Synthesis method of polysubstituted 1, 3-conjugated diene

Abstract

The invention belongs to the technical field of organic synthesis, and discloses a synthesis method of polysubstituted 1, 3-conjugated diene. The synthesis method of the polysubstituted 1, 3-conjugated diene comprises the following steps: in a protective atmosphere, with an organic solvent as a reaction medium, carrying out a reaction on a carboxylic acid compound, isonitrile and propargyl ester under the action of a weakly alkaline salt, a catalyst and a ligand to obtain the polysubstituted 1, 3-conjugated diene. The structure of the polysubstituted 1, 3-conjugated diene is shown in the specification. The method is simple, the raw materials are cheap and easy to obtain, the polysubstituted 1, 3-conjugated diene compound with rich and diversified structures can be constructed in one step, the yield is high, the substrate applicability is wide, and the atom economy is high. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a method for synthesizing a polysubstituted 1,3-conjugated diene. Background Art

[0002] 1,3-conjugated diene compounds are a class of versatile synthons that are widely used in organic synthesis. Some famous reactions, such as the Diels-Alder cycloaddition reaction (The Diels-Alder Reaction in Total Synthesis. Angew. Chem., Int. Ed. 2002, 41, 1668; Catalytic Enantioselective Diels-Alder Reactions: Methods, Mechanistic Fundamentals, Pathways, and Applications. Angew. Chem., Int. Ed. 2002, 41, 1650) and pericyclic reactions, are all initiated with 1,3-conjugated dienes as raw materials. Moreover, 1,3-conjugated dienes are also key skeletons in many natural products and bioactive molecules, such as the antiproliferative agent dolatrienoic acid (Synthesis of (7S, 15S)-and (7R, 15S)-Dolatrienoic Acid. J. Nat. Prod. 2001, 64, 472.), (-)-zampanolide (Zampanolide, a Potent New Microtubule-Stabilizing Agent, Covalently Reacts with the Taxane Luminal Site in Tubulin α, β-Heterodimers and Microtubules. JF Chem. Biol. 2012, 19, 686.), the antitumor antibiotic antramycin (Isolation and Characterization of Anthramycin, a New Antitumor Antibiotic. J. Am. Chem. Soc. 1965, 87, 5791.) and the antibacterial antibiotic (-)-macrolide A (The Macrolactins, a Novel Class of Antiviral and Cytotoxic Macrolides from a Deep-sea Marine Bacterium. J. Am. Chem. Soc. 1989, 111, 7519.) etc. It is precisely because of the unique reaction characteristics and wide application of this type of compound that the synthesis of 1,3-conjugated dienes has attracted much attention.

[0003] Organic synthetic chemists have conducted extensive research on the construction of 1,3-conjugated diene compounds, such as olefination, metathesis, and coupling reactions. Among them, the cross-coupling of two different olefins promoted by transition metals (including CH bonds, CX bonds (X=Br, I, B, Si, etc.) is the most direct and atom-economical method, and has therefore attracted widespread attention. However, they also have some obvious disadvantages, such as the need to use toxic or air- and water-sensitive reagents, substrate limitations, and the inability to obtain multi-substituted olefins (Stereoselective Synthesis of Conjugated 2,4-Alkadienoates via the Palladium Catalyzed Cross-Coupling of 1-Alkenylboronates with 3-Bromo-2-alkenoates. Bull. Chem. Soc. Jpn. 1989, 62, 3892; Synthesis of Highly Substituted 1,3-Dienes and 1,3,5-Trienes by the Palladium-Catalyzed Coupling of Vinylic Halides, Internal Alkynes, and Organoboranes. Org. Lett. 2003, 5, 2993; Stereoselective E-and Z-Olefin Formation by Wittig Olefination of Aldehydeswith Allylic Phosphorus Ylides. Stereochemistry. J. Org. Chem. 1988, 53, 2723.). Therefore, it is still a very meaningful research topic to develop a modular and unified method with cheap and readily available raw materials to obtain multi-substituted 1,3-conjugated dienes. Summary of the invention

[0004] In view of the problems and shortcomings of the prior art, the present invention aims to provide a method with cheap and readily available raw materials, simple operation, modularization and uniformity to obtain polysubstituted 1,3-conjugated dienes. The present invention uses abundant and cheap and readily available carboxylic acids, commercially available isonitriles and easily prepared tertiary propargyl esters as raw materials, and obtains a series of polysubstituted 1,3-conjugated dienes with high yield, wide functional group compatibility and high atom economy under the catalysis of cheap metal iron.

[0005] The purpose of the present invention is achieved through the following technical solutions:

[0006] A method for synthesizing a polysubstituted 1,3-conjugated diene comprises the following steps: in a protective atmosphere, with an organic solvent as a reaction medium, a carboxylic acid compound, an isonitrile and a propargyl ester react under the action of a weakly alkaline salt, a catalyst and a ligand to obtain a polysubstituted 1,3-conjugated diene.

