Method for synthesizing polysubstituted cyclohexadiene carboxylic ester by palladium-catalyzed conjugated eneyne hydroesterification cyclization cascade reaction

Abstract

The invention discloses a method for synthesizing polysubstituted cyclohexadiene carboxylate through palladium-catalyzed conjugated eneyne hydrogen esterification cyclization cascade reaction, and belongs to the field of organic synthesis. Two synthesis methods are adopted, the first method is that conjugated enyne and formic acid aryl ester are subjected to preparation and synthesis of polysubstituted cyclohexadiene carboxylic ester with good regioselectivity under the combined action of a ligand and a palladium catalyst; according to the second method, conjugated dienoic acid ester and conjugated enyne are used as raw materials under the same reaction system, and preparation and synthesis of polysubstituted cyclohexadiene carboxylic ester with different substituent groups, which is excellent in regioselectivity and yield, are realized. The method is wide in applicable substrate range, good in functional group compatibility, easy to amplify and high in atom economy, and is superior to a traditional synthesis method in multiple aspects. The invention provides a practical synthesis method for one-step synthesis of high-value polysubstituted cyclohexadiene from simple unsaturated hydrocarbon raw materials, and the method has atom economy and industrial application prospects.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing polysubstituted cyclohexadiene carboxylates by a palladium-catalyzed conjugated ene and alkyne hydroesterification and cyclization tandem reaction. Background Art

[0002] Polysubstituted cyclohexadiene carboxylates have broad applications in diverse fields, including organic synthesis, medicinal chemistry, materials science, natural product synthesis, catalysis, biochemistry, and analytical chemistry, demonstrating their versatility and importance. They contain multiple carbon-carbon double bonds, and the diversity of substituent groups and ester groups impart unique biological activities and physicochemical properties. They are often key synthetic intermediates for many active pharmaceutical ingredients. Therefore, developing novel reaction strategies or catalytic systems for the synthesis of novel polysubstituted cyclohexadiene carboxylates is of great significance.

[0003] The efficient construction of carboxylate-functionalized cyclohexadiene skeletons is of great value in the field of organic synthesis and has attracted the attention of researchers in recent years. Traditional synthetic routes mainly rely on the intramolecular cyclization transformation of non-cyclic precursor compounds, but such methods generally have significant defects such as severe reaction conditions (such as strong acid / strong base environment, high temperature and high pressure, etc.) and limited functional group compatibility, which seriously restricts the scope of practical application. In response to these synthetic bottlenecks, the development of innovative synthetic strategies with mild conditions and strong universality has become the current research focus and difficulty in this field. The latest research shows that the introduction of new catalytic systems such as transition metal catalysis and photoredox catalysis has provided a breakthrough idea for solving this synthetic challenge. The transition metal-catalyzed carbon-hydrogen bond activation reaction assisted by directing groups is an effective tool for constructing important ring skeletons. Some of these methods have the advantages of simple steps, environmental protection and good atom economy, and have made great progress.

[0004] Palladium-catalyzed systems, through allylpalladium intermediates or carbon-hydrogen bond activation strategies, enable the efficient cyclization of non-classical dienes such as conjugated enynes and allenes, demonstrating unique advantages in the construction of six-membered ring systems and heterocyclic compounds. Rhodium catalysis focuses on asymmetric synthesis, successfully achieving the highly enantioselective preparation of polysubstituted cyclohexene compounds with the aid of chiral ligands, providing an important means for the synthesis of chiral drugs. Furthermore, the development of inexpensive metal catalysts such as cobalt, nickel, and copper has further expanded the applicability of the reaction, showing great potential in multicomponent cascade reactions and the synthesis of complex heterocycles. Therefore, transition-metal-catalyzed selective functional cyclization of unsaturated hydrocarbons has become a powerful synthetic tool, offering great potential for simplifying synthetic routes and enabling the modification of complex organic molecules. This method, with its abundant and inexpensive raw materials and the avoidance of substrate preactivation, allows for the more efficient and mild synthesis of functional polysubstituted cyclohexadiene carboxylate skeletons, with improved atom and step economy, and is expected to have a lasting impact on the field of synthetic organic chemistry. However, due to the lack of functional groups that can guide positional or regioselectivity, the diverse reaction sites of unsaturated hydrocarbons often lead to complex products, making regioselectivity control a significant challenge in most transformation processes. This characteristic greatly limits their synthetic application value. Therefore, the development of highly selective catalytic systems has become a core issue in this field of research. In particular, the precise control of reaction selectivity through strategies such as ligand selection and catalyst regulation is of great scientific significance. Summary of the Invention

[0005] The present invention addresses the deficiencies of the prior art and provides a method for synthesizing polysubstituted cyclohexadiene carboxylates by a palladium-catalyzed conjugated ene and alkyne hydroesterification and cyclization tandem reaction. The method overcomes the shortcomings of conventional catalytic systems, such as cumbersome steps, poor substrate regioselectivity, the need for pre-functionalized substrates, reliance on expensive transition metal catalysts, the use of toxic and hazardous CO gas and air- and moisture-sensitive organometallic reagents, difficulty in preparation and storage, harsh reaction conditions, multiple reaction steps, poor efficiency, a limited substrate range, and the generation of a large amount of metal waste.

