Method for synthesizing monoterpene through nickel catalysis

Abstract

The invention relates to a method for preparing monoterpene from isoprene. Specifically, simple arylboronic acid and isoprene are taken as initial raw materials, and the aryl-substituted non-natural terpene can be obtained under the promotion condition of a nickel catalyst / ligand / additive. The method has the advantages that raw materials are simple and easy to obtain, synthesis is simple, environment friendliness is achieved, conditions are mild, atom economy is high, and the telomer obtained from bulk chemical isoprene is similar to natural terpene in structure and is an important terpenoid.

Description

Technical Field

[0001] This invention relates to a method for synthesizing aryl-substituted terpenes. Specifically, using arylboronic acid and isoprene as raw materials, isoprene aryl telomerization products can be obtained under the promotion of a nickel catalyst / ligand / additive. This invention has the following advantages: the raw materials are readily available; both isoprene and arylboronic acid are commercially available and inexpensive; the terpene structure can be introduced directly and selectively in one step; and simple arylboronic acid can participate in the reaction. Background Technology

[0002] Terpenes are among the most widespread and structurally diverse natural products, present in almost all organisms. In nature, the biosynthesis of terpenes begins with the condensation of isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) under the catalysis of geranyl pyrophosphate synthase (GPPase) to form geranyl pyrophosphate (GPP). Under enzymatic catalysis, GPP can produce various biologically active monoterpenes. For example, linalool is an important fragrance ingredient used in floral fragrances, perfumes, soaps, and the aromatics industry. It is also used as an intermediate in the pharmaceutical industry and as a precursor in the synthesis of vitamin E and isophytol. Citral is mainly used in the formulation of lemon flavorings and the manufacture of citrus fragrances. It is also used to synthesize ionone (a raw material for the synthesis of vitamin A), citrate, methyl ionone, hydroxycitronellol, isoprene, dihydrodamascone, and other compounds, and also possesses antibacterial and pheromone functions. Cyclic monoterpenes, such as perillyl alcohol, have unique therapeutic effects in treating tumors such as ovarian tumors, esophageal cancer, and breast cancer; menthol has also been widely used in biomedicine. Therefore, exploring simple and efficient catalytic systems for the synthesis of terpenoid compounds is of great significance.

[0003]

[0004] A literature search revealed (Equation 2) that in 2000, Finn et al. reported a metal-mediated telomerization reaction of isoprene and amines. In 2007, Beller et al. reported a telomerization reaction of isoprene and alcohols. In 2022, Chen et al. reported metal-mediated linear and cyclic telomerization processes of isoprene. However, most existing reports are limited to substrates containing heteroatoms or nucleophiles. In 2024, Leyva-Pérez et al. reported a telomerization reaction of arylboronic acid and butadiene, but due to regioselectivity, the products were a mixture. Therefore, developing a simple, efficient, mild, and highly regioselective aryl telomerization catalytic system for isoprene is particularly important.

[0005]

[0006] Conjugated dienes are a major industrial chemical, inexpensive, readily available, and produced in high annual quantities. This patent develops a nickel-catalyzed reaction of conjugated dienes and arylboronic acids, which can selectively introduce terpene structures into aromatic rings. Summary of the Invention

[0007] The purpose of this invention is to develop a nickel catalyst / ligand / additive system using simple chemicals, conjugated dienes and arylboronic acid, as raw materials, which can selectively introduce terpene structures onto aromatic rings.

[0008] This invention is achieved through the following technical solution:

[0009] Arylboronic acid 1 and a conjugated diene (or a substituted conjugated diene) can introduce a terpene (or a substituted terpene) onto the aromatic ring in the presence of a nickel catalyst, ligands, and additives, as shown in the following reaction formula:

[0010]

[0011] The specific operating steps are as follows:

[0012] Under an argon or nitrogen atmosphere, nickel metal precursor, ligand, additive, and arylboronic acid 1 are added sequentially, followed by the addition of a certain amount of solvent to dissolve them. Finally, conjugated diene (or substituted conjugated diene) 2 is added, and the reaction is carried out at a certain temperature. The reaction system is monitored by TLC. After the reaction is completed, the target product 3 is obtained.

[0013] After the reaction was completed, the solvent was evaporated and column chromatography (mobile phase: petroleum ether) was performed to obtain the target product 3; the mobile phase was ethyl acetate; the volume ratio of mobile phase to petroleum ether was 100:1.