[0007] The structure of the carboxylic acid compound is

[0008]

[0009] The structure of the isonitrile is

[0010]

[0011] The structure of the propargyl ester is

[0012] Opiv is pivaloyloxy

[0013] In the formula, R 1 is a C1-C12 straight or branched alkyl, cyclic alkyl, phenyl, substituted phenyl, heteroaryl, alkenyl, substituted alkenyl, 1-methyl-1H-indazolyl;

[0014] The cyclic alkyl group is a three-membered, four-membered, five-membered, or six-membered cycloalkyl group;

[0015] The substituent in the substituted phenyl is one or two or three of methylamino (CH3-NH-), -NMe2, -CHO, -OAc, -CF3, -F, -Cl, -Br, -I, -OH, -NH2, -SMe, -OMe, -Me; preferably 4-methylamino (4-CH3-NH-), 4-NMe2, 4-CHO, 4-OAc, 4-OTs, 4-CF3, 4-Cl, 3-F, 3-Cl, 3-Br, 3-I, 3-OH, 3-NH2, 2-SMe, 2-OMe, 2-Me, 2-Br, 2-Cl, 3-OH-4-I, 2-Cl-4-Br, 2-Cl-4-OMe, 2-Cl-4-NH2, 2-methoxy-4-bromo, 1,2,3-trimethoxy;

[0016] The heteroaryl group is 3-quinolyl, 3-thienyl, 5-benzofuranyl, 5-pyrimidinyl;

[0017] The substituted alkenyl is 1-substituted alkenyl, 2-substituted alkenyl or 1,1- and 1,2-substituted alkenyl, such as: C6H5-CH=CH-, CH2=C(C6H5)-, CH3-CH=CH-CH=CH-

[0018] R2 It is a tertiary alkyl group, such as tert-butyl, adamantyl (structural formula is ).

[0019] R 3 It is a C1-C6 straight chain or branched alkyl group, phenyl, substituted phenyl, 2-pyridyl, 3-pyridyl, 6-chloro-3-pyridyl, 5-fluoro-2-pyridyl, 2-benzofuranyl, 2-furanyl, 3-furanyl, 2-furyl, dibenzo[b,d]furan-4-yl, 2-thienyl, 2-quinolyl, 2-quinoxalinyl, and 4-pyridazinyl.

[0020] R 3 In the above-mentioned, the substituents in the substituted phenyl group are 4-I, 4-Br, 4-Cl, 4-OMe, 4-SMe, 4-OCF3, 4-CO2Et, 4-CONMe2, and 3,4,5-trimethoxy.

[0021] The organic solvent is one or more of tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, tert-butanol, and tert-amyl alcohol, preferably one or more of dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylformamide, and N,N-dimethylacetamide.

[0022] The weak alkaline salt is one or more of potassium formate, sodium formate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, cesium bicarbonate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium phosphate, lithium phosphate, trisodium phosphate dodecahydrate, potassium acetate, sodium acetate, cesium acetate, cesium fluoride, sodium ethoxide, sodium methoxide, sodium tert-butoxide, and sodium pivalate, preferably one or more of sodium bicarbonate, potassium carbonate, potassium bicarbonate, and cesium carbonate.

[0023] The catalyst is a transition metal nickel, a palladium catalyst, a cobalt catalyst or an iron catalyst;

[0024] The transition metal nickel is Ni(cod)2 (bis-(1,5-cyclooctadiene) nickel), Ni(acac)2 (nickel acetylacetonate), Ni(OTf)2 (nickel trifluoromethanesulfonate), NiCl2, NiCl 2· One or more of 6H2O, NiCl2(PPh3)2, NiCl2(dme)(nickel chloride dimethoxyethane), NiBr2, NiBr2(dme)(nickel bromide dimethoxyethane), NiBr2(PPh3)2, and NiI2.

[0025] The palladium catalyst is one or more of PdCl2, PdBr2, PdI2, Pd(OAc)2, Pd(TFA)2 (palladium trifluoroacetate), Pd(dba)2 (bis(dibenzylideneacetone)palladium), Pd(PPh3)4, Pd(PPh3)2Cl2, and Pd(DPPF)Cl2 (1,1'-bis(diphenylphosphinoferrocene)palladium dichloride).

[0026] The cobalt catalyst is one or more of CoCl2, CoBr2, CoI2, Co(acac)2 (cobalt acetylacetonate), and Co(OAc)2.

[0027] The iron catalyst is FeCl2, FeBr2, Fe(acac)2, Fe(OAc)2).

[0028] The catalyst is preferably one or more of FeCl2, FeBr2, Fe(acac)2, and Fe(OAc)2.

[0029] The ligand is a nitrogen or phosphine compound, specifically py (bipyridine), 4,4'-di-tert-butyl-2,2'-bipyridine, 2,2'-bipyridine-4,4'-dicarboxylic acid, terpyridine, 1,10-phenanthroline, PPh3 (triphenylphosphine), PCy3 (tricyclohexylphosphine), DPPE (1,2-bis(diphenylphosphine)ethane), DPPP (1,3-bis(diphenylphosphine)propane), DPPB (1,4-bis(diphenylphosphine)butane), BINAP (1,1'-binaphthyl-2,2'-bisdiphenylphosphine), preferably one or more of DPPE, DPPP, and DPPB.

[0030] The molar ratio of the propargyl ester, carboxylic acid and isonitrile is 1:(1.2-1.7):(2.5-3.5); the molar ratio of the propargyl ester to the catalyst is 1:(0.05-0.15); the molar ratio of the propargyl ester to the ligand is 1:(0.05-0.15); the molar ratio of the propargyl ester to the weakly alkaline salt is 1:(1.5-2.5).