[0006] The present invention discloses a method for synthesizing polysubstituted cyclohexadiene carboxylates by a palladium-catalyzed conjugated ene and alkyne hydroesterification and cyclization tandem reaction, wherein one route comprises the following steps:

[0007] Under nitrogen protection, conjugated ene-yne and aryl formate are used as raw materials, and a heating reaction is carried out in an organic solvent system containing a palladium catalyst, a ligand, and a base additive to prepare a polysubstituted cyclohexadiene carboxylate compound.

[0008] The synthetic route is as follows:

[0009]

[0010] R is selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted saturated or unsaturated cycloalkyl. Ar represents an aryl or substituted aryl group.

[0011] The substituents include alkyl substitution, halogen substitution, heteroatom substitution, alkyl ester substitution, -OH substitution and the like.

[0012] in:

[0013] The conjugated ene-yne is selected from but-3-ene-1-yn-1-ylbenzene, substituted but-3-ene-1-yn-1-ylbenzene, but-3-ene-1-yn-1-ylnaphthalene, alkyl-substituted but-3-ene-1-yne or heterocyclic-substituted but-3-ene-1-yne.

[0014] The aryl formate is selected from phenyl formate, naphth-2-yl formate or substituted phenyl formate.

[0015] The palladium catalyst is selected from any one of palladium acetate, di(acetylacetonate)palladium, palladium chloride, palladium pivalate, and allylpalladium chloride dimer, or a combination thereof.

[0016] The ligand is dimethyl-p-tolylphosphine, triphenylphosphine, tri-p-phenylmethylphosphine, 4-(dimethylamino)triphenylphosphine or tris(4-dimethylaminophenyl)phosphine.

[0017] The base is anhydrous potassium carbonate, anhydrous sodium bicarbonate, anhydrous sodium carbonate, and anhydrous cesium carbonate.

[0018] The organic solvent is one of acetone, 1,4-dioxane, ethyl acetate, toluene, tetrahydrofuran, ethyl acetate, and N,N-diethylamide, preferably ethyl acetate.

[0019] In the reaction system:

[0020] The molar ratio of conjugated enyne to aryl formate is 1:3.

[0021] The molar ratio of the conjugated ene-yne to the palladium catalyst is controlled to be 1:0.01 to 1:0.20, preferably 1:0.05.

[0022] The molar ratio of the conjugated enyne to the ligand is controlled to be 1:0.05 to 1:0.30, preferably 1:0.20.

[0023] The molar ratio of conjugated ene-yne to sodium carbonate is controlled to be 1:0.1 to 1:2, preferably 1:1.

[0024] The reaction temperature is 80-110°C, preferably 100°C; the reaction time is 12-36 hours, preferably 24 hours.

[0025] The present invention provides a method for synthesizing polysubstituted cyclohexadiene carboxylates by a palladium-catalyzed conjugated ene and alkyne hydroesterification and cyclization tandem reaction, route 2, comprising the following steps:

[0026] Under nitrogen protection, conjugated diene and conjugated enyne are used as raw materials, and a multi-substituted cyclohexadiene carboxylate compound is prepared by heating reaction in an organic solvent system containing a palladium catalyst, a ligand and sodium carbonate.

[0027] The synthetic route is as follows:

[0028]

[0029] R is selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted saturated or unsaturated cycloalkyl. R1 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl. Ar represents an aryl or substituted aryl group.

[0030] The substituents include alkyl substitution, halogen substitution, heteroatom substitution, alkyl ester substitution, -OH substitution and the like.

[0031] in:

[0032] The conjugated ene-yne is selected from but-3-ene-1-yn-1-ylbenzene, substituted but-3-ene-1-yn-1-ylbenzene, but-3-ene-1-yn-1-ylnaphthalene, alkyl-substituted but-3-ene-1-yne or heterocyclic-substituted but-3-ene-1-yne.

[0033] The palladium catalyst is selected from any one of palladium acetate, di(acetylacetonate)palladium, palladium chloride, palladium pivalate, and allylpalladium chloride dimer, or a combination thereof.

