the present invention is not limited thereto.

Example 1

In a sealed 10 mL tube, 1-(2,2-diphenylvinyl)tetrahydro-1H-thiophene-1-trifluoromethanesulfonate 2a (124.9 mg, 0.3 mmol), CuCN (40.3 mg , 0.45mmol), palladium acetate Pd(OAc) ₂ (13.5mg, 0.06mmol), potassium tert-butoxide KO ^t Bu (101.0mg, 0.9mmol) and 2-dicyclohexylphosphine-2,4,6-triiso Propylbiphenyl X-PHOS (43.0mg, 0.09mmol), and then replace nitrogen 3 times, then add 3mL N,N-dimethylformamide DMF, and stir at 80°C for 18 hours. After cooling to room temperature, the insoluble matter was removed by diatomite filtration, and the volatile components were removed under reduced pressure, and then separated by silica gel column chromatography (eluent was petroleum ether (60-90°C)/ethyl acetate, v/v =4:1), the target product 1a (59.2 mg, yield 96%) was obtained, and the target product was confirmed by nuclear magnetic resonance spectroscopy.

Typical Compound Characterization Data

3,3-Diphenylacrylonitrile (1a), pale yellow oily liquid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.51-7.48(m, 6H, aromatic CH), 7.41-7.37(m, 2H, aromatic CH), 7.33-7.30(m, 2H, aromatic CH), 5.75(s ,1H,CH) ^.13 CNMR(100MHz,CDCl ₃ )δ163.2,139.0,137.1,130.5,130.1,129.6,128.7,128.6,128.5,118.0(CN),94.9(CH).HRMS theory of C ₁₅ H ₁₁ N Value ([M+H] ⁺ ): 206.2675; Found: 206.2677.

Comparative example 1

The reaction steps and operation are the same as in Example 1, and the difference from Example 1 is that palladium acetate is not added. The reaction was stopped, and the target product 1a was not obtained after post-treatment. It shows that palladium acetate is indispensable in the reaction.

Example 2

The reaction steps and operations are the same as in Example 1, except that the ligand is triphenylphosphine. The reaction was stopped, and the target product 1a (27.7 mg, yield 45%) was obtained after post-processing. It shows that triphenylphosphine can also be used as a ligand in the reaction, but it is not the best ligand.

Example 3

The reaction steps and operations are the same as in Example 1, except that the alkali is sodium hydride NaH. The reaction was stopped, and the target product 1a (3.2 mg, yield 5%) was obtained after post-processing. It shows that a strong base is not conducive to the reaction.

Example 4

The reaction steps and operations are the same as those in Example 1, except that the solvent used in the reaction is toluene. The reaction was stopped, and the target product 1a (6.5 mg, yield 10%) was obtained after post-processing. It shows that toluene is not conducive to the progress of the reaction.

Example 5

The reaction steps and operations are the same as those in Example 1, except that the solvent used in the reaction is dimethyl sulfoxide. The reaction was stopped, and the target product 1a (48.1 mg, yield 78%) was obtained after post-processing. It shows that dimethyl sulfoxide can be used as a solvent for the reaction, but it is not the best solvent for the reaction.

Example 6

The reaction steps and operation are the same as in Example 1, except that the reaction time is shortened to 8 hours. The reaction was stopped, and the target product 1a (32.7 mg, yield 53%) was obtained after post-processing. It shows that shortening the reaction time is not conducive to the progress of the reaction.

Example 7

The reaction steps and operations are the same as in Example 1, except that the reaction temperature is 50°C. The reaction was stopped, and the target product 1a (18.6 mg, yield 30%) was obtained after post-processing. It shows that lowering the reaction temperature is not conducive to the progress of the reaction.

Example 8

The reaction steps and operations are the same as in Example 1, except that the alkenylsulfonium salt added to the reaction system is 2b (133.4 mg, 0.3 mmol). The reaction was stopped, and the target product 1b (53.2 mg, yield 76%) was obtained as a colorless waxy solid after post-processing. The target product was confirmed by NMR and high-resolution mass spectrometry.

