阅读说明：本技术 一种多取代4-苯基色满类化合物的合成方法 (Synthesis method of polysubstituted 4-phenyl chroman compounds ) 是由 吕健 宋然 司雯 于 2019-10-15 设计创作，主要内容包括：本发明公开了一种属于有机合成领域,涉及一种多取代4-苯基色满类化合物的合成方法。所述多取代4-苯基色满类化合物结构式如式I所示。所述方法涉及利用非金属催化的温和条件下的氧杂迈克尔加成及1,6-共轭加成的串联反应。本发明中所使用的催化剂为商品化的非金属碱,成本较低、环境友好且易于操作；本发明中所涉及的方法产率较高、非对映选择性优秀、条件温和、后处理方便且产物易分离纯化；本发明所述的方法易于大规模生产,而且放大后产率及非对映选择性都能够保持。(The invention discloses a method for synthesizing a polysubstituted 4-phenyl chroman compound, belonging to the field of organic synthesis. The structural formula of the polysubstituted 4-phenyl chroman compound is shown as a formula I. The process involves a tandem reaction of an oxamichael addition and a 1, 6-conjugate addition under mild conditions using non-metal catalysis. The catalyst used in the invention is commercialized nonmetal alkali, and has the advantages of low cost, environmental protection and easy operation; the method has the advantages of high yield, excellent diastereoselectivity, mild conditions, convenient post-treatment and easy separation and purification of the product; the process of the invention is easy to mass produce and yields and diastereoselectivities are maintained after scale-up.)

1. a method for synthesizing polysubstituted 4-phenyl chroman compounds is characterized by comprising the following steps: preparing a polysubstituted 4-phenyl chroman compound shown as a formula I by an oxaMichael addition and 1, 6-conjugate addition tandem method:

wherein R is¹Is one of methyl, ethyl, isopropyl or tert-butyl; r²Is one of alkyl, alkoxy, halogen or substituted or unsubstituted naphthalene ring, and is positioned at the 3, 4 or 5 position of the benzene ring; r³Is one of substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C6-C20 aryl and substituted or unsubstituted heterocyclic group; r⁴Is one of methyl, ethyl or isopropyl.

2. The process for preparing polysubstituted 4-phenyl chroman compounds according to claim 1, characterized by the following steps:

the specific reaction operation is as follows:

dissolving o-hydroxyphenyl p-methylene benzoquinone (p-QMs) and beta, gamma-unsaturated-alpha-keto ester in the molar ratio of 1:1.5:1.5 in 1, 2-Dichloroethane (DCE), adding 1, 8-diazabicyclo [5.4.0]]Undec-7-ene (DBU) with the addition of p-QMs 50% by massAnd (3) a molecular sieve. Stirred at room temperature for 40 hours. After the reaction is finished, the reaction system is concentrated to obtain a crude product. And (3) adding the crude product to a silica gel chromatographic column, and using petroleum ether and ethyl acetate as eluent to obtain a white solid which is the product shown in the formula (I).

Technical Field

The invention belongs to the field of organic synthesis, and mainly relates to a synthesis method of a polysubstituted 4-phenyl chroman compound.

Background

4-phenyl chromans are widely present in biologically active molecules and natural products, such as: oxymetafene, a selective estrogen receptor modulator; and MyristinA, a flavonoid extracted from the fruit of Myristica species, having antifungal activity.

Because the 4-phenyl chroman compounds have potential medicinal value and wide application, the synthesis and report of the compounds are long-term research directions of chemists and have very important significance. Currently, the strategies for synthesizing such compounds are mainly of the following two types: oxadiene synthesis reactions (Angew. chem., Int. Ed.2015,54, 5460-5464; org. biomol. chem.2017,15,7272-7276.) and the [4+2] cycloaddition reaction of o-hydroxyphenyl p-methylenebenzoquinone (p-QMs) with olefinic compounds (Angew. chem., Int. Ed.2016,55, 12104-12108; J. org. chem.2019,84, 7883-7893; adv. Synth. Cat. 2018,360, 4225-4235.). However, most of the above reported synthesis systems have some disadvantages, such as large amount of catalyst, harsh synthesis conditions, long reaction time, etc.