[0031] The reaction temperature is 80-130°C, preferably 115-125°C.

[0032] The reaction time is 6-12 hours, and the completion of the reaction is detected by thin layer chromatography.

[0033] After the reaction is completed, cool and quench with saturated aqueous ammonium chloride solution, then extract with water and ethyl acetate, dry the organic phase with anhydrous sodium sulfate or anhydrous magnesium sulfate, remove the solvent with a reduced pressure rotary evaporator to obtain a crude product, and then select an eluent of appropriate polarity for separation by column chromatography.

[0034] Reaction equation of the present invention:

[0035]

[0036] Compared with the prior art, the present invention has the following beneficial effects:

[0037] (1) The raw materials of the present invention are cheap and readily available, and a multi-substituted 1,3-conjugated diene compound with rich and diverse structures can be constructed in one step, with high yield and wide substrate applicability;

[0038] (2) The metal used is cheap and non-biotoxic metallic iron, which is easy to operate and has high atom economy. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 This is the hydrogen spectrum (1H NMR: 400MHz, CDCl3) of compound 4a;

[0040] Figure 2 This is the carbon spectrum (13C NMR: 101MHz, CDCl3) of compound 4a;

[0041] Figure 3 This is the hydrogen spectrum (1H NMR: 400MHz, CDCl3) of compound 4b;

[0042] Figure 4 This is the carbon spectrum (13C NMR: 126MHz, CDCl3) of compound 4b;

[0043] Figure 5 This is the hydrogen spectrum (1H NMR: 400MHz, CDCl3) of compound 4c;

[0044] Figure 6 This is the carbon spectrum (13C NMR: 101MHz, CDCl3) of compound 4c;

[0045] Figure 7 This is the hydrogen spectrum (1H NMR: 400MHz, CDCl3) of compound 4d;

[0046] Figure 8 It is the carbon spectrum (13C NMR: 101MHz, CDCl3) of compound 4d;

[0047] Fig. 9 This is the hydrogen spectrum (1H NMR: 400MHz, CDCl3) of compound 4e;

[0048] Fig.10 This is the carbon spectrum (13C NMR: 101MHz, CDCl3) of compound 4e;

[0049] Fig.11 This is the hydrogen spectrum (1H NMR: 400MHz, CDCl3) of compound 4f;

[0050] Fig.12 This is the carbon spectrum (13C NMR: 126MHz, CDCl3) of compound 4f;

[0051] Fig.13 This is the hydrogen spectrum (1H NMR: 400MHz, CDCl3) of compound 4g;

[0052] Fig.14 This is the carbon spectrum (13C NMR: 101MHz, CDCl3) of compound 4g;

[0053] Fig.15 This is the hydrogen spectrum (1H NMR: 400MHz, CDCl3) of compound 4h;

[0054] Fig.16 This is the carbon spectrum (13C NMR: 101MHz, CDCl3) of compound 4h. DETAILED DESCRIPTION

[0055] The present invention is further described in detail below in conjunction with specific examples, but the embodiments of the present invention are not limited thereto.

[0056] Example 1

[0057] 4-Chlorobenzoic acid 1a (0.30 mmol), tert-butyl isocyanide 2a (0.6 mmol) and phenyl tert-propargyl ester were used to prepare a 3-hydroxy-1,2-dihydro-1,2-dihydro-2-phenyl-2-yl ester. 3a (0.20 mmol) was used as the initial raw material, and ferrous chloride (0.020 mmol), 1,4-bis(diphenylphosphino)butane (DPPB) (0.020 mmol) and sodium bicarbonate (0.40 mmol) were added, and finally 4 ml of N,N-dimethylacetamide was added, and the mixture was heated and stirred in an oil bath at 120°C. After the reaction of compound 3a was completed (detected by thin layer chromatography spot plate), the reaction bottle was taken out from the oil bath, cooled to room temperature, quenched with saturated aqueous ammonium chloride solution, and then extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent was removed by a reduced pressure rotary evaporator to obtain a crude product. The crude product was further purified by column chromatography (the eluent was a mixed solvent of petroleum ether: ethyl acetate in a volume ratio of 5:1) to obtain compound 4a with a yield of 73%.

[0058] Structural characterization data of 4a: yellow solid. 1 H NMR (400MHz, CDCl3) δ7.24-7.12(m,5H),7.08-6.99(m,4H),5.40(s,1H),5.31(s,1H),5.25(t,J=1.8Hz,1H),1.78(s,3H),1.39(s,9H);13 CNMR (101MHz,CDCl3)δ171.2,152.1,137.5,135.7,134.3,133.4,133.1,128.9,128.6,128.4,128.2,119.4,66.1,55.9,28.6,22.4. The hydrogen and carbon spectra of compound 4a are shown in Figure 1 and 2 shown.

[0059] Example 2

[0060] 4-Methylaminobenzoic acid 1b (0.30mmol), tert-butyl isonitrile 2a (0.6mmol) and phenyl tertiary propargyl ester 3a (0.20mmol) were used as the starting materials, ferrous chloride (0.020mmol), 1,4-bis(diphenylphosphino)butane (0.020mmol) and sodium bicarbonate (0.40mmol) were added, and finally 4 ml of N,N-dimethylacetamide was added, and the mixture was heated and stirred in an oil bath at 120°C. After the reaction of compound 3a was complete, the reaction bottle was taken out of the oil bath, cooled to room temperature, quenched with saturated ammonium chloride aqueous solution, and then extracted with water and ethyl acetate. The organic phase was dried with anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent was removed by a reduced pressure rotary evaporator to obtain a crude product. The crude product was further purified by column chromatography (the eluent was a mixed solvent of petroleum ether: ethyl acetate with a volume ratio of 5:1) to obtain compound 4b with a yield of 61%.