Typical Compound Characterization Data

3,3-Di-p-tolylacrylonitrile (1b), colorless waxy solid, melting point: 45-47°C. ¹ H NMR (400MHz, CDCl ₃ ) δ7.36-7.38(m, 2H, aromatic CH), 7.29-7.27(m, 2H, aromatic CH), 7.24-7.19(m, 3H, aromatic CH), 5.69(s ,1H,CH),2.45(s,3H,CH ₃ ),2.42(s,3H,CH ₃ ). ¹³ C NMR(100MHz,CDCl ₃ )δ163.2,140.8,140.2,136.4,134.4,129.6,129.4,129.2 , 128.5, 118.4 (CN), 93.4 (CH), 21.5 (CH ₃ ) and 21.4 (CH ₃ ). HRMS theoretical value of C ₁₇ H ₁₅ N ([M+H] ⁺ ): 234.3215; measured value: 234.3218 .

Example 9

The reaction steps and operations are the same as those in Example 1, except that the alkenylsulfonium salt added to the reaction system is 2c (135.6 mg, 0.3 mmol). The reaction was stopped, and the target product 1c (72 mg, yield 99%) was obtained as a white solid after post-processing. The target product was confirmed by NMR and high-resolution mass spectrometry.

Typical Compound Characterization Data

3,3-Di-p-fluorophenylacrylonitrile (1c), white solid, melting point: 59-62°C. ¹ H NMR (400MHz, CDCl ₃ ) δ7.45(t, J=6.0Hz, 2H, aromatic CH), 7.31(t, J=6.0Hz, 2H, aromatic CH), 7.17(t, J=8.0Hz, 2H, aromatic CH), 7.10 (t, J=8.0Hz, 2H, aromatic CH), 5.71 (s, 1H, CH). ¹³ C NMR (100MHz, CDCl ₃ ) δ165.4, 165.0, 162.9, 162.5, 160.9, 134.9 (d, J=4.0Hz), 132.9(d, J=3.0Hz), 131.7(d, J=9.0Hz), 130.5(d, J=9.0Hz), 117.7(CH), 116.0(d, J= 6.0 Hz), 115.8 (d, J=6.0 Hz), 94.92 (CH). HRMS theoretical value for C ₁₅ H ₉ F ₂ N ([M+H] ⁺ ): 242.2483; found value: 242.2482.

Example 10

The reaction steps and operations are the same as in Example 1, except that the alkenylsulfonium salt added to the reaction system is 2d (129.2 mg, 0.3 mmol). The reaction was stopped, and the target product 1d (47.4 mg, yield 72%) was obtained as a colorless oily liquid after post-processing. The target product was confirmed by NMR and high-resolution mass spectrometry.

Typical Compound Characterization Data

3-Phenyl-3-(p-tolyl)acrylonitrile (1d), colorless oily liquid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.47-7.43 (m, 3H, aromatic CH), 7.40-7.30 (m, 4H, aromatic CH), 7.22-7.17 (m, 2H, aromatic CH), 5.72 (s, 1H,CH),2.42(s,3H,CH ₃ ). ¹³ C NMR(100MHz,CDCl ₃ )δ162.4,139.9,137.5,137.0,134.4,128.8,128.5,128.2,127.8,116.8(CN),4.18(CH ), 21.3 (CH ₃ ). HRMS calcd for C ₁₆ H ₁₃ N ([M+H] ⁺ ): 220.1048; Found: 220.1045.

Example 11

The reaction steps and operations are the same as in Example 1, except that the alkenylsulfonium salt added to the reaction system is 2e (124.9 mg, 0.3 mmol). The reaction was stopped, and the target product 1e (46.1 mg, yield 75%) was obtained as a colorless oily liquid after post-processing. The target product was confirmed by NMR and high-resolution mass spectrometry.