[0014] The present invention has the following advantages:

[0015] The present invention has the following advantages: the raw materials are simple and readily available, the synthesis is simple, the environment is friendly, the conditions are mild, and the regioselectivity is high. This type of compound is an important class of terpenoids and synthetic intermediates, with a wide range of biological activities, such as anticancer and anti-allergy, and is a common dominant skeleton in natural products. Detailed Implementation

[0016] The present invention will be described below with specific embodiments, but the scope of protection of the present invention is not limited to these examples.

[0017] 1. Ni-catalyzed reaction of phenylboronic acid and conjugated diene

[0018] In a 2.0 mL sealed tube, a nickel metal precursor (5 mol% relative to phenylboronic acid 1a), a ligand (5 mol% relative to phenylboronic acid 1a), DABCO (50 mol% relative to phenylboronic acid 1a), an additive (2.0 equiv. relative to phenylboronic acid 1a), and phenylboronic acid 1a (0.2 mmol, 24.2 mg) were added sequentially and dissolved in 1 mL of solvent. Then, conjugated diene (or substituted conjugated diene) 2 (0.8 mmol, 80 μL) was added, and the reaction was carried out at room temperature for 18 h. After the reaction was completed, trimethylbenzene was added as an internal standard, and the yield of the target product 3a was detected by GC-FID.

[0019]

[0020] Table 1. Effects of ligands and solvents on the reaction

[0021]

[0022]

[0023] As shown in Table 1, when the molar ratio of phenylboronic acid 1a to conjugated diene 2 is 1:4, the reaction is carried out at room temperature with bis-(1,5-cyclooctadiene)nickel as the catalyst, DABCO as the base, and isopropanol as the additive. With triphenylphosphine as the ligand, the target product was obtained in 7% yield (Example 1). When the ligand was tris(4-trifluoromethylphenyl)phosphine, the yield of the target product remained unchanged (Example 2). When electron-rich ligands tris(4-methoxyphenyl)phosphine and tris(2-methoxyphenyl)phosphine were used, the yield could be increased to 56% (Examples 3-4). When sterically hindered ligands tris(2,4,6-trimethoxyphenyl)phosphine and tris(2,6-dimethoxyphenyl)phosphine were used, the yield could be increased to 85% (Examples 5-6). Further increasing the steric hindrance of the ligand increased the yield to 96% (Example 7). However, when tris(2,6-diisopropoxyphenyl)phosphine was used as the ligand, the yield decreased (Example 8). The yield decreased when the solvent was changed from 1,4-dioxane to tetrahydrofuran or isopropanol (Examples 9-10). The yield also decreased when using nonpolar solvents such as n-hexane or toluene as mixed solvents (Examples 11-12). Therefore, the preferred catalyst is bis-(1,5-cyclooctadiene)nickel, the ligand is tris(2,6-diethoxyphenyl)phosphine, the base is triethylenediamine, the additive is isopropanol, the solvent is 1,4-dioxane, the reaction temperature is room temperature, and the reaction time is 18 h.

[0024] 2. Substrate type

[0025] In a glove box, Ni(COD)2 (2.8 mg, 5 mol% relative to phenylboronic acid 1), tris(2,6-diethoxyphenyl)phosphine (5.3 mg, 5 mol% relative to phenylboronic acid 1), DABCO (11.3 mg, 50 mol% relative to phenylboronic acid 1), and phenylboronic acid 1 (0.2 mmol) were added sequentially to a 2.0 mL sealed tube and dissolved in 1.0 mL of 1,4-Dioxane. Then, isopropanol (31 μL, 2.0 equiv. relative to phenylboronic acid 1) and conjugated diene 2 (8.0 mmol) were added. The reaction was carried out at room temperature for 18 h. After the reaction was completed, the tube was washed with water, extracted with ethyl acetate, the solvent was evaporated, and the mixture was separated by column chromatography with petroleum ether as the mobile phase.

[0026]

[0027] (E)-(3,6-Dimethylocta-2,7-dien-1-yl)benzene(3a): Colorless liquid, 41.6 mg, 97% yield. 1 H NMR(400MHz,Chloroform-d)δ7.22–7.17(m,2H),7.13–7.07(m,3H),5.62(ddd,J=17.7,10.3,7.6Hz,1H),5.29–5.24(m,1H),4.91 –4.78(m,2H),3.28(d,J=7.3Hz,2H),2.08–1.99(m,1H),1.97–1.92(m,2H),1.63(s,3H),1.37–1.32(m,2H),0.92(d,J=6.7Hz,3H). 13 HRMS calculated for C 16 H 22 [M] + 214.1716, found 214.1719.

