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CN-121990911-A - Method for synthesizing monoterpene by nickel catalysis

CN121990911ACN 121990911 ACN121990911 ACN 121990911ACN-121990911-A

Abstract

The present invention relates to a process for preparing monoterpenes from isoprene. Specifically, the aryl-substituted non-natural terpene can be obtained by taking simple aryl boric acid and isoprene as starting materials under the promotion condition of nickel catalyst/ligand/additive. The invention has the advantages of simple and easily obtained raw materials, simple synthesis, environment friendliness, mild conditions and high atom economy, and telomers obtained from bulk chemicals isoprene have similar structures to natural terpenes, thus being an important terpenoid.

Inventors

  • CHEN QINGAN
  • WANG XIAOYU

Assignees

  • 中国科学院大连化学物理研究所

Dates

Publication Date
20260508
Application Date
20241108

Claims (6)

  1. 1. A method for synthesizing monoterpene by nickel catalysis, which is characterized by comprising the following steps: The aryl boric acid and isoprene can introduce terpene structures on the aromatic rings under the action of nickel catalysts, ligands and additives, and the reaction formula is shown as follows: The specific operation steps are as follows: Under the atmosphere of argon and/or nitrogen, dissolving a nickel metal precursor, a ligand, an additive and arylboronic acid 1 in a solvent, adding conjugated diene 2, reacting, and obtaining a target product 3 after the reaction is finished.
  2. 2. The method according to claim 1, characterized in that: the substituent R on the reactant arylboronic acid can be one or more than two of hydrogen, alkyl, aryl, methyl ester, fluorine, chlorine, bromine, trifluoromethyl and other substituents; R 1 on the diene may be one or more of C1-C20 alkyl groups (one or more of conjugated dienes or substituted conjugated dienes).
  3. 3. The method according to claim 1, characterized in that: the catalyst in the reaction process is a complex of a nickel metal precursor and a monophosphorus ligand; the nickel metal precursor is bis- (1, 5-cyclooctadiene) nickel; the monodentate phosphorus ligand comprises 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 the nickel metal precursor relative to the arylboronic acid is between 0.005 and 0.5 times, preferably between 0.005 and 0.01 times, more preferably between 0.005 and 0.008 times.
  4. 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 the arylboronic acid is between 0.1 and 2 times, preferably between 0.5 and 1 times, more preferably between 0.5 and 0.8 times; the amount of isopropanol used is between 0.5 and 32 times, preferably 2 to 8 times, relative to the arylboronic acid.
  5. 5. The method according to claim 1, characterized in that: the solvent is one or more than two solvents selected from 1, 4-dioxane, tetrahydrofuran, etc., preferably 1, 4-dioxane; The concentration of the arylboronic acid in the solvent is in the range of 0.01 to 1.5mol/L, preferably 0.2 to 0.4mol/L, more preferably 0.2 to 0.3mol/L.
  6. 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 25-40 deg.C (preferably 25-30 deg.C), the reaction system is monitored by a dot plate, and the reaction time is usually 12-24 hours (preferably 18-24 hours).

Description

Method for synthesizing monoterpene by nickel catalysis Technical Field The invention relates to a synthesis method of aryl-substituted terpene. Specifically, arylboronic acid and isoprene are used as raw materials, and under the promotion of a nickel catalyst/ligand/additive, an isoprene aryl telomerization product can be obtained. The invention has the advantages that the raw materials are easy to obtain, the isoprene and the arylboronic acid can be directly obtained commercially, the price is low, the terpene structure can be directly and selectively introduced in one step, and the simple arylboronic acid can participate in the reaction. Background Terpenoids are found in almost all organisms as the most widely and structurally diverse natural products. In nature, the biosynthesis of terpenoids begins with the condensation of isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) under the catalysis of geranyl pyrophosphate synthase (GPPase) to produce geranyl pyrophosphate (GPP). Under enzyme-catalyzed conditions, GPP can produce various biologically active monoterpene compounds. For example, linalool is an important perfume for use in floral type fragrances, perfumes, soaps, and aromatic industries, and is also useful as an intermediate in the pharmaceutical industry and as a synthetic precursor for vitamin E and isophytol, and citral is mainly used for preparing lemon fragrances and citrus perfumes, and is also used for synthesizing ionone (raw material for vitamin A synthesis), compounds such as citral, methyl ionone, hydroxycitronellal, isopulegol, and dihydrodamascone, and also has antibacterial and pheromone functions. Cyclic monoterpenes such as perillyl alcohol have unique therapeutic effects on tumors such as ovarian tumor, esophageal cancer, breast cancer and the like, and menthol is widely applied to biological medicines. Therefore, the method for synthesizing the terpenoid by exploring a simple and efficient catalytic system has important significance. Through literature search, it was found (formula 2), in 2000, finn et al reported a metal-mediated telomerization of isoprene and amine. In 2007, beller et al reported telomerization of isoprene and alcohols. In 2022, chen et al reported metal-mediated linear and cyclic telomerization of isoprene. However, it has been reported that most are limited to substrates containing heteroatoms or nucleophilicity. In 2024 Leyva-parez et al reported telomerization of arylboronic acids with butadiene, but the product was a mixture due to regioselectivity. Therefore, it is important to develop a simple, efficient, mild and regioselective catalytic system for aryl telomerization of isoprene. Conjugated dienes are a large industrial chemical, are cheap and easy to obtain and have high annual output. The patent develops a nickel-catalyzed reaction of conjugated diene and arylboronic acid, which can introduce terpene structure into aromatic ring with high selectivity. Disclosure of Invention The invention aims to develop a nickel catalyst/ligand/additive system by taking conjugated diene and arylboronic acid which are simple chemicals as raw materials, and terpene structures can be introduced on an aromatic ring with high selectivity. The invention is realized by the following technical scheme: The aryl boric acid 1 and the conjugated diene (or substituted conjugated diene) can introduce terpene (or substituted terpene) on the aromatic ring under the action of nickel catalyst, ligand and additive, and the reaction formula is shown as follows: The specific operation steps are as follows: Sequentially adding a nickel metal precursor, a ligand, an additive and arylboronic acid 1 in an argon or nitrogen atmosphere, adding a certain amount of solvent for dissolution, finally adding conjugated diene (or substituted conjugated diene) 2, reacting at a certain temperature, monitoring a reaction system by a dot plate, and obtaining a target product 3 after the reaction is finished. After the reaction, spin-drying the solvent, and performing column chromatography (mobile phase: petroleum ether) to obtain a target product 3, wherein the mobile phase is ethyl acetate, and the volume ratio of the mobile phase to the petroleum ether is 100:1. The invention has the following advantages: the invention has the advantages of simple and easily obtained raw materials, simple synthesis, environment friendliness, mild conditions and high regioselectivity, is an important terpenoid compound and a synthesis intermediate, has wide biological activity, such as anticancer, antiallergic and the like, and is a common dominant skeleton in natural products. Detailed Description The present invention will be described with reference to specific examples, but the scope of the present invention is not limited to these examples. Ni catalyzes the reaction of phenylboronic acid and conjugated diene In a 2.0mL tube sealer, nickel metal precursor (5 mol% relative to phenylboronic ac