[0034] The ligand is dimethyl-p-tolylphosphine, triphenylphosphine, tri-p-phenylmethylphosphine, 4-(dimethylamino)triphenylphosphine or tris(4-dimethylaminophenyl)phosphine.

[0035] The base is one of anhydrous potassium carbonate, anhydrous sodium bicarbonate, anhydrous sodium carbonate, and anhydrous cesium carbonate, preferably anhydrous sodium carbonate.

[0036] The organic solvent is one of acetone, 1,4-dioxane, ethyl acetate, toluene, tetrahydrofuran, ethyl acetate, and N,N-diethylamide, preferably ethyl acetate.

[0037] In the reaction system:

[0038] The molar ratio of the conjugated diene to the conjugated enyne is 1:1.

[0039] The molar ratio of the conjugated diene to the palladium catalyst is controlled to be 1:0.01 to 1:0.20, preferably 1:0.05.

[0040] The molar ratio of the conjugated diene to the ligand is controlled to be 1:0.05 to 1:0.30, preferably 1:0.20.

[0041] The molar ratio of the conjugated diene to the sodium carbonate is controlled to be 1:0.1 to 1:2, preferably 1:1.

[0042] The reaction temperature is 80-110°C, preferably 100°C; the reaction time is 12-36 hours, preferably 24 hours.

[0043] Compared with the prior art, the present invention has the following advantages:

[0044] This invention reports for the first time a method for synthesizing polysubstituted cyclohexadiene carboxylates via an ester-directed, palladium-catalyzed tandem hydroesterification and cyclization reaction of conjugated ene and alkynes. This method boasts a wide substrate range, good functional group compatibility, ease of scale-up, and high atom economy, surpassing conventional synthetic methods in many respects. This invention provides a practical, atom-efficient, and promising industrial synthesis method for the one-step synthesis of high-value polysubstituted cyclohexadienes from simple unsaturated hydrocarbon feedstocks.

[0045] 2. The present invention uses conjugated ene-yne as raw material, which is cheap and easily available, does not require substrate pre-activation, is simple to operate, and has higher atom economy.

[0046] 3. The present invention uses abundant palladium as a catalyst, resulting in low reaction costs, mild conditions, a wide substrate range, good functional group compatibility, good tolerance of various conjugated enynes and conjugated dienes, and ease of scale-up. This provides a practical, one-step synthesis method for high-value-added functionalized polysubstituted cyclohexadiene carboxylates from simple unsaturated hydrocarbon feedstocks, demonstrating atom economy and promising industrial applications. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] The present invention will be further described below in conjunction with the accompanying drawings and specific embodiments, and the above and other advantages of the present invention will become more apparent.

[0048] Figure 1 It is a reaction pathway diagram of the present invention.

[0049] Figure 2 is the hydrogen spectrum of compound 3a.

[0050] Figure 3 This is the carbon spectrum of compound 3a.

[0051] Figure 4 is the hydrogen spectrum of compound 3c.

[0052] Figure 5 This is the carbon spectrum of compound 3c.

[0053] Figure 6This is the hydrogen spectrum of compound 3g.

[0054] Figure 7 This is the carbon spectrum of compound 3g.

[0055] Figure 8 is the hydrogen spectrum of compound 3j.

[0056] Figure 9 is the carbon spectrum of compound 3j.

[0057] Figure 10 is the hydrogen spectrum of compound 3l.

[0058] Figure 11 This is the carbon spectrum of compound 3l.

[0059] Figure 12 This is the hydrogen spectrum of compound 3m.

[0060] Figure 13 This is the carbon spectrum of compound 3m. DETAILED DESCRIPTION

[0061] The present invention can be better understood according to the following examples. However, it is easy for those skilled in the art to understand that the contents described in the examples are only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the claims.

[0062] The following examples were reacted according to the following steps:

[0063]

[0064] Method 1: Under a nitrogen atmosphere, palladium acetate (0.0022 g, 5 mol%), diphenyl-p-tolylphosphine (0.0111 g, 20 mol%), and 0.20 mmol of anhydrous sodium carbonate were added to a reaction tube. A aryl formate (0.6 mmol, 3.0 equiv), ethyl acetate (0.5 mL), and a conjugated enyne (0.2 mmol, 1.0 equiv) were then added sequentially. The mixture was stirred at 100°C for 24 hours. After the reaction, dichloromethane was added and the mixture was filtered through celite. The filtrate was concentrated to obtain a crude product. After vacuum concentration, the residue was purified by flash column chromatography on silica gel (200-300 mesh) using petroleum ether / ethyl acetate (19:1) as the eluent to obtain the desired product 3. The yield was calculated by weight.

