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Method for preparing methyl (hetero) arene through decarbonylation coupling of (hetero) aryl formic acid and trimethylcyclotrioxane under catalysis of transition metal

A technology of trimethylcyclotrioxaborane and methyl heteroaromatic hydrocarbons, which is applied in the fields of organic synthesis and methyl aromatic hydrocarbon synthesis, can solve the problems of poor tolerance of reactive functional groups, expensive halogen-containing wastes, difficult separation and the like, and achieves the The effect of avoiding halogen-containing waste, easy column chromatography separation, good functional group tolerance

Pending Publication Date: 2022-03-29
INST OF BOTANY JIANGSU PROVINCE & CHINESE ACADEMY OF SCI
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Transition metal palladium or nickel-catalyzed coupling reaction of halo(hetero)arene with nucleophilic methylating reagent is one of the most effective methods for preparing methyl(hetero)arene, but it has the following disadvantages: (1) halo(hetero)arene Hetero)aromatics need to be prepared under harsh reaction conditions, which are expensive and easy to produce a large amount of halogen-containing waste; (2) nucleophilic methylating reagents are usually highly active reagents such as methyl Grignard reagents and methyl boronic acid. Poor functional group tolerance; (3) The polarity of halogenated raw materials and methylated products is similar, so it is difficult to separate them by column chromatography

Method used

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  • Method for preparing methyl (hetero) arene through decarbonylation coupling of (hetero) aryl formic acid and trimethylcyclotrioxane under catalysis of transition metal
  • Method for preparing methyl (hetero) arene through decarbonylation coupling of (hetero) aryl formic acid and trimethylcyclotrioxane under catalysis of transition metal
  • Method for preparing methyl (hetero) arene through decarbonylation coupling of (hetero) aryl formic acid and trimethylcyclotrioxane under catalysis of transition metal

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] The structural formula of the target product is as follows:

[0028]

[0029] At room temperature, add 0.2 mmol of 2-naphthoic acid and 0.01 mmol of Pd(OAc) to a 50 mL reaction tube equipped with a magnetic stir bar 2 , 0.03mmol of XantPhos, after replacing the reaction tube with nitrogen, add 0.3mmol of Piv 2 O, 0.4 mmol of trimethylboroxine and 2 mL of 1,4-dioxane, after sealing the reaction system, place it in an oil bath heater with magnetic stirring, and react at 160°C for 24 hours . After the reaction was completed, dichloromethane was added for extraction and separation, and the product was obtained by column chromatography.

[0030] The product is a colorless liquid, the yield is 88%

[0031] 1 H NMR (400MHz, CDCl 3 )δ=2.53(s,3H),7.33(dd,J=8.4Hz,1.6,1H),7.39–7.48(m,2H),7.63(s,1H),7.75–7.78(m,2H),7.81 (d,J=8.0Hz,1H)ppm. 13 C NMR (101MHz, CDCl 3 )δ=21.9, 125.1, 126.0, 127.0, 127.4, 127.7, 127.8, 128.2, 131.8, 133.8, 135.6ppm.

Embodiment 2

[0033] The structural formula of the target product is as follows:

[0034]

[0035] The steps are the same as in Example 1, using o-phenylbenzoic acid as a raw material, and the reaction time is 12 hours.

[0036] The product was a pale yellow liquid with a yield of 82%.

[0037] 1 H NMR (400MHz, CDCl 3 ): δ=2.27(s,3H),7.22–7.28(m,3H),7.30–7.36(m,3H),7.37–7.62(m,3H)ppm; 13 C NMR (100MHz, CDCl 3 ): δ=20.6, 125.9, 126.9, 127.3, 127.4, 128.2, 128.9, 129.3, 129.9, 130.4, 135.5ppm.

Embodiment 3

[0039] The structural formula of the target product is as follows:

[0040]

[0041] Step is with embodiment 1, is raw material with o-nitrobenzoic acid.

[0042]The product was a yellow liquid with a yield of 84%.

[0043] 1 H NMR (400MHz, CDCl 3 ):δ=2.61(s,3H),7.30–7.39(m,2H),7.50(t,J=7.6Hz,1H),7.97(d,J=8.4Hz,1H)ppm. 13 C NMR (100MHz, CDCl 3 ): δ=20.6, 124.8, 127.0, 132.9, 133.1, 133.7, 149.5ppm.

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Abstract

The invention discloses a method for preparing methyl (hetero) arene through decarbonylation coupling of (hetero) aryl formic acid and trimethylcyclotrioxane under catalysis of transition metal. According to the method, (hetero) aryl formic acid, trimethylcycloborane, a palladium-containing catalyst, a phosphine ligand, an anhydride additive and a solvent are mixed and react in an inert gas atmosphere to obtain a methyl (hetero) aromatic hydrocarbon product. The method uses stable, cheap and easily available (hetero) aryl formic acid as a raw material to synthesize methyl (hetero) aromatic hydrocarbon, can make up for the defects existing in the traditional coupling reaction of transition metal catalyzed halogenated (hetero) aromatic hydrocarbon and a nucleophilic methylation reagent, and has the following advantages: (1) use of expensive and difficult-to-prepare halogenated (hetero) aromatic hydrocarbon is avoided, and generation of halogen-containing waste is avoided; (2) the use of unstable raw materials such as a methyl Grignard reagent and methylboronic acid is avoided, and the reaction has better functional group tolerance; and (3) the (hetero) aryl formic acid raw material and the product have large polarity difference, and are easy to separate through column chromatography.

Description

technical field [0001] The invention relates to a method for synthesizing methyl (hetero) aromatics, which is characterized in that (hetero) aryl formic acid is used as an electrophile, and is decarbonylated with trimethylcyclotrioxaborane under the catalysis of a transition metal to synthesize Methyl(hetero)arenes, belonging to the field of organic synthesis. Background technique [0002] Methyl group is the most basic and widely existing non-polar functional group in organic compounds, and it is generally inert in chemical reactions. For medicinal chemistry, especially for many bioactive molecules, the introduction of a simple methyl group will greatly change its solubility, hydrophilicity and drug conformation, which is also known as the "methylation effect". ". Among the 200 best-selling small molecule drugs, more than 70% have more than one methyl group in the molecule. At the same time, the methyl group on the (hetero)aryl group can also be derivatized into other fu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07B37/04C07C1/32C07C15/24C07C15/14C07C41/30C07C43/21C07C45/68C07C49/76C07C201/12C07C205/06C07C253/30C07C255/50C07C303/40C07C311/16C07D215/04C07D235/18C07D277/30C07D307/79
CPCC07B37/04C07C1/321C07C201/12C07C45/68C07C253/30C07D215/04C07D307/79C07D235/18C07D277/30C07C41/30C07C303/40C07C2603/74C07C15/24C07C15/14C07C205/06C07C49/76C07C255/50C07C43/21C07C311/16
Inventor 冯博雅陈雨冯煦管福琴张国栋
Owner INST OF BOTANY JIANGSU PROVINCE & CHINESE ACADEMY OF SCI
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