The beta, gamma-unsaturated-alpha-keto acid ester compound is an important intermediate in organic synthesis, and researches on [4+2] cycloaddition reaction of the beta, gamma-unsaturated-alpha-keto acid ester compound and o-hydroxyphenyl p-methylene benzoquinone (p-QMs) not only can successfully prepare the polysubstituted 4-phenyl chroman compound, but also can introduce a ketonic acid ester skeleton which is convenient to convert into a product, thereby further enriching the structure of the compound.

Disclosure of Invention

The invention aims to overcome the defects of use of noble metal catalysts, harsh synthesis conditions and the like in the existing method for preparing the polysubstituted 4-phenyl chroman compounds, and provides a preparation method of the nonmetallic catalysis mild polysubstituted 4-phenyl chroman compounds.

In order to achieve the aim, the invention provides a preparation method for synthesizing a multi-substituted 4-phenyl chroman compound shown in the formula (I) in series by using an oxaMichael addition and a 1, 6-conjugate addition.

Wherein R is¹Is one of methyl, ethyl, isopropyl or tert-butyl; r²Is one of alkyl, alkoxy, halogen or substituted or unsubstituted naphthalene ring, and is positioned at the 3, 4 or 5 position of the benzene ring; r³Is one of substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C6-C20 aryl and substituted or unsubstituted heterocyclic group; r⁴Is one of methyl, ethyl or isopropyl.

The method for preparing the 4-phenyl chroman compound (I) comprises the following steps:

the specific reaction operation is as follows:

dissolving o-hydroxyphenyl p-methylene benzoquinone (p-QMs) and beta, gamma-unsaturated-alpha-keto ester in the molar ratio of 1:1.5:1.5 in 1, 2-Dichloroethane (DCE), adding 1, 8-diazabicyclo [5.4.0]]Undec-7-ene (DBU) with the addition of p-QMs 50% by massAnd (3) a molecular sieve. Stirred at room temperature for 40 hours. After the reaction is finished, the reaction system is concentrated to obtain a crude product. And (3) adding the crude product to a silica gel chromatographic column, and using petroleum ether and ethyl acetate as eluent to obtain a white solid which is the product shown in the formula (I).

Compared with the early reports, the experimental method for synthesizing the polysubstituted 4-phenyl chroman compound has the following advantages:

the catalyst used in the invention is commercialized nonmetal alkali, and has the advantages of low cost, environmental protection and easy operation;

the method has the advantages of high yield, excellent diastereoselectivity, mild conditions, convenient post-treatment and easy separation and purification of the product;

the process of the invention is easy to mass produce and yields and diastereoselectivities are maintained after scale-up.

Drawings

FIG. 1 is an NMR spectrum of a compound (3a) prepared in example 1.

FIG. 2 is an NMR spectrum of compound (3b) prepared in example 2.

FIG. 3 is an NMR spectrum of compound (3c) prepared in example 3.

FIG. 4 is an NMR spectrum of compound (3d) prepared in example 4.

FIG. 5 is an NMR spectrum of compound (3e) prepared in example 5.

Detailed Description

In the present invention, g represents "g"; mmol stands for "mmol"; mL represents "mL"; h represents "hour"; DEG C stands for "centigrade"; μ L for "microliter"; V/V represents "volume ratio"; m% represents "mass ratio"; DBU represents "1, 8-diazabicyclo [5.4.0] undec-7-ene"; DCE stands for "1, 2-dichloroethane" and MS for "molecular sieves".

The method of the present invention is described herein by way of specific examples, but the present invention is not limited thereto, and any modifications, equivalents, improvements, etc. are intended to be included within the scope of the present invention.