[0065] Optimization of conditions:

[0066]

[0067]

[0068] Method 2: Under a nitrogen atmosphere, palladium acetate (0.0022 g, 5 mol%), diphenyl-p-tolylphosphine (0.0111 g, 20 mol%), and 0.20 mmol of anhydrous sodium carbonate were added to a reaction tube. A conjugated aryl diene carboxylate (0.2 mmol, 1.0 equiv), ethyl acetate (0.5 mL), and conjugated enyne (0.2 mmol, 1.0 equiv) were then added sequentially. The mixture was stirred at 100°C for 24 hours. After the reaction, dichloromethane was added and the mixture was filtered through celite. The filtrate was concentrated to obtain the crude product. After vacuum concentration, the residue was purified by flash column chromatography on silica gel (200-300 mesh) using petroleum ether / ethyl acetate (19:1) as the eluent to obtain the desired product 3. The yield was calculated by weight.

[0069] The following examples 1-15 provide the synthesis of polysubstituted cyclohexadiene carboxylate compounds with different structures, and are confirmed by NMR characterization. Some examples of NMR spectra are as follows: Figure 2-13 shown.

[0070] Example 1: Synthesis of Compound 3a

[0071]

[0072] Method 1: Under a nitrogen atmosphere, palladium acetate (0.0022 g, 5 mol%), diphenyl-p-tolylphosphine (0.0111 g, 20 mol%), and 0.20 mmol of anhydrous sodium carbonate were added to a reaction tube. Phenyl formate (0.6 mmol, 3.0 equiv), ethyl acetate (0.5 mL), and conjugated enyne 1a (0.2 mmol, 1.0 equiv) were then added sequentially. The mixture was stirred at 100°C for 24 hours. After the reaction, dichloromethane was added and the mixture was filtered through celite. The filtrate was concentrated to obtain the crude product. After vacuum concentration, the residue was purified by flash column chromatography on silica gel (200-300 mesh) using petroleum ether / ethyl acetate (19:1) as the eluent to obtain the desired product 3a. The isolated yield was 75%.

[0073] 1 H NMR (600MHz, CDCl3) δ7.49 (t, J = 4.2Hz, 1H), 7.33-7.28 (m, 2H), 7.22-7.10 (m, 7H), 7.08-7.01 (m, 2H), 6.96-6.78 (m, 4H), 6.38(dd,J=17.6,11.0Hz,1H), 5.27(d,J=17.7Hz,1H), 5.03(d,J=11.0Hz,1H), 4.71(d,J=5.6Hz,1H), 3.49-3.35(m,2H).

[0074] 13 C NMR(151MHz,cdcl3)δ164.58,150.78,142.16,140.29,140.20,137.47,135.59,131.79,129.29, 129.26,128.92,128.08,127.80,126.84,126.55,126.15,125.58,121.56,113.18,48.64,27.92.

[0075] Example 2: Synthesis of Compound 3b

[0076]

[0077] The method was the same as that in Example 1, except that the compound 1b, 1-(3-butene-1-yn-1-yl)-4-methylbenzene, was used in the reaction. The yield was 67%, and product 3b was obtained after column chromatography separation.

[0078] 1 H NMR (600MHz, CDCl3) δ7.46 (t, J = 4.0Hz, 1H), 7.34-7.29 (m, 2H), 7.20-7.15 (m, 1H),7.02(d,J=7.7Hz,2H),6.97(s,4H),6.94(d,J=8.0Hz,2H),6.77(d,J=7.6 Hz,2H),6.41(dd,J=17.6,11.0Hz,1H),5.25(d,J=17.5Hz,1H),5.02(d,J=11. 0Hz, 1H), 4.67 (t, J = 5.2Hz, 1H), 3.48-3.31 (m, 2H), 2.30 (s, 3H), 2.27 (s, 3H).

[0079] 13 C NMR (151MHz, cdcl3) δ164.60,150.86,140.46,139.19,137.31,137.22,136.35,135.93,135.83,132.15 ,129.23,129.17,128.79,128.75,128.48,126.08,125.51,121.60,112.73,48.16,27.97,21.12,21.05.

[0080] Example 3: Synthesis of Compound 3c

[0081]

[0082] The method was the same as that in Example 1, except that compound 1c, 2-(3-butene-1-yn-1-yl)naphthalene, was used in the reaction. The yield was 60%, and product 3c was obtained after column chromatography separation.

[0083] 1 H NMR (600MHz, CDCl3) δ7.79-7.74(m,2H),7.70-7.62(m,4H),7.62-7.57(m,2H),7.49-7.36(m,5H),7.32-7.23(m,3H),7.20-7.14(m,1H ),7.04-6.98(m,1H),6.95-6.86(m,2H),6.46(dd,J=17.6,11.0Hz,1H),5.36(d,J=17.5Hz,1H),5.11-5.02(m,2H),3.68-3.45(m,2H).