[0028]

[0029] (E)-1-(3,6-Dimethylocta-2,7-dien-1-yl)-4-methylbenzene(3b): Colorless liquid, 45.0 mg, 99% yield. 1H NMR(400 MHz,Chloroform-d)δ7.07(t,J=2.6Hz,4H),5.68(ddd,J=17.6,10.3,7.6 Hz,1H),5.35–5.28(m,1H),4.97–4.86(m,2H),3.30(d,J=7.3 Hz,2H),2.31(s,3H),2.15–2.05(m,1H),2.03–2.00(m,2H),1.69(s,3H),1.45–1.37(m,2H),0.99(d,J=6.7 Hz,3H). 13 CNMR(100 MHz,CDCl3)δ144.72,138.77,136.20,135.13,129.06,128.22,123.16,112.61,37.53,37.36,34.97,33.82,21.03,20.21,16.23.HRMScalculated for C 17 H 24 [M] + 228.1873,found 228.1872.

[0030]

[0031] (E)-4-(3,6-Dimethylocta-2,7-dien-1-yl)-1,1'-biphenyl(3c):Colorlessliquid,57.0 mg,98%yield. 1 H NMR(400 MHz,Chloroform-d)δ7.58–7.55(m,2H),7.52–7.49(m,2H),7.43–7.39(m,2H),7.33–7.29(m,1H),7.24(d,J=8.3 Hz,2H),5.69(ddd,J=17.6,10.3,7.6 Hz,1H),5.39–5.35(m,1H),4.99–4.87(m,2H),3.39(d,J=7.3Hz,2H),2.17–2.08(m,1H),2.06–2.01(m,2H),1.72(s,3H),1.46–1.40(m,2H),1.00(d,J=6.7 Hz,3H). 13C NMR(100 MHz,CDCl3)δ144.71,141.20,140.99,138.75,136.70,128.78,127.17,127.06,127.03,122.73,112.70,37.58,37.41,35.00,33.92,20.26,16.32.HRMScalculated for C 22 H 26 [M] + 290.2029,found 290.2024.

[0032]

[0033] (E)-1-(3,6-Dimethylocta-2,7-dien-1-yl)-4-methoxybenzene(3d):Colorlessliquid,30.4 mg,83%yield. 1 H NMR(400 MHz,Chloroform-d)δ7.08(d,J=8.7 Hz,2H),6.82(d,J=8.7 Hz,2H),5.69(ddd,J=17.6,10.3,7.6Hz,1H),5.33–5.29(m,1H),4.98–4.87(m,2H),3.78(s,3H),3.29(d,J=7.3Hz,2H),2.15–2.05(m,1H),2.03–1.99(m,2H),1.69(s,3H),1.44–1.38(m,2H),0.99(d,J=6.7 Hz,3H). 13 C NMR(100 MHz,CDCl3)δ157.71,144.71,136.13,133.90,129.18,123.28,113.78,112.61,55.28,37.52,37.35,34.97,33.31,20.20,16.20.HRMS calculated for C 17 H 25 O[M+H] + 245.1900,found245.1902.

[0034]

[0035] (E)-1-(4-(3,6-Dimethylocta-2,7-dien-1-yl)phenyl)ethan-1-one(3e):Colorless liquid,39.2 mg,76%yield. 1 H NMR(400 MHz,Chloroform-d)δ7.90–7.86(m,2H),7.26(d,J=8.5 Hz,2H),5.68(ddd,J=17.7,10.3,7.6 Hz,1H),5.34–5.29(m,1H),4.98–4.88(m,2H),3.40(d,J=7.3 Hz,2H),2.58(s,3H),2.15–2.06(m,1H),2.06–1.98(m,2H),1.72–1.68(m,3H),1.44–1.39(m,2H),0.99(d,J=6.7 Hz,3H). 13 C NMR(100 MHz,CDCl3)δ197.87,147.70,144.57,137.51,134.96,128.57,121.66,112.70,37.50,37.31,34.89,34.27,26.59,20.20,16.29.HRMS calculated for C 18 H 24 ONa[M+Na] + 279.1719,found 279.1724.