[0061]

[0062] Structural characterization data of 4b: yellow solid. 1 H NMR (400MHz, CDCl3) δ7.24-7.14(m,3H),7.12-7.02(m,2H),6.93-6.83(m,2H),6.49-6.36(m, 2H),5.31(s,1H),5.29(s,1H),5.23(s,1H),2.76(s,3H),1.80(d,J=1.3Hz,3H),1.40(s,9H); 13 C NMR (126MHz, CDCl3)δ171.1,152.5,148.7,136.2,133.8,133.7,128.5,128.2,128.0,126.1,118.9,66.5,55.6,30.7,28.6,22.6. The hydrogen and carbon spectra of compound 4b are shown in Figure 3 and 4 shown.

[0063] Example 3

[0064] 2-Methoxy-4-bromo-carboxylic acid 1c (0.30 mmol), tert-butyl isocyanide 2a (0.6 mmol) and phenyl tertiary propargyl ester 3a (0.20 mmol) were used as the starting materials, ferrous chloride (0.020 mmol), 1,4-bis(diphenylphosphino)butane (0.020 mmol) and sodium bicarbonate (0.40 mmol) were added, and finally 4 ml of N,N-dimethylacetamide was added. The mixture was heated and stirred in an oil bath at 120°C. After the reaction of compound 3a was completed, the reaction bottle was taken out from the oil bath, cooled to room temperature, quenched with saturated aqueous ammonium chloride solution, and then extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent was removed by a reduced pressure rotary evaporator to obtain a crude product. The crude product was further purified by column chromatography (the eluent was a mixed solvent of petroleum ether:ethyl acetate in a volume ratio of 5:1) to obtain compound 4c with a yield of 63%.

[0065]

[0066] Structural characterization data of 4c: white solid. 1 H NMR (400MHz, CDCl3) δ7.22-7.11(m,5H),7.01-6.93(m,1H),6.87(d,J=8.2Hz,1H),6.82(d,J =1.8Hz,1H),6.06(s,1H),5.28(s,1H),5.24(s,1H),3.71(s,3H),1.81(s,3H),1.35(s,9H); 13 C NMR (101MHz, CDCl3) δ171.6, 156.8, 152.7, 136.0, 134.5, 133.0, 128.5, 128.4, 127.9, 127.7, 126.5, 124.2, 121.9, 119.1, 114.8, 57.6, 55.8, 55.5, 28.1, 22.5. The hydrogen and carbon spectra of compound 4c are shown in Figure 5 and 6 shown.

[0067] Example 4

[0068] 1-Methyl-1H-indazole-3-carboxylic acid 1d (0.30 mmol), tert-butyl isocyanide 2a (0.6 mmol) and phenyl tert-propargyl ester 3a (0.20 mmol) were used as starting materials, ferrous chloride (0.020 mmol), 1,4-bis(diphenylphosphino)butane (0.020 mmol) and sodium bicarbonate (0.40 mmol) were added, and finally 4 ml of N,N-dimethylacetamide was added. The mixture was heated and stirred in an oil bath at 120°C. After the reaction of compound 3a was completed, the reaction bottle was taken out from the oil bath, cooled to room temperature, quenched with saturated aqueous ammonium chloride solution, and then extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent was removed by a reduced pressure rotary evaporator to obtain a crude product. The crude product was further purified by column chromatography (the eluent was a mixed solvent of petroleum ether:ethyl acetate in a volume ratio of 5:1) to obtain compound 4d with a yield of 85%.

[0069]

[0070] Structural characterization data of 4d: white solid. 1 H NMR (400MHz, CDCl3) δ7.56-7.47(m,1H),7.32-7.22(m,4H),7.20-7.11(m,3H),7.06-6 .99(m,1H),6.04(s,1H),5.33(d,J=1.6Hz,2H),3.90(s,3H),1.92(s,3H),1.38(s,9H); 13 C NMR (101MHz, CDCl3) δ171.0, 149.3, 141.2, 140.9, 136.4, 135.3, 132.6, 128.5, 128.1, 126.4, 120.8, 120.7, 119.0, 109.2, 61.7, 56.0, 35.5, 28.5, 22.3. The hydrogen and carbon spectra of compound 4d are shown in Figure 7 and 8 shown.

[0071] Example 5

[0072] 4-Oxo-4-phenylbutyric acid 1e (0.30 mmol), tert-butyl isocyanide 2a (0.6 mmol) and phenyl tert-propargyl ester 3a (0.20 mmol) were used as the starting materials, ferrous chloride (0.020 mmol), 1,4-bis(diphenylphosphino)butane (0.020 mmol) and sodium bicarbonate (0.40 mmol) were added, and finally 4 ml of N,N-dimethylacetamide was added. The mixture was heated and stirred in an oil bath at 120°C. After the reaction of compound 3a was completed, the reaction bottle was taken out from the oil bath, cooled to room temperature, quenched with saturated aqueous ammonium chloride solution, and then extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent was removed by a reduced pressure rotary evaporator to obtain a crude product. The crude product was further purified by column chromatography (the eluent was a mixed solvent of petroleum ether:ethyl acetate in a volume ratio of 5:1) to obtain compound 4e with a yield of 76%.