[0084] 13 C NMR (101MHz, CDCl3) δ164.59,150.74,140.04,139.61,137.75,137.68,1 35.63,133.37,132.98,132.46,132.31,131.83,129.32,128.15,127.94, 127.91,127.88,127.80,127.64,127.57,127.55,127.46,127.16,126.95 ,125.95,125.83,125.73,125.66,125.46,121.60,113.62,48.78,28.15.

[0085] Example 4: Synthesis of Compound 3d

[0086]

[0087] The method was the same as that in Example 1, except that compound 1d, 1-(3-butene-1-yn-1-yl)-4-fluorobenzene, was used in the reaction. The yield was 71%, and product 3d was obtained after column chromatography separation.

[0088] 1H NMR (600MHz, CDCl3) δ7.49 (t, J = 3.8Hz, 1H), 7.35-7.29 (m, 2H), 7.19 (s, 1H), 7.04-6.98 (m, 2H), 6.96-6.70 (m, 8H), 6. 32(dd,J=17.5,11.1Hz,1H),5.29(d,J=17.5Hz,1H),5.07(d,J=11.0Hz,1H),4.63(d,J=5.7Hz,1H),3.48-3.33(m,2H).

[0089] 13 C NMR (151MHz, CDCl3) δ164.38, 161.80 (d, J = 246.2Hz), δ 161.62 (d, J = 245.4Hz), 150.67, 138.89, 137.46 (d, J = 3.6Hz), 135.83 (d, J = 3.5Hz), 131.44 ,130.87(d,J=8.0Hz),130.29(d,J=8.0Hz),129.33,126.76,125.70,121 .48,115.04(d,J=16.1Hz),114.89(d,J=16.0Hz),113.86,47.92,27.85. 19 FNMR (376MHz, CDCl3) δ-115.14,-115.99.

[0090] Example 5: Synthesis of Compound 3e

[0091]

[0092] The method was the same as that in Example 1, except that the compound 1e, 1-(3-butene-1-yn-1-yl)-4-tert-butylbenzene, was used in the reaction. The yield was 52%, and the product 3e was obtained after column chromatography separation.

[0093] 1 H NMR (600MHz, CDCl3) δ7.45(t,J=4.0Hz,1H),7.34-7.28(m,2H),7.23-7.15(m,5H),7.05-6.78(m,6H),6.46(dd,J=17.5,11.0H z, 1H), 5.26 (d, J = 17.5Hz, 1H), 5.02 (d, J = 11.0Hz, 1H), 4.70 (t, J = 4.9Hz, 1H), 3.40 (t, J = 4.4Hz, 2H), 1.29 (s, 9H), 1.27 (s, 9H).

[0094] 13C NMR (151MHz, CDCl3) δ164.66,150.89,149.60,149.25,140.48,139.20,137.34,137.31,135.98,132.43,129.23,12 8.93,128.42,126.40,125.50,124.95,124.54,121.62,121.54,112.59,47.90,34.42,34.33,31.36,31.31,28.03.

[0095] Example 6: Synthesis of Compound 3f

[0096]

[0097] The method was the same as that in Example 1, except that the compound 1f was 2-(3-butene-1-yn-1-yl)thiophene. The yield was 32%, and the product 3f was obtained after column chromatography separation.

[0098] 1 H NMR (400MHz, CDCl3) δ7.41(dd,J=4.8,3.2Hz,1H),7.37-7.32(m,2H),7.25-7.22(m,1H),7.14-7.10(m,1H),7.04-7.00(m,2H),6.96-6.92(m,1 H),6.87-6.84(m,2H),6.82-6.75(m,2H),5.38(dd,J=17.7,1.1Hz,1H),5.19(dd,J=10.9,1.0Hz,1H),5.10(t,J=4.5Hz,1H),3.49-3.28(m,2H).

[0099] 13 C NMR (101MHz, CDCl3) δ164.20,150.77,146.04,140.95,137.41,135.33,132.25,131.65,129.82, 129.41,128.24,126.65,126.48,126.23,125.77,125.63,124.39,121.65,114.85,43.77,28.19.

[0100] Example 7: Synthesis of Compound 3g

[0101]

[0102] The method was the same as that in Example 1, except that 2 g of 3-methylphenylformate was used in the reaction. The yield was 42%, and 3 g of the product was obtained after column chromatography separation.