[0036]

[0037] (E)-1-Chloro-4-(3,6-dimethylocta-2,7-dien-1-yl)benzene(3f):Colorlessliquid,47.9 mg,96%yield. 1 H NMR(400 MHz,Chloroform-d)δ7.22(m,2H),7.09(d,J=8.5 Hz,2H),5.68(ddd,J=17.6,10.3,7.6 Hz,1H),5.31–5.26(m,1H),4.98–4.88(m,2H),3.30(d,J=7.3 Hz,2H),2.15–2.06(m,1H),2.04–2.00(m,2H),1.68(s,3H),1.44–1.38(m,2H),0.99(d,J=6.7 Hz,3H). 13CNMR(100MHz,CDCl3)δ144.60,140.25,137.05,131.39,129.63,128.40,122.28,112.67,37.51,37.31,34.94,33.56,20.19,16.23.HRMS calculated forC 16 H 22 Cl[M+H] + 249.1405,found 249.1404.

[0038]

[0039] (E)-1-(3,6-Dimethylocta-2,7-dien-1-yl)-4-fluorobenzene(3g):Colorlessliquid,45.3 mg,98%yield. 1 H NMR(400 MHz,Chloroform-d)δ7.13–7.09(m,2H),6.98–6.91(m,2H),5.69(ddd,J=17.4,10.3,7.6 Hz,1H),5.32–5.27(m,1H),4.97–4.88(m,2H),3.31(d,J=7.3 Hz,2H),2.15–2.06(m,1H),2.04–2.00(m,2H),1.69(s,3H),1.44–1.38(m,2H),0.99(d,J=6.7 Hz,3H). 13 CNMR(100 MHz,Chloroform-d)δ161.22(d,J=243.1 Hz),144.63,137.37(d,J=3.2 Hz),136.71,129.57(d,J=7.7 Hz),122.71,115.01(d,J=21.0 Hz),112.64,37.51,37.32,34.95,33.38,20.19,16.19. 19 F NMR(376 MHz,Chloroform-d)δ-118.06.HRMS calculated for C 16 H 21 F[M] + 232.1622,found232.1619.

Claims

1. A method for nickel-catalyzed synthesis of monoterpenes, characterized in that: Arylboronic acid and isoprene can be introduced into a terpene structure onto the aromatic ring under the action of nickel catalyst, ligand and additives, as shown in the following reaction formula: The specific operating steps are as follows: Under an argon and / or nitrogen atmosphere, nickel metal precursor, ligand, additive, arylboronic acid 1 are dissolved in a solvent, then conjugated diene 2 is added and reacted. After the reaction is complete, the target product 3 is obtained.

2. The method according to claim 1, characterized in that: The substituent R on the reactant arylboronic acid can be one or more of the following: hydrogen, alkyl, aryl, methyl ester, fluorine, chlorine, bromine, trifluoromethyl, etc. R on diene 1 It can be one or more of C1-C20 alkyl groups (one or more of conjugated dienes or substituted conjugated dienes).

3. The method according to claim 1, characterized in that: The catalyst for the reaction process is a complex of a nickel metal precursor and a single phosphorus ligand; The nickel metal precursor is bis-(1,5-cyclooctadiene)nickel; The monodentate phosphorus ligand includes one or more of triphenylphosphine, tris(2-methoxyphenyl)phosphine, tris(2,6-dimethoxyphenyl)phosphine, and tris(2,6-diethoxyphenyl)phosphine, preferably tris(2,6-diethoxyphenyl)phosphine; The molar ratio of nickel metal precursor to monophosphorus ligand is 1:1-1:2, preferably 1:1-1.2; The molar amount of nickel metal precursor relative to arylboronic acid is between 0.005 and 0.5 times, preferably 0.005 to 0.01 times, and more preferably 0.005 to 0.008 times.

4. The method according to claim 1, characterized in that: The additives used are DABCO (triethylenediamine) and isopropanol; The molar amount of DABCO relative to arylboronic acid is between 0.1 and 2 times, preferably 0.5 to 1 times, and more preferably 0.5 to 0.8 times; The amount of isopropanol relative to arylboronic acid is between 0.5 and 32 times, preferably 2 to 8 times.

5. The method according to claim 1, characterized in that: The solvent used is one or more of the following: 1,4-dioxane, tetrahydrofuran, etc., with 1,4-dioxane being the preferred solvent. The concentration range of arylboronic acid in the solvent is 0.01-1.5 mol / L, preferably 0.2-0.4 mol / L, and more preferably 0.2-0.3 mol / L.

6. The method according to claim 1, characterized in that: The amount of conjugated diene 2 is 0.5-10 (preferably 2-5, more preferably 3-4) times the molar amount of arylboronic acid; the reaction temperature is between 25-40℃ (preferably 25-30℃); the reaction system is monitored by TLC, and the reaction time is usually between 12-24h (preferably 18-24h).

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