[0073]

[0074] Structural characterization data of 4e: yellow solid. 1 H NMR (400MHz, CDCl3) δ7.44-7.38(m,5H),7.20-7.07(m,3H),6.90-6.82(m,2H),5.26(s,1H),5.19(s, 1H),4.78(s,1H),2.47-2.31(m,1H),2.25-2.12(m,2H),1.87(s,3H),1.84-1.75(m,1H),1.61(s,9H); 13 C NMR (101MHz, CDCl3)δ171.1,150.2,141.4,136.1,136.0,133.1,129.0,128.7,128.5,128.4,128.4,128.2,125.9,118.7,60.7,55.2,34.0,28.7,27.2,22.3. The hydrogen and carbon spectra of compound 4e are shown in Fig. 9 and 10 shown.

[0075] Example 6

[0076] Cyclobutanecarboxylic acid 1f (0.30 mmol), tert-butyl isonitrile 2a (0.6 mmol) and phenyl tert-propargyl ester 3a (0.20 mmol) were used as the starting materials, ferrous chloride (0.020 mmol), 1,4-bis(diphenylphosphino)butane (0.020 mmol) and sodium bicarbonate (0.40 mmol) were added, and finally 4 ml of N,N-dimethylacetamide was added. The mixture was heated and stirred in an oil bath at 120°C. After the reaction of compound 3a was completed, the reaction bottle was taken out from the oil bath, cooled to room temperature, quenched with saturated aqueous ammonium chloride solution, and then extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent was removed by a reduced pressure rotary evaporator to obtain a crude product. The crude product was further purified by column chromatography (the eluent was a mixed solvent of petroleum ether:ethyl acetate in a volume ratio of 5:1) to obtain compound 4f with a yield of 50%.

[0077]

[0078] Structural characterization data of 4f: light yellow solid. 1 H NMR (400MHz, CDCl3) δ7.47-7.32(m,5H),5.22(t,J=1.8Hz,1H),5.06(s,1H),4.62(d,J=4.4 Hz,1H),2.92-2.77(m,1H),1.83(s,3H),1.78-1.58(m,3H),1.54(s,9H),1.40-1.22(m,3H); 13 C NMR (126MHz, CDCl3) δ170.8,150.4,136.7,136.4,134.9,128.8,128.5,128.5,118.4,62.8,54.8,39.6,28.7,24.2,24.0,22.3,17.4. The hydrogen and carbon spectra of compound 4f are shown in Fig.11 and 12 shown.

[0079] Example 7

[0080] 1 g (0.30 mmol) of 2-phenylacrylic acid, tert-butyl isocyanide 2a (0.6 mmol) and tert-phenyl propargyl ester 3a (0.20 mmol) were used as the initial raw materials, ferrous chloride (0.020 mmol), 1,4-bis(diphenylphosphino)butane (0.020 mmol) and sodium bicarbonate (0.40 mmol) were added, and finally 4 ml of N,N-dimethylacetamide was added. The mixture was heated and stirred in an oil bath at 120°C. After the reaction of compound 3a was completed, the reaction bottle was taken out from the oil bath, cooled to room temperature, quenched with saturated aqueous ammonium chloride solution, and then extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent was removed by a reduced pressure rotary evaporator to obtain a crude product. The crude product was further purified by column chromatography (the eluent was a mixed solvent of petroleum ether: ethyl acetate in a volume ratio of 5:1) to obtain compound 4g with a yield of 58%.

[0081]

[0082] Structural characterization data of 4g: orange solid. 1 H NMR (400MHz, CDCl3) δ7.29-7.14(m,8H),7.13-7.07(m,2H),5.42(s,1H),5.30-5.17(m,4H),1.76(d,J=1.3Hz,3H),1.45(s,9H); 13 C NMR (101MHz, CDCl3) δ171.3, 146.7, 135.9, 133.2, 128.9, 128.5, 128.2, 128.0, 127.9, 127.2, 119.0, 56.1, 28.4, 22.2. The hydrogen and carbon spectra of compound 4g are shown in Fig.13 and 14 shown.

[0083] Example 8

[0084] Sorbic acid 1h (0.30 mmol), tert-butyl isocyanide 2a (0.6 mmol) and phenyl tert-propargyl ester 3a (0.20 mmol) were used as the initial raw materials, ferrous chloride (0.020 mmol), 1,4-bis(diphenylphosphino)butane (0.020 mmol) and sodium bicarbonate (0.40 mmol) were added, and finally 4 ml of N,N-dimethylacetamide was added. The mixture was heated and stirred in an oil bath at 120°C. After the reaction of compound 3a was completed, the reaction bottle was taken out from the oil bath, cooled to room temperature, quenched with saturated aqueous ammonium chloride solution, and then extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent was removed by a reduced pressure rotary evaporator to obtain a crude product. The crude product was further purified by column chromatography (the eluent was a mixed solvent of petroleum ether:ethyl acetate in a volume ratio of 5:1) to obtain compound 4h with a yield of 57%.