[0103] 1 H NMR (600MHz, CDCl3) δ7.48(t,J=3.9Hz,1H),7.22-7.10(m,7H),7.07-6.96(m,3H),6.90-6.81(m,2H),6.76-6.63(m,2H),6.37( dd,J=17.6,11.0Hz,1H),5.27(d,J=17.6Hz,1H),5.03(d,J=11.0Hz,1H),4.70(t,J=5.4Hz,1H),3.55-3.28(m,2H),2.29(s,3H).

[0104] 13 C NMR (151MHz, CDCl3) δ164.66,150.72,142.16,140.31,140.22,139.42,137.33,135.60,131.85,129.28,128 .97,128.93,128.06,127.78,126.82,126.51,126.38,126.16,122.14,118.47,113.14,48.64,27.91,21.21.

[0105] Example 8: Synthesis of Compound 3h

[0106]

[0107] The method was the same as that in Example 1, except that the compound involved in the reaction was 2h-naphthalene-2-ylcarboxylate. The yield was 78%, and the product 3h was obtained after column chromatography separation.

[0108] 1 H NMR (600MHz, CDCl3) δ7.80-7.71(m,3H),7.55(t,J=3.8Hz,1H),7.45-7.38(m,3H),7.21-7.13(m,6H),7.10-7.07(m,2H),7.06-7.00(m,1H), 6.90-6.84(m,2H),6.39(dd,J=17.6,11.0Hz,1H),5.28(d,J=17.5Hz,1H),5.04(d,J=11.0Hz,1H),4.75(t,J=5.5Hz,1H), 3.50-3.39(m,2H).

[0109] 13 C NMR (151MHz, CDCl3) δ164.73,148.42,142.18,140.30,140.20,137.64,135.60,133.70,131.81,131.34,129.29,129.21, 128.95,128.11,127.80,127.67,127.57,126.85,126.58,126.39,126.16,125.53,121.12,118.48,113.20,48.67,27.96.

[0110] Example 9: Synthesis of Compound 3i

[0111]

[0112] The method was the same as that in Example 1, except that the compound 2i 4-chlorophenylformate was used in the reaction. The yield was 60%, and the product 3i was obtained after column chromatography separation.

[0113] 1 H NMR (600MHz, CDCl3) δ7.49 (t, J = 3.9Hz, 1H), 7.27-7.24 (m, 2H), 7.23-7.09 (m, 6H), 7.07-7.00 (m, 2H), 6.89-6.79 (m, 4H), 6.36 (dd, J = 17.6, 11.0 Hz, 1H), 5.26 (d, J = 17.4 Hz, 1H), 5.03 (d, J = 11.0 Hz, 1H), 4.68 (t, J = 5.5 Hz, 1H), 3.56-3.22 (m, 2H).

[0114] 13 C NMR (151MHz, CDCl3) δ164.30,149.24,142.07,140.16,140.11,137.97,135.53,131.52,130.97, 129.31,129.26,128.87,128.11,127.81,126.88,126.62,126.09,122.92,113.26,48.59,27.94.

[0115] Example 10: Synthesis of Compound 3j

[0116]

[0117] Using method 2, under a nitrogen atmosphere, palladium acetate (0.0022 g, 5 mol%), diphenyl-p-tolylphosphine (0.0111 g, 20 mol%), and 0.20 mmol of anhydrous sodium carbonate were added to a reaction tube. (E)-2-benzylidene-3-butenoic acid phenyl ester 2aa (0.2 mmol, 1.0 equiv), ethyl acetate (0.5 mL), and (E)-1,4-diphenyl-1-butene-3-yne 1j (0.2 mmol, 1.0 equiv) were then added sequentially. The mixture was stirred at 100°C for 24 hours. After completion of the reaction, dichloromethane was added, and the mixture was filtered through celite. The filtrate was concentrated to obtain the crude product. After vacuum concentration, the residue was purified by flash column chromatography on silica gel (200-300 mesh) using petroleum ether / ethyl acetate (19:1) as the eluent to obtain the desired product 3j. The yield was 60%.

[0118] 1 H NMR (600MHz, CDCl3) δ7.39-7.37(m,3H),7.33-7.28(m,3H),7.24-7.14(m,8H),7.06-6.96(m,2H),6.95-6.87(m, 2H), 6.40 (d, J = 12.1Hz, 1H), 6.08 (d, J = 12.1Hz, 1H), 4.83 (t, J = 5.3Hz, 1H), 3.45-3.31 (m, 1H), 3.06-2.93 (m, 1H).

[0119] 13 C NMR (101MHz, CDCl3) δ164.62,150.81,142.67,140.64,139.26,138.66,138.14,131.51,130.58,130.32,129.31, 128.87,128.66,128.51,128.33,128.22,127.87,127.49,127.30,127.06,126.59,125.62,121.61,47.85,31.51.