Typical Compound Characterization Data

3,3-Diphenylacrylonitrile (1e), colorless oily liquid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.43-7.34 (m, 6H, aromatic CH and vinyl CH), 7.34-7.30 (m, 1H, aromatic CH), 7.28-7.24 (m, 2H, aromatic CH), 7.21 _C ¹⁵ _H HRMS theoretical value for ₁₁ N ([M+H] ⁺ ): 206.2647; found value: 206.2649.

Claims (8)

1. A method for synthesizing polysubstituted alkenyl cyanide is characterized in that: taking a polysubstituted alkenyl sulfonium salt II as an initial raw material, palladium salt as a catalyst and an organophosphorus compound as a ligand, and reacting with cuprous cyanide under an alkaline condition to generate a polysubstituted alkenyl cyanide I;

the reaction formula of the synthetic route is as follows:

R ¹ selected from methyl, ethyl or aryl;

R ² selected from methyl, ethyl, aryl, naphthalene ring, furan ring, thiophene ring or pyridine ring;

R ³ selected from hydrogen, methyl, ethyl, benzyl, aryl, naphthalene rings, furan rings, thiophene rings or pyridine rings;

wherein, the aryl is selected from phenyl, the benzene ring has substituent groups, the substituent groups on the benzene ring are selected from 1 to 5 of methyl, methoxy, fluorine, chlorine, bromine, iodine, trifluoromethyl and nitro, and the number of the substituent groups is 1 to 5;

n is an integer from 0 to 3;

the palladium salt is one or more of palladium chloride, palladium trifluoroacetate, palladium acetate, palladium hydroxide, tetraacetonitrile palladium tetrafluoroborate, bis (acetonitrile) palladium chloride and palladium acetylacetonate;

the base is selected from one of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium acetate, potassium acetate, cesium acetate, potassium hydroxide, potassium tert-butoxide, lithium tert-butoxide and sodium hydride;

the ligand is one or more than two of triphenylphosphine, 2-dicyclohexyl phosphine-2, 4, 6-triisopropyl biphenyl, 2-dicyclohexyl phosphine-2 ',6' -dimethoxy biphenyl, tricyclohexyl phosphine and tri- (4-methylphenyl) phosphine;

the reaction solvent is one or a mixture of more than two of N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, toluene, 1, 4-dioxane, dichloromethane, ethyl acetate or methanol.

2. The method of synthesis according to claim 1, characterized in that:

the molar ratio of the polysubstituted alkenyl sulfonium salt II to the cuprous cyanide is 1-1;

the molar ratio of the polysubstituted alkenyl sulfonium salt II to the palladium salt is 1;

the molar ratio of the polysubstituted alkenyl sulfonium salt II to the alkali is 1;

the molar ratio of the polysubstituted alkenyl sulfonium salt II to the ligand is 1.1-1;

the reaction solvent is one or a mixture of more than two of N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, toluene, 1, 4-dioxane, dichloromethane, ethyl acetate or methanol, and the molar concentration of the polysubstituted alkenyl sulfonium salt II in the reaction solvent is 0.5-1.5M.

3. The method of synthesis according to claim 2, characterized in that: the reaction time is 8-24 hours; the reaction temperature is 0-120 ℃; the reaction atmosphere is nitrogen or inert atmosphere.

4. The method of synthesis according to claim 2, characterized in that: and after the reaction is finished, separating the product according to a conventional separation and purification method to obtain the polysubstituted alkenyl cyanide I.

5. The method of synthesis according to claim 2, characterized in that: the molar ratio of the polysubstituted alkenyl sulfonium salt II to the palladium salt is 1.

6. The method of synthesis according to claim 2, characterized in that: the molar ratio of the polysubstituted alkenylsulfonium salt II to the base is 1 to 1.

7. The method of synthesis according to claim 2, characterized in that: the molar concentration of the polysubstituted alkenyl sulfonium salt II in the reaction solvent is 1-1.5M.

8. The method of synthesis according to claim 2, characterized in that: the reaction time is 12-24 hours; the reaction temperature is 30-100 ℃.