[0085]

[0086] Structural characterization data of 4h: reddish brown liquid. 1 H NMR (400MHz, CDCl3) δ7.35-7.27(m,5H),6.05(dd,J=15.2,10.4Hz,1H),5.94-5.81(m,1H),5.57(dq,J=13.5,6.7Hz,1H),5.28-5 .19(m,2H),5.08(dd,J=15.2,8.7Hz,1H),4.93(d,J=8.8Hz,1H),1.80(t,J=1.2Hz,3H),1.67(dd,J=6.8,1.6Hz,3H),1.52(s,9H); 13 C NMR (101MHz, CDCl3)δ170.3,150.0,136.2,135.1,134.2,133.3,130.5,130.2,128.9,128.6,128.6,128.3,119.0,64.7,55.4,28.8,22.4,18.2. The hydrogen and carbon spectra of compound 4h are shown in Fig.15 and 16 shown.

[0087] Example 9

[0088] Benzoic acid 1i (0.30 mmol), tert-butyl isocyanide 2a (0.6 mmol) and phenyl tert-propargyl ester 3a (0.20 mmol) were used as the starting materials, nickel chloride (0.020 mmol), 1,4-bis(diphenylphosphino)butane (0.020 mmol) and sodium bicarbonate (0.40 mmol) were added, and finally 4 ml of N,N-dimethylacetamide was added. The mixture was heated and stirred in an oil bath at 120 °C. After the reaction of compound 3a was completed (detected by thin layer chromatography spot plate), the reaction bottle was taken out from the oil bath, cooled to room temperature, quenched with saturated aqueous ammonium chloride solution, and then extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent was removed by a reduced pressure rotary evaporator to obtain a crude product. The crude product was further purified by column chromatography (the eluent was a mixed solvent of petroleum ether:ethyl acetate with a volume ratio of 5:1) to obtain compound 4i with a yield of 19%.

[0089]

[0090] Example 10

[0091] Benzoic acid 1i (0.30mmol), tert-butyl isocyanide 2a (0.6mmol) and phenyl tri-propargyl ester 3a (0.20mmol) were used as the starting materials, cobalt chloride (0.020mmol), 1,4-bis(diphenylphosphino)butane (0.020mmol) and sodium bicarbonate (0.40mmol) were added, and finally 4 ml of N,N-dimethylacetamide was added, and the mixture was heated and stirred in an oil bath at 120°C. After the reaction of compound 3a was complete (detected by thin layer chromatography spot plate), the reaction bottle was taken out from the oil bath, cooled to room temperature, quenched with saturated ammonium chloride aqueous solution, and then extracted with water and ethyl acetate. The organic phase was dried with anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent was removed by a reduced pressure rotary evaporator to obtain a crude product. The crude product was further purified by column chromatography (the eluent was a mixed solvent of petroleum ether:ethyl acetate with a volume ratio of 5:1) to obtain compound 4i with a yield of 23%.

[0092]

[0093] Embodiment 11

[0094] Benzoic acid 1i (0.30mmol), tert-butyl isocyanide 2a (0.6mmol) and phenyl tri-propargyl ester 3a (0.20mmol) were used as the starting materials, palladium chloride (0.020mmol), 1,4-bis(diphenylphosphino)butane (0.020mmol) and sodium bicarbonate (0.40mmol) were added, and finally 4 ml of N,N-dimethylacetamide was added, and the mixture was heated and stirred in an oil bath at 120°C. After the reaction of compound 3a was complete (detected by thin layer chromatography spot plate), the reaction bottle was taken out from the oil bath, cooled to room temperature, quenched with saturated ammonium chloride aqueous solution, and then extracted with water and ethyl acetate. The organic phase was dried with anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent was removed by a reduced pressure rotary evaporator to obtain a crude product. The crude product was further purified by column chromatography (the eluent was a mixed solvent of petroleum ether:ethyl acetate with a volume ratio of 5:1) to obtain compound 4i with a yield of 30%.

[0095]

[0096] Example 12

[0097] Benzoic acid 1i (0.30mmol), tert-butyl isocyanide 2a (0.6mmol) and phenyl tri-propargyl ester 3a (0.20mmol) were used as the starting materials, ferrous chloride (0.020mmol), 1,4-bis(diphenylphosphino)butane (0.020mmol) and sodium phosphate dodecahydrate (0.40mmol) were added, and finally 4 ml of N,N-dimethylacetamide was added, and the mixture was heated and stirred in an oil bath at 120°C. After the reaction of compound 3a was complete (detected by thin layer chromatography spot plate), the reaction bottle was taken out from the oil bath, cooled to room temperature, quenched with saturated ammonium chloride aqueous solution, and then extracted with water and ethyl acetate. The organic phase was dried with anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent was removed by a reduced pressure rotary evaporator to obtain a crude product. The crude product was further purified by column chromatography (the eluent was a mixed solvent of petroleum ether:ethyl acetate with a volume ratio of 5:1) to obtain compound 4i with a yield of 25%.

[0098]

[0099] Comparative Example 1

[0100] Use (3R,4S,5R)-3,4,5-trihydroxycyclohex-1-ene-1-carboxylic acid 1j (0.30 mmol), tert-butyl isocyanide 2a (0.6 mmol) and phenyl tripropargyl ester 3a (0.20 mmol) as starting materials, add ferrous chloride (0.020 mmol), 1,4-bis(diphenylphosphino)butane (0.020 mmol) and sodium phosphate dodecahydrate (0.40 mmol), and finally add 4 ml of N,N-dimethylacetamide, and heat with stirring in an oil bath at 120°C. After the reaction of compound 3a is complete (detected by thin layer chromatography spot plate), the reaction bottle is taken out from the oil bath, cooled to room temperature, quenched with saturated aqueous ammonium chloride solution, and then extracted with water and ethyl acetate. The organic phase is dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent is removed by a reduced pressure rotary evaporator to obtain a crude product. The crude product is further purified by column chromatography (the eluent is a mixed solvent of petroleum ether: ethyl acetate in a volume ratio of 5:1) to obtain compound 4j with a yield of 0%.

[0101]

[0102] Comparative Example 2

[0103] Pyridazine-4-carboxylic acid 1k (0.30 mmol), tert-butyl isonitrile 2a (0.6 mmol) and phenyl tertiary propargyl ester 3a (0.20 mmol) were used as the starting materials, and ferrous chloride (0.020 mmol), 1,4-bis(diphenylphosphino)butane (0.020 mmol) and sodium phosphate dodecahydrate (0.40 mmol) were added, and finally 4 ml of N,N-dimethylacetamide was added, and the mixture was heated and stirred in an oil bath at 120°C. After the reaction of compound 3a was complete (detected by thin layer chromatography spot plate), the reaction bottle was taken out from the oil bath, cooled to room temperature, quenched with saturated ammonium chloride aqueous solution, and then extracted with water and ethyl acetate. The organic phase was dried with anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent was removed by a reduced pressure rotary evaporator to obtain a crude product. The crude product was further purified by column chromatography (the eluent was a mixed solvent of petroleum ether:ethyl acetate with a volume ratio of 5:1) to obtain compound 4j with a yield of 2%.

[0104]

[0105] Comparative Example 3

[0106] Benzoic acid 1i (0.30 mmol), tert-butyl isocyanide 2a (0.6 mmol) and phenyl tert-propargyl ester 3b (0.20mmol) was used as the initial raw material, ferrous chloride (0.020mmol), 1,4-bis(diphenylphosphino)butane (0.020mmol) and sodium phosphate dodecahydrate (0.40mmol) were added, and finally 4 ml of N,N-dimethylacetamide was added. The mixture was heated and stirred in an oil bath at 120°C. After the reaction of compound 3b was completed (detected by thin layer chromatography spot plate), the reaction bottle was taken out from the oil bath, cooled to room temperature, quenched with saturated aqueous ammonium chloride solution, and then extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent was removed by a reduced pressure rotary evaporator to obtain a crude product. The crude product was further purified by column chromatography (the eluent was a mixed solvent of petroleum ether:ethyl acetate in a volume ratio of 5:1) to obtain compound 4l with a yield of 27%.

[0107] Comparative Example 4

[0108] Benzoic acid 1i (0.30 mmol), cyclohexyl isocyanide 2b (0.6 mmol) and phenyl tert-propargyl ester 3a (0.20 mmol) were used as the starting materials, ferrous chloride (0.020 mmol), 1,4-bis(diphenylphosphino)butane (0.020 mmol) and sodium phosphate dodecahydrate (0.40 mmol) were added, and finally 4 ml of N,N-dimethylacetamide was added. The mixture was heated and stirred in an oil bath at 120°C. After the reaction of compound 3a was completed (detected by thin layer chromatography spot plate), the reaction bottle was taken out from the oil bath, cooled to room temperature, quenched with saturated aqueous ammonium chloride solution, and then extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent was removed by a reduced pressure rotary evaporator to obtain a crude product. The crude product was further purified by column chromatography (the eluent was a mixed solvent of petroleum ether:ethyl acetate in a volume ratio of 5:1) to obtain compound 4m with a yield of 3%.

[0109]

[0110] It is easy for those skilled in the art to understand that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention. Any modification, equivalent replacement or improvement made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for synthesizing a polysubstituted 1,3-conjugated diene, characterized in that: The method comprises the following steps: in a protective atmosphere, with an organic solvent as a reaction medium, a carboxylic acid compound, an isonitrile and a propargyl ester react under the action of a weakly alkaline salt, a catalyst and a ligand to obtain a multi-substituted 1,3-conjugated diene; The structure of the carboxylic acid compound is The structure of the isonitrile is The structure of the propargyl ester is In the formula, R 1 is a C1-C12 straight or branched alkyl, cyclic alkyl, phenyl, substituted phenyl, heteroaryl, alkenyl, substituted alkenyl, 1-methyl-1H-indazolyl; The cyclic alkyl group is a three-membered, four-membered, five-membered, or six-membered cycloalkyl group; The substituents in the substituted phenyl are one, two or three of CH3-NH-, -NMe2, -CHO, -OAc, -CF3, -F, -Cl, -Br, -I, -OH, -NH2, -SMe, -OMe, -Me; The heteroaryl group is 3-quinolyl, 3-thienyl, 5-benzofuranyl, 5-pyrimidinyl; The substituted alkenyl group is a 1-substituted alkenyl group, a 2-substituted alkenyl group, or a 1,1- and 1,2-substituted alkenyl group; R 2 is a tertiary alkyl group; R 3 is a C1-C6 straight chain or branched alkyl group, phenyl, substituted phenyl, 2-pyridyl, 3-pyridyl, 6-chloro-3-pyridyl, 5-fluoro-2-pyridyl, 2-benzofuranyl, 2-furanyl, 3-furan, 2-furylvinyl, dibenzo[b,d]furan-4-yl, 2-thienylvinyl, 2-quinolyl, 2-quinoxalinyl or 4-pyridazinyl; R 3 wherein the substituent in the substituted phenyl is 4-I, 4-Br, 4-Cl, 4-OMe, 4-SMe, 4-OCF3, 4-CO2Et, 4-CONMe2, 3,4,5-trimethoxy; The weakly alkaline salt is one or more of potassium formate, sodium formate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, cesium bicarbonate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium phosphate, lithium phosphate, trisodium phosphate dodecahydrate, potassium acetate, sodium acetate, cesium acetate, cesium fluoride, sodium ethoxide, sodium methoxide, sodium tert-butoxide, and sodium pivalate; The catalyst is a transition metal nickel, a palladium catalyst, a cobalt catalyst or an iron catalyst; The transition metal nickel is Ni(cod)2), Ni(acac)2, Ni(OTf2), NiCl2, NiCl 2· One or more of 6H2O, NiCl2(PPh3)2, NiCl2(dme), NiBr2, NiBr2(dme), NiBr2(PPh3)2, NiI2; The palladium catalyst is one or more of PdCl2, PdBr2, PdI2, Pd(OAc)2, Pd(TFA)2, Pd(dba)2, Pd(PPh3)4, Pd(PPh3)2Cl2, and Pd(DPPF)Cl2; The cobalt catalyst is one or more of CoCl2, CoBr2, CoI2, Co(acac)2, and Co(OAc)2; The iron catalyst is FeCl2, FeBr2, Fe(acac)2, Fe(OAc)2).

2. The method for synthesizing a polysubstituted 1,3-conjugated diene according to claim 1, characterized in that: R 1 wherein the substituent in the substituted phenyl is 4-CH3-NH-, 4-NMe2, 4-CHO, 4-OAc, 4-OTs, 4-CF3, 4-Cl, 3-F, 3-Cl, 3-Br, 3-I, 3-OH, 3-NH2, 2-SMe, 2-OMe, 2-Me, 2-Br, 2-Cl, 3-OH-4-I, 2-Cl-4-Br, 2-Cl-4-OMe, 2-Cl-4-NH2, 2-methoxy-4-bromo, 1,2,3-trimethoxy; The substituted alkenyl group is C6H5-CH=CH-, CH2=C(C6H5)-, CH3-CH=CH-CH=CH-; R 2 is tert-butyl, adamantyl; The weakly alkaline salt is one or more of sodium bicarbonate, potassium carbonate, potassium bicarbonate, and cesium carbonate; The catalyst is one or more of FeCl2, FeBr2, Fe(acac)2, and Fe(OAc)2.

3. The method for synthesizing a polysubstituted 1,3-conjugated diene according to claim 1, characterized in that: The organic solvent is one or more of tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, tert-butanol, and tert-amyl alcohol.

4. The method for synthesizing a polysubstituted 1,3-conjugated diene according to claim 3, characterized in that: The organic solvent is one or more of dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylformamide and N,N-dimethylacetamide.

5. The method for synthesizing a polysubstituted 1,3-conjugated diene according to claim 1, characterized in that: The ligand is a nitrogen or phosphine compound, specifically bipyridine, 4,4'-di-tert-butyl-2,2'-bipyridine, 2,2'-bipyridine-4,4'-dicarboxylic acid, terpyridine, 1,10-phenanthroline, triphenylphosphine, tricyclohexylphosphine, 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, 1,4-bis(diphenylphosphino)butane, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine.

6. The method for synthesizing a polysubstituted 1,3-conjugated diene according to claim 5, characterized in that: The ligand is one or more of 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane and 1,4-bis(diphenylphosphino)butane.

7. The method for synthesizing a polysubstituted 1,3-conjugated diene according to claim 1, characterized in that: The molar ratio of the propargyl ester, carboxylic acid and isonitrile is 1:(1.2-1.7):(2.5-3.5); the molar ratio of the propargyl ester to the catalyst is 1:(0.05-0.15); the molar ratio of the propargyl ester to the ligand is 1:(0.05-0.15); the molar ratio of the propargyl ester to the weakly alkaline salt is 1:(1.5-2.5).

8. The method for synthesizing a polysubstituted 1,3-conjugated diene according to claim 1, characterized in that: The reaction temperature is 80-130°C; The reaction time is 6-12 hours, and the completion of the reaction is detected by thin layer chromatography.

9. The method for synthesizing a polysubstituted 1,3-conjugated diene according to claim 1, characterized in that: After the reaction is completed, cool and quench with saturated aqueous ammonium chloride solution, then extract with water and ethyl acetate, dry the organic phase with anhydrous sodium sulfate or anhydrous magnesium sulfate, remove the solvent with a reduced pressure rotary evaporator to obtain a crude product, and then select an eluent of appropriate polarity for separation by column chromatography.

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