[0120] Example 11: Synthesis of Compound 3k

[0121]

[0122] The method was the same as that of Example 10, except that compound 1k (6-heptene-4-yn-1-ol) was used in the reaction. The yield was 81%, and product 3k was obtained after column chromatography separation.

[0123] 1H NMR (600MHz, CDCl3) δ7.38 (t, J = 3.9Hz, 1H), 7.34-7.28 (m, 2H), 7.27-7.24 (m, 4H), 7.2 2-7.13(m,2H),6.94-6.89(m,2H),6.89-6.84(m,1H),5.29(d,J=17.4Hz,1H),5.18(d,J =11.0Hz,1H),4.45(t,J=5.3Hz,1H),3.68-3.51(m,2H),3.28(t,J=4.7Hz,2H),2.54-2. 33(m,1H),2.11-1.95(m,1H),1.75-1.65(m,1H),1.49-1.40(m,1H),1.30-1.21(m,1H).

[0124] 13 C NMR (101MHz, CDCl3) δ164.68,150.78,143.14,137.96,137.54,133.58,131.56,129.31,12 9.09,128.35,126.84,125.62,124.84,121.62,113.35,62.56,46.56,31.96,28.00,26.91.

[0125] Example 12: Synthesis of Compound 31

[0126]

[0127] The method was the same as that of Example 10, except that the compound 11 (1-nonen-3-yne) was used in the reaction. The yield was 91%, and the product 31 was obtained after column chromatography separation.

[0128] 1 H NMR (600MHz, CDCl3) δ7.39 (t, J = 4.0Hz, 1H), 7.34-7.29 (m, 2H), 7.28-7.24 (m, 4H),7.23-7.15(m,2H),6.94-6.88(m,2H),5.27(d,J=17.4Hz,1H),5.17(d,J=1 1.0Hz,1H),4.46(t,J=5.3Hz,1H),3.31-3.24(m,2H),2.38-2.27(m,1H),1.93- 1.81(m,1H),1.53-1.44(m,1H),1.26(d,J=12.3Hz,7H),0.87(t,J=6.8Hz,3H).

[0129] 13C NMR (101MHz, CDCl3) δ164.75,150.83,143.36,139.14,137.68,133.83,131.65,129.30,129.10,128. 27,126.71,125.59,124.11,121.65,112.75,46.53,31.60,30.73,29.50,29.14,27.97,22.59,14.09.

[0130] Example 13: Synthesis of Compound 3m

[0131]

[0132] The method was the same as that of Example 10, except that the compound 1m was 1-(3-butene-1-yn-1-yl)-4-tert-butylbenzene. The yield was 95%, and the product 3m was obtained after column chromatography separation.

[0133] 1 H NMR (600MHz, CDCl3) δ7.49(t,J=4.2Hz,1H),7.35-7.29(m,2H),7.24-7.20(m,2H),7.19-7.15(m,3H),7.13-7.08(m,2H),6.97-6.89(m, 2H),6.83-6.77(m,2H),6.46(dd,J=17.5,11.0Hz,1H),5.27(d,J=17.6Hz,1H),5.04(d,J=11.0Hz,1H),4.74(t,J=7.1,5.3,1.8Hz,1H),

[0134] 3.56-3.27(m,2H),1.29(s,9H).

[0135] 13 C NMR (101MHz, CDCl3) δ164.63,150.81,149.67,142.42,140.31,137.58,137.14,135.89,132.03,129.31 ,128.98,128.90,128.08,126.52,126.30,125.61,124.66,121.62,112.89,48.51,34.46,31.34,28.04.

[0136] Example 14: Synthesis of Compound 3n

[0137]

[0138] The method was the same as that in Example 10, except that the compounds involved in the reaction were (E)-2-(thiophen-2-ylmethylene)-3-butenoic acid phenyl ester and 1n 4-(3-butene-1-yn-1-yl)benzoic acid methyl ester. The yield was 93%, and the product 3n was obtained after column chromatography separation.

[0139] 1 H NMR (600MHz, CDCl3) δ8.01-7.90(m,2H),7.47(t,J=4.0Hz,1H),7.34(t,J= 7.9Hz,2H),7.23-7.18(m,1H),7.14-7.05(m,3H),7.03-6.97(m,2H),6.79 (dd,J=5.1,3.5Hz,1H),6.69-6.64(m,1H),6.35(dd,J=17.6,11.0Hz,1H), 5.34(d,J=17.5Hz,1H),5.13-5.04(m,2H),3.90(s,3H),3.46-3.34(m,2H).

[0140] 13 C NMR (101MHz, CDCl3) δ166.91,164.24,150.75,145.51,144.92,138.49,137.72,134.94,131.47,129.52, 129.39,129.33,128.97,127.56,126.64,126.02,125.77,124.29,121.61,114.65,52.12,43.06,27.73.

[0141] Example 15: Synthesis of Compound 3o

[0142]

[0143] The method was the same as that in Example 10, except that the compound involved in the reaction was (E)-2-(4-methylbenzylidene)-3-butenoic acid phenyl ester. The yield was 96%, and the product 3o was obtained after column chromatography separation.

[0144] 1H NMR(600MHz, CDCl3)δ7.50(t,J=4.9,3.0Hz,1H),7.35-7.29(m,2H),7.25-7.14(m,4H),7.07-7.02(m,1H),6.97-6.90(m,3H),6.90-6.81(m ,4H),6.39(dd,J=17.6,11.0Hz,1H),5.28(d,J=17.6Hz,1H),5.04(d,J=11.0Hz,1H),4.69(t,J=5.4Hz,1H),3.51-3.34(m,2H),2.23(s,3H).

[0145] 13 C NMR (101MHz, CDCl3) δ164.68,150.82,141.99,140.43,140.30,137.55,137.44,135.70,131.88,129.59,129 .34,129.31,127.93,127.80,127.38,126.85,126.14,126.11,125.62,121.63,113.12,48.54,27.94,21.47.

[0146] The present invention provides a method for synthesizing polysubstituted cyclohexadiene carboxylates via a palladium-catalyzed tandem reaction of conjugated ene and alkyne hydroesterification and cyclization. Numerous methods and approaches exist for implementing this technical solution. The foregoing description is merely a preferred embodiment of the present invention. It should be noted that those skilled in the art may make various improvements and modifications without departing from the principles of the present invention, and such improvements and modifications are also within the scope of the present invention. Any components not specified in this embodiment may be implemented using existing technologies.

Claims

1. A method for synthesizing polysubstituted cyclohexadiene carboxylates by palladium-catalyzed conjugated ene and alkyne hydroesterification and cyclization tandem reaction, characterized in that The steps include: Under nitrogen protection, conjugated ene-yne and aryl formate as raw materials are heated to react in an organic solvent system containing a palladium catalyst, a ligand, and a base additive to prepare a polysubstituted cyclohexadiene carboxylate compound; The synthetic route is as follows: R is selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted saturated or unsaturated cycloalkyl; Ar represents an aryl or substituted aryl; the substituents include alkyl substitution, halogen substitution, heteroatom substitution, alkyl ester substitution, and -OH substitution.

2. The method according to claim 1, wherein: The palladium catalyst is selected from any one of palladium acetate, di(acetylacetonate)palladium, palladium chloride, palladium pivalate, and allylpalladium chloride dimer, or a combination thereof.

3. The method according to claim 1, wherein: The ligand is dimethyl-p-tolylphosphine, triphenylphosphine, tri-p-phenylmethylphosphine, 4-(dimethylamino)triphenylphosphine or tris(4-dimethylaminophenyl)phosphine.

4. The method according to claim 1, wherein: The base is anhydrous potassium carbonate, anhydrous sodium bicarbonate, anhydrous sodium carbonate or anhydrous cesium carbonate.

5. The method according to claim 1, wherein: The reaction temperature is 80-110° C., and the reaction time is 12-36 hours.

6. A method for synthesizing polysubstituted cyclohexadiene carboxylates by palladium-catalyzed conjugated ene and alkyne hydroesterification and cyclization tandem reaction, characterized in that The steps include: Under nitrogen protection, conjugated diene and conjugated enyne are used as raw materials, and heated to react in an organic solvent system containing a palladium catalyst, a ligand, and sodium carbonate to prepare a polysubstituted cyclohexadiene carboxylate compound; The synthetic route is as follows: R is selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted saturated or unsaturated cycloalkyl; R1 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl; Ar represents an aryl or substituted aryl; the substituents include alkyl substitution, halogen substitution, heteroatom substitution, alkyl ester substitution, and -OH substitution.

7. The method according to claim 6, characterized in that: The palladium catalyst is selected from any one of palladium acetate, di(acetylacetonate)palladium, palladium chloride, palladium pivalate, and allylpalladium chloride dimer, or a combination thereof.

8. The method according to claim 6, wherein: The ligand is dimethyl-p-tolylphosphine, triphenylphosphine, tri-p-phenylmethylphosphine, 4-(dimethylamino)triphenylphosphine or tris(4-dimethylaminophenyl)phosphine.

9. The method according to claim 6, wherein: The base is one of anhydrous potassium carbonate, anhydrous sodium bicarbonate, anhydrous sodium carbonate and anhydrous cesium carbonate.

10. The method according to claim 6, wherein: The reaction temperature is 80-110° C., and the reaction time is 12-36 